Clinical Care Conundrums

A 58‐year‐old man presented to the emergency department with a 1‐month history of progressive, severe left hip pain that had become unbearable. The pain was constant and significantly worse with weight‐bearing, and the patient was now confined to bed. He denied back pain, falls, or trauma.

Although hip pain is a common complaint and a frequent manifestation of chronic degenerative joint disease, the debilitating and subacute nature of the pain suggests a potentially more serious underlying cause. Patients and even clinicians may refer to hip pain when the actual symptoms are periarticular, often presenting over the trochanter laterally, or muscular, presenting as posterior pain. The true hip joint is located in the anterior hip and groin area and often causes symptoms that radiate to the buttock. Pain can also be referred to the hip area from the spine, pelvis, or retroperitoneum, so it is crucial not to restrict the differential diagnosis to hip pathology.

Key diagnostic considerations include (1) inflammatory conditions such as trochanteric bursitis or gout; (2) bacterial infection of the hip joint, adjacent bone, or a nearby structure; (3) benign nerve compression (such as meralgia paresthetica); and (4) tumor (particularly myeloma or metastatic disease to the bone, but also potentially a pelvic or spinal mass with nerve compression). Polymyalgia rheumatica and other systemic rheumatologic complaints are a consideration, but because a single joint is involved, these conditions are less likely. The hip would be an unusual location for a first gout flare, and the duration of symptoms would be unusually long for gout. Avascular necrosis should be considered if the patient has received glucocorticoids for his previously diagnosed rheumatologic disease. If the patient is anticoagulated, consideration of spontaneous hematoma is reasonable, but usually this would present over a course of days, not weeks. The absence of trauma makes a fracture of the hip or pelvis less likely, and the insidious progression of symptoms makes a pathologic fracture less likely.

The patient reported 6 months of worsening proximal upper and lower extremity myalgia and weakness, with arthralgia of the hips and shoulders. The weakness was most notable in his proximal lower extremities, although he had remained ambulatory until the hip pain became limiting. He maintained normal use of his arms. The patient denied current rash but noted photosensitivity and a mild facial rash several months earlier. He described having transient mouth sores intermittently for several years. He denied fever, chills, night sweats, weight loss, dyspnea, recent travel, and outdoor exposures. Several months previously, he had been evaluated for these symptoms at another institution and given the diagnoses of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). At that time, he had initiated treatment with weekly dosing of methotrexate and etanercept.

The patient's medical history was also notable for hypertension, Graves' disease treated previously with radioiodine ablation, quiescent ulcerative colitis, and depression. Current medications included methotrexate, etanercept, levothyroxine, enalapril, hydrochlorothiazide, fluoxetine, ibuprofen, and oxycodone‐acetaminophen. He denied tobacco, alcohol, and recreational drug use.

Weakness occurring in the proximal lower extremities is the classic distribution for polymyositis and dermatomyositis. In contrast to polymyalgia rheumatica, dermatomyositis and polymyositis do not generally feature severe muscle pain, but they can be associated with a painful polyarthritis. Oral ulcers, photosensitivity, and facial rash are consistent with SLE, but dermatomyositis can also lead to a symmetrical erythema of the eyelids (commonly referred to as a heliotrope rash, named after the flower bearing that name) and sometimes can be associated with photosensitivity. Oral ulcers, particularly the painful ones known as canker sores, are extraordinarily common in the general population, and patients and providers may miss the mucosal lesions of SLE because they are usually painless. As methotrexate and etanercept are immunosuppressive, opportunistic pathogens such as typical or atypical mycobacteria and disseminated fungal infections should be considered, with special attention to the possibility of infection in or near the left hip. Given that SLE and RA rarely coexist, it would be helpful to seek outside medical records to know what the prior serologic evaluation entailed, but it is unlikely that this presentation is a manifestation of a diffuse connective tissue process.

Physical examination should focus on the features of dermatomyositis including heliotrope rash, truncal erythema, and papules over the knuckles (Gottron's papules); objective proximal muscle weakness in the shoulder and hip girdle; and findings that might suggest antisynthetase syndrome such as hyperkeratotic mechanic hand palmar and digital changes, and interstitial crackles on lung exam. If necrotic skin lesions are found, this would raise concern for a disseminated infection. The joints should be examined for inflammation and effusions.

His temperature was 36.6C, heart rate 74 beats per minute, blood pressure 134/76 mm Hg, respiratory rate 16 breaths per minute, and O₂ saturation 97% on room air. He was obese but did not have moon facies or a buffalo hump. There were no rashes or mucosal lesions. Active and passive motion of his left hip joint elicited pain with both flexion/extension and internal/external rotation. Muscle strength was limited by pain in the left hip flexors and extenders, but was 5/5 in all other muscle groups. Palpation of the proximal muscles of his arms and legs did not elicit pain. His extremities were without edema, and examination of his shoulders, elbows, wrists, hands, knees, ankles, and feet did not reveal any erythema, synovial thickening, effusion, or deformity. Examination of the heart, chest, and abdomen was normal.

Given the reassuring strength examination, the absence of rashes or skin lesions, and the reassuring joint exam aside from the left hip, a focal infectious, inflammatory, or malignant process seems most likely. The pain with range of motion of the hip does not definitively localize the pathology to the hip joint, because pathology of the nearby structures can lead to pain when the hip is moved. Laboratory evaluation should include a complete blood count to screen for evidence of infection or marrow suppression, complete metabolic panel, and creatine kinase. The history of ulcerative colitis raises the possibility of an enthesitis (inflammation of tendons or ligaments) occurring near the hip. Enthesitis is sometimes a feature of the seronegative spondyloarthropathy‐associated conditions and can occur in the absence of sacroiliitis or spondyloarthropathy.

The patient's myalgias and arthralgias had recently been evaluated in the rheumatology clinic. Laboratory evaluation from that visit was remarkable only for an antinuclear antibody (ANA) test that was positive at a titer of 1:320 in a homogeneous pattern, creatine phosphokinase 366 IU/L (normal range [NR] 38240), and alkaline phosphatase 203 IU/L (NR 30130). All of the following labs from that visit were within normal ranges: cyclic citrullinated peptide, rheumatoid factor, antidouble stranded DNA, aldolase, complement levels, serum and urine protein electrophoresis, thyroglobulin antibody, thyroid microsomal antibody, thyroid‐stimulating hormone, erythrocyte sedimentation rate (10 mm/h), and C‐reactive protein (0.3 mg/dL).

The patient was admitted to the hospital. Initial blood test results on admission included sodium 139 mEq/L, potassium 3.9 mEq/L, chloride 105 mEq/L, bicarbonate 27 mEq/L, urea nitrogen 16 mg/dL, creatinine 0.6 mg/dL, glucose 85 mg/dL, calcium 9.2 mg/dL (NR 8.810.3), phosphate 1.3 mg/dL (NR 2.74.6), albumin 4.7 g/dL (NR 3.54.9), and alkaline phosphatase 195 IU/L (NR 30130). The remainder of a comprehensive metabolic profile, complete blood count with differential, and coagulation studies were all normal.

The homogeneous ANA titer of 1:320 is high enough to raise eyebrows, but is nonspecific for lupus and other ANA‐associated rheumatologic conditions, and may be a red herring, particularly given the low likelihood of a systemic inflammatory process explaining this new focal hip pain. The alkaline phosphatase is only mildly elevated and could be of bone or liver origin. The reassuringly low inflammatory markers are potentially helpful, because if checked now and substantially increased from the prior outpatient visit, they would be suggestive of a new inflammatory process. However, this would not point to a specific cause of inflammation.

Given the focality of the symptoms, imaging is warranted. As opposed to plain films, contrast‐enhanced computed tomography (CT) of the pelvis or magnetic resonance imaging (MRI) may be an efficient first step, because there is low suspicion for fracture and high suspicion for an inflammatory, neoplastic, or infectious process. MRI is more expensive and usually cannot be obtained as rapidly as CT. There is a chance that CT imaging alone will provide enough information to guide the next diagnostic steps, such as aspiration of an abscess or joint, or biopsy of a suspicious lesion. However, for soft tissue lesions and many bone lesions, including osteomyelitis, MRI offers better delineation of pathology.

CT scan of the left femur demonstrated a large lytic lesion in the femoral neck that contained macroscopic fat and had an aggressive appearance with significant thinning of the cortex. MRI confirmed these findings and demonstrated a nondisplaced subtrochanteric femur fracture in the proximity of the lesion (Figure 1). Contrast‐enhanced CT scans of the thorax, abdomen, and pelvis revealed no other neoplastic lesions. Prostate‐specific antigen level was normal. The patient's significant hypophosphatemia persisted, with levels dropping to as low as 0.9 mg/dL despite aggressive oral phosphate replacement.

Figure 1

Although hypophosphatemia is often a nonspecific finding in hospitalized patients and is usually of little clinical importance, profound hypophosphatemia that is refractory to supplementation suggests an underlying metabolic disorder. Phosphate levels less than 1.0 mg/dL, particularly if prolonged, can lead to decreased adenosine triphosphate production and subsequent weakness of respiratory and cardiac muscles. Parathyroid hormone (PTH) excess and production of parathyroid hormone‐related protein (PTHrP) by a malignancy can cause profound hypophosphatemia, but are generally associated with hypercalcemia, a finding not seen in this case. Occasionally, tumors can lead to renal phosphate wasting via nonPTH‐related mechanisms. The best characterized example of this is the paraneoplastic syndrome oncogenic osteomalacia caused by tumor production of a fibroblast growth factor. Tumors that lead to this syndrome are usually benign mesenchymal tumors. This patient's tumor may be of this type, causing local destruction and metabolic disturbance. The next step would be consultation with orthopedic surgery for resection of the tumor and total hip arthroplasty with aggressive perioperative repletion of phosphate. Assessment of intact PTH, ionized calcium, 24‐hour urinary phosphate excretion, and even PTHrP levels may help to rule out other etiologies of hypophosphatemia, but given that surgery is needed regardless, it might be reasonable to proceed to the operating room without these diagnostics. If the phosphate levels return to normal postoperatively, then the diagnosis is clear and no further metabolic testing is needed.

PTH level was 47 pg/mL (NR 1065), 25‐hydroxyvitamin D level was 25 ng/mL (NR 2580), and 1,25‐dihydroxyvitamin D level was 18 pg/mL (NR 1872). Urinalysis was normal without proteinuria or glucosuria. A 24‐hour urine collection contained 1936 mg of phosphate (NR 4001200). The ratio of maximum rate of renal tubular reabsorption of phosphate to glomerular filtration rate (TmP/GFR) was 1.3 mg/dL (NR 2.44.2). Tissue obtained by CT‐guided needle biopsy of the femoral mass was consistent with a benign spindle cell neoplasm.

With normal calcium levels, the PTH level is appropriate, and hyperparathyroidism is excluded. The levels of 25‐hydroxyvitamin D and 1‐25‐dihydroxyvitamin D are not low enough to suggest that vitamin D deficiency is driving the impressive hypophosphatemia. What is impressive is the phosphate wasting demonstrated by the 24‐hour urine collection, consistent with paraneoplastic overproduction of fibroblast growth factor 23 (FGF23) by the benign bone tumor. Overproduction of this protein can be detected by blood tests or staining of the tumor specimen, but surgery should be performed as soon as possible independent of any further test results. Once the tumor is resected, phosphate metabolism should normalize.

FGF23 level was 266 RU/mL (NR < 180). The patient was diagnosed with tumor‐induced osteomalacia (TIO). He underwent complete resection of the femoral tumor as well as open reduction and internal fixation of the fracture. After surgery, his symptoms of pain and subjective muscle weakness improved, his serum phosphate level normalized, his need for phosphate supplementation resolved, and his blood levels of FGF23 decreased into the normal range (111 RU/mL). The rapid improvement of his symptoms after surgery suggested that they were related to TIO, and not manifestations of SLE or RA. His immunosuppressant medications were discontinued. Surgical pathology demonstrated a heterogeneous tumor consisting of sheets of uniform spindle cells interspersed with mature adipose tissue. This was diagnosed descriptively as a benign spindle cell and lipomatous neoplasm without further classification. Two months later, the patient was ambulating without pain, and muscle strength was subjectively normal.

DISCUSSION

TIO is a rare paraneoplastic syndrome affecting phosphate and vitamin D metabolism, leading to hypophosphatemia and osteomalacia.[1] TIO is caused by the inappropriate tumor secretion of the phosphatonin hormone, FGF23.

The normal physiology of FGF23 is illustrated in Figure 2. Osteocytes appear to be the primary source of FGF23, but the regulation of FGF23 production is not completely understood. FGF23 production may be influenced by several factors, including 1,25 dihydroxyvitamin D levels, and serum phosphate and PTH concentrations. This hormone binds to the FGF receptor and its coreceptor, Klotho,[2] causing 2 major physiological effects. First, it decreases the expression of the sodium‐phosphate cotransporters in the renal proximal tubular cells,[3, 4] resulting in increased tubular phosphate wasting. This effect appears to be partly PTH dependent.[5] Second, it has effects on vitamin D metabolism, decreasing renal production of activated vitamin D.[3, 4, 6]

Figure 2

In overproduction states, the elevated FGF23 leads to chronically low serum phosphate levels (with renal phosphate wasting) and the clinical syndrome of osteomalacia, manifested by bone pain, fractures, and deformities. Hypophosphatemia can also lead to painful proximal myopathy, cardiorespiratory dysfunction, and a spectrum of neuropsychiatric findings. The clinical findings in TIO are similar to those seen in genetic diseases in which hypophosphatemia results from the same mechanism.[3, 4]

In this case, measurement of the serum phosphate level was important in reaching the diagnosis. Although hypophosphatemia in the hospitalized patient is often easily explained, severe or persistent hypophosphatemia requires a focused evaluation. Causes of hypophosphatemia are categorized in Table 1.[7, 8, 9] In patients with hypophosphatemia that is not explained by the clinical situation (eg, osmotic diuresis, insulin treatment, refeeding syndrome, postparathyroidectomy, chronic diarrhea), measurement of serum calcium, PTH, and 25‐hydroxyvitamin D are used to investigate possible primary or secondary hyperparathyroidism. In addition, low‐normal or low serum 1,25‐dihydroxyvitamin D with normal PTH, normal 25‐hydroxyvitamin D stores, and normal renal function are clues to the presence of TIO. Urine phosphate wasting can be measured by collecting a 24‐hour urine sample. Calculation of the TmP/GFR (a measure of the maximum tubular resorption of phosphate relative to the glomerular filtration rate), as described by the nomogram of Walton and Bijvoet, may improve the accuracy of this assessment and confirm a renal source of the hypophosphatemia.[10]

The patient presented here had inappropriate urinary phosphate losses, and laboratory testing ruled out primary and secondary hyperparathyroidism and Fanconi syndrome. The patient was not taking medications known to cause tubular phosphate wasting. The patient's age and clinical history made hereditary syndromes unlikely. Therefore, the urinary phosphate wasting had to be related to an acquired defect in phosphate metabolism. The diagnostic characteristics of TIO are summarized in Table 2.

The presence of a known neoplasm makes the diagnosis of TIO considerably easier. However, osteomalacia often precedes the tumor diagnosis. In these cases, the discovery of this clinical syndrome necessitates a search for the tumor. The tumors can be small, occult, and often located in the extremities. In addition to standard cross‐sectional imaging, specialized diagnostic modalities can be helpful in localizing culprit tumors. These include F‐18 flourodeoxyglucose positron emission tomography with computed tomography, 111‐Indium octreotide single photon emission CT/CT, 68‐Gallium‐DOTA‐octreotide positron emission tomography with computed tomography, and even selective venous sampling for FGF23 levels.[1, 11] The octreotide tests capitalize on the fact that culprit tumors often express somatostatin receptors.

TIO is most often associated with mesenchymal tumors of the bone or soft tissue. It has also been reported in association with several malignancies (small cell carcinoma, hematologic malignancies, prostate cancer), and with polyostotic fibrous dysplasia, neurofibromatosis, and the epidermal nevus syndrome. The mesenchymal tumors are heterogeneous in appearance and can be variably classified as hemangiopericytomas, hemangiomas, sarcomas, ossifying fibromas, granulomas, giant cell tumors, or osteoblastomas.[1] However, 1 review suggests that most of these tumors actually represent a distinct but heterogeneous, under‐recognized entity that is best classified as a phosphaturic mesenchymal tumor.[11]

TIO is only cured by complete resection of the tumor.[1] Local recurrences have been described, as have rare occurrences of metastatic disease.[1, 12] Medical treatment can be used to normalize serum phosphate levels in patients who are unable to be cured by surgery. The goal is to bring serum phosphate into the low‐normal range via phosphate supplementation (typically 13 g/day of elemental phosphorus is required) and treatment with either calcitriol or alfacalcidol. Due to the inhibition of 1,25‐dihydroxyvitamin D activation in TIO, relatively large doses of calcitriol are needed. A reasonable starting dose of calcitriol is 1.5 g/day, and most patients require 15 to 60 ng/kg per day. Because PTH action is involved in FGF23‐mediated hypophosphatemia, suppression of PTH may also be useful in these patients.[13]

This patient presented with a painful femoral tumor in the setting of muscle and joint pain that had been erroneously attributed to connective tissue disease. However, recognition and thorough evaluation of the patient's hypophosphatemia led to a unifying diagnosis of TIO. This diagnosis altered the surgical approach (emphasizing complete resection to eradicate the FGF23 production) and helped alleviate the patient's painful losses of phosphate.

TEACHING POINTS

1. Hypophosphatemia, especially if severe or persistent, should not be dismissed as an unimportant laboratory finding. A focused evaluation should be performed to determine the etiology.
2. In patients with unexplained hypophosphatemia, the measurement of serum calcium, parathyroid hormone, and vitamin D levels can identify primary or secondary hyperparathyroidism.
3. The differential diagnosis of hypophosphatemia is narrowed if there is clinical evidence of inappropriate urinary phosphate wasting (ie, urinary phosphate levels remain high, despite low serum levels).
4. TIO is a rare paraneoplastic syndrome caused by FGF23, a phosphatonin hormone that causes renal phosphate wasting, hypophosphatemia, and osteomalacia.

Disclosure: Nothing to report.

A 58‐year‐old man presented to the emergency department with a 1‐month history of progressive, severe left hip pain that had become unbearable. The pain was constant and significantly worse with weight‐bearing, and the patient was now confined to bed. He denied back pain, falls, or trauma.

Although hip pain is a common complaint and a frequent manifestation of chronic degenerative joint disease, the debilitating and subacute nature of the pain suggests a potentially more serious underlying cause. Patients and even clinicians may refer to hip pain when the actual symptoms are periarticular, often presenting over the trochanter laterally, or muscular, presenting as posterior pain. The true hip joint is located in the anterior hip and groin area and often causes symptoms that radiate to the buttock. Pain can also be referred to the hip area from the spine, pelvis, or retroperitoneum, so it is crucial not to restrict the differential diagnosis to hip pathology.

Key diagnostic considerations include (1) inflammatory conditions such as trochanteric bursitis or gout; (2) bacterial infection of the hip joint, adjacent bone, or a nearby structure; (3) benign nerve compression (such as meralgia paresthetica); and (4) tumor (particularly myeloma or metastatic disease to the bone, but also potentially a pelvic or spinal mass with nerve compression). Polymyalgia rheumatica and other systemic rheumatologic complaints are a consideration, but because a single joint is involved, these conditions are less likely. The hip would be an unusual location for a first gout flare, and the duration of symptoms would be unusually long for gout. Avascular necrosis should be considered if the patient has received glucocorticoids for his previously diagnosed rheumatologic disease. If the patient is anticoagulated, consideration of spontaneous hematoma is reasonable, but usually this would present over a course of days, not weeks. The absence of trauma makes a fracture of the hip or pelvis less likely, and the insidious progression of symptoms makes a pathologic fracture less likely.

The patient reported 6 months of worsening proximal upper and lower extremity myalgia and weakness, with arthralgia of the hips and shoulders. The weakness was most notable in his proximal lower extremities, although he had remained ambulatory until the hip pain became limiting. He maintained normal use of his arms. The patient denied current rash but noted photosensitivity and a mild facial rash several months earlier. He described having transient mouth sores intermittently for several years. He denied fever, chills, night sweats, weight loss, dyspnea, recent travel, and outdoor exposures. Several months previously, he had been evaluated for these symptoms at another institution and given the diagnoses of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). At that time, he had initiated treatment with weekly dosing of methotrexate and etanercept.

The patient's medical history was also notable for hypertension, Graves' disease treated previously with radioiodine ablation, quiescent ulcerative colitis, and depression. Current medications included methotrexate, etanercept, levothyroxine, enalapril, hydrochlorothiazide, fluoxetine, ibuprofen, and oxycodone‐acetaminophen. He denied tobacco, alcohol, and recreational drug use.

Weakness occurring in the proximal lower extremities is the classic distribution for polymyositis and dermatomyositis. In contrast to polymyalgia rheumatica, dermatomyositis and polymyositis do not generally feature severe muscle pain, but they can be associated with a painful polyarthritis. Oral ulcers, photosensitivity, and facial rash are consistent with SLE, but dermatomyositis can also lead to a symmetrical erythema of the eyelids (commonly referred to as a heliotrope rash, named after the flower bearing that name) and sometimes can be associated with photosensitivity. Oral ulcers, particularly the painful ones known as canker sores, are extraordinarily common in the general population, and patients and providers may miss the mucosal lesions of SLE because they are usually painless. As methotrexate and etanercept are immunosuppressive, opportunistic pathogens such as typical or atypical mycobacteria and disseminated fungal infections should be considered, with special attention to the possibility of infection in or near the left hip. Given that SLE and RA rarely coexist, it would be helpful to seek outside medical records to know what the prior serologic evaluation entailed, but it is unlikely that this presentation is a manifestation of a diffuse connective tissue process.

Physical examination should focus on the features of dermatomyositis including heliotrope rash, truncal erythema, and papules over the knuckles (Gottron's papules); objective proximal muscle weakness in the shoulder and hip girdle; and findings that might suggest antisynthetase syndrome such as hyperkeratotic mechanic hand palmar and digital changes, and interstitial crackles on lung exam. If necrotic skin lesions are found, this would raise concern for a disseminated infection. The joints should be examined for inflammation and effusions.

His temperature was 36.6C, heart rate 74 beats per minute, blood pressure 134/76 mm Hg, respiratory rate 16 breaths per minute, and O₂ saturation 97% on room air. He was obese but did not have moon facies or a buffalo hump. There were no rashes or mucosal lesions. Active and passive motion of his left hip joint elicited pain with both flexion/extension and internal/external rotation. Muscle strength was limited by pain in the left hip flexors and extenders, but was 5/5 in all other muscle groups. Palpation of the proximal muscles of his arms and legs did not elicit pain. His extremities were without edema, and examination of his shoulders, elbows, wrists, hands, knees, ankles, and feet did not reveal any erythema, synovial thickening, effusion, or deformity. Examination of the heart, chest, and abdomen was normal.

Given the reassuring strength examination, the absence of rashes or skin lesions, and the reassuring joint exam aside from the left hip, a focal infectious, inflammatory, or malignant process seems most likely. The pain with range of motion of the hip does not definitively localize the pathology to the hip joint, because pathology of the nearby structures can lead to pain when the hip is moved. Laboratory evaluation should include a complete blood count to screen for evidence of infection or marrow suppression, complete metabolic panel, and creatine kinase. The history of ulcerative colitis raises the possibility of an enthesitis (inflammation of tendons or ligaments) occurring near the hip. Enthesitis is sometimes a feature of the seronegative spondyloarthropathy‐associated conditions and can occur in the absence of sacroiliitis or spondyloarthropathy.

The patient's myalgias and arthralgias had recently been evaluated in the rheumatology clinic. Laboratory evaluation from that visit was remarkable only for an antinuclear antibody (ANA) test that was positive at a titer of 1:320 in a homogeneous pattern, creatine phosphokinase 366 IU/L (normal range [NR] 38240), and alkaline phosphatase 203 IU/L (NR 30130). All of the following labs from that visit were within normal ranges: cyclic citrullinated peptide, rheumatoid factor, antidouble stranded DNA, aldolase, complement levels, serum and urine protein electrophoresis, thyroglobulin antibody, thyroid microsomal antibody, thyroid‐stimulating hormone, erythrocyte sedimentation rate (10 mm/h), and C‐reactive protein (0.3 mg/dL).

The patient was admitted to the hospital. Initial blood test results on admission included sodium 139 mEq/L, potassium 3.9 mEq/L, chloride 105 mEq/L, bicarbonate 27 mEq/L, urea nitrogen 16 mg/dL, creatinine 0.6 mg/dL, glucose 85 mg/dL, calcium 9.2 mg/dL (NR 8.810.3), phosphate 1.3 mg/dL (NR 2.74.6), albumin 4.7 g/dL (NR 3.54.9), and alkaline phosphatase 195 IU/L (NR 30130). The remainder of a comprehensive metabolic profile, complete blood count with differential, and coagulation studies were all normal.

The homogeneous ANA titer of 1:320 is high enough to raise eyebrows, but is nonspecific for lupus and other ANA‐associated rheumatologic conditions, and may be a red herring, particularly given the low likelihood of a systemic inflammatory process explaining this new focal hip pain. The alkaline phosphatase is only mildly elevated and could be of bone or liver origin. The reassuringly low inflammatory markers are potentially helpful, because if checked now and substantially increased from the prior outpatient visit, they would be suggestive of a new inflammatory process. However, this would not point to a specific cause of inflammation.

Given the focality of the symptoms, imaging is warranted. As opposed to plain films, contrast‐enhanced computed tomography (CT) of the pelvis or magnetic resonance imaging (MRI) may be an efficient first step, because there is low suspicion for fracture and high suspicion for an inflammatory, neoplastic, or infectious process. MRI is more expensive and usually cannot be obtained as rapidly as CT. There is a chance that CT imaging alone will provide enough information to guide the next diagnostic steps, such as aspiration of an abscess or joint, or biopsy of a suspicious lesion. However, for soft tissue lesions and many bone lesions, including osteomyelitis, MRI offers better delineation of pathology.

CT scan of the left femur demonstrated a large lytic lesion in the femoral neck that contained macroscopic fat and had an aggressive appearance with significant thinning of the cortex. MRI confirmed these findings and demonstrated a nondisplaced subtrochanteric femur fracture in the proximity of the lesion (Figure 1). Contrast‐enhanced CT scans of the thorax, abdomen, and pelvis revealed no other neoplastic lesions. Prostate‐specific antigen level was normal. The patient's significant hypophosphatemia persisted, with levels dropping to as low as 0.9 mg/dL despite aggressive oral phosphate replacement.

Figure 1

Although hypophosphatemia is often a nonspecific finding in hospitalized patients and is usually of little clinical importance, profound hypophosphatemia that is refractory to supplementation suggests an underlying metabolic disorder. Phosphate levels less than 1.0 mg/dL, particularly if prolonged, can lead to decreased adenosine triphosphate production and subsequent weakness of respiratory and cardiac muscles. Parathyroid hormone (PTH) excess and production of parathyroid hormone‐related protein (PTHrP) by a malignancy can cause profound hypophosphatemia, but are generally associated with hypercalcemia, a finding not seen in this case. Occasionally, tumors can lead to renal phosphate wasting via nonPTH‐related mechanisms. The best characterized example of this is the paraneoplastic syndrome oncogenic osteomalacia caused by tumor production of a fibroblast growth factor. Tumors that lead to this syndrome are usually benign mesenchymal tumors. This patient's tumor may be of this type, causing local destruction and metabolic disturbance. The next step would be consultation with orthopedic surgery for resection of the tumor and total hip arthroplasty with aggressive perioperative repletion of phosphate. Assessment of intact PTH, ionized calcium, 24‐hour urinary phosphate excretion, and even PTHrP levels may help to rule out other etiologies of hypophosphatemia, but given that surgery is needed regardless, it might be reasonable to proceed to the operating room without these diagnostics. If the phosphate levels return to normal postoperatively, then the diagnosis is clear and no further metabolic testing is needed.

PTH level was 47 pg/mL (NR 1065), 25‐hydroxyvitamin D level was 25 ng/mL (NR 2580), and 1,25‐dihydroxyvitamin D level was 18 pg/mL (NR 1872). Urinalysis was normal without proteinuria or glucosuria. A 24‐hour urine collection contained 1936 mg of phosphate (NR 4001200). The ratio of maximum rate of renal tubular reabsorption of phosphate to glomerular filtration rate (TmP/GFR) was 1.3 mg/dL (NR 2.44.2). Tissue obtained by CT‐guided needle biopsy of the femoral mass was consistent with a benign spindle cell neoplasm.

With normal calcium levels, the PTH level is appropriate, and hyperparathyroidism is excluded. The levels of 25‐hydroxyvitamin D and 1‐25‐dihydroxyvitamin D are not low enough to suggest that vitamin D deficiency is driving the impressive hypophosphatemia. What is impressive is the phosphate wasting demonstrated by the 24‐hour urine collection, consistent with paraneoplastic overproduction of fibroblast growth factor 23 (FGF23) by the benign bone tumor. Overproduction of this protein can be detected by blood tests or staining of the tumor specimen, but surgery should be performed as soon as possible independent of any further test results. Once the tumor is resected, phosphate metabolism should normalize.

FGF23 level was 266 RU/mL (NR < 180). The patient was diagnosed with tumor‐induced osteomalacia (TIO). He underwent complete resection of the femoral tumor as well as open reduction and internal fixation of the fracture. After surgery, his symptoms of pain and subjective muscle weakness improved, his serum phosphate level normalized, his need for phosphate supplementation resolved, and his blood levels of FGF23 decreased into the normal range (111 RU/mL). The rapid improvement of his symptoms after surgery suggested that they were related to TIO, and not manifestations of SLE or RA. His immunosuppressant medications were discontinued. Surgical pathology demonstrated a heterogeneous tumor consisting of sheets of uniform spindle cells interspersed with mature adipose tissue. This was diagnosed descriptively as a benign spindle cell and lipomatous neoplasm without further classification. Two months later, the patient was ambulating without pain, and muscle strength was subjectively normal.

DISCUSSION

TIO is a rare paraneoplastic syndrome affecting phosphate and vitamin D metabolism, leading to hypophosphatemia and osteomalacia.[1] TIO is caused by the inappropriate tumor secretion of the phosphatonin hormone, FGF23.

The normal physiology of FGF23 is illustrated in Figure 2. Osteocytes appear to be the primary source of FGF23, but the regulation of FGF23 production is not completely understood. FGF23 production may be influenced by several factors, including 1,25 dihydroxyvitamin D levels, and serum phosphate and PTH concentrations. This hormone binds to the FGF receptor and its coreceptor, Klotho,[2] causing 2 major physiological effects. First, it decreases the expression of the sodium‐phosphate cotransporters in the renal proximal tubular cells,[3, 4] resulting in increased tubular phosphate wasting. This effect appears to be partly PTH dependent.[5] Second, it has effects on vitamin D metabolism, decreasing renal production of activated vitamin D.[3, 4, 6]

Figure 2

In overproduction states, the elevated FGF23 leads to chronically low serum phosphate levels (with renal phosphate wasting) and the clinical syndrome of osteomalacia, manifested by bone pain, fractures, and deformities. Hypophosphatemia can also lead to painful proximal myopathy, cardiorespiratory dysfunction, and a spectrum of neuropsychiatric findings. The clinical findings in TIO are similar to those seen in genetic diseases in which hypophosphatemia results from the same mechanism.[3, 4]

In this case, measurement of the serum phosphate level was important in reaching the diagnosis. Although hypophosphatemia in the hospitalized patient is often easily explained, severe or persistent hypophosphatemia requires a focused evaluation. Causes of hypophosphatemia are categorized in Table 1.[7, 8, 9] In patients with hypophosphatemia that is not explained by the clinical situation (eg, osmotic diuresis, insulin treatment, refeeding syndrome, postparathyroidectomy, chronic diarrhea), measurement of serum calcium, PTH, and 25‐hydroxyvitamin D are used to investigate possible primary or secondary hyperparathyroidism. In addition, low‐normal or low serum 1,25‐dihydroxyvitamin D with normal PTH, normal 25‐hydroxyvitamin D stores, and normal renal function are clues to the presence of TIO. Urine phosphate wasting can be measured by collecting a 24‐hour urine sample. Calculation of the TmP/GFR (a measure of the maximum tubular resorption of phosphate relative to the glomerular filtration rate), as described by the nomogram of Walton and Bijvoet, may improve the accuracy of this assessment and confirm a renal source of the hypophosphatemia.[10]

The patient presented here had inappropriate urinary phosphate losses, and laboratory testing ruled out primary and secondary hyperparathyroidism and Fanconi syndrome. The patient was not taking medications known to cause tubular phosphate wasting. The patient's age and clinical history made hereditary syndromes unlikely. Therefore, the urinary phosphate wasting had to be related to an acquired defect in phosphate metabolism. The diagnostic characteristics of TIO are summarized in Table 2.

The presence of a known neoplasm makes the diagnosis of TIO considerably easier. However, osteomalacia often precedes the tumor diagnosis. In these cases, the discovery of this clinical syndrome necessitates a search for the tumor. The tumors can be small, occult, and often located in the extremities. In addition to standard cross‐sectional imaging, specialized diagnostic modalities can be helpful in localizing culprit tumors. These include F‐18 flourodeoxyglucose positron emission tomography with computed tomography, 111‐Indium octreotide single photon emission CT/CT, 68‐Gallium‐DOTA‐octreotide positron emission tomography with computed tomography, and even selective venous sampling for FGF23 levels.[1, 11] The octreotide tests capitalize on the fact that culprit tumors often express somatostatin receptors.

TIO is most often associated with mesenchymal tumors of the bone or soft tissue. It has also been reported in association with several malignancies (small cell carcinoma, hematologic malignancies, prostate cancer), and with polyostotic fibrous dysplasia, neurofibromatosis, and the epidermal nevus syndrome. The mesenchymal tumors are heterogeneous in appearance and can be variably classified as hemangiopericytomas, hemangiomas, sarcomas, ossifying fibromas, granulomas, giant cell tumors, or osteoblastomas.[1] However, 1 review suggests that most of these tumors actually represent a distinct but heterogeneous, under‐recognized entity that is best classified as a phosphaturic mesenchymal tumor.[11]

TIO is only cured by complete resection of the tumor.[1] Local recurrences have been described, as have rare occurrences of metastatic disease.[1, 12] Medical treatment can be used to normalize serum phosphate levels in patients who are unable to be cured by surgery. The goal is to bring serum phosphate into the low‐normal range via phosphate supplementation (typically 13 g/day of elemental phosphorus is required) and treatment with either calcitriol or alfacalcidol. Due to the inhibition of 1,25‐dihydroxyvitamin D activation in TIO, relatively large doses of calcitriol are needed. A reasonable starting dose of calcitriol is 1.5 g/day, and most patients require 15 to 60 ng/kg per day. Because PTH action is involved in FGF23‐mediated hypophosphatemia, suppression of PTH may also be useful in these patients.[13]

This patient presented with a painful femoral tumor in the setting of muscle and joint pain that had been erroneously attributed to connective tissue disease. However, recognition and thorough evaluation of the patient's hypophosphatemia led to a unifying diagnosis of TIO. This diagnosis altered the surgical approach (emphasizing complete resection to eradicate the FGF23 production) and helped alleviate the patient's painful losses of phosphate.

TEACHING POINTS

1. Hypophosphatemia, especially if severe or persistent, should not be dismissed as an unimportant laboratory finding. A focused evaluation should be performed to determine the etiology.
2. In patients with unexplained hypophosphatemia, the measurement of serum calcium, parathyroid hormone, and vitamin D levels can identify primary or secondary hyperparathyroidism.
3. The differential diagnosis of hypophosphatemia is narrowed if there is clinical evidence of inappropriate urinary phosphate wasting (ie, urinary phosphate levels remain high, despite low serum levels).
4. TIO is a rare paraneoplastic syndrome caused by FGF23, a phosphatonin hormone that causes renal phosphate wasting, hypophosphatemia, and osteomalacia.

Disclosure: Nothing to report.

A 58‐year‐old man presented to the emergency department with a 1‐month history of progressive, severe left hip pain that had become unbearable. The pain was constant and significantly worse with weight‐bearing, and the patient was now confined to bed. He denied back pain, falls, or trauma.

Although hip pain is a common complaint and a frequent manifestation of chronic degenerative joint disease, the debilitating and subacute nature of the pain suggests a potentially more serious underlying cause. Patients and even clinicians may refer to hip pain when the actual symptoms are periarticular, often presenting over the trochanter laterally, or muscular, presenting as posterior pain. The true hip joint is located in the anterior hip and groin area and often causes symptoms that radiate to the buttock. Pain can also be referred to the hip area from the spine, pelvis, or retroperitoneum, so it is crucial not to restrict the differential diagnosis to hip pathology.

Key diagnostic considerations include (1) inflammatory conditions such as trochanteric bursitis or gout; (2) bacterial infection of the hip joint, adjacent bone, or a nearby structure; (3) benign nerve compression (such as meralgia paresthetica); and (4) tumor (particularly myeloma or metastatic disease to the bone, but also potentially a pelvic or spinal mass with nerve compression). Polymyalgia rheumatica and other systemic rheumatologic complaints are a consideration, but because a single joint is involved, these conditions are less likely. The hip would be an unusual location for a first gout flare, and the duration of symptoms would be unusually long for gout. Avascular necrosis should be considered if the patient has received glucocorticoids for his previously diagnosed rheumatologic disease. If the patient is anticoagulated, consideration of spontaneous hematoma is reasonable, but usually this would present over a course of days, not weeks. The absence of trauma makes a fracture of the hip or pelvis less likely, and the insidious progression of symptoms makes a pathologic fracture less likely.

The patient reported 6 months of worsening proximal upper and lower extremity myalgia and weakness, with arthralgia of the hips and shoulders. The weakness was most notable in his proximal lower extremities, although he had remained ambulatory until the hip pain became limiting. He maintained normal use of his arms. The patient denied current rash but noted photosensitivity and a mild facial rash several months earlier. He described having transient mouth sores intermittently for several years. He denied fever, chills, night sweats, weight loss, dyspnea, recent travel, and outdoor exposures. Several months previously, he had been evaluated for these symptoms at another institution and given the diagnoses of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). At that time, he had initiated treatment with weekly dosing of methotrexate and etanercept.

The patient's medical history was also notable for hypertension, Graves' disease treated previously with radioiodine ablation, quiescent ulcerative colitis, and depression. Current medications included methotrexate, etanercept, levothyroxine, enalapril, hydrochlorothiazide, fluoxetine, ibuprofen, and oxycodone‐acetaminophen. He denied tobacco, alcohol, and recreational drug use.

Weakness occurring in the proximal lower extremities is the classic distribution for polymyositis and dermatomyositis. In contrast to polymyalgia rheumatica, dermatomyositis and polymyositis do not generally feature severe muscle pain, but they can be associated with a painful polyarthritis. Oral ulcers, photosensitivity, and facial rash are consistent with SLE, but dermatomyositis can also lead to a symmetrical erythema of the eyelids (commonly referred to as a heliotrope rash, named after the flower bearing that name) and sometimes can be associated with photosensitivity. Oral ulcers, particularly the painful ones known as canker sores, are extraordinarily common in the general population, and patients and providers may miss the mucosal lesions of SLE because they are usually painless. As methotrexate and etanercept are immunosuppressive, opportunistic pathogens such as typical or atypical mycobacteria and disseminated fungal infections should be considered, with special attention to the possibility of infection in or near the left hip. Given that SLE and RA rarely coexist, it would be helpful to seek outside medical records to know what the prior serologic evaluation entailed, but it is unlikely that this presentation is a manifestation of a diffuse connective tissue process.

Physical examination should focus on the features of dermatomyositis including heliotrope rash, truncal erythema, and papules over the knuckles (Gottron's papules); objective proximal muscle weakness in the shoulder and hip girdle; and findings that might suggest antisynthetase syndrome such as hyperkeratotic mechanic hand palmar and digital changes, and interstitial crackles on lung exam. If necrotic skin lesions are found, this would raise concern for a disseminated infection. The joints should be examined for inflammation and effusions.

His temperature was 36.6C, heart rate 74 beats per minute, blood pressure 134/76 mm Hg, respiratory rate 16 breaths per minute, and O₂ saturation 97% on room air. He was obese but did not have moon facies or a buffalo hump. There were no rashes or mucosal lesions. Active and passive motion of his left hip joint elicited pain with both flexion/extension and internal/external rotation. Muscle strength was limited by pain in the left hip flexors and extenders, but was 5/5 in all other muscle groups. Palpation of the proximal muscles of his arms and legs did not elicit pain. His extremities were without edema, and examination of his shoulders, elbows, wrists, hands, knees, ankles, and feet did not reveal any erythema, synovial thickening, effusion, or deformity. Examination of the heart, chest, and abdomen was normal.

Given the reassuring strength examination, the absence of rashes or skin lesions, and the reassuring joint exam aside from the left hip, a focal infectious, inflammatory, or malignant process seems most likely. The pain with range of motion of the hip does not definitively localize the pathology to the hip joint, because pathology of the nearby structures can lead to pain when the hip is moved. Laboratory evaluation should include a complete blood count to screen for evidence of infection or marrow suppression, complete metabolic panel, and creatine kinase. The history of ulcerative colitis raises the possibility of an enthesitis (inflammation of tendons or ligaments) occurring near the hip. Enthesitis is sometimes a feature of the seronegative spondyloarthropathy‐associated conditions and can occur in the absence of sacroiliitis or spondyloarthropathy.

The patient's myalgias and arthralgias had recently been evaluated in the rheumatology clinic. Laboratory evaluation from that visit was remarkable only for an antinuclear antibody (ANA) test that was positive at a titer of 1:320 in a homogeneous pattern, creatine phosphokinase 366 IU/L (normal range [NR] 38240), and alkaline phosphatase 203 IU/L (NR 30130). All of the following labs from that visit were within normal ranges: cyclic citrullinated peptide, rheumatoid factor, antidouble stranded DNA, aldolase, complement levels, serum and urine protein electrophoresis, thyroglobulin antibody, thyroid microsomal antibody, thyroid‐stimulating hormone, erythrocyte sedimentation rate (10 mm/h), and C‐reactive protein (0.3 mg/dL).

The patient was admitted to the hospital. Initial blood test results on admission included sodium 139 mEq/L, potassium 3.9 mEq/L, chloride 105 mEq/L, bicarbonate 27 mEq/L, urea nitrogen 16 mg/dL, creatinine 0.6 mg/dL, glucose 85 mg/dL, calcium 9.2 mg/dL (NR 8.810.3), phosphate 1.3 mg/dL (NR 2.74.6), albumin 4.7 g/dL (NR 3.54.9), and alkaline phosphatase 195 IU/L (NR 30130). The remainder of a comprehensive metabolic profile, complete blood count with differential, and coagulation studies were all normal.

The homogeneous ANA titer of 1:320 is high enough to raise eyebrows, but is nonspecific for lupus and other ANA‐associated rheumatologic conditions, and may be a red herring, particularly given the low likelihood of a systemic inflammatory process explaining this new focal hip pain. The alkaline phosphatase is only mildly elevated and could be of bone or liver origin. The reassuringly low inflammatory markers are potentially helpful, because if checked now and substantially increased from the prior outpatient visit, they would be suggestive of a new inflammatory process. However, this would not point to a specific cause of inflammation.

Given the focality of the symptoms, imaging is warranted. As opposed to plain films, contrast‐enhanced computed tomography (CT) of the pelvis or magnetic resonance imaging (MRI) may be an efficient first step, because there is low suspicion for fracture and high suspicion for an inflammatory, neoplastic, or infectious process. MRI is more expensive and usually cannot be obtained as rapidly as CT. There is a chance that CT imaging alone will provide enough information to guide the next diagnostic steps, such as aspiration of an abscess or joint, or biopsy of a suspicious lesion. However, for soft tissue lesions and many bone lesions, including osteomyelitis, MRI offers better delineation of pathology.

CT scan of the left femur demonstrated a large lytic lesion in the femoral neck that contained macroscopic fat and had an aggressive appearance with significant thinning of the cortex. MRI confirmed these findings and demonstrated a nondisplaced subtrochanteric femur fracture in the proximity of the lesion (Figure 1). Contrast‐enhanced CT scans of the thorax, abdomen, and pelvis revealed no other neoplastic lesions. Prostate‐specific antigen level was normal. The patient's significant hypophosphatemia persisted, with levels dropping to as low as 0.9 mg/dL despite aggressive oral phosphate replacement.

Figure 1

Although hypophosphatemia is often a nonspecific finding in hospitalized patients and is usually of little clinical importance, profound hypophosphatemia that is refractory to supplementation suggests an underlying metabolic disorder. Phosphate levels less than 1.0 mg/dL, particularly if prolonged, can lead to decreased adenosine triphosphate production and subsequent weakness of respiratory and cardiac muscles. Parathyroid hormone (PTH) excess and production of parathyroid hormone‐related protein (PTHrP) by a malignancy can cause profound hypophosphatemia, but are generally associated with hypercalcemia, a finding not seen in this case. Occasionally, tumors can lead to renal phosphate wasting via nonPTH‐related mechanisms. The best characterized example of this is the paraneoplastic syndrome oncogenic osteomalacia caused by tumor production of a fibroblast growth factor. Tumors that lead to this syndrome are usually benign mesenchymal tumors. This patient's tumor may be of this type, causing local destruction and metabolic disturbance. The next step would be consultation with orthopedic surgery for resection of the tumor and total hip arthroplasty with aggressive perioperative repletion of phosphate. Assessment of intact PTH, ionized calcium, 24‐hour urinary phosphate excretion, and even PTHrP levels may help to rule out other etiologies of hypophosphatemia, but given that surgery is needed regardless, it might be reasonable to proceed to the operating room without these diagnostics. If the phosphate levels return to normal postoperatively, then the diagnosis is clear and no further metabolic testing is needed.

PTH level was 47 pg/mL (NR 1065), 25‐hydroxyvitamin D level was 25 ng/mL (NR 2580), and 1,25‐dihydroxyvitamin D level was 18 pg/mL (NR 1872). Urinalysis was normal without proteinuria or glucosuria. A 24‐hour urine collection contained 1936 mg of phosphate (NR 4001200). The ratio of maximum rate of renal tubular reabsorption of phosphate to glomerular filtration rate (TmP/GFR) was 1.3 mg/dL (NR 2.44.2). Tissue obtained by CT‐guided needle biopsy of the femoral mass was consistent with a benign spindle cell neoplasm.

With normal calcium levels, the PTH level is appropriate, and hyperparathyroidism is excluded. The levels of 25‐hydroxyvitamin D and 1‐25‐dihydroxyvitamin D are not low enough to suggest that vitamin D deficiency is driving the impressive hypophosphatemia. What is impressive is the phosphate wasting demonstrated by the 24‐hour urine collection, consistent with paraneoplastic overproduction of fibroblast growth factor 23 (FGF23) by the benign bone tumor. Overproduction of this protein can be detected by blood tests or staining of the tumor specimen, but surgery should be performed as soon as possible independent of any further test results. Once the tumor is resected, phosphate metabolism should normalize.

FGF23 level was 266 RU/mL (NR < 180). The patient was diagnosed with tumor‐induced osteomalacia (TIO). He underwent complete resection of the femoral tumor as well as open reduction and internal fixation of the fracture. After surgery, his symptoms of pain and subjective muscle weakness improved, his serum phosphate level normalized, his need for phosphate supplementation resolved, and his blood levels of FGF23 decreased into the normal range (111 RU/mL). The rapid improvement of his symptoms after surgery suggested that they were related to TIO, and not manifestations of SLE or RA. His immunosuppressant medications were discontinued. Surgical pathology demonstrated a heterogeneous tumor consisting of sheets of uniform spindle cells interspersed with mature adipose tissue. This was diagnosed descriptively as a benign spindle cell and lipomatous neoplasm without further classification. Two months later, the patient was ambulating without pain, and muscle strength was subjectively normal.

DISCUSSION

TIO is a rare paraneoplastic syndrome affecting phosphate and vitamin D metabolism, leading to hypophosphatemia and osteomalacia.[1] TIO is caused by the inappropriate tumor secretion of the phosphatonin hormone, FGF23.

The normal physiology of FGF23 is illustrated in Figure 2. Osteocytes appear to be the primary source of FGF23, but the regulation of FGF23 production is not completely understood. FGF23 production may be influenced by several factors, including 1,25 dihydroxyvitamin D levels, and serum phosphate and PTH concentrations. This hormone binds to the FGF receptor and its coreceptor, Klotho,[2] causing 2 major physiological effects. First, it decreases the expression of the sodium‐phosphate cotransporters in the renal proximal tubular cells,[3, 4] resulting in increased tubular phosphate wasting. This effect appears to be partly PTH dependent.[5] Second, it has effects on vitamin D metabolism, decreasing renal production of activated vitamin D.[3, 4, 6]

Figure 2

In overproduction states, the elevated FGF23 leads to chronically low serum phosphate levels (with renal phosphate wasting) and the clinical syndrome of osteomalacia, manifested by bone pain, fractures, and deformities. Hypophosphatemia can also lead to painful proximal myopathy, cardiorespiratory dysfunction, and a spectrum of neuropsychiatric findings. The clinical findings in TIO are similar to those seen in genetic diseases in which hypophosphatemia results from the same mechanism.[3, 4]

In this case, measurement of the serum phosphate level was important in reaching the diagnosis. Although hypophosphatemia in the hospitalized patient is often easily explained, severe or persistent hypophosphatemia requires a focused evaluation. Causes of hypophosphatemia are categorized in Table 1.[7, 8, 9] In patients with hypophosphatemia that is not explained by the clinical situation (eg, osmotic diuresis, insulin treatment, refeeding syndrome, postparathyroidectomy, chronic diarrhea), measurement of serum calcium, PTH, and 25‐hydroxyvitamin D are used to investigate possible primary or secondary hyperparathyroidism. In addition, low‐normal or low serum 1,25‐dihydroxyvitamin D with normal PTH, normal 25‐hydroxyvitamin D stores, and normal renal function are clues to the presence of TIO. Urine phosphate wasting can be measured by collecting a 24‐hour urine sample. Calculation of the TmP/GFR (a measure of the maximum tubular resorption of phosphate relative to the glomerular filtration rate), as described by the nomogram of Walton and Bijvoet, may improve the accuracy of this assessment and confirm a renal source of the hypophosphatemia.[10]

The patient presented here had inappropriate urinary phosphate losses, and laboratory testing ruled out primary and secondary hyperparathyroidism and Fanconi syndrome. The patient was not taking medications known to cause tubular phosphate wasting. The patient's age and clinical history made hereditary syndromes unlikely. Therefore, the urinary phosphate wasting had to be related to an acquired defect in phosphate metabolism. The diagnostic characteristics of TIO are summarized in Table 2.

The presence of a known neoplasm makes the diagnosis of TIO considerably easier. However, osteomalacia often precedes the tumor diagnosis. In these cases, the discovery of this clinical syndrome necessitates a search for the tumor. The tumors can be small, occult, and often located in the extremities. In addition to standard cross‐sectional imaging, specialized diagnostic modalities can be helpful in localizing culprit tumors. These include F‐18 flourodeoxyglucose positron emission tomography with computed tomography, 111‐Indium octreotide single photon emission CT/CT, 68‐Gallium‐DOTA‐octreotide positron emission tomography with computed tomography, and even selective venous sampling for FGF23 levels.[1, 11] The octreotide tests capitalize on the fact that culprit tumors often express somatostatin receptors.

TIO is most often associated with mesenchymal tumors of the bone or soft tissue. It has also been reported in association with several malignancies (small cell carcinoma, hematologic malignancies, prostate cancer), and with polyostotic fibrous dysplasia, neurofibromatosis, and the epidermal nevus syndrome. The mesenchymal tumors are heterogeneous in appearance and can be variably classified as hemangiopericytomas, hemangiomas, sarcomas, ossifying fibromas, granulomas, giant cell tumors, or osteoblastomas.[1] However, 1 review suggests that most of these tumors actually represent a distinct but heterogeneous, under‐recognized entity that is best classified as a phosphaturic mesenchymal tumor.[11]

TIO is only cured by complete resection of the tumor.[1] Local recurrences have been described, as have rare occurrences of metastatic disease.[1, 12] Medical treatment can be used to normalize serum phosphate levels in patients who are unable to be cured by surgery. The goal is to bring serum phosphate into the low‐normal range via phosphate supplementation (typically 13 g/day of elemental phosphorus is required) and treatment with either calcitriol or alfacalcidol. Due to the inhibition of 1,25‐dihydroxyvitamin D activation in TIO, relatively large doses of calcitriol are needed. A reasonable starting dose of calcitriol is 1.5 g/day, and most patients require 15 to 60 ng/kg per day. Because PTH action is involved in FGF23‐mediated hypophosphatemia, suppression of PTH may also be useful in these patients.[13]

This patient presented with a painful femoral tumor in the setting of muscle and joint pain that had been erroneously attributed to connective tissue disease. However, recognition and thorough evaluation of the patient's hypophosphatemia led to a unifying diagnosis of TIO. This diagnosis altered the surgical approach (emphasizing complete resection to eradicate the FGF23 production) and helped alleviate the patient's painful losses of phosphate.

TEACHING POINTS

1. Hypophosphatemia, especially if severe or persistent, should not be dismissed as an unimportant laboratory finding. A focused evaluation should be performed to determine the etiology.
2. In patients with unexplained hypophosphatemia, the measurement of serum calcium, parathyroid hormone, and vitamin D levels can identify primary or secondary hyperparathyroidism.
3. The differential diagnosis of hypophosphatemia is narrowed if there is clinical evidence of inappropriate urinary phosphate wasting (ie, urinary phosphate levels remain high, despite low serum levels).
4. TIO is a rare paraneoplastic syndrome caused by FGF23, a phosphatonin hormone that causes renal phosphate wasting, hypophosphatemia, and osteomalacia.

Disclosure: Nothing to report.

A previously healthy 58‐year‐old man presented to a community hospital's emergency department 1 day after the sudden onset of a severe headache, fever, diffuse abdominal pain, nausea, vomiting, and disorientation. The patient had a history of allergic rhinitis and his only medication was a daily multivitamin.

Key features of this patient's presentation include the abrupt onset of severe headache, disorientation, fever, and abdominal pain. The list of entities likely to make a previously healthy individual this ill this quickly is typically circumscribed. His presentation raises the possibility of bacterial meningitis (including Listeria, given his age), viral encephalitis, or other extraneural etiologies of sepsis. Noninfectious explanations seem much less likely given the rapid tempo of illness.

He lived in the upper Midwestern United States and denied any recent travel outside of the region. His family reported he had recently seen a tick on his clothing but had not noticed a bite. He worked in a beer‐bottling plant, was an avid gardener, and owned a dog. He had no history of tobacco, alcohol, or illicit drug abuse.

His proclivity for gardening and apparent tick exposure raise the question of tick‐borne illnesses. This would constitute a rather explosive onset for any of these; however, babesiosis, Rocky Mountain spotted fever (RMSF), ehrlichiosis, and anaplasmosis could present this abruptly, with dog exposure linked to RMSF.

On physical examination, his temperature was 40.7C, heart rate was 115 beats per minute, respiratory rate was 16 breaths per minute, and blood pressure was 92/45 mm Hg. Pulse oximetry was 98% on ambient air. He was disoriented to place and situation, and somnolent but arousable with stimulation. Cardiopulmonary exam was notable for tachycardia. Abdominal exam revealed diffuse tenderness without rebound or guarding. His spleen was palpable just below the left costal margin. Skin examination revealed an erythematous, morbilliform rash covering his entire body including his palms and soles. Pupils were equal, round, and reactive to light. Reflexes were symmetric and 2+ throughout, and the remainder of his neurologic exam was normal. There was no nuchal rigidity.

The potential causes of fever and rash are myriad, although the severity and acuity of this patient's illness narrow the differential considerably, likely to an infectious cause. Diagnoses that typically include a generalized exanthem involving the palms and soles are meningococcal meningitis, overwhelming Staphylococcus aureus sepsis, RMSF (realizing that this disease is not common in the upper Midwest), and toxic shock syndrome. The rash described is not the classic and/or fully developed rash typical of any of these; subsequent evolution to a petechial appearance would lend further support to the first 3 diagnoses. Ehrlichiosis is still a possibility, although the palm and sole involvement would be unusual. The presence of a rash makes anaplasmosis very unlikely, although not entirely excluded. The finding of modest splenomegaly does not help further distinguish between these possibilities.

Empiric antimicrobials should be immediately administered after blood cultures, a complete blood count, and coagulation studies are obtained. Doxycycline would be appropriate to treat the possible tick‐borne diseases already mentioned, whereas antimicrobials appropriate to cover community‐acquired bacterial meningitis in a 58‐year‐old (ie, vancomycin, ampicillin, and a third‐generation cephalosporin) should also be empirically administered. Given the patient's altered mentation, a brain computed tomography (CT) should be urgently obtained. Provided this did not show evidence of increased intracranial pressure and that coagulation studies and a platelet count did not suggest a contraindication, a lumbar puncture should then be performed promptly. The patient should be placed in droplet precautions until meningococcal disease is excluded. Although most patients with bacterial meningitis will exhibit meningismus, a substantial minority will not.

The white blood cell count was 13,300/mm³ with 84% neutrophils, 5.6% lymphocytes, and 5% monocytes. The hemoglobin was 13.6 g/dL and the platelet count was 86,000/mm³. Serum sodium was 137 mmol/L, potassium 4.2 mmol/L, chloride 104 mmol/L, bicarbonate 22 mmol/L, blood urea nitrogen 29 mg/dL, creatinine 1.08 mg/dL (baseline 0.8 mg/dL) and glucose 123 mg/dL. Total protein was 4.7 g/dL (normal 6.08.3 g/dL), albumin 2.5 g/dL (normal 3.54.9 g/dL), aspartate aminotransferase 68 IU/L (normal 830 IU/L), alanine aminotransferase 68 IU/L (normal 735 IU/L), alkaline phosphatase 106 IU/L (normal 30130 IU/L), and total bilirubin 0.5 mg/dL (normal 0.21.2 mg/dL). Troponin was 0.84 ng/mL (normal <0.3 ng/mL). C‐reactive protein was 24.2 mg/dL (normal 0.00.6 mg/dL) and erythrocyte sedimentation rate was 30 mm (normal 015 mm).

These laboratory results do not significantly affect the differential diagnosis. Although nonspecific, moderate thrombocytopenia and modest elevation of hepatic transaminases are typical for tick‐borne diseases, whereas leukocytosis is somewhat atypical for these entities. Marked elevation of the C‐reactive protein with a less striking increase in the erythrocyte sedimentation rate, along with significant hypoalbuminemia, are commonly encountered early in the course of critical infectious illnesses. The elevated troponin likely reflects severe sepsis and demand ischemia, and is associated with a less favorable prognosis; an electrocardiogram and serial cardiac biomarkers are appropriate to help exclude an acute coronary syndrome. As already noted, blood cultures need to be obtained and a lumbar puncture should be performed, provided this can be safely accomplished.

CT of the head was normal. A lumbar puncture was performed. Cerebrospinal fluid was acellular with a protein level of 58 mg/dL (normal <45 mg/dL). Blood, urine, and cerebrospinal fluid cultures were obtained. An electrocardiogram demonstrated sinus tachycardia without signs of ischemia, and a transthoracic echocardiogram showed normal ventricular function. CT of the chest, abdomen, and pelvis revealed dependent bilateral atelectasis and a mildly enlarged spleen of 14 cm.

Results of the lumbar puncture exclude bacterial meningitis as the explanation of this patient's illness; the mildly elevated protein is nonspecific. These studies do not otherwise change the differential diagnosis.

The treating clinicians made a presumptive diagnosis of community‐acquired pneumonia and initiated levofloxacin. He remained febrile for the next 4 days, his maximum temperature reaching 41C, and had intermittent hypotension with systolic blood pressure dropping to 88 mm Hg despite intravenous fluid resuscitation. On hospital day 5 he developed worsening agitation, for which he was sedated and subsequently intubated for airway protection. The same day, vancomycin and piperacillin/tazobactam were added for presumed severe pneumonia as well as doxycycline for empiric treatment of RMSF. The patient was transferred to a tertiary care center for further care.

Supporting data for a diagnosis of pneumonia, such as pulmonary infiltrates or supplemental oxygen requirement, are lacking. Given his critical illness, broad spectrum antimicrobial coverage is indicated, and as a primary central nervous system (CNS) infection now appears unlikely, piperacillin/tazobactam (which does not have adequate CNS penetration) and vancomycin are reasonable. Empiric treatment for RMSF is appropriate, and should have been initiated earlier in the patient's course, despite the upper Midwest being out of the typical range for this disease. Doxycycline will also provide excellent coverage for ehrlichiosis and anaplasmosis.

Given the patient's deterioration, it is important to stop and reconsider the differential diagnosis in an attempt to avoid anchoring bias and premature closure. The patient's illness is almost certainly infectious in nature, and the differential is not substantially altered by the most recent information. A skin biopsy should be performed in an attempt to secure the diagnosis.

On arrival to the tertiary care facility the patient quickly defervesced, self‐extubated, and after 3 days was transitioned to doxycycline monotherapy with continued clinical improvement. At the recommendation of the infectious diseases consultant, serologies for Ehrlichia chaffeensis, Anaplasma phagocytophilum, Leptospira, Mycoplasma pneumoniae, and Rickettsia rickettsia were drawn in addition to fungal serologies for blastomycosis, coccidioidomycosis and histoplasmosis, and Legionella urinary antigen. Rapid human immunodeficiency virus testing and all cultures were negative. He was discharged home to complete a 2‐week course of doxycycline for presumed RMSF.

The patient's overall course, including rapid onset of severe illness and especially the apparent dramatic response to doxycycline, make tick‐borne illness very likely. Completing a course of doxycycline is certainly appropriate, typically for 7 to 14 days. The acute serologies drawn prior to discharge may well reveal the causative agent, but convalescent serology should also be obtained at the time of an outpatient follow‐up visit as immunoglobulin G has a delayed rise. Without hyponatremia or respiratory symptoms, Legionella seems unlikely.

Twelve days later he returned to the clinic for follow‐up. He was overall feeling much improved and his fever, confusion, abdominal pain, and headache had resolved. He complained of mild fatigue, occasional myalgias, and rare nonexertional chest pain, but overall felt well. His leukocyte and platelet counts normalized, though his transaminases remained slightly elevated. His C‐reactive protein decreased to 1.3 mg/dL, whereas his erythrocyte sedimentation rate rose to 83 mm. All acute serologies returned negative. Repeat convalescent serologies also returned negative. His rash had slowly faded and disappeared by his outpatient appointment; however, he was noted to have desquamation of his palms and soles (Figure 1).

Figure 1

The appearance of late desquamation of the palms and soles is an unexpected and important sign. Desquamation in this pattern following an illness of this nature strongly suggests a diagnosis of staphylococcal toxic shock syndrome (TSS), and in conjunction with the negative serologies, argues that tick‐borne disease is unlikely. The list of other entities that might lead to desquamation in this setting is very short, namely adult Kawasaki disease and drug reaction. The former seems reasonably excluded based on details of the case, whereas a doxycycline‐related drug reaction, although not entirely implausible, seems quite unlikely as this medication was started after the onset of the initial rash. This patient most likely had staphylococcal TSS secondary to a minor and unappreciated skin lesion.

The patient was diagnosed with TSS, thought to be acquired through cuts and abrasions sustained while gardening. Doxycycline was discontinued and he recovered without long‐term sequelae. In the following weeks, his chest pain and myalgias abated, and his palmar rash improved followed by desquamation of his soles.

DISCUSSION

TSS is a systemic illness resulting in multiorgan dysfunction.[1] Infection by S aureus or Streptococcus pyogenes causes TSS by stimulating maladaptive T‐cell proliferation and cytokine release resulting in shock.[1, 2] A definitive diagnosis requires fever, a diffuse macular erythematous rash (often resembling a sunburn), with subsequent desquamation, hypotension, and involvement of at least 3 organ systems. Blood cultures, cerebrospinal cultures, and serologies for other organisms should be negative; although Staphylococcus and Streptococcus species may be isolated, they frequently are not (Table 1).[3]

A rare cause of shock, TSS is most associated with a surge of menstruation‐related cases linked to tampon use in young women in the 1980s.[4] However, in Centers for Disease Control and Prevention (CDC) surveillance between 1987 and 1996, only 59% of the 1069 cases identified were noted to be menstruation‐related, as compared to nearly 80% of all cases earlier in the decade.[4, 5] Today, the syndrome is more likely to present after musculoskeletal and cutaneous trauma, oropharyngeal infections, surgical procedures, and device implantation.[1, 6] Despite the disease's evolving epidemiology, the illness script used by physicians likely continues to focus on young women as the primary at risk population for TSS, causing physicians to neglect the diagnosis in other populations.[1, 6, 7, 8, 9] Given this change in risk factors, it is imperative that clinicians rewrite their scripts and recognize the early signs of TSS in all patients to enable quick and effective treatment.

In addition to its shifting epidemiology and rarity, the diagnosis of TSS vexes clinicians for several reasons. First, TSS cannot be quickly and definitively diagnosed because 2 diagnostic criteria cannot be fulfilled during the acute illness. The disease's hallmarka desquamative rashoccurs only if the patient survives.[3] Serologies often take weeks to return, further delaying diagnosis. During this period of diagnostic delay, the illness has usually already resolved or resulted in death. In addition, the presenting symptoms of rash, fever, and shock are nonspecific. Alternative etiologies include meningococcal meningitis, which can also present dramatically as with this patient; RMSF, which can occasionally have a fulminant presentation; bacterial sepsis, usually from Staphylococcus or Streptococcus species; acute viral syndromes; and severe drug reactions.[6, 10, 11, 12] Palmoplantar desquamation, as in this case, can further narrow the differential as this presentation is uncommon but characteristic of TSS, RMSF, and secondary syphilis.[11] Other diagnostic clues offered by the pattern of the rash may be limited by physician discomfort with diagnosing and describing rashes. Because of this lack of a definitive diagnostic test in the acute setting, it is imperative that the clinician include TSS in the differential of fever, shock, and rash, as mortality from TSS can exceed 20% in patients who are untreated.[13]

Treatment of TSS is straightforward once considered and includes the administration of antibiotics that cover both Staphylococcus and Streptococcus species, in addition to aggressive hydration and supportive care.[14] The final critical detail in this case was the appropriate arrangement of follow‐up. Given the patient's drastic improvement, the complicated process of arranging follow‐up for a transferred patient, and the current model where the hospitalists providing inpatient care do not typically follow their patients in clinic, patients such as these can easily be lost to follow‐up. Had this occurred, the desquamation would have been missed, and the patient's diagnosis would have been incomplete.

This patient was eventually diagnosed with TSS by fulfilling all 5 CDC criteria (Table 1).[3] He made a full recovery, likely aided by the administration of broad‐spectrum antibiotics (followed by doxycycline, which provided community‐acquired methicillin‐resistant S aureus coverage) and his lack of serious comorbidities. This case should serve as a reminder to hospitalists that with a discerning eye, a careful assessment of the clinical facts, and appropriate follow‐up, perhaps the next case of TSS can be caught red‐handed.

KEY POINTS

1. When presented with a patient with fever, rash, and shock, hospitalists should consider meningococcal meningitis, RMSF bacterial sepsis, acute viral illness, severe drug reaction, and TSS.
2. TSS, caused by S aureus or S pyogenes, is no longer predominantly associated with tampon use. Postsurgical infection and cutaneous trauma have become important present‐day risk factors.
3. The initial presentation of TSS is nonspecific. Definitive diagnosis requires proper follow‐up, allowing time for infectious serologies to return negative and for the disease's hallmark desquamation to occur.

A previously healthy 58‐year‐old man presented to a community hospital's emergency department 1 day after the sudden onset of a severe headache, fever, diffuse abdominal pain, nausea, vomiting, and disorientation. The patient had a history of allergic rhinitis and his only medication was a daily multivitamin.

Key features of this patient's presentation include the abrupt onset of severe headache, disorientation, fever, and abdominal pain. The list of entities likely to make a previously healthy individual this ill this quickly is typically circumscribed. His presentation raises the possibility of bacterial meningitis (including Listeria, given his age), viral encephalitis, or other extraneural etiologies of sepsis. Noninfectious explanations seem much less likely given the rapid tempo of illness.

He lived in the upper Midwestern United States and denied any recent travel outside of the region. His family reported he had recently seen a tick on his clothing but had not noticed a bite. He worked in a beer‐bottling plant, was an avid gardener, and owned a dog. He had no history of tobacco, alcohol, or illicit drug abuse.

His proclivity for gardening and apparent tick exposure raise the question of tick‐borne illnesses. This would constitute a rather explosive onset for any of these; however, babesiosis, Rocky Mountain spotted fever (RMSF), ehrlichiosis, and anaplasmosis could present this abruptly, with dog exposure linked to RMSF.

On physical examination, his temperature was 40.7C, heart rate was 115 beats per minute, respiratory rate was 16 breaths per minute, and blood pressure was 92/45 mm Hg. Pulse oximetry was 98% on ambient air. He was disoriented to place and situation, and somnolent but arousable with stimulation. Cardiopulmonary exam was notable for tachycardia. Abdominal exam revealed diffuse tenderness without rebound or guarding. His spleen was palpable just below the left costal margin. Skin examination revealed an erythematous, morbilliform rash covering his entire body including his palms and soles. Pupils were equal, round, and reactive to light. Reflexes were symmetric and 2+ throughout, and the remainder of his neurologic exam was normal. There was no nuchal rigidity.

The potential causes of fever and rash are myriad, although the severity and acuity of this patient's illness narrow the differential considerably, likely to an infectious cause. Diagnoses that typically include a generalized exanthem involving the palms and soles are meningococcal meningitis, overwhelming Staphylococcus aureus sepsis, RMSF (realizing that this disease is not common in the upper Midwest), and toxic shock syndrome. The rash described is not the classic and/or fully developed rash typical of any of these; subsequent evolution to a petechial appearance would lend further support to the first 3 diagnoses. Ehrlichiosis is still a possibility, although the palm and sole involvement would be unusual. The presence of a rash makes anaplasmosis very unlikely, although not entirely excluded. The finding of modest splenomegaly does not help further distinguish between these possibilities.

Empiric antimicrobials should be immediately administered after blood cultures, a complete blood count, and coagulation studies are obtained. Doxycycline would be appropriate to treat the possible tick‐borne diseases already mentioned, whereas antimicrobials appropriate to cover community‐acquired bacterial meningitis in a 58‐year‐old (ie, vancomycin, ampicillin, and a third‐generation cephalosporin) should also be empirically administered. Given the patient's altered mentation, a brain computed tomography (CT) should be urgently obtained. Provided this did not show evidence of increased intracranial pressure and that coagulation studies and a platelet count did not suggest a contraindication, a lumbar puncture should then be performed promptly. The patient should be placed in droplet precautions until meningococcal disease is excluded. Although most patients with bacterial meningitis will exhibit meningismus, a substantial minority will not.

The white blood cell count was 13,300/mm³ with 84% neutrophils, 5.6% lymphocytes, and 5% monocytes. The hemoglobin was 13.6 g/dL and the platelet count was 86,000/mm³. Serum sodium was 137 mmol/L, potassium 4.2 mmol/L, chloride 104 mmol/L, bicarbonate 22 mmol/L, blood urea nitrogen 29 mg/dL, creatinine 1.08 mg/dL (baseline 0.8 mg/dL) and glucose 123 mg/dL. Total protein was 4.7 g/dL (normal 6.08.3 g/dL), albumin 2.5 g/dL (normal 3.54.9 g/dL), aspartate aminotransferase 68 IU/L (normal 830 IU/L), alanine aminotransferase 68 IU/L (normal 735 IU/L), alkaline phosphatase 106 IU/L (normal 30130 IU/L), and total bilirubin 0.5 mg/dL (normal 0.21.2 mg/dL). Troponin was 0.84 ng/mL (normal <0.3 ng/mL). C‐reactive protein was 24.2 mg/dL (normal 0.00.6 mg/dL) and erythrocyte sedimentation rate was 30 mm (normal 015 mm).

These laboratory results do not significantly affect the differential diagnosis. Although nonspecific, moderate thrombocytopenia and modest elevation of hepatic transaminases are typical for tick‐borne diseases, whereas leukocytosis is somewhat atypical for these entities. Marked elevation of the C‐reactive protein with a less striking increase in the erythrocyte sedimentation rate, along with significant hypoalbuminemia, are commonly encountered early in the course of critical infectious illnesses. The elevated troponin likely reflects severe sepsis and demand ischemia, and is associated with a less favorable prognosis; an electrocardiogram and serial cardiac biomarkers are appropriate to help exclude an acute coronary syndrome. As already noted, blood cultures need to be obtained and a lumbar puncture should be performed, provided this can be safely accomplished.

CT of the head was normal. A lumbar puncture was performed. Cerebrospinal fluid was acellular with a protein level of 58 mg/dL (normal <45 mg/dL). Blood, urine, and cerebrospinal fluid cultures were obtained. An electrocardiogram demonstrated sinus tachycardia without signs of ischemia, and a transthoracic echocardiogram showed normal ventricular function. CT of the chest, abdomen, and pelvis revealed dependent bilateral atelectasis and a mildly enlarged spleen of 14 cm.

Results of the lumbar puncture exclude bacterial meningitis as the explanation of this patient's illness; the mildly elevated protein is nonspecific. These studies do not otherwise change the differential diagnosis.

The treating clinicians made a presumptive diagnosis of community‐acquired pneumonia and initiated levofloxacin. He remained febrile for the next 4 days, his maximum temperature reaching 41C, and had intermittent hypotension with systolic blood pressure dropping to 88 mm Hg despite intravenous fluid resuscitation. On hospital day 5 he developed worsening agitation, for which he was sedated and subsequently intubated for airway protection. The same day, vancomycin and piperacillin/tazobactam were added for presumed severe pneumonia as well as doxycycline for empiric treatment of RMSF. The patient was transferred to a tertiary care center for further care.

Supporting data for a diagnosis of pneumonia, such as pulmonary infiltrates or supplemental oxygen requirement, are lacking. Given his critical illness, broad spectrum antimicrobial coverage is indicated, and as a primary central nervous system (CNS) infection now appears unlikely, piperacillin/tazobactam (which does not have adequate CNS penetration) and vancomycin are reasonable. Empiric treatment for RMSF is appropriate, and should have been initiated earlier in the patient's course, despite the upper Midwest being out of the typical range for this disease. Doxycycline will also provide excellent coverage for ehrlichiosis and anaplasmosis.

Given the patient's deterioration, it is important to stop and reconsider the differential diagnosis in an attempt to avoid anchoring bias and premature closure. The patient's illness is almost certainly infectious in nature, and the differential is not substantially altered by the most recent information. A skin biopsy should be performed in an attempt to secure the diagnosis.

On arrival to the tertiary care facility the patient quickly defervesced, self‐extubated, and after 3 days was transitioned to doxycycline monotherapy with continued clinical improvement. At the recommendation of the infectious diseases consultant, serologies for Ehrlichia chaffeensis, Anaplasma phagocytophilum, Leptospira, Mycoplasma pneumoniae, and Rickettsia rickettsia were drawn in addition to fungal serologies for blastomycosis, coccidioidomycosis and histoplasmosis, and Legionella urinary antigen. Rapid human immunodeficiency virus testing and all cultures were negative. He was discharged home to complete a 2‐week course of doxycycline for presumed RMSF.

The patient's overall course, including rapid onset of severe illness and especially the apparent dramatic response to doxycycline, make tick‐borne illness very likely. Completing a course of doxycycline is certainly appropriate, typically for 7 to 14 days. The acute serologies drawn prior to discharge may well reveal the causative agent, but convalescent serology should also be obtained at the time of an outpatient follow‐up visit as immunoglobulin G has a delayed rise. Without hyponatremia or respiratory symptoms, Legionella seems unlikely.

Twelve days later he returned to the clinic for follow‐up. He was overall feeling much improved and his fever, confusion, abdominal pain, and headache had resolved. He complained of mild fatigue, occasional myalgias, and rare nonexertional chest pain, but overall felt well. His leukocyte and platelet counts normalized, though his transaminases remained slightly elevated. His C‐reactive protein decreased to 1.3 mg/dL, whereas his erythrocyte sedimentation rate rose to 83 mm. All acute serologies returned negative. Repeat convalescent serologies also returned negative. His rash had slowly faded and disappeared by his outpatient appointment; however, he was noted to have desquamation of his palms and soles (Figure 1).

Figure 1

The appearance of late desquamation of the palms and soles is an unexpected and important sign. Desquamation in this pattern following an illness of this nature strongly suggests a diagnosis of staphylococcal toxic shock syndrome (TSS), and in conjunction with the negative serologies, argues that tick‐borne disease is unlikely. The list of other entities that might lead to desquamation in this setting is very short, namely adult Kawasaki disease and drug reaction. The former seems reasonably excluded based on details of the case, whereas a doxycycline‐related drug reaction, although not entirely implausible, seems quite unlikely as this medication was started after the onset of the initial rash. This patient most likely had staphylococcal TSS secondary to a minor and unappreciated skin lesion.

The patient was diagnosed with TSS, thought to be acquired through cuts and abrasions sustained while gardening. Doxycycline was discontinued and he recovered without long‐term sequelae. In the following weeks, his chest pain and myalgias abated, and his palmar rash improved followed by desquamation of his soles.

DISCUSSION

TSS is a systemic illness resulting in multiorgan dysfunction.[1] Infection by S aureus or Streptococcus pyogenes causes TSS by stimulating maladaptive T‐cell proliferation and cytokine release resulting in shock.[1, 2] A definitive diagnosis requires fever, a diffuse macular erythematous rash (often resembling a sunburn), with subsequent desquamation, hypotension, and involvement of at least 3 organ systems. Blood cultures, cerebrospinal cultures, and serologies for other organisms should be negative; although Staphylococcus and Streptococcus species may be isolated, they frequently are not (Table 1).[3]

A rare cause of shock, TSS is most associated with a surge of menstruation‐related cases linked to tampon use in young women in the 1980s.[4] However, in Centers for Disease Control and Prevention (CDC) surveillance between 1987 and 1996, only 59% of the 1069 cases identified were noted to be menstruation‐related, as compared to nearly 80% of all cases earlier in the decade.[4, 5] Today, the syndrome is more likely to present after musculoskeletal and cutaneous trauma, oropharyngeal infections, surgical procedures, and device implantation.[1, 6] Despite the disease's evolving epidemiology, the illness script used by physicians likely continues to focus on young women as the primary at risk population for TSS, causing physicians to neglect the diagnosis in other populations.[1, 6, 7, 8, 9] Given this change in risk factors, it is imperative that clinicians rewrite their scripts and recognize the early signs of TSS in all patients to enable quick and effective treatment.

In addition to its shifting epidemiology and rarity, the diagnosis of TSS vexes clinicians for several reasons. First, TSS cannot be quickly and definitively diagnosed because 2 diagnostic criteria cannot be fulfilled during the acute illness. The disease's hallmarka desquamative rashoccurs only if the patient survives.[3] Serologies often take weeks to return, further delaying diagnosis. During this period of diagnostic delay, the illness has usually already resolved or resulted in death. In addition, the presenting symptoms of rash, fever, and shock are nonspecific. Alternative etiologies include meningococcal meningitis, which can also present dramatically as with this patient; RMSF, which can occasionally have a fulminant presentation; bacterial sepsis, usually from Staphylococcus or Streptococcus species; acute viral syndromes; and severe drug reactions.[6, 10, 11, 12] Palmoplantar desquamation, as in this case, can further narrow the differential as this presentation is uncommon but characteristic of TSS, RMSF, and secondary syphilis.[11] Other diagnostic clues offered by the pattern of the rash may be limited by physician discomfort with diagnosing and describing rashes. Because of this lack of a definitive diagnostic test in the acute setting, it is imperative that the clinician include TSS in the differential of fever, shock, and rash, as mortality from TSS can exceed 20% in patients who are untreated.[13]

Treatment of TSS is straightforward once considered and includes the administration of antibiotics that cover both Staphylococcus and Streptococcus species, in addition to aggressive hydration and supportive care.[14] The final critical detail in this case was the appropriate arrangement of follow‐up. Given the patient's drastic improvement, the complicated process of arranging follow‐up for a transferred patient, and the current model where the hospitalists providing inpatient care do not typically follow their patients in clinic, patients such as these can easily be lost to follow‐up. Had this occurred, the desquamation would have been missed, and the patient's diagnosis would have been incomplete.

This patient was eventually diagnosed with TSS by fulfilling all 5 CDC criteria (Table 1).[3] He made a full recovery, likely aided by the administration of broad‐spectrum antibiotics (followed by doxycycline, which provided community‐acquired methicillin‐resistant S aureus coverage) and his lack of serious comorbidities. This case should serve as a reminder to hospitalists that with a discerning eye, a careful assessment of the clinical facts, and appropriate follow‐up, perhaps the next case of TSS can be caught red‐handed.

KEY POINTS

1. When presented with a patient with fever, rash, and shock, hospitalists should consider meningococcal meningitis, RMSF bacterial sepsis, acute viral illness, severe drug reaction, and TSS.
2. TSS, caused by S aureus or S pyogenes, is no longer predominantly associated with tampon use. Postsurgical infection and cutaneous trauma have become important present‐day risk factors.
3. The initial presentation of TSS is nonspecific. Definitive diagnosis requires proper follow‐up, allowing time for infectious serologies to return negative and for the disease's hallmark desquamation to occur.

A previously healthy 58‐year‐old man presented to a community hospital's emergency department 1 day after the sudden onset of a severe headache, fever, diffuse abdominal pain, nausea, vomiting, and disorientation. The patient had a history of allergic rhinitis and his only medication was a daily multivitamin.

Key features of this patient's presentation include the abrupt onset of severe headache, disorientation, fever, and abdominal pain. The list of entities likely to make a previously healthy individual this ill this quickly is typically circumscribed. His presentation raises the possibility of bacterial meningitis (including Listeria, given his age), viral encephalitis, or other extraneural etiologies of sepsis. Noninfectious explanations seem much less likely given the rapid tempo of illness.

He lived in the upper Midwestern United States and denied any recent travel outside of the region. His family reported he had recently seen a tick on his clothing but had not noticed a bite. He worked in a beer‐bottling plant, was an avid gardener, and owned a dog. He had no history of tobacco, alcohol, or illicit drug abuse.

His proclivity for gardening and apparent tick exposure raise the question of tick‐borne illnesses. This would constitute a rather explosive onset for any of these; however, babesiosis, Rocky Mountain spotted fever (RMSF), ehrlichiosis, and anaplasmosis could present this abruptly, with dog exposure linked to RMSF.

On physical examination, his temperature was 40.7C, heart rate was 115 beats per minute, respiratory rate was 16 breaths per minute, and blood pressure was 92/45 mm Hg. Pulse oximetry was 98% on ambient air. He was disoriented to place and situation, and somnolent but arousable with stimulation. Cardiopulmonary exam was notable for tachycardia. Abdominal exam revealed diffuse tenderness without rebound or guarding. His spleen was palpable just below the left costal margin. Skin examination revealed an erythematous, morbilliform rash covering his entire body including his palms and soles. Pupils were equal, round, and reactive to light. Reflexes were symmetric and 2+ throughout, and the remainder of his neurologic exam was normal. There was no nuchal rigidity.

The potential causes of fever and rash are myriad, although the severity and acuity of this patient's illness narrow the differential considerably, likely to an infectious cause. Diagnoses that typically include a generalized exanthem involving the palms and soles are meningococcal meningitis, overwhelming Staphylococcus aureus sepsis, RMSF (realizing that this disease is not common in the upper Midwest), and toxic shock syndrome. The rash described is not the classic and/or fully developed rash typical of any of these; subsequent evolution to a petechial appearance would lend further support to the first 3 diagnoses. Ehrlichiosis is still a possibility, although the palm and sole involvement would be unusual. The presence of a rash makes anaplasmosis very unlikely, although not entirely excluded. The finding of modest splenomegaly does not help further distinguish between these possibilities.

Empiric antimicrobials should be immediately administered after blood cultures, a complete blood count, and coagulation studies are obtained. Doxycycline would be appropriate to treat the possible tick‐borne diseases already mentioned, whereas antimicrobials appropriate to cover community‐acquired bacterial meningitis in a 58‐year‐old (ie, vancomycin, ampicillin, and a third‐generation cephalosporin) should also be empirically administered. Given the patient's altered mentation, a brain computed tomography (CT) should be urgently obtained. Provided this did not show evidence of increased intracranial pressure and that coagulation studies and a platelet count did not suggest a contraindication, a lumbar puncture should then be performed promptly. The patient should be placed in droplet precautions until meningococcal disease is excluded. Although most patients with bacterial meningitis will exhibit meningismus, a substantial minority will not.

The white blood cell count was 13,300/mm³ with 84% neutrophils, 5.6% lymphocytes, and 5% monocytes. The hemoglobin was 13.6 g/dL and the platelet count was 86,000/mm³. Serum sodium was 137 mmol/L, potassium 4.2 mmol/L, chloride 104 mmol/L, bicarbonate 22 mmol/L, blood urea nitrogen 29 mg/dL, creatinine 1.08 mg/dL (baseline 0.8 mg/dL) and glucose 123 mg/dL. Total protein was 4.7 g/dL (normal 6.08.3 g/dL), albumin 2.5 g/dL (normal 3.54.9 g/dL), aspartate aminotransferase 68 IU/L (normal 830 IU/L), alanine aminotransferase 68 IU/L (normal 735 IU/L), alkaline phosphatase 106 IU/L (normal 30130 IU/L), and total bilirubin 0.5 mg/dL (normal 0.21.2 mg/dL). Troponin was 0.84 ng/mL (normal <0.3 ng/mL). C‐reactive protein was 24.2 mg/dL (normal 0.00.6 mg/dL) and erythrocyte sedimentation rate was 30 mm (normal 015 mm).

These laboratory results do not significantly affect the differential diagnosis. Although nonspecific, moderate thrombocytopenia and modest elevation of hepatic transaminases are typical for tick‐borne diseases, whereas leukocytosis is somewhat atypical for these entities. Marked elevation of the C‐reactive protein with a less striking increase in the erythrocyte sedimentation rate, along with significant hypoalbuminemia, are commonly encountered early in the course of critical infectious illnesses. The elevated troponin likely reflects severe sepsis and demand ischemia, and is associated with a less favorable prognosis; an electrocardiogram and serial cardiac biomarkers are appropriate to help exclude an acute coronary syndrome. As already noted, blood cultures need to be obtained and a lumbar puncture should be performed, provided this can be safely accomplished.

CT of the head was normal. A lumbar puncture was performed. Cerebrospinal fluid was acellular with a protein level of 58 mg/dL (normal <45 mg/dL). Blood, urine, and cerebrospinal fluid cultures were obtained. An electrocardiogram demonstrated sinus tachycardia without signs of ischemia, and a transthoracic echocardiogram showed normal ventricular function. CT of the chest, abdomen, and pelvis revealed dependent bilateral atelectasis and a mildly enlarged spleen of 14 cm.

Results of the lumbar puncture exclude bacterial meningitis as the explanation of this patient's illness; the mildly elevated protein is nonspecific. These studies do not otherwise change the differential diagnosis.

The treating clinicians made a presumptive diagnosis of community‐acquired pneumonia and initiated levofloxacin. He remained febrile for the next 4 days, his maximum temperature reaching 41C, and had intermittent hypotension with systolic blood pressure dropping to 88 mm Hg despite intravenous fluid resuscitation. On hospital day 5 he developed worsening agitation, for which he was sedated and subsequently intubated for airway protection. The same day, vancomycin and piperacillin/tazobactam were added for presumed severe pneumonia as well as doxycycline for empiric treatment of RMSF. The patient was transferred to a tertiary care center for further care.

Supporting data for a diagnosis of pneumonia, such as pulmonary infiltrates or supplemental oxygen requirement, are lacking. Given his critical illness, broad spectrum antimicrobial coverage is indicated, and as a primary central nervous system (CNS) infection now appears unlikely, piperacillin/tazobactam (which does not have adequate CNS penetration) and vancomycin are reasonable. Empiric treatment for RMSF is appropriate, and should have been initiated earlier in the patient's course, despite the upper Midwest being out of the typical range for this disease. Doxycycline will also provide excellent coverage for ehrlichiosis and anaplasmosis.

Given the patient's deterioration, it is important to stop and reconsider the differential diagnosis in an attempt to avoid anchoring bias and premature closure. The patient's illness is almost certainly infectious in nature, and the differential is not substantially altered by the most recent information. A skin biopsy should be performed in an attempt to secure the diagnosis.

On arrival to the tertiary care facility the patient quickly defervesced, self‐extubated, and after 3 days was transitioned to doxycycline monotherapy with continued clinical improvement. At the recommendation of the infectious diseases consultant, serologies for Ehrlichia chaffeensis, Anaplasma phagocytophilum, Leptospira, Mycoplasma pneumoniae, and Rickettsia rickettsia were drawn in addition to fungal serologies for blastomycosis, coccidioidomycosis and histoplasmosis, and Legionella urinary antigen. Rapid human immunodeficiency virus testing and all cultures were negative. He was discharged home to complete a 2‐week course of doxycycline for presumed RMSF.

The patient's overall course, including rapid onset of severe illness and especially the apparent dramatic response to doxycycline, make tick‐borne illness very likely. Completing a course of doxycycline is certainly appropriate, typically for 7 to 14 days. The acute serologies drawn prior to discharge may well reveal the causative agent, but convalescent serology should also be obtained at the time of an outpatient follow‐up visit as immunoglobulin G has a delayed rise. Without hyponatremia or respiratory symptoms, Legionella seems unlikely.

Twelve days later he returned to the clinic for follow‐up. He was overall feeling much improved and his fever, confusion, abdominal pain, and headache had resolved. He complained of mild fatigue, occasional myalgias, and rare nonexertional chest pain, but overall felt well. His leukocyte and platelet counts normalized, though his transaminases remained slightly elevated. His C‐reactive protein decreased to 1.3 mg/dL, whereas his erythrocyte sedimentation rate rose to 83 mm. All acute serologies returned negative. Repeat convalescent serologies also returned negative. His rash had slowly faded and disappeared by his outpatient appointment; however, he was noted to have desquamation of his palms and soles (Figure 1).

Figure 1

The appearance of late desquamation of the palms and soles is an unexpected and important sign. Desquamation in this pattern following an illness of this nature strongly suggests a diagnosis of staphylococcal toxic shock syndrome (TSS), and in conjunction with the negative serologies, argues that tick‐borne disease is unlikely. The list of other entities that might lead to desquamation in this setting is very short, namely adult Kawasaki disease and drug reaction. The former seems reasonably excluded based on details of the case, whereas a doxycycline‐related drug reaction, although not entirely implausible, seems quite unlikely as this medication was started after the onset of the initial rash. This patient most likely had staphylococcal TSS secondary to a minor and unappreciated skin lesion.

The patient was diagnosed with TSS, thought to be acquired through cuts and abrasions sustained while gardening. Doxycycline was discontinued and he recovered without long‐term sequelae. In the following weeks, his chest pain and myalgias abated, and his palmar rash improved followed by desquamation of his soles.

DISCUSSION

TSS is a systemic illness resulting in multiorgan dysfunction.[1] Infection by S aureus or Streptococcus pyogenes causes TSS by stimulating maladaptive T‐cell proliferation and cytokine release resulting in shock.[1, 2] A definitive diagnosis requires fever, a diffuse macular erythematous rash (often resembling a sunburn), with subsequent desquamation, hypotension, and involvement of at least 3 organ systems. Blood cultures, cerebrospinal cultures, and serologies for other organisms should be negative; although Staphylococcus and Streptococcus species may be isolated, they frequently are not (Table 1).[3]

A rare cause of shock, TSS is most associated with a surge of menstruation‐related cases linked to tampon use in young women in the 1980s.[4] However, in Centers for Disease Control and Prevention (CDC) surveillance between 1987 and 1996, only 59% of the 1069 cases identified were noted to be menstruation‐related, as compared to nearly 80% of all cases earlier in the decade.[4, 5] Today, the syndrome is more likely to present after musculoskeletal and cutaneous trauma, oropharyngeal infections, surgical procedures, and device implantation.[1, 6] Despite the disease's evolving epidemiology, the illness script used by physicians likely continues to focus on young women as the primary at risk population for TSS, causing physicians to neglect the diagnosis in other populations.[1, 6, 7, 8, 9] Given this change in risk factors, it is imperative that clinicians rewrite their scripts and recognize the early signs of TSS in all patients to enable quick and effective treatment.

In addition to its shifting epidemiology and rarity, the diagnosis of TSS vexes clinicians for several reasons. First, TSS cannot be quickly and definitively diagnosed because 2 diagnostic criteria cannot be fulfilled during the acute illness. The disease's hallmarka desquamative rashoccurs only if the patient survives.[3] Serologies often take weeks to return, further delaying diagnosis. During this period of diagnostic delay, the illness has usually already resolved or resulted in death. In addition, the presenting symptoms of rash, fever, and shock are nonspecific. Alternative etiologies include meningococcal meningitis, which can also present dramatically as with this patient; RMSF, which can occasionally have a fulminant presentation; bacterial sepsis, usually from Staphylococcus or Streptococcus species; acute viral syndromes; and severe drug reactions.[6, 10, 11, 12] Palmoplantar desquamation, as in this case, can further narrow the differential as this presentation is uncommon but characteristic of TSS, RMSF, and secondary syphilis.[11] Other diagnostic clues offered by the pattern of the rash may be limited by physician discomfort with diagnosing and describing rashes. Because of this lack of a definitive diagnostic test in the acute setting, it is imperative that the clinician include TSS in the differential of fever, shock, and rash, as mortality from TSS can exceed 20% in patients who are untreated.[13]

Treatment of TSS is straightforward once considered and includes the administration of antibiotics that cover both Staphylococcus and Streptococcus species, in addition to aggressive hydration and supportive care.[14] The final critical detail in this case was the appropriate arrangement of follow‐up. Given the patient's drastic improvement, the complicated process of arranging follow‐up for a transferred patient, and the current model where the hospitalists providing inpatient care do not typically follow their patients in clinic, patients such as these can easily be lost to follow‐up. Had this occurred, the desquamation would have been missed, and the patient's diagnosis would have been incomplete.

This patient was eventually diagnosed with TSS by fulfilling all 5 CDC criteria (Table 1).[3] He made a full recovery, likely aided by the administration of broad‐spectrum antibiotics (followed by doxycycline, which provided community‐acquired methicillin‐resistant S aureus coverage) and his lack of serious comorbidities. This case should serve as a reminder to hospitalists that with a discerning eye, a careful assessment of the clinical facts, and appropriate follow‐up, perhaps the next case of TSS can be caught red‐handed.

KEY POINTS

1. When presented with a patient with fever, rash, and shock, hospitalists should consider meningococcal meningitis, RMSF bacterial sepsis, acute viral illness, severe drug reaction, and TSS.
2. TSS, caused by S aureus or S pyogenes, is no longer predominantly associated with tampon use. Postsurgical infection and cutaneous trauma have become important present‐day risk factors.
3. The initial presentation of TSS is nonspecific. Definitive diagnosis requires proper follow‐up, allowing time for infectious serologies to return negative and for the disease's hallmark desquamation to occur.

A previously healthy 11‐year‐old boy presented to the emergency department after referral from his pediatrician for 1 week of fevers. Seven days prior to admission he developed a fever to 40.8C, vomiting, and mild left knee pain. The vomiting resolved within 2 days. Five days prior to admission he developed a pruritic, pinpoint rash over his abdomen that resolved within 24 hours. He also developed red, cracked lips, redness of his tongue, redness surrounding his eyes, and slight swelling of his hands. Three days prior to admission his pediatrician noted a 1‐cm anterior cervical lymph node. His fevers occurred throughout each of the prior 7 days without a discernible pattern, and his mild knee pain persisted at the time of presentation.

This preteen has had high fevers for 1 week associated with arthralgia, pruritic rash, emesis, and oral mucosal erythema. His rash, lip and tongue erythema, and swollen hands are classic features of Kawasaki disease (KD), but he lacks the other characteristic physical examination findings. The diagnosis of KD requires fever for at least 5 days accompanied by 4 of the following 5 signs: polymorphous rash, oral mucous membrane changes, peripheral extremity changes such as swelling or skin desquamation, bilateral bulbar conjunctival injection, and cervical lymphadenopathy >1.5 cm in diameter. Children meeting fewer than 4 of these criteria may have an incomplete form of KD.

Because most patients with KD (80%) are under 5 years old, alternative diagnoses such as autoimmune illnesses or a hypersensitivity reaction should be considered. Travel, medication, and animal exposure histories may reveal clues to an infectious or drug‐induced etiology of his fever. Immunization status should be assessed, as measles is also associated with fever, rash, and mucosal changes. Arthralgia or arthritis may occur in KD, but these findings suggest the need to entertain other possibilities, including bone or joint infection, infective endocarditis, inflammatory bowel disease, juvenile idiopathic arthritis (JIA), or systemic lupus erythematosus (SLE).

The child's only past medical history was an episode of croup as an infant. There was no family history of autoimmune diseases. He was not taking any medications and had no known allergies. His immunizations were up to date, including measles, mumps, rubella, and varicella. He lived with his parents and his dog. He swam in fresh water during a trip to Maine 2 months earlier. Neither he nor his family recalled a tick bite. He had no exposure to raw meat or unpasteurized dairy products.

The travel to New England raises the possibility of Lyme disease, although a 2‐month interval between exposure and a high, prolonged fever would be very unusual. Knee arthralgia or arthritis is common in children with late‐stage Lyme disease, but can also be seen in early‐disseminated disease. The prior description of the rash is not suggestive of erythema chronicum migrans, which is seen in early‐stage Lyme disease.

C‐reactive protein (CRP) was 189 mg/L (normal <6.3 mg/L). An echocardiogram was normal. Intravenous immunoglobulin (IVIG) was administered for presumed KD, with immediate improvement of the periorbital erythema, tongue redness, and hand swelling. He was discharged the next day on aspirin with cardiology clinic follow‐up.

Improvement after IVIG supports the diagnosis of KD. It is typical to discharge KD patients from the hospital when they have been afebrile for 24 hours or when the CRP level has declined by approximately 50%.

Over the next 48 hours he felt unwell with high‐grade fevers, continued left knee pain, and new left hip pain. He was readmitted to the hospital. His temperature was 39.4C, respiratory rate was 22 breaths per minute, heart rate was 122 beats per minute, blood pressure was 103/50 mm Hg, and oxygen saturation was 100% while breathing ambient air. He appeared mildly uncomfortable. His conjunctivae were normal. His lips were dry, red, and cracked, and his tongue was red with prominent papillae. His neck was supple without lymphadenopathy. His lungs were clear to auscultation. His heart exam was without murmurs. His abdomen was soft, and the liver and spleen were not enlarged. He had no swelling or erythema of his joints; however, he experienced pain with range of motion of his left knee, and tenderness and restricted range of motion of his left hip. His neurologic exam was normal. There were no rashes.

He has persistent fever, tachycardia, and tachypnea, now without features of KD except oral mucosal changes including prominent tongue papillae consistent with a strawberry tongue. Continued or recurrent fever may suggest persistent KD with ongoing inflammation or the need to search for an alternative diagnoses. An echocardiogram should be repeated, as the coronary artery abnormalities in KD can evolve rapidly, particularly when inflammation persists. Additional findings may include decreased left ventricular function, mitral regurgitation, or pericardial effusion. A second dose of IVIG is necessary to control fever and inflammation in about 15% of patients with KD, although in this case IVIG should be withheld pending further evaluation.

Arthralgia occurs commonly in KD, whereas frank arthritis is less typical. Polyarticular or oligoarticular arthritis involving small or large joints (especially knee or ankle) affects 5% to 10% of patients. The severity of findings in his left hip warrants consideration of septic arthritis with pain referred to the knee; pelvic or femoral osteomyelitis; psoas abscess; or pyomyositis. Following basic lab tests, imaging of the left hip region is indicated.

Laboratory evaluation revealed: white blood cell (WBC) count 10,000/L (absolute neutrophil count 8,460/L, absolute lymphocyte count 530/L), hemoglobin 10.6 g/dL, platelet count 208,000/L, serum sodium 130 mmol/L, serum potassium 3.3 mmol/L, serum urea nitrogen 11 mg/dL, serum creatinine 0.54 mg/dL, aspartate transaminase (AST) 26 U/L, alanine transaminase (ALT) 31 U/L, albumin 1.7 g/dL, erythrocyte sedimentation rate (ESR) > 100 mm/h, and CRP 263 mg/L. No blast cells were seen on peripheral blood smear.

Hypoalbuminemia and markedly elevated inflammatory markers indicate an inflammatory condition that has been active for more than a week. Assessing ESR after IVIG therapy is not useful because exogenous globulins increase the ESR; however, CRP is useful to monitor inflammation and remains elevated here.

Incomplete KD is still possible. Hyponatremia, hypoalbuminemia, and anemia are all features of persistent KD, and have been utilized in several clinical scoring systems in Japan to identify KD patients at increased risk for developing coronary complications. A neoplastic process cannot be excluded, but does not appear likely based on the acuity of his presentation and peripheral blood smear review.

Upon readmission he received a second dose of 2 g/kg IVIG. He remained on aspirin and continued to have fevers. A repeat echocardiogram was normal. He had worsening pain in his left knee and hip with difficulty straightening his left leg. Physical examination was notable for tenderness to palpation over his left hip joint, refusal to bear weight, and resistance to passive range of motion. On hospital day 2, an ultrasound of his left hip and knee revealed a complex left hip effusion and small left knee effusion.

KD becomes less likely in the presence of persistent fevers after IVIG and a repeatedly normal echocardiogram. Worsening left leg symptoms including impaired hip extension with a complex hip effusion suggests an infectious process in or adjacent to the left hip, such as septic arthritis, myositis, or osteomyelitis of the pelvis or proximal femur. A complex hip effusion is less likely to be present with arthritis related to JIA or SLE. The patient needs an emergent hip aspiration and possibly magnetic resonance imaging (MRI) to evaluate adjacent structures.

Arthrotomy and open drainage of his left hip revealed purulent fluid with a WBC count of 49,000/L with 89% neutrophils and 2% lymphocytes. Gram stain was negative. A left knee aspirate demonstrated straw‐colored synovial fluid (which was not sent for cell counts). Bacterial, fungal, and acid‐fast bacilli cultures were requested from hip and knee aspirates. Intravenous ceftriaxone and vancomycin were administered.

The most likely organism in pediatric pyogenic arthritis is Staphylococcus aureus, but there is a long list of other potential pathogens, including Streptococcus pyogenes (group A streptococcus) and Streptococcus pneumoniae. Most pediatric patients with acute pyogenic arthritis have synovial fluid WBC counts in excess of 75,000 to 100,000/L. The protracted course and the initial lack of hip symptoms raise the possibility of a primary osteomyelitis of the femur (particularly the intracapsular portion of the femoral neck or head) or of the acetabulum, with subsequent extension into the hip joint. Pyogenic myositis involving muscle groups adjacent to the hip would be unlikely to spread into the hip space, but can lead to synovial irritation, characterized by sterile joint fluid and WBC counts that fall short of the usual numbers seen in septic arthritis. The blood supply to the femoral head can become compromised with prolonged inflammation and increased intracapsular pressure, resulting in aseptic necrosis.

All cultures from his hip and knee aspirations were sterile. He continued to have daily fevers and persistent tachycardia while receiving intravenous ceftriaxone and vancomycin. Additional testing was notable for: antinuclear antibody (ANA) 1:80, anti‐streptolysin O (ASO) titer 344 IU (normal <150 IU), AST and ALT within normal limits, ferritin 568 ng/mL (normal <322 ng/mL), and lactate dehydrogenase (LDH) 212 units/L (normal <257 units/L). Abdominal ultrasound revealed borderline hepatosplenomegaly. An ophthalmologic examination was normal.

On postoperative day 4 he developed left upper thigh swelling. An MRI showed rim‐enhancing juxta‐articular complex fluid collections surrounding the left femur with decreased marrow enhancement of the left proximal femur (Figure 1).

Figure 1

The limited rheumatologic evaluation is unrevealing; the ANA result is nondiagnostic and the ASO titer is normal for age. Laboratories generally report adult normal values for streptococcal antibodies regardless of the patient's age; children from ages 7 to 12 years are at their life peak frequency of group A streptococcal pharyngitis and typically have higher normal values of streptococcal antibodies, including ASO (up to about 480640 IU). The moderately elevated ferritin level is most likely an acute phase reactant and not high enough to suggest macrophage activation syndrome, which is unlikely with the normal AST, ALT, and LDH levels, the absence of significant splenomegaly, and the lack of cytopenias. Continued fever with progressive left upper thigh swelling point to osteomyelitis of the proximal femur, which may have initially ruptured into the hip and then infiltrated the femoral cortex and spread infection into the adjacent soft tissues. Surgical debridement is indicated.

The relative prevalence of methicillin‐sensitive S aureus (MSSA) and methicillin‐resistant S aureus vary widely with geography. MSSA strains are more likely to be highly toxigenic. The elaboration of 1 or more extracellular toxins could account for the patient's initial symptoms.

The patient was brought back to the operating room for drainage of the juxta‐articular fluid collections and a biopsy of his femur. The fluid collections were grossly purulent. His intraoperative cultures were positive for MSSA. The bone biopsy revealed necrotic tissue, acute inflammation, and bacterial colonies, consistent with acute osteomyelitis. Further testing of his S aureus isolate was positive for staphylococcal enterotoxin B. He completed a 4‐week course of oral clindamycin with subsequent normalization of his hip exam and inflammatory markers. At a follow‐up visit the patient was feeling better, but had developed skin peeling on the lateral aspects of his feet consistent with late sequelae of toxin‐mediated disease (Figure 2). Three months after discharge the patient had returned to his baseline activity level and remained asymptomatic.

Figure 2

COMMENTARY

The patient presented with a constellation of symptoms that was initially mistaken for incomplete KD until focal progression of his symptoms exposed an underlying femoral osteomyelitis with periarticular abscess formation. Bacterial cultures and subsequent toxin assay revealed an enterotoxin B‐producing strain of S aureus.

Certain staphylococcal strains secrete superantigens that may lead to the development of a systemic toxin‐mediated syndrome. Toxins elaborated by S aureus include toxic shock syndrome toxin‐1 (TSST‐1) and enterotoxins, which have been implicated in menstrual and nonmenstrual toxic shock syndromes.[1, 2] Enterotoxin B is a staphylococcal superantigen found in most strains of the USA400 clonal group, and has been frequently associated with skin and soft tissue infections.[3] Enterotoxin B production has been reported in nearly half of S aureus isolates from skin, soft tissue, and bone infections.[4]

Staphylococcal and streptococcal toxin‐mediated diseases can mimic vasculitis, systemic juvenile idiopathic arthritis, viral infections, and Stevens‐Johnson syndrome. Glossitis in toxin‐mediated syndromes manifests with a swollen, red tongue with overlying enlarged papillae, giving the appearance of a strawberry. Although pediatric providers often equate strawberry tongue, conjunctival injection, rash, and erythematous lips with KD, these findings are also seen in toxin‐mediated diseases, such as scarlet fever or staphylococcal toxic shock syndrome. Enterotoxin B mediated staphylococcal disease masquerading as KD has been reported in 2 cases: a 7‐month‐old boy with multifocal S aureus osteomyelitis and a 5‐year‐old boy with S aureus bacteremia. Both staphylococcal isolates produced enterotoxin B but were negative for other staphylococcus‐related toxins including TSST‐1.[5]

The Institute of Medicine (IOM) recently released its report Improving Diagnosis in Health Care, highlighting the under‐recognized quality and safety issue of diagnostic error.[6] The report uses the following broad and patient‐centered definition of diagnostic error: the failure to (a) establish an accurate and timely explanation of the patient's health problem(s) or (b) communicate that explanation to the patient. The IOM's conceptual model of diagnosis emphasizes the iterative nature of the diagnostic process, including the importance of generating a working diagnosis, gathering and incorporating new information in the reassessment of that diagnosis, and integrating treatment response into the formulation of the final diagnosis (Figure 3).

Figure 3

Even though the patient initially had several features consistent with KD, the increasing number of atypical features could have prompted the clinical team to reconsider their working diagnosis. The patient's age was atypical for KD, he had progressive knee and hip arthritis, and his fevers persisted after IVIG. An expanded differential should have included toxic shock syndrome; the resolution of conjunctival and mucosal injection and edema after IVIG may have been the result of antibodies in the IVIG preparation with neutralizing activity against superantigens. This antitoxin activity has established a role for IVIG in the management of staphylococcal toxic shock syndrome.[7] Ultimately, his imaging and surgical drainage revealed a focal staphylococcal toxin‐producing infectious source from which his fevers, rash, and mucosal and extremity changes emanated. This case reminds us that the more atypical a working diagnosis iseither in its presentation or treatment responsethe more readily clinicians should take it for another spin around the diagnostic wheel in search of a more suitable alternative.

KEY LEARNING POINTS

1. Staphylococcal toxin‐mediated disease may mimic KD, with common features including strawberry tongue, oral and conjunctival injection, and skin desquamation.
2. Improvement after treatment with IVIG is characteristic but not diagnostic of KD, and may be seen in toxin‐mediated disease.
3. KD may present with arthralgia or arthritis, but severe joint abnormalities warrant consideration of infectious and other autoimmune conditions.
4. The more atypical a working diagnosis iseither in its presentation or treatment responsethe more readily clinicians should gather, interpret, and integrate new information in search of a more suitable alternative.

Disclosure: Nothing to report.

A previously healthy 11‐year‐old boy presented to the emergency department after referral from his pediatrician for 1 week of fevers. Seven days prior to admission he developed a fever to 40.8C, vomiting, and mild left knee pain. The vomiting resolved within 2 days. Five days prior to admission he developed a pruritic, pinpoint rash over his abdomen that resolved within 24 hours. He also developed red, cracked lips, redness of his tongue, redness surrounding his eyes, and slight swelling of his hands. Three days prior to admission his pediatrician noted a 1‐cm anterior cervical lymph node. His fevers occurred throughout each of the prior 7 days without a discernible pattern, and his mild knee pain persisted at the time of presentation.

This preteen has had high fevers for 1 week associated with arthralgia, pruritic rash, emesis, and oral mucosal erythema. His rash, lip and tongue erythema, and swollen hands are classic features of Kawasaki disease (KD), but he lacks the other characteristic physical examination findings. The diagnosis of KD requires fever for at least 5 days accompanied by 4 of the following 5 signs: polymorphous rash, oral mucous membrane changes, peripheral extremity changes such as swelling or skin desquamation, bilateral bulbar conjunctival injection, and cervical lymphadenopathy >1.5 cm in diameter. Children meeting fewer than 4 of these criteria may have an incomplete form of KD.

Because most patients with KD (80%) are under 5 years old, alternative diagnoses such as autoimmune illnesses or a hypersensitivity reaction should be considered. Travel, medication, and animal exposure histories may reveal clues to an infectious or drug‐induced etiology of his fever. Immunization status should be assessed, as measles is also associated with fever, rash, and mucosal changes. Arthralgia or arthritis may occur in KD, but these findings suggest the need to entertain other possibilities, including bone or joint infection, infective endocarditis, inflammatory bowel disease, juvenile idiopathic arthritis (JIA), or systemic lupus erythematosus (SLE).

The child's only past medical history was an episode of croup as an infant. There was no family history of autoimmune diseases. He was not taking any medications and had no known allergies. His immunizations were up to date, including measles, mumps, rubella, and varicella. He lived with his parents and his dog. He swam in fresh water during a trip to Maine 2 months earlier. Neither he nor his family recalled a tick bite. He had no exposure to raw meat or unpasteurized dairy products.

The travel to New England raises the possibility of Lyme disease, although a 2‐month interval between exposure and a high, prolonged fever would be very unusual. Knee arthralgia or arthritis is common in children with late‐stage Lyme disease, but can also be seen in early‐disseminated disease. The prior description of the rash is not suggestive of erythema chronicum migrans, which is seen in early‐stage Lyme disease.

C‐reactive protein (CRP) was 189 mg/L (normal <6.3 mg/L). An echocardiogram was normal. Intravenous immunoglobulin (IVIG) was administered for presumed KD, with immediate improvement of the periorbital erythema, tongue redness, and hand swelling. He was discharged the next day on aspirin with cardiology clinic follow‐up.

Improvement after IVIG supports the diagnosis of KD. It is typical to discharge KD patients from the hospital when they have been afebrile for 24 hours or when the CRP level has declined by approximately 50%.

Over the next 48 hours he felt unwell with high‐grade fevers, continued left knee pain, and new left hip pain. He was readmitted to the hospital. His temperature was 39.4C, respiratory rate was 22 breaths per minute, heart rate was 122 beats per minute, blood pressure was 103/50 mm Hg, and oxygen saturation was 100% while breathing ambient air. He appeared mildly uncomfortable. His conjunctivae were normal. His lips were dry, red, and cracked, and his tongue was red with prominent papillae. His neck was supple without lymphadenopathy. His lungs were clear to auscultation. His heart exam was without murmurs. His abdomen was soft, and the liver and spleen were not enlarged. He had no swelling or erythema of his joints; however, he experienced pain with range of motion of his left knee, and tenderness and restricted range of motion of his left hip. His neurologic exam was normal. There were no rashes.

He has persistent fever, tachycardia, and tachypnea, now without features of KD except oral mucosal changes including prominent tongue papillae consistent with a strawberry tongue. Continued or recurrent fever may suggest persistent KD with ongoing inflammation or the need to search for an alternative diagnoses. An echocardiogram should be repeated, as the coronary artery abnormalities in KD can evolve rapidly, particularly when inflammation persists. Additional findings may include decreased left ventricular function, mitral regurgitation, or pericardial effusion. A second dose of IVIG is necessary to control fever and inflammation in about 15% of patients with KD, although in this case IVIG should be withheld pending further evaluation.

Arthralgia occurs commonly in KD, whereas frank arthritis is less typical. Polyarticular or oligoarticular arthritis involving small or large joints (especially knee or ankle) affects 5% to 10% of patients. The severity of findings in his left hip warrants consideration of septic arthritis with pain referred to the knee; pelvic or femoral osteomyelitis; psoas abscess; or pyomyositis. Following basic lab tests, imaging of the left hip region is indicated.

Laboratory evaluation revealed: white blood cell (WBC) count 10,000/L (absolute neutrophil count 8,460/L, absolute lymphocyte count 530/L), hemoglobin 10.6 g/dL, platelet count 208,000/L, serum sodium 130 mmol/L, serum potassium 3.3 mmol/L, serum urea nitrogen 11 mg/dL, serum creatinine 0.54 mg/dL, aspartate transaminase (AST) 26 U/L, alanine transaminase (ALT) 31 U/L, albumin 1.7 g/dL, erythrocyte sedimentation rate (ESR) > 100 mm/h, and CRP 263 mg/L. No blast cells were seen on peripheral blood smear.

Hypoalbuminemia and markedly elevated inflammatory markers indicate an inflammatory condition that has been active for more than a week. Assessing ESR after IVIG therapy is not useful because exogenous globulins increase the ESR; however, CRP is useful to monitor inflammation and remains elevated here.

Incomplete KD is still possible. Hyponatremia, hypoalbuminemia, and anemia are all features of persistent KD, and have been utilized in several clinical scoring systems in Japan to identify KD patients at increased risk for developing coronary complications. A neoplastic process cannot be excluded, but does not appear likely based on the acuity of his presentation and peripheral blood smear review.

Upon readmission he received a second dose of 2 g/kg IVIG. He remained on aspirin and continued to have fevers. A repeat echocardiogram was normal. He had worsening pain in his left knee and hip with difficulty straightening his left leg. Physical examination was notable for tenderness to palpation over his left hip joint, refusal to bear weight, and resistance to passive range of motion. On hospital day 2, an ultrasound of his left hip and knee revealed a complex left hip effusion and small left knee effusion.

KD becomes less likely in the presence of persistent fevers after IVIG and a repeatedly normal echocardiogram. Worsening left leg symptoms including impaired hip extension with a complex hip effusion suggests an infectious process in or adjacent to the left hip, such as septic arthritis, myositis, or osteomyelitis of the pelvis or proximal femur. A complex hip effusion is less likely to be present with arthritis related to JIA or SLE. The patient needs an emergent hip aspiration and possibly magnetic resonance imaging (MRI) to evaluate adjacent structures.

Arthrotomy and open drainage of his left hip revealed purulent fluid with a WBC count of 49,000/L with 89% neutrophils and 2% lymphocytes. Gram stain was negative. A left knee aspirate demonstrated straw‐colored synovial fluid (which was not sent for cell counts). Bacterial, fungal, and acid‐fast bacilli cultures were requested from hip and knee aspirates. Intravenous ceftriaxone and vancomycin were administered.

The most likely organism in pediatric pyogenic arthritis is Staphylococcus aureus, but there is a long list of other potential pathogens, including Streptococcus pyogenes (group A streptococcus) and Streptococcus pneumoniae. Most pediatric patients with acute pyogenic arthritis have synovial fluid WBC counts in excess of 75,000 to 100,000/L. The protracted course and the initial lack of hip symptoms raise the possibility of a primary osteomyelitis of the femur (particularly the intracapsular portion of the femoral neck or head) or of the acetabulum, with subsequent extension into the hip joint. Pyogenic myositis involving muscle groups adjacent to the hip would be unlikely to spread into the hip space, but can lead to synovial irritation, characterized by sterile joint fluid and WBC counts that fall short of the usual numbers seen in septic arthritis. The blood supply to the femoral head can become compromised with prolonged inflammation and increased intracapsular pressure, resulting in aseptic necrosis.

All cultures from his hip and knee aspirations were sterile. He continued to have daily fevers and persistent tachycardia while receiving intravenous ceftriaxone and vancomycin. Additional testing was notable for: antinuclear antibody (ANA) 1:80, anti‐streptolysin O (ASO) titer 344 IU (normal <150 IU), AST and ALT within normal limits, ferritin 568 ng/mL (normal <322 ng/mL), and lactate dehydrogenase (LDH) 212 units/L (normal <257 units/L). Abdominal ultrasound revealed borderline hepatosplenomegaly. An ophthalmologic examination was normal.

On postoperative day 4 he developed left upper thigh swelling. An MRI showed rim‐enhancing juxta‐articular complex fluid collections surrounding the left femur with decreased marrow enhancement of the left proximal femur (Figure 1).

Figure 1

The limited rheumatologic evaluation is unrevealing; the ANA result is nondiagnostic and the ASO titer is normal for age. Laboratories generally report adult normal values for streptococcal antibodies regardless of the patient's age; children from ages 7 to 12 years are at their life peak frequency of group A streptococcal pharyngitis and typically have higher normal values of streptococcal antibodies, including ASO (up to about 480640 IU). The moderately elevated ferritin level is most likely an acute phase reactant and not high enough to suggest macrophage activation syndrome, which is unlikely with the normal AST, ALT, and LDH levels, the absence of significant splenomegaly, and the lack of cytopenias. Continued fever with progressive left upper thigh swelling point to osteomyelitis of the proximal femur, which may have initially ruptured into the hip and then infiltrated the femoral cortex and spread infection into the adjacent soft tissues. Surgical debridement is indicated.

The relative prevalence of methicillin‐sensitive S aureus (MSSA) and methicillin‐resistant S aureus vary widely with geography. MSSA strains are more likely to be highly toxigenic. The elaboration of 1 or more extracellular toxins could account for the patient's initial symptoms.

The patient was brought back to the operating room for drainage of the juxta‐articular fluid collections and a biopsy of his femur. The fluid collections were grossly purulent. His intraoperative cultures were positive for MSSA. The bone biopsy revealed necrotic tissue, acute inflammation, and bacterial colonies, consistent with acute osteomyelitis. Further testing of his S aureus isolate was positive for staphylococcal enterotoxin B. He completed a 4‐week course of oral clindamycin with subsequent normalization of his hip exam and inflammatory markers. At a follow‐up visit the patient was feeling better, but had developed skin peeling on the lateral aspects of his feet consistent with late sequelae of toxin‐mediated disease (Figure 2). Three months after discharge the patient had returned to his baseline activity level and remained asymptomatic.

Figure 2

COMMENTARY

The patient presented with a constellation of symptoms that was initially mistaken for incomplete KD until focal progression of his symptoms exposed an underlying femoral osteomyelitis with periarticular abscess formation. Bacterial cultures and subsequent toxin assay revealed an enterotoxin B‐producing strain of S aureus.

Certain staphylococcal strains secrete superantigens that may lead to the development of a systemic toxin‐mediated syndrome. Toxins elaborated by S aureus include toxic shock syndrome toxin‐1 (TSST‐1) and enterotoxins, which have been implicated in menstrual and nonmenstrual toxic shock syndromes.[1, 2] Enterotoxin B is a staphylococcal superantigen found in most strains of the USA400 clonal group, and has been frequently associated with skin and soft tissue infections.[3] Enterotoxin B production has been reported in nearly half of S aureus isolates from skin, soft tissue, and bone infections.[4]

Staphylococcal and streptococcal toxin‐mediated diseases can mimic vasculitis, systemic juvenile idiopathic arthritis, viral infections, and Stevens‐Johnson syndrome. Glossitis in toxin‐mediated syndromes manifests with a swollen, red tongue with overlying enlarged papillae, giving the appearance of a strawberry. Although pediatric providers often equate strawberry tongue, conjunctival injection, rash, and erythematous lips with KD, these findings are also seen in toxin‐mediated diseases, such as scarlet fever or staphylococcal toxic shock syndrome. Enterotoxin B mediated staphylococcal disease masquerading as KD has been reported in 2 cases: a 7‐month‐old boy with multifocal S aureus osteomyelitis and a 5‐year‐old boy with S aureus bacteremia. Both staphylococcal isolates produced enterotoxin B but were negative for other staphylococcus‐related toxins including TSST‐1.[5]

The Institute of Medicine (IOM) recently released its report Improving Diagnosis in Health Care, highlighting the under‐recognized quality and safety issue of diagnostic error.[6] The report uses the following broad and patient‐centered definition of diagnostic error: the failure to (a) establish an accurate and timely explanation of the patient's health problem(s) or (b) communicate that explanation to the patient. The IOM's conceptual model of diagnosis emphasizes the iterative nature of the diagnostic process, including the importance of generating a working diagnosis, gathering and incorporating new information in the reassessment of that diagnosis, and integrating treatment response into the formulation of the final diagnosis (Figure 3).

Figure 3

Even though the patient initially had several features consistent with KD, the increasing number of atypical features could have prompted the clinical team to reconsider their working diagnosis. The patient's age was atypical for KD, he had progressive knee and hip arthritis, and his fevers persisted after IVIG. An expanded differential should have included toxic shock syndrome; the resolution of conjunctival and mucosal injection and edema after IVIG may have been the result of antibodies in the IVIG preparation with neutralizing activity against superantigens. This antitoxin activity has established a role for IVIG in the management of staphylococcal toxic shock syndrome.[7] Ultimately, his imaging and surgical drainage revealed a focal staphylococcal toxin‐producing infectious source from which his fevers, rash, and mucosal and extremity changes emanated. This case reminds us that the more atypical a working diagnosis iseither in its presentation or treatment responsethe more readily clinicians should take it for another spin around the diagnostic wheel in search of a more suitable alternative.

KEY LEARNING POINTS

1. Staphylococcal toxin‐mediated disease may mimic KD, with common features including strawberry tongue, oral and conjunctival injection, and skin desquamation.
2. Improvement after treatment with IVIG is characteristic but not diagnostic of KD, and may be seen in toxin‐mediated disease.
3. KD may present with arthralgia or arthritis, but severe joint abnormalities warrant consideration of infectious and other autoimmune conditions.
4. The more atypical a working diagnosis iseither in its presentation or treatment responsethe more readily clinicians should gather, interpret, and integrate new information in search of a more suitable alternative.

Disclosure: Nothing to report.

A previously healthy 11‐year‐old boy presented to the emergency department after referral from his pediatrician for 1 week of fevers. Seven days prior to admission he developed a fever to 40.8C, vomiting, and mild left knee pain. The vomiting resolved within 2 days. Five days prior to admission he developed a pruritic, pinpoint rash over his abdomen that resolved within 24 hours. He also developed red, cracked lips, redness of his tongue, redness surrounding his eyes, and slight swelling of his hands. Three days prior to admission his pediatrician noted a 1‐cm anterior cervical lymph node. His fevers occurred throughout each of the prior 7 days without a discernible pattern, and his mild knee pain persisted at the time of presentation.

This preteen has had high fevers for 1 week associated with arthralgia, pruritic rash, emesis, and oral mucosal erythema. His rash, lip and tongue erythema, and swollen hands are classic features of Kawasaki disease (KD), but he lacks the other characteristic physical examination findings. The diagnosis of KD requires fever for at least 5 days accompanied by 4 of the following 5 signs: polymorphous rash, oral mucous membrane changes, peripheral extremity changes such as swelling or skin desquamation, bilateral bulbar conjunctival injection, and cervical lymphadenopathy >1.5 cm in diameter. Children meeting fewer than 4 of these criteria may have an incomplete form of KD.

Because most patients with KD (80%) are under 5 years old, alternative diagnoses such as autoimmune illnesses or a hypersensitivity reaction should be considered. Travel, medication, and animal exposure histories may reveal clues to an infectious or drug‐induced etiology of his fever. Immunization status should be assessed, as measles is also associated with fever, rash, and mucosal changes. Arthralgia or arthritis may occur in KD, but these findings suggest the need to entertain other possibilities, including bone or joint infection, infective endocarditis, inflammatory bowel disease, juvenile idiopathic arthritis (JIA), or systemic lupus erythematosus (SLE).

The child's only past medical history was an episode of croup as an infant. There was no family history of autoimmune diseases. He was not taking any medications and had no known allergies. His immunizations were up to date, including measles, mumps, rubella, and varicella. He lived with his parents and his dog. He swam in fresh water during a trip to Maine 2 months earlier. Neither he nor his family recalled a tick bite. He had no exposure to raw meat or unpasteurized dairy products.

The travel to New England raises the possibility of Lyme disease, although a 2‐month interval between exposure and a high, prolonged fever would be very unusual. Knee arthralgia or arthritis is common in children with late‐stage Lyme disease, but can also be seen in early‐disseminated disease. The prior description of the rash is not suggestive of erythema chronicum migrans, which is seen in early‐stage Lyme disease.

C‐reactive protein (CRP) was 189 mg/L (normal <6.3 mg/L). An echocardiogram was normal. Intravenous immunoglobulin (IVIG) was administered for presumed KD, with immediate improvement of the periorbital erythema, tongue redness, and hand swelling. He was discharged the next day on aspirin with cardiology clinic follow‐up.

Improvement after IVIG supports the diagnosis of KD. It is typical to discharge KD patients from the hospital when they have been afebrile for 24 hours or when the CRP level has declined by approximately 50%.

Over the next 48 hours he felt unwell with high‐grade fevers, continued left knee pain, and new left hip pain. He was readmitted to the hospital. His temperature was 39.4C, respiratory rate was 22 breaths per minute, heart rate was 122 beats per minute, blood pressure was 103/50 mm Hg, and oxygen saturation was 100% while breathing ambient air. He appeared mildly uncomfortable. His conjunctivae were normal. His lips were dry, red, and cracked, and his tongue was red with prominent papillae. His neck was supple without lymphadenopathy. His lungs were clear to auscultation. His heart exam was without murmurs. His abdomen was soft, and the liver and spleen were not enlarged. He had no swelling or erythema of his joints; however, he experienced pain with range of motion of his left knee, and tenderness and restricted range of motion of his left hip. His neurologic exam was normal. There were no rashes.

He has persistent fever, tachycardia, and tachypnea, now without features of KD except oral mucosal changes including prominent tongue papillae consistent with a strawberry tongue. Continued or recurrent fever may suggest persistent KD with ongoing inflammation or the need to search for an alternative diagnoses. An echocardiogram should be repeated, as the coronary artery abnormalities in KD can evolve rapidly, particularly when inflammation persists. Additional findings may include decreased left ventricular function, mitral regurgitation, or pericardial effusion. A second dose of IVIG is necessary to control fever and inflammation in about 15% of patients with KD, although in this case IVIG should be withheld pending further evaluation.

Arthralgia occurs commonly in KD, whereas frank arthritis is less typical. Polyarticular or oligoarticular arthritis involving small or large joints (especially knee or ankle) affects 5% to 10% of patients. The severity of findings in his left hip warrants consideration of septic arthritis with pain referred to the knee; pelvic or femoral osteomyelitis; psoas abscess; or pyomyositis. Following basic lab tests, imaging of the left hip region is indicated.

Laboratory evaluation revealed: white blood cell (WBC) count 10,000/L (absolute neutrophil count 8,460/L, absolute lymphocyte count 530/L), hemoglobin 10.6 g/dL, platelet count 208,000/L, serum sodium 130 mmol/L, serum potassium 3.3 mmol/L, serum urea nitrogen 11 mg/dL, serum creatinine 0.54 mg/dL, aspartate transaminase (AST) 26 U/L, alanine transaminase (ALT) 31 U/L, albumin 1.7 g/dL, erythrocyte sedimentation rate (ESR) > 100 mm/h, and CRP 263 mg/L. No blast cells were seen on peripheral blood smear.

Hypoalbuminemia and markedly elevated inflammatory markers indicate an inflammatory condition that has been active for more than a week. Assessing ESR after IVIG therapy is not useful because exogenous globulins increase the ESR; however, CRP is useful to monitor inflammation and remains elevated here.

Incomplete KD is still possible. Hyponatremia, hypoalbuminemia, and anemia are all features of persistent KD, and have been utilized in several clinical scoring systems in Japan to identify KD patients at increased risk for developing coronary complications. A neoplastic process cannot be excluded, but does not appear likely based on the acuity of his presentation and peripheral blood smear review.

Upon readmission he received a second dose of 2 g/kg IVIG. He remained on aspirin and continued to have fevers. A repeat echocardiogram was normal. He had worsening pain in his left knee and hip with difficulty straightening his left leg. Physical examination was notable for tenderness to palpation over his left hip joint, refusal to bear weight, and resistance to passive range of motion. On hospital day 2, an ultrasound of his left hip and knee revealed a complex left hip effusion and small left knee effusion.

KD becomes less likely in the presence of persistent fevers after IVIG and a repeatedly normal echocardiogram. Worsening left leg symptoms including impaired hip extension with a complex hip effusion suggests an infectious process in or adjacent to the left hip, such as septic arthritis, myositis, or osteomyelitis of the pelvis or proximal femur. A complex hip effusion is less likely to be present with arthritis related to JIA or SLE. The patient needs an emergent hip aspiration and possibly magnetic resonance imaging (MRI) to evaluate adjacent structures.

Arthrotomy and open drainage of his left hip revealed purulent fluid with a WBC count of 49,000/L with 89% neutrophils and 2% lymphocytes. Gram stain was negative. A left knee aspirate demonstrated straw‐colored synovial fluid (which was not sent for cell counts). Bacterial, fungal, and acid‐fast bacilli cultures were requested from hip and knee aspirates. Intravenous ceftriaxone and vancomycin were administered.

The most likely organism in pediatric pyogenic arthritis is Staphylococcus aureus, but there is a long list of other potential pathogens, including Streptococcus pyogenes (group A streptococcus) and Streptococcus pneumoniae. Most pediatric patients with acute pyogenic arthritis have synovial fluid WBC counts in excess of 75,000 to 100,000/L. The protracted course and the initial lack of hip symptoms raise the possibility of a primary osteomyelitis of the femur (particularly the intracapsular portion of the femoral neck or head) or of the acetabulum, with subsequent extension into the hip joint. Pyogenic myositis involving muscle groups adjacent to the hip would be unlikely to spread into the hip space, but can lead to synovial irritation, characterized by sterile joint fluid and WBC counts that fall short of the usual numbers seen in septic arthritis. The blood supply to the femoral head can become compromised with prolonged inflammation and increased intracapsular pressure, resulting in aseptic necrosis.

All cultures from his hip and knee aspirations were sterile. He continued to have daily fevers and persistent tachycardia while receiving intravenous ceftriaxone and vancomycin. Additional testing was notable for: antinuclear antibody (ANA) 1:80, anti‐streptolysin O (ASO) titer 344 IU (normal <150 IU), AST and ALT within normal limits, ferritin 568 ng/mL (normal <322 ng/mL), and lactate dehydrogenase (LDH) 212 units/L (normal <257 units/L). Abdominal ultrasound revealed borderline hepatosplenomegaly. An ophthalmologic examination was normal.

On postoperative day 4 he developed left upper thigh swelling. An MRI showed rim‐enhancing juxta‐articular complex fluid collections surrounding the left femur with decreased marrow enhancement of the left proximal femur (Figure 1).

Figure 1

The limited rheumatologic evaluation is unrevealing; the ANA result is nondiagnostic and the ASO titer is normal for age. Laboratories generally report adult normal values for streptococcal antibodies regardless of the patient's age; children from ages 7 to 12 years are at their life peak frequency of group A streptococcal pharyngitis and typically have higher normal values of streptococcal antibodies, including ASO (up to about 480640 IU). The moderately elevated ferritin level is most likely an acute phase reactant and not high enough to suggest macrophage activation syndrome, which is unlikely with the normal AST, ALT, and LDH levels, the absence of significant splenomegaly, and the lack of cytopenias. Continued fever with progressive left upper thigh swelling point to osteomyelitis of the proximal femur, which may have initially ruptured into the hip and then infiltrated the femoral cortex and spread infection into the adjacent soft tissues. Surgical debridement is indicated.

The relative prevalence of methicillin‐sensitive S aureus (MSSA) and methicillin‐resistant S aureus vary widely with geography. MSSA strains are more likely to be highly toxigenic. The elaboration of 1 or more extracellular toxins could account for the patient's initial symptoms.

The patient was brought back to the operating room for drainage of the juxta‐articular fluid collections and a biopsy of his femur. The fluid collections were grossly purulent. His intraoperative cultures were positive for MSSA. The bone biopsy revealed necrotic tissue, acute inflammation, and bacterial colonies, consistent with acute osteomyelitis. Further testing of his S aureus isolate was positive for staphylococcal enterotoxin B. He completed a 4‐week course of oral clindamycin with subsequent normalization of his hip exam and inflammatory markers. At a follow‐up visit the patient was feeling better, but had developed skin peeling on the lateral aspects of his feet consistent with late sequelae of toxin‐mediated disease (Figure 2). Three months after discharge the patient had returned to his baseline activity level and remained asymptomatic.

Figure 2

COMMENTARY

The patient presented with a constellation of symptoms that was initially mistaken for incomplete KD until focal progression of his symptoms exposed an underlying femoral osteomyelitis with periarticular abscess formation. Bacterial cultures and subsequent toxin assay revealed an enterotoxin B‐producing strain of S aureus.

Certain staphylococcal strains secrete superantigens that may lead to the development of a systemic toxin‐mediated syndrome. Toxins elaborated by S aureus include toxic shock syndrome toxin‐1 (TSST‐1) and enterotoxins, which have been implicated in menstrual and nonmenstrual toxic shock syndromes.[1, 2] Enterotoxin B is a staphylococcal superantigen found in most strains of the USA400 clonal group, and has been frequently associated with skin and soft tissue infections.[3] Enterotoxin B production has been reported in nearly half of S aureus isolates from skin, soft tissue, and bone infections.[4]

Staphylococcal and streptococcal toxin‐mediated diseases can mimic vasculitis, systemic juvenile idiopathic arthritis, viral infections, and Stevens‐Johnson syndrome. Glossitis in toxin‐mediated syndromes manifests with a swollen, red tongue with overlying enlarged papillae, giving the appearance of a strawberry. Although pediatric providers often equate strawberry tongue, conjunctival injection, rash, and erythematous lips with KD, these findings are also seen in toxin‐mediated diseases, such as scarlet fever or staphylococcal toxic shock syndrome. Enterotoxin B mediated staphylococcal disease masquerading as KD has been reported in 2 cases: a 7‐month‐old boy with multifocal S aureus osteomyelitis and a 5‐year‐old boy with S aureus bacteremia. Both staphylococcal isolates produced enterotoxin B but were negative for other staphylococcus‐related toxins including TSST‐1.[5]

The Institute of Medicine (IOM) recently released its report Improving Diagnosis in Health Care, highlighting the under‐recognized quality and safety issue of diagnostic error.[6] The report uses the following broad and patient‐centered definition of diagnostic error: the failure to (a) establish an accurate and timely explanation of the patient's health problem(s) or (b) communicate that explanation to the patient. The IOM's conceptual model of diagnosis emphasizes the iterative nature of the diagnostic process, including the importance of generating a working diagnosis, gathering and incorporating new information in the reassessment of that diagnosis, and integrating treatment response into the formulation of the final diagnosis (Figure 3).

Figure 3

Even though the patient initially had several features consistent with KD, the increasing number of atypical features could have prompted the clinical team to reconsider their working diagnosis. The patient's age was atypical for KD, he had progressive knee and hip arthritis, and his fevers persisted after IVIG. An expanded differential should have included toxic shock syndrome; the resolution of conjunctival and mucosal injection and edema after IVIG may have been the result of antibodies in the IVIG preparation with neutralizing activity against superantigens. This antitoxin activity has established a role for IVIG in the management of staphylococcal toxic shock syndrome.[7] Ultimately, his imaging and surgical drainage revealed a focal staphylococcal toxin‐producing infectious source from which his fevers, rash, and mucosal and extremity changes emanated. This case reminds us that the more atypical a working diagnosis iseither in its presentation or treatment responsethe more readily clinicians should take it for another spin around the diagnostic wheel in search of a more suitable alternative.

KEY LEARNING POINTS

1. Staphylococcal toxin‐mediated disease may mimic KD, with common features including strawberry tongue, oral and conjunctival injection, and skin desquamation.
2. Improvement after treatment with IVIG is characteristic but not diagnostic of KD, and may be seen in toxin‐mediated disease.
3. KD may present with arthralgia or arthritis, but severe joint abnormalities warrant consideration of infectious and other autoimmune conditions.
4. The more atypical a working diagnosis iseither in its presentation or treatment responsethe more readily clinicians should gather, interpret, and integrate new information in search of a more suitable alternative.

Disclosure: Nothing to report.

A 65‐year‐old man with a 6‐month history of diabetes mellitus presented to the emergency department in May with 1 week of fevers, headaches, myalgia, polydipsia, and polyuria.

The patient presents with symptoms suggestive of uncontrolled diabetes and infection. The broad diagnostic categories include acute infection, an emerging chronic process aggravating his diabetes, or a noninfectious mimic such as autoimmune disease or lymphoproliferative disease. New onset headache in an older patient is concerning. Although it may be attributed to fever and dehydration, primary central nervous system processes such as meningitis or encephalitis must be considered. At this stage, a detailed exposure history, including travel, food, pets, hobbies, and sick contacts as well as occupation and national origins is needed. This patient presented in May, making illnesses that peak in other seasons such as influenza and West Nile fever less likely.

He had no other medical problems except diabetes. He was not taking any medications; he had been started on glipizide but had stopped taking it 1 month prior. He denied fever, cough, chest pain, palpitations, abdominal pain, nausea, vomiting, dysuria, focal weakness, visual changes, or photophobia. He was born in Mexico and emigrated at the age of 25 years. Two months prior to presentation he visited a cattle farm in Mexico; he denied any direct contact with farm animals or dairy products. He denied ill contacts, pets, known tuberculosis exposures, and sexual partners other than his wife.

The history of recent travel to Mexico with a visit to a farm raises concerns about zoonoses. The endemic zoonoses that should be considered include parasitic (toxoplasmosis), fungal (coccidiodomycosis), and bacterial (brucellosis, Q fever, leptospirosis, tularemia, salmonellosis) infections. Nonzoonotic granulomatous infections such as cytomegalovirus (CMV) and Epstein‐Barr virus (EBV), mycobacteria, fungi (histoplasmosis, blastomycosis, cryptococcosis, aspergillosis), and bacteria (actinomycosis) should also be considered.

On examination, he was an elderly Hispanic male who appeared ill but in no acute distress. He was overweight, with a BMI of 29. His temperature was 39C, pulse 66 beats/minute, blood pressure 108/68 mm Hg, respiratory rate 18 per minute, and oxygen saturation was 96% on room air. There were no ulcerations, exudates, or erythema in the oropharynx. There was no sinus tenderness or lymphadenopathy. Cardiac examination revealed normal heart sounds with no murmurs. Respiratory examination demonstrated clear lungs. His abdomen was soft and nontender, whereas the liver and spleen were not palpable. There was no nuchal rigidity, and his mental status was normal. There were no cranial nerve deficits or weakness in his extremities. There was no skin rash or peripheral stigmata of infectious endocarditis. Genitourinary examination revealed no ulcerations, inguinal lymphadenopathy, or urethral discharge. There was no tenderness, warmth, or erythema on examination of all joints.

The physical exam is notable for temperaturepulse dissociation. Heart rate should increase by about 10 beats/minute for every 1‐degree increase in Fahrenheit temperature. The infectious causes of temperaturepulse dissociation are largely intracellular pathogens such as Salmonella, Coxiella, Chlamydia, Leptospira, Legionella, Francisella, Mycoplasma, and dengue virus. This patient is at increased risk for infection by any of these pathogens based on his recent travel to Mexico. Drug fever is the most common noninfectious cause of temperaturepulse dissociation, but this patient took no medications. At this point, a complete blood count and differential, urinalysis, blood cultures, chest x‐ray, and electrocardiogram should be ordered. Testing for human immunodeficiency virus (HIV) is appropriate, as up to 50% of patients with newly diagnosed HIV have no acknowledged risk factors. Serological studies for the aforementioned pathogens may be indicated depending on the results of these initial diagnostic tests.

Serum sodium concentration was 122 mEq/L, potassium 4.0 mEq/L, chloride 88 mEq/L, bicarbonate 14 mEq/L, blood urea nitrogen 17 mg/dL, creatinine 0.7 mg/dL, glucose 402 mg/dL, and calcium 8.5 mg/dL. Total protein was 5.4 g/dL, albumin 2.9 g/dL, total bilirubin 0.9 mg/dL, direct bilirubin 0.4 mg/dL, alkaline phosphatase 126 U/L (normal 53128), gamma‐glutamyl transferase 264 U/L (normal 360), aspartate aminotransferase 51 U/L (normal 840), alanine aminotransferase 62 U/L (normal 556), and lactate dehydrogenase 248 U/L (normal 85210). The white blood cell (WBC) count was 6800 mm³ (51% band forms, 38% segmented neutrophils, 6% monocytes, 5% lymphocytes). The hemoglobin was 15.7 g/dL, with mean corpuscular volume (MCV) of 102 fL and platelet count 59,000/mm³. Peripheral‐blood smear showed occasional macrocytes. Prothrombin time was 13.6 seconds and partial thromboplastin time was 34.5 seconds. C‐reactive protein was 11.8 mg/dL. Urinalysis revealed 80 mg of ketones per deciliter, no cells, and nitrite was negative. Hemoglobin A1c was 13%, and HIV antibody testing was negative.

Elevated circulating bands and thrombocytopenia suggest infection; however, bone marrow infiltration by infectious or neoplastic process is also possible and should be investigated. The increased gamma‐glutamyl transferase, alkaline phosphatase, and mild increases in transaminases suggest hepatic pathology. The combination of unexplained fever, hyponatremia, thrombocytopenia, elevated liver enzymes, and travel to Mexico mandates investigation for infectious diseases that often involve both the bone marrow and liver such as Brucella, Coxiella, and fungal infections such as histoplasmosis. Autoimmune diseases such as systemic lupus erythematosus and malignancy should also be considered. Blood cultures should be incubated beyond the usual 5 days because of the slower growth of Brucella or Salmonella typhi. An HIV viral load should be obtained to evaluate for acute retroviral syndrome. Serologic tests for Rickettsia, Coccidiodes, and hepatitis A, B, and C viruses should be obtained. Urine should be tested for Histoplasma and Legionella antigens. Abdominal imaging should be obtained to evaluate for hepatobiliary disease, occult intra‐abdominal abscess, or malignancy. Because the patient has unexplained fever and headache, imaging of the central nervous system and lumbar puncture are warranted.

His diabetic ketoacidosis (DKA) was treated with intravenous fluids and insulin. Lumbar puncture and cerebrospinal fluid (CSF) analysis revealed opening pressure of 18 cm H₂0 (normal 1025), cell count WBC 3/L (normal 05), red blood cell 204/L (normal 0), CSF protein 25 mg/dL (normal 2050), and glucose 68 mg/dL (normal 5070). Blood cultures showed no growth. HIV RNA was undetectable. Hepatitis C antibody was negative, and hepatitis A and B serologies were not consistent with an acute infection. Serum ferritin was 1147 ng/mL. Histoplasma and Legionella urine antigen tests were negative. CMV, EBV, and herpes simplex virus DNA were not detected in blood samples. Anti‐neutrophil antibody, anti‐mitochondrial antibody and anti‐neutrophil cytoplasmic antibodies were undetectable. Anti‐smooth muscle antibody was positive at a titer of 1:80. Transthoracic echocardiogram revealed normal heart valves without vegetations. A chest radiograph was normal. Brain computed tomography (CT) revealed atrophic frontal lobes. CT of his chest, abdomen, and pelvis demonstrated focal inflammatory changes of a loop of distal small bowel with surrounding fluid collection, suggesting small bowel diverticulitis. There were no pulmonary infiltrates noted, and the remainder of the CT was unremarkable.

Because the patient remains ill and additional serological test results will take time to return, a key consideration at this point is empiric treatment while awaiting test results. The CSF examination was normal. A history of travel including animal and tick exposures should be reevaluated. The timing of the trip to Mexico was outside the usual incubation period for many pathogens except for Coxiella or Brucella, and empiric therapy for both would be appropriate. The abdominal CT suggests small bowel diverticulitis, which is a rare clinical entity.

The benign abdominal examination suggests the finding is incidental. However, there are several infections that may involve the distal small bowel and proximal colon, such as yersiniosis, salmonellosis, tuberculosis, actinomycosis, histoplasmosis, and noninfectious processes including Crohn's disease and neoplasia. The absence of diarrhea or hematochezia makes yersiniosis, salmonellosis, and Crohn's disease unlikely. Histoplasmosis is unlikely given the negative urine antigen. Evaluation for neoplasia of the distal small bowel requires histologic examination. A colonoscopy with random biopsies of the colon and terminal ileum is the next step if other tests are unrevealing.

The patient was empirically treated for small bowel diverticulitis with ceftriaxone and metronidazole. Because of continued daily fevers as high as 39C, his therapy was changed to vancomycin and piperacillin‐tazobactam to cover methicillin‐resistant Staphylococcus aureus and resistant gram‐negative bacilli. The patient developed new scleral icterus on hospital day 6; the remainder of his examination was unchanged. Serum sodium concentration was 127 mEq/L, potassium 2.7 mEq/L, phosphorus 1.3 mg/dL, magnesium 1.6 mg/dL, total bilirubin 5.6 mg/dL, direct bilirubin 3.6 mg/dL, alkaline phosphatase 193 U/L, gamma‐glutamyl transferase 300 U/L, aspartate aminotransferase 91 U/L, alanine aminotransferase 52 U/L. Brucella serology was negative.

His liver enzymes remain elevated with new onset jaundice consistent with hepatitis and intrahepatic cholestasis. His persistent hypophosphatemia, hypokalemia, and hypomagnesaemia well after resolution of diabetic ketoacidosis suggests acute tubulointerstitial dysfunction, which may be a complication of empiric antibiotic treatment or renal involvement by his underlying condition. Additional blood cultures, and tissue examination and culture are the next appropriate steps. Liver or bone marrow biopsy may suggest a diagnosis that can be confirmed by tissue culture or immunohistochemistry. Histologic findings such as fibrin ringed granulomas, caseating or noncaseating granulomas, or lymphomatous infiltration may suggest Coxiella (Q fever), tuberculosis, or lymphoma respectively. Because a liver biopsy is invasive and usually provides less tissue for culture, bone marrow examination should be obtained first.

A gallium 67 scan showed nonhomogenous increased uptake in both lungs and kidneys, consistent with interstitial nephritis and bilateral pneumonia. Serum protein electrophoresis demonstrated a monoclonal immunoglobulin (Ig)G lambda band with a kappa/lambda ratio of 0.9 (normal 1.42.8). Bone marrow biopsy showed normal hematopoiesis; no plasma or malignant cells, granulomas, or evidence of hemophagocytosis; and fungal and mycobacterial stains and cultures were negative. Colonoscopy revealed normal‐appearing mucosa. Histologic examination and culture of random biopsies from the colon and terminal ileum were negative for fungi, viruses, and mycobacteria. An ultrasound‐guided liver biopsy revealed numerous noncaseating granulomas formed of histiocytes and neutrophils with occasional fibrin rings. Fungal, viral, and mycobacterial stains and cultures were negative. The patient's fever resolved after 14 days, and he was discharged home without a diagnosis and close outpatient follow‐up.

The hepatic granulomas with fibrin rings are highly suggestive of Q fever, although ring granulomas may be seen in tuberculosis, typhoid fever, lymphoma, drug reactions, sarcoidosis, and CMV infections. Competing diagnoses such as CMV have been excluded by negative serology. Microscopic examination, tissue staining, and culture from liver and bone marrow biopsies were negative for S typhi, mycobacteria, and lymphoma. Gallium scan findings are generally nonspecific and of little utility in cases such as this. The kidney involvement correlates with the biochemical evidence of tubulointerstitial dysfunction; pulmonary involvement may reflect subclinical pulmonary infection with Coxiella. Given the normal bone marrow biopsy, the monoclonal gammopathy is of undetermined significance. The positive anti‐smooth muscle antibody can be related to Q fever. Anti‐smooth muscle antibodies frequently occur in Q fever, especially in those patients with hepatitis. Given the history of exposure to cattle, unexplained fever with temperaturepulse dissociation and liver biopsy findings, Q fever is the most likely diagnosis and empiric treatment with doxycycline is warranted.

Results of serology for Coxiella burnetii sent during admission were returned after the patient's discharge. C burnetii phase I IgG and IgM antibody titers were positive (1:512 each). C burnetii phase II IgG and IgM titers also were positive (1:1024 each). The patient was seen within a week and started on doxycycline 100 mg twice daily for 2 weeks for acute Q fever. His symptoms improved; hyponatremia, liver function tests, and thrombocytopenia normalized after treatment.

DISCUSSION

Q fever was first described in 1937 as a febrile illness affecting Australian slaughterhouse workers.[1] The Q in Q fever stands for query and reflected the initial uncertainty surrounding the underlying cause of the illness. The causative organism, C burnetti, is an obligate intracellular bacterium that resides within macrophage lysosomes. It can be found in the urine, feces, milk, placenta, and amniotic fluid of ungulates (cattle, sheep, and other ruminants), and other animals such as domestic cats and dogs. C burnetii is transmitted via inhalation, ingestion, occupational, or common source exposures, and in 1 case report by person‐to‐person sexual transmission.[2] In addition to slaughterhouse workers, pregnant women and immunosuppressed patients are more susceptible to developing Q fever.[3] For patients with suspected Q fever, a detailed occupational history, including specific job duties and potential exposure to animal products, is imperative.

Q fever has both acute and chronic presentations, which are differentiated based on the clinical illness and serologies. The symptoms of acute Q fever are nonspecific and may include influenza‐like illness, fever, pneumonia, and hepatitis. It presents less commonly with hemolytic anemia, interstitial nephritis, monoclonal gammopathy, or aseptic meningitis.[4, 5, 6, 7] Symptoms typically begin between 1 and 3 weeks after animal exposure and may persist for several months. Chronic Q fever occurs when unrecognized or untreated infection persists for greater than 6 months. It commonly presents with culture‐negative endocarditis, although infected aneurysms, osteomyelitis, or other distant sites of infection may also occur.

C burnetti is present in 2 antigenic forms that can be assessed by serology. Phase I is the more virulent, infectious form of C burnetti, which transitions to the avirulent phase II form during laboratory handling. In acute Q fever, phase II serologies are typically elevated out of proportion to phase I serologies, whereas this pattern is reversed in chronic Q fever. The diagnostic gold standard of acute Q fever is a 4‐fold rise in phase II antibody titers taken 3 to 6 weeks apart.[8] Histologic examination of affected organs can support a diagnosis of Q fever. The presence of ringed granulomas on liver or bone marrow biopsy specimens is highly suggestive, but not pathognomonic, of Q fever.[9]

Q fever is highly susceptible to several classes of antibiotics. For acute Q fever, doxycycline and tetracycline are typically used, with fluoroquinolones and chloramphenicol as alternatives.[8, 10] Patients with chronic Q fever should be treated with doxycycline and hydroxychloroquine. The addition of hydroxychloroquine alkalinizes the macrophage lysosome and enhances bacterial eradication.[8] For patients with acute Q fever, physicians should determine the risk of progression to chronic Q fever because closer monitoring is necessary. Patients with valvular heart lesions, immunosuppression, and pregnant women are at elevated risk of chronic Q fever. Trimethoprim/sulfamethoxazole can be used in place of doxycycline in pregnant women, as doxycycline and fluoroquinolones are contraindicated in pregnancy.[8]

This patient presented with a nonspecific febrile illness. Although the treating clinicians obtained a history of exposure to cattle early in his course, both the diagnosis and treatment were delayed. There are several possible explanations for the delay. First, although Q fever is a relatively common zoonosis, it remains an uncommon diagnosis, particularly among hospitalized patients. As a result, clinicians often focus on more common conditions. In this case, typical infections, malignancies, and inflammatory diseases were considered more likely. Second, the patient presented with hepatitis, an uncommon presentation of Q fever. Classical clinical reasoning suggests that atypical presentations of common diseases will occur more frequently than typical presentations of uncommon diseases. This case presented with an atypical presentation of an uncommon disease. The resultant lower pretest probability further dissuaded the patient's physicians from consideration of Q fever. Third, the finding of small bowel diverticulitis was a potential distractor. In patients with nonspecific febrile illnesses, it is common for physicians to anchor on any abnormal findings. In this case, the small bowel diverticulitis led to antibiotic treatment that was ineffective against C burnetti.

There were several clues to the diagnosis of Q fever in this patient's presentation. First, the pulsetemperature dissociation suggested infection with an intracellular pathogen. Hospitalists should recognize this association and be mindful of this often‐subtle clinical finding when faced with diagnostic uncertainty. Second, the patient was exposed to cattle prior to the onset of his illness. The fact that he did not have a direct exposure to animals underscores the infectivity of C burnetti. Finally, elevated alkaline phosphatase and transaminases were suggestive of an infiltrative disease; in the setting of a nonspecific febrile illness, Q fever was an important diagnostic consideration.

The key treatment decision in this case was the initiation and choice of antibiotics. Because of this patient's history of exposure to cattle and lack of a compelling alternative diagnosis, empiric treatment with doxycycline would have been appropriate. Hospitalists must weigh the potential benefit of early treatment of Q fever against the risks associated with antibiotic overuse. In patients presenting with a febrile illness after ungulate exposure, the decision to bet the farm with empiric doxycycline therapy may lead to clinical improvement, obviating a more invasive or extensive diagnostic evaluation.

TEACHING POINTS

1. Acute Q fever typically presents 2 to 3 weeks after ungulate exposure with a febrile illness, pneumonia, and granulomatous hepatitis.
2. Pulsetemperature dissociation is suggestive of infection by intracellular pathogens such as Coxiella, Salmonella, Leptospira, Legionella, and Mycoplasma.
3. Clinicians should consider empiric doxycycline therapy in patients with suspected zoonosis (eg, Q fever, brucellosis, anaplasmosis, leptospirosis, Rocky Mountain spotted fever) while awaiting confirmatory tests, as improvement may obviate invasive testing.

Disclosure: Nothing to report.

A 65‐year‐old man with a 6‐month history of diabetes mellitus presented to the emergency department in May with 1 week of fevers, headaches, myalgia, polydipsia, and polyuria.

The patient presents with symptoms suggestive of uncontrolled diabetes and infection. The broad diagnostic categories include acute infection, an emerging chronic process aggravating his diabetes, or a noninfectious mimic such as autoimmune disease or lymphoproliferative disease. New onset headache in an older patient is concerning. Although it may be attributed to fever and dehydration, primary central nervous system processes such as meningitis or encephalitis must be considered. At this stage, a detailed exposure history, including travel, food, pets, hobbies, and sick contacts as well as occupation and national origins is needed. This patient presented in May, making illnesses that peak in other seasons such as influenza and West Nile fever less likely.

He had no other medical problems except diabetes. He was not taking any medications; he had been started on glipizide but had stopped taking it 1 month prior. He denied fever, cough, chest pain, palpitations, abdominal pain, nausea, vomiting, dysuria, focal weakness, visual changes, or photophobia. He was born in Mexico and emigrated at the age of 25 years. Two months prior to presentation he visited a cattle farm in Mexico; he denied any direct contact with farm animals or dairy products. He denied ill contacts, pets, known tuberculosis exposures, and sexual partners other than his wife.

The history of recent travel to Mexico with a visit to a farm raises concerns about zoonoses. The endemic zoonoses that should be considered include parasitic (toxoplasmosis), fungal (coccidiodomycosis), and bacterial (brucellosis, Q fever, leptospirosis, tularemia, salmonellosis) infections. Nonzoonotic granulomatous infections such as cytomegalovirus (CMV) and Epstein‐Barr virus (EBV), mycobacteria, fungi (histoplasmosis, blastomycosis, cryptococcosis, aspergillosis), and bacteria (actinomycosis) should also be considered.

On examination, he was an elderly Hispanic male who appeared ill but in no acute distress. He was overweight, with a BMI of 29. His temperature was 39C, pulse 66 beats/minute, blood pressure 108/68 mm Hg, respiratory rate 18 per minute, and oxygen saturation was 96% on room air. There were no ulcerations, exudates, or erythema in the oropharynx. There was no sinus tenderness or lymphadenopathy. Cardiac examination revealed normal heart sounds with no murmurs. Respiratory examination demonstrated clear lungs. His abdomen was soft and nontender, whereas the liver and spleen were not palpable. There was no nuchal rigidity, and his mental status was normal. There were no cranial nerve deficits or weakness in his extremities. There was no skin rash or peripheral stigmata of infectious endocarditis. Genitourinary examination revealed no ulcerations, inguinal lymphadenopathy, or urethral discharge. There was no tenderness, warmth, or erythema on examination of all joints.

The physical exam is notable for temperaturepulse dissociation. Heart rate should increase by about 10 beats/minute for every 1‐degree increase in Fahrenheit temperature. The infectious causes of temperaturepulse dissociation are largely intracellular pathogens such as Salmonella, Coxiella, Chlamydia, Leptospira, Legionella, Francisella, Mycoplasma, and dengue virus. This patient is at increased risk for infection by any of these pathogens based on his recent travel to Mexico. Drug fever is the most common noninfectious cause of temperaturepulse dissociation, but this patient took no medications. At this point, a complete blood count and differential, urinalysis, blood cultures, chest x‐ray, and electrocardiogram should be ordered. Testing for human immunodeficiency virus (HIV) is appropriate, as up to 50% of patients with newly diagnosed HIV have no acknowledged risk factors. Serological studies for the aforementioned pathogens may be indicated depending on the results of these initial diagnostic tests.

Serum sodium concentration was 122 mEq/L, potassium 4.0 mEq/L, chloride 88 mEq/L, bicarbonate 14 mEq/L, blood urea nitrogen 17 mg/dL, creatinine 0.7 mg/dL, glucose 402 mg/dL, and calcium 8.5 mg/dL. Total protein was 5.4 g/dL, albumin 2.9 g/dL, total bilirubin 0.9 mg/dL, direct bilirubin 0.4 mg/dL, alkaline phosphatase 126 U/L (normal 53128), gamma‐glutamyl transferase 264 U/L (normal 360), aspartate aminotransferase 51 U/L (normal 840), alanine aminotransferase 62 U/L (normal 556), and lactate dehydrogenase 248 U/L (normal 85210). The white blood cell (WBC) count was 6800 mm³ (51% band forms, 38% segmented neutrophils, 6% monocytes, 5% lymphocytes). The hemoglobin was 15.7 g/dL, with mean corpuscular volume (MCV) of 102 fL and platelet count 59,000/mm³. Peripheral‐blood smear showed occasional macrocytes. Prothrombin time was 13.6 seconds and partial thromboplastin time was 34.5 seconds. C‐reactive protein was 11.8 mg/dL. Urinalysis revealed 80 mg of ketones per deciliter, no cells, and nitrite was negative. Hemoglobin A1c was 13%, and HIV antibody testing was negative.

Elevated circulating bands and thrombocytopenia suggest infection; however, bone marrow infiltration by infectious or neoplastic process is also possible and should be investigated. The increased gamma‐glutamyl transferase, alkaline phosphatase, and mild increases in transaminases suggest hepatic pathology. The combination of unexplained fever, hyponatremia, thrombocytopenia, elevated liver enzymes, and travel to Mexico mandates investigation for infectious diseases that often involve both the bone marrow and liver such as Brucella, Coxiella, and fungal infections such as histoplasmosis. Autoimmune diseases such as systemic lupus erythematosus and malignancy should also be considered. Blood cultures should be incubated beyond the usual 5 days because of the slower growth of Brucella or Salmonella typhi. An HIV viral load should be obtained to evaluate for acute retroviral syndrome. Serologic tests for Rickettsia, Coccidiodes, and hepatitis A, B, and C viruses should be obtained. Urine should be tested for Histoplasma and Legionella antigens. Abdominal imaging should be obtained to evaluate for hepatobiliary disease, occult intra‐abdominal abscess, or malignancy. Because the patient has unexplained fever and headache, imaging of the central nervous system and lumbar puncture are warranted.

His diabetic ketoacidosis (DKA) was treated with intravenous fluids and insulin. Lumbar puncture and cerebrospinal fluid (CSF) analysis revealed opening pressure of 18 cm H₂0 (normal 1025), cell count WBC 3/L (normal 05), red blood cell 204/L (normal 0), CSF protein 25 mg/dL (normal 2050), and glucose 68 mg/dL (normal 5070). Blood cultures showed no growth. HIV RNA was undetectable. Hepatitis C antibody was negative, and hepatitis A and B serologies were not consistent with an acute infection. Serum ferritin was 1147 ng/mL. Histoplasma and Legionella urine antigen tests were negative. CMV, EBV, and herpes simplex virus DNA were not detected in blood samples. Anti‐neutrophil antibody, anti‐mitochondrial antibody and anti‐neutrophil cytoplasmic antibodies were undetectable. Anti‐smooth muscle antibody was positive at a titer of 1:80. Transthoracic echocardiogram revealed normal heart valves without vegetations. A chest radiograph was normal. Brain computed tomography (CT) revealed atrophic frontal lobes. CT of his chest, abdomen, and pelvis demonstrated focal inflammatory changes of a loop of distal small bowel with surrounding fluid collection, suggesting small bowel diverticulitis. There were no pulmonary infiltrates noted, and the remainder of the CT was unremarkable.

Because the patient remains ill and additional serological test results will take time to return, a key consideration at this point is empiric treatment while awaiting test results. The CSF examination was normal. A history of travel including animal and tick exposures should be reevaluated. The timing of the trip to Mexico was outside the usual incubation period for many pathogens except for Coxiella or Brucella, and empiric therapy for both would be appropriate. The abdominal CT suggests small bowel diverticulitis, which is a rare clinical entity.

The benign abdominal examination suggests the finding is incidental. However, there are several infections that may involve the distal small bowel and proximal colon, such as yersiniosis, salmonellosis, tuberculosis, actinomycosis, histoplasmosis, and noninfectious processes including Crohn's disease and neoplasia. The absence of diarrhea or hematochezia makes yersiniosis, salmonellosis, and Crohn's disease unlikely. Histoplasmosis is unlikely given the negative urine antigen. Evaluation for neoplasia of the distal small bowel requires histologic examination. A colonoscopy with random biopsies of the colon and terminal ileum is the next step if other tests are unrevealing.

The patient was empirically treated for small bowel diverticulitis with ceftriaxone and metronidazole. Because of continued daily fevers as high as 39C, his therapy was changed to vancomycin and piperacillin‐tazobactam to cover methicillin‐resistant Staphylococcus aureus and resistant gram‐negative bacilli. The patient developed new scleral icterus on hospital day 6; the remainder of his examination was unchanged. Serum sodium concentration was 127 mEq/L, potassium 2.7 mEq/L, phosphorus 1.3 mg/dL, magnesium 1.6 mg/dL, total bilirubin 5.6 mg/dL, direct bilirubin 3.6 mg/dL, alkaline phosphatase 193 U/L, gamma‐glutamyl transferase 300 U/L, aspartate aminotransferase 91 U/L, alanine aminotransferase 52 U/L. Brucella serology was negative.

His liver enzymes remain elevated with new onset jaundice consistent with hepatitis and intrahepatic cholestasis. His persistent hypophosphatemia, hypokalemia, and hypomagnesaemia well after resolution of diabetic ketoacidosis suggests acute tubulointerstitial dysfunction, which may be a complication of empiric antibiotic treatment or renal involvement by his underlying condition. Additional blood cultures, and tissue examination and culture are the next appropriate steps. Liver or bone marrow biopsy may suggest a diagnosis that can be confirmed by tissue culture or immunohistochemistry. Histologic findings such as fibrin ringed granulomas, caseating or noncaseating granulomas, or lymphomatous infiltration may suggest Coxiella (Q fever), tuberculosis, or lymphoma respectively. Because a liver biopsy is invasive and usually provides less tissue for culture, bone marrow examination should be obtained first.

A gallium 67 scan showed nonhomogenous increased uptake in both lungs and kidneys, consistent with interstitial nephritis and bilateral pneumonia. Serum protein electrophoresis demonstrated a monoclonal immunoglobulin (Ig)G lambda band with a kappa/lambda ratio of 0.9 (normal 1.42.8). Bone marrow biopsy showed normal hematopoiesis; no plasma or malignant cells, granulomas, or evidence of hemophagocytosis; and fungal and mycobacterial stains and cultures were negative. Colonoscopy revealed normal‐appearing mucosa. Histologic examination and culture of random biopsies from the colon and terminal ileum were negative for fungi, viruses, and mycobacteria. An ultrasound‐guided liver biopsy revealed numerous noncaseating granulomas formed of histiocytes and neutrophils with occasional fibrin rings. Fungal, viral, and mycobacterial stains and cultures were negative. The patient's fever resolved after 14 days, and he was discharged home without a diagnosis and close outpatient follow‐up.

The hepatic granulomas with fibrin rings are highly suggestive of Q fever, although ring granulomas may be seen in tuberculosis, typhoid fever, lymphoma, drug reactions, sarcoidosis, and CMV infections. Competing diagnoses such as CMV have been excluded by negative serology. Microscopic examination, tissue staining, and culture from liver and bone marrow biopsies were negative for S typhi, mycobacteria, and lymphoma. Gallium scan findings are generally nonspecific and of little utility in cases such as this. The kidney involvement correlates with the biochemical evidence of tubulointerstitial dysfunction; pulmonary involvement may reflect subclinical pulmonary infection with Coxiella. Given the normal bone marrow biopsy, the monoclonal gammopathy is of undetermined significance. The positive anti‐smooth muscle antibody can be related to Q fever. Anti‐smooth muscle antibodies frequently occur in Q fever, especially in those patients with hepatitis. Given the history of exposure to cattle, unexplained fever with temperaturepulse dissociation and liver biopsy findings, Q fever is the most likely diagnosis and empiric treatment with doxycycline is warranted.

Results of serology for Coxiella burnetii sent during admission were returned after the patient's discharge. C burnetii phase I IgG and IgM antibody titers were positive (1:512 each). C burnetii phase II IgG and IgM titers also were positive (1:1024 each). The patient was seen within a week and started on doxycycline 100 mg twice daily for 2 weeks for acute Q fever. His symptoms improved; hyponatremia, liver function tests, and thrombocytopenia normalized after treatment.

DISCUSSION

Q fever was first described in 1937 as a febrile illness affecting Australian slaughterhouse workers.[1] The Q in Q fever stands for query and reflected the initial uncertainty surrounding the underlying cause of the illness. The causative organism, C burnetti, is an obligate intracellular bacterium that resides within macrophage lysosomes. It can be found in the urine, feces, milk, placenta, and amniotic fluid of ungulates (cattle, sheep, and other ruminants), and other animals such as domestic cats and dogs. C burnetii is transmitted via inhalation, ingestion, occupational, or common source exposures, and in 1 case report by person‐to‐person sexual transmission.[2] In addition to slaughterhouse workers, pregnant women and immunosuppressed patients are more susceptible to developing Q fever.[3] For patients with suspected Q fever, a detailed occupational history, including specific job duties and potential exposure to animal products, is imperative.

Q fever has both acute and chronic presentations, which are differentiated based on the clinical illness and serologies. The symptoms of acute Q fever are nonspecific and may include influenza‐like illness, fever, pneumonia, and hepatitis. It presents less commonly with hemolytic anemia, interstitial nephritis, monoclonal gammopathy, or aseptic meningitis.[4, 5, 6, 7] Symptoms typically begin between 1 and 3 weeks after animal exposure and may persist for several months. Chronic Q fever occurs when unrecognized or untreated infection persists for greater than 6 months. It commonly presents with culture‐negative endocarditis, although infected aneurysms, osteomyelitis, or other distant sites of infection may also occur.

C burnetti is present in 2 antigenic forms that can be assessed by serology. Phase I is the more virulent, infectious form of C burnetti, which transitions to the avirulent phase II form during laboratory handling. In acute Q fever, phase II serologies are typically elevated out of proportion to phase I serologies, whereas this pattern is reversed in chronic Q fever. The diagnostic gold standard of acute Q fever is a 4‐fold rise in phase II antibody titers taken 3 to 6 weeks apart.[8] Histologic examination of affected organs can support a diagnosis of Q fever. The presence of ringed granulomas on liver or bone marrow biopsy specimens is highly suggestive, but not pathognomonic, of Q fever.[9]

Q fever is highly susceptible to several classes of antibiotics. For acute Q fever, doxycycline and tetracycline are typically used, with fluoroquinolones and chloramphenicol as alternatives.[8, 10] Patients with chronic Q fever should be treated with doxycycline and hydroxychloroquine. The addition of hydroxychloroquine alkalinizes the macrophage lysosome and enhances bacterial eradication.[8] For patients with acute Q fever, physicians should determine the risk of progression to chronic Q fever because closer monitoring is necessary. Patients with valvular heart lesions, immunosuppression, and pregnant women are at elevated risk of chronic Q fever. Trimethoprim/sulfamethoxazole can be used in place of doxycycline in pregnant women, as doxycycline and fluoroquinolones are contraindicated in pregnancy.[8]

This patient presented with a nonspecific febrile illness. Although the treating clinicians obtained a history of exposure to cattle early in his course, both the diagnosis and treatment were delayed. There are several possible explanations for the delay. First, although Q fever is a relatively common zoonosis, it remains an uncommon diagnosis, particularly among hospitalized patients. As a result, clinicians often focus on more common conditions. In this case, typical infections, malignancies, and inflammatory diseases were considered more likely. Second, the patient presented with hepatitis, an uncommon presentation of Q fever. Classical clinical reasoning suggests that atypical presentations of common diseases will occur more frequently than typical presentations of uncommon diseases. This case presented with an atypical presentation of an uncommon disease. The resultant lower pretest probability further dissuaded the patient's physicians from consideration of Q fever. Third, the finding of small bowel diverticulitis was a potential distractor. In patients with nonspecific febrile illnesses, it is common for physicians to anchor on any abnormal findings. In this case, the small bowel diverticulitis led to antibiotic treatment that was ineffective against C burnetti.

There were several clues to the diagnosis of Q fever in this patient's presentation. First, the pulsetemperature dissociation suggested infection with an intracellular pathogen. Hospitalists should recognize this association and be mindful of this often‐subtle clinical finding when faced with diagnostic uncertainty. Second, the patient was exposed to cattle prior to the onset of his illness. The fact that he did not have a direct exposure to animals underscores the infectivity of C burnetti. Finally, elevated alkaline phosphatase and transaminases were suggestive of an infiltrative disease; in the setting of a nonspecific febrile illness, Q fever was an important diagnostic consideration.

The key treatment decision in this case was the initiation and choice of antibiotics. Because of this patient's history of exposure to cattle and lack of a compelling alternative diagnosis, empiric treatment with doxycycline would have been appropriate. Hospitalists must weigh the potential benefit of early treatment of Q fever against the risks associated with antibiotic overuse. In patients presenting with a febrile illness after ungulate exposure, the decision to bet the farm with empiric doxycycline therapy may lead to clinical improvement, obviating a more invasive or extensive diagnostic evaluation.

TEACHING POINTS

1. Acute Q fever typically presents 2 to 3 weeks after ungulate exposure with a febrile illness, pneumonia, and granulomatous hepatitis.
2. Pulsetemperature dissociation is suggestive of infection by intracellular pathogens such as Coxiella, Salmonella, Leptospira, Legionella, and Mycoplasma.
3. Clinicians should consider empiric doxycycline therapy in patients with suspected zoonosis (eg, Q fever, brucellosis, anaplasmosis, leptospirosis, Rocky Mountain spotted fever) while awaiting confirmatory tests, as improvement may obviate invasive testing.

Disclosure: Nothing to report.

A 65‐year‐old man with a 6‐month history of diabetes mellitus presented to the emergency department in May with 1 week of fevers, headaches, myalgia, polydipsia, and polyuria.

The patient presents with symptoms suggestive of uncontrolled diabetes and infection. The broad diagnostic categories include acute infection, an emerging chronic process aggravating his diabetes, or a noninfectious mimic such as autoimmune disease or lymphoproliferative disease. New onset headache in an older patient is concerning. Although it may be attributed to fever and dehydration, primary central nervous system processes such as meningitis or encephalitis must be considered. At this stage, a detailed exposure history, including travel, food, pets, hobbies, and sick contacts as well as occupation and national origins is needed. This patient presented in May, making illnesses that peak in other seasons such as influenza and West Nile fever less likely.

He had no other medical problems except diabetes. He was not taking any medications; he had been started on glipizide but had stopped taking it 1 month prior. He denied fever, cough, chest pain, palpitations, abdominal pain, nausea, vomiting, dysuria, focal weakness, visual changes, or photophobia. He was born in Mexico and emigrated at the age of 25 years. Two months prior to presentation he visited a cattle farm in Mexico; he denied any direct contact with farm animals or dairy products. He denied ill contacts, pets, known tuberculosis exposures, and sexual partners other than his wife.

The history of recent travel to Mexico with a visit to a farm raises concerns about zoonoses. The endemic zoonoses that should be considered include parasitic (toxoplasmosis), fungal (coccidiodomycosis), and bacterial (brucellosis, Q fever, leptospirosis, tularemia, salmonellosis) infections. Nonzoonotic granulomatous infections such as cytomegalovirus (CMV) and Epstein‐Barr virus (EBV), mycobacteria, fungi (histoplasmosis, blastomycosis, cryptococcosis, aspergillosis), and bacteria (actinomycosis) should also be considered.

On examination, he was an elderly Hispanic male who appeared ill but in no acute distress. He was overweight, with a BMI of 29. His temperature was 39C, pulse 66 beats/minute, blood pressure 108/68 mm Hg, respiratory rate 18 per minute, and oxygen saturation was 96% on room air. There were no ulcerations, exudates, or erythema in the oropharynx. There was no sinus tenderness or lymphadenopathy. Cardiac examination revealed normal heart sounds with no murmurs. Respiratory examination demonstrated clear lungs. His abdomen was soft and nontender, whereas the liver and spleen were not palpable. There was no nuchal rigidity, and his mental status was normal. There were no cranial nerve deficits or weakness in his extremities. There was no skin rash or peripheral stigmata of infectious endocarditis. Genitourinary examination revealed no ulcerations, inguinal lymphadenopathy, or urethral discharge. There was no tenderness, warmth, or erythema on examination of all joints.

The physical exam is notable for temperaturepulse dissociation. Heart rate should increase by about 10 beats/minute for every 1‐degree increase in Fahrenheit temperature. The infectious causes of temperaturepulse dissociation are largely intracellular pathogens such as Salmonella, Coxiella, Chlamydia, Leptospira, Legionella, Francisella, Mycoplasma, and dengue virus. This patient is at increased risk for infection by any of these pathogens based on his recent travel to Mexico. Drug fever is the most common noninfectious cause of temperaturepulse dissociation, but this patient took no medications. At this point, a complete blood count and differential, urinalysis, blood cultures, chest x‐ray, and electrocardiogram should be ordered. Testing for human immunodeficiency virus (HIV) is appropriate, as up to 50% of patients with newly diagnosed HIV have no acknowledged risk factors. Serological studies for the aforementioned pathogens may be indicated depending on the results of these initial diagnostic tests.

Serum sodium concentration was 122 mEq/L, potassium 4.0 mEq/L, chloride 88 mEq/L, bicarbonate 14 mEq/L, blood urea nitrogen 17 mg/dL, creatinine 0.7 mg/dL, glucose 402 mg/dL, and calcium 8.5 mg/dL. Total protein was 5.4 g/dL, albumin 2.9 g/dL, total bilirubin 0.9 mg/dL, direct bilirubin 0.4 mg/dL, alkaline phosphatase 126 U/L (normal 53128), gamma‐glutamyl transferase 264 U/L (normal 360), aspartate aminotransferase 51 U/L (normal 840), alanine aminotransferase 62 U/L (normal 556), and lactate dehydrogenase 248 U/L (normal 85210). The white blood cell (WBC) count was 6800 mm³ (51% band forms, 38% segmented neutrophils, 6% monocytes, 5% lymphocytes). The hemoglobin was 15.7 g/dL, with mean corpuscular volume (MCV) of 102 fL and platelet count 59,000/mm³. Peripheral‐blood smear showed occasional macrocytes. Prothrombin time was 13.6 seconds and partial thromboplastin time was 34.5 seconds. C‐reactive protein was 11.8 mg/dL. Urinalysis revealed 80 mg of ketones per deciliter, no cells, and nitrite was negative. Hemoglobin A1c was 13%, and HIV antibody testing was negative.

Elevated circulating bands and thrombocytopenia suggest infection; however, bone marrow infiltration by infectious or neoplastic process is also possible and should be investigated. The increased gamma‐glutamyl transferase, alkaline phosphatase, and mild increases in transaminases suggest hepatic pathology. The combination of unexplained fever, hyponatremia, thrombocytopenia, elevated liver enzymes, and travel to Mexico mandates investigation for infectious diseases that often involve both the bone marrow and liver such as Brucella, Coxiella, and fungal infections such as histoplasmosis. Autoimmune diseases such as systemic lupus erythematosus and malignancy should also be considered. Blood cultures should be incubated beyond the usual 5 days because of the slower growth of Brucella or Salmonella typhi. An HIV viral load should be obtained to evaluate for acute retroviral syndrome. Serologic tests for Rickettsia, Coccidiodes, and hepatitis A, B, and C viruses should be obtained. Urine should be tested for Histoplasma and Legionella antigens. Abdominal imaging should be obtained to evaluate for hepatobiliary disease, occult intra‐abdominal abscess, or malignancy. Because the patient has unexplained fever and headache, imaging of the central nervous system and lumbar puncture are warranted.

His diabetic ketoacidosis (DKA) was treated with intravenous fluids and insulin. Lumbar puncture and cerebrospinal fluid (CSF) analysis revealed opening pressure of 18 cm H₂0 (normal 1025), cell count WBC 3/L (normal 05), red blood cell 204/L (normal 0), CSF protein 25 mg/dL (normal 2050), and glucose 68 mg/dL (normal 5070). Blood cultures showed no growth. HIV RNA was undetectable. Hepatitis C antibody was negative, and hepatitis A and B serologies were not consistent with an acute infection. Serum ferritin was 1147 ng/mL. Histoplasma and Legionella urine antigen tests were negative. CMV, EBV, and herpes simplex virus DNA were not detected in blood samples. Anti‐neutrophil antibody, anti‐mitochondrial antibody and anti‐neutrophil cytoplasmic antibodies were undetectable. Anti‐smooth muscle antibody was positive at a titer of 1:80. Transthoracic echocardiogram revealed normal heart valves without vegetations. A chest radiograph was normal. Brain computed tomography (CT) revealed atrophic frontal lobes. CT of his chest, abdomen, and pelvis demonstrated focal inflammatory changes of a loop of distal small bowel with surrounding fluid collection, suggesting small bowel diverticulitis. There were no pulmonary infiltrates noted, and the remainder of the CT was unremarkable.

Because the patient remains ill and additional serological test results will take time to return, a key consideration at this point is empiric treatment while awaiting test results. The CSF examination was normal. A history of travel including animal and tick exposures should be reevaluated. The timing of the trip to Mexico was outside the usual incubation period for many pathogens except for Coxiella or Brucella, and empiric therapy for both would be appropriate. The abdominal CT suggests small bowel diverticulitis, which is a rare clinical entity.

The benign abdominal examination suggests the finding is incidental. However, there are several infections that may involve the distal small bowel and proximal colon, such as yersiniosis, salmonellosis, tuberculosis, actinomycosis, histoplasmosis, and noninfectious processes including Crohn's disease and neoplasia. The absence of diarrhea or hematochezia makes yersiniosis, salmonellosis, and Crohn's disease unlikely. Histoplasmosis is unlikely given the negative urine antigen. Evaluation for neoplasia of the distal small bowel requires histologic examination. A colonoscopy with random biopsies of the colon and terminal ileum is the next step if other tests are unrevealing.

The patient was empirically treated for small bowel diverticulitis with ceftriaxone and metronidazole. Because of continued daily fevers as high as 39C, his therapy was changed to vancomycin and piperacillin‐tazobactam to cover methicillin‐resistant Staphylococcus aureus and resistant gram‐negative bacilli. The patient developed new scleral icterus on hospital day 6; the remainder of his examination was unchanged. Serum sodium concentration was 127 mEq/L, potassium 2.7 mEq/L, phosphorus 1.3 mg/dL, magnesium 1.6 mg/dL, total bilirubin 5.6 mg/dL, direct bilirubin 3.6 mg/dL, alkaline phosphatase 193 U/L, gamma‐glutamyl transferase 300 U/L, aspartate aminotransferase 91 U/L, alanine aminotransferase 52 U/L. Brucella serology was negative.

His liver enzymes remain elevated with new onset jaundice consistent with hepatitis and intrahepatic cholestasis. His persistent hypophosphatemia, hypokalemia, and hypomagnesaemia well after resolution of diabetic ketoacidosis suggests acute tubulointerstitial dysfunction, which may be a complication of empiric antibiotic treatment or renal involvement by his underlying condition. Additional blood cultures, and tissue examination and culture are the next appropriate steps. Liver or bone marrow biopsy may suggest a diagnosis that can be confirmed by tissue culture or immunohistochemistry. Histologic findings such as fibrin ringed granulomas, caseating or noncaseating granulomas, or lymphomatous infiltration may suggest Coxiella (Q fever), tuberculosis, or lymphoma respectively. Because a liver biopsy is invasive and usually provides less tissue for culture, bone marrow examination should be obtained first.

A gallium 67 scan showed nonhomogenous increased uptake in both lungs and kidneys, consistent with interstitial nephritis and bilateral pneumonia. Serum protein electrophoresis demonstrated a monoclonal immunoglobulin (Ig)G lambda band with a kappa/lambda ratio of 0.9 (normal 1.42.8). Bone marrow biopsy showed normal hematopoiesis; no plasma or malignant cells, granulomas, or evidence of hemophagocytosis; and fungal and mycobacterial stains and cultures were negative. Colonoscopy revealed normal‐appearing mucosa. Histologic examination and culture of random biopsies from the colon and terminal ileum were negative for fungi, viruses, and mycobacteria. An ultrasound‐guided liver biopsy revealed numerous noncaseating granulomas formed of histiocytes and neutrophils with occasional fibrin rings. Fungal, viral, and mycobacterial stains and cultures were negative. The patient's fever resolved after 14 days, and he was discharged home without a diagnosis and close outpatient follow‐up.

The hepatic granulomas with fibrin rings are highly suggestive of Q fever, although ring granulomas may be seen in tuberculosis, typhoid fever, lymphoma, drug reactions, sarcoidosis, and CMV infections. Competing diagnoses such as CMV have been excluded by negative serology. Microscopic examination, tissue staining, and culture from liver and bone marrow biopsies were negative for S typhi, mycobacteria, and lymphoma. Gallium scan findings are generally nonspecific and of little utility in cases such as this. The kidney involvement correlates with the biochemical evidence of tubulointerstitial dysfunction; pulmonary involvement may reflect subclinical pulmonary infection with Coxiella. Given the normal bone marrow biopsy, the monoclonal gammopathy is of undetermined significance. The positive anti‐smooth muscle antibody can be related to Q fever. Anti‐smooth muscle antibodies frequently occur in Q fever, especially in those patients with hepatitis. Given the history of exposure to cattle, unexplained fever with temperaturepulse dissociation and liver biopsy findings, Q fever is the most likely diagnosis and empiric treatment with doxycycline is warranted.

Results of serology for Coxiella burnetii sent during admission were returned after the patient's discharge. C burnetii phase I IgG and IgM antibody titers were positive (1:512 each). C burnetii phase II IgG and IgM titers also were positive (1:1024 each). The patient was seen within a week and started on doxycycline 100 mg twice daily for 2 weeks for acute Q fever. His symptoms improved; hyponatremia, liver function tests, and thrombocytopenia normalized after treatment.

DISCUSSION

Q fever was first described in 1937 as a febrile illness affecting Australian slaughterhouse workers.[1] The Q in Q fever stands for query and reflected the initial uncertainty surrounding the underlying cause of the illness. The causative organism, C burnetti, is an obligate intracellular bacterium that resides within macrophage lysosomes. It can be found in the urine, feces, milk, placenta, and amniotic fluid of ungulates (cattle, sheep, and other ruminants), and other animals such as domestic cats and dogs. C burnetii is transmitted via inhalation, ingestion, occupational, or common source exposures, and in 1 case report by person‐to‐person sexual transmission.[2] In addition to slaughterhouse workers, pregnant women and immunosuppressed patients are more susceptible to developing Q fever.[3] For patients with suspected Q fever, a detailed occupational history, including specific job duties and potential exposure to animal products, is imperative.

Q fever has both acute and chronic presentations, which are differentiated based on the clinical illness and serologies. The symptoms of acute Q fever are nonspecific and may include influenza‐like illness, fever, pneumonia, and hepatitis. It presents less commonly with hemolytic anemia, interstitial nephritis, monoclonal gammopathy, or aseptic meningitis.[4, 5, 6, 7] Symptoms typically begin between 1 and 3 weeks after animal exposure and may persist for several months. Chronic Q fever occurs when unrecognized or untreated infection persists for greater than 6 months. It commonly presents with culture‐negative endocarditis, although infected aneurysms, osteomyelitis, or other distant sites of infection may also occur.

C burnetti is present in 2 antigenic forms that can be assessed by serology. Phase I is the more virulent, infectious form of C burnetti, which transitions to the avirulent phase II form during laboratory handling. In acute Q fever, phase II serologies are typically elevated out of proportion to phase I serologies, whereas this pattern is reversed in chronic Q fever. The diagnostic gold standard of acute Q fever is a 4‐fold rise in phase II antibody titers taken 3 to 6 weeks apart.[8] Histologic examination of affected organs can support a diagnosis of Q fever. The presence of ringed granulomas on liver or bone marrow biopsy specimens is highly suggestive, but not pathognomonic, of Q fever.[9]

Q fever is highly susceptible to several classes of antibiotics. For acute Q fever, doxycycline and tetracycline are typically used, with fluoroquinolones and chloramphenicol as alternatives.[8, 10] Patients with chronic Q fever should be treated with doxycycline and hydroxychloroquine. The addition of hydroxychloroquine alkalinizes the macrophage lysosome and enhances bacterial eradication.[8] For patients with acute Q fever, physicians should determine the risk of progression to chronic Q fever because closer monitoring is necessary. Patients with valvular heart lesions, immunosuppression, and pregnant women are at elevated risk of chronic Q fever. Trimethoprim/sulfamethoxazole can be used in place of doxycycline in pregnant women, as doxycycline and fluoroquinolones are contraindicated in pregnancy.[8]

This patient presented with a nonspecific febrile illness. Although the treating clinicians obtained a history of exposure to cattle early in his course, both the diagnosis and treatment were delayed. There are several possible explanations for the delay. First, although Q fever is a relatively common zoonosis, it remains an uncommon diagnosis, particularly among hospitalized patients. As a result, clinicians often focus on more common conditions. In this case, typical infections, malignancies, and inflammatory diseases were considered more likely. Second, the patient presented with hepatitis, an uncommon presentation of Q fever. Classical clinical reasoning suggests that atypical presentations of common diseases will occur more frequently than typical presentations of uncommon diseases. This case presented with an atypical presentation of an uncommon disease. The resultant lower pretest probability further dissuaded the patient's physicians from consideration of Q fever. Third, the finding of small bowel diverticulitis was a potential distractor. In patients with nonspecific febrile illnesses, it is common for physicians to anchor on any abnormal findings. In this case, the small bowel diverticulitis led to antibiotic treatment that was ineffective against C burnetti.

There were several clues to the diagnosis of Q fever in this patient's presentation. First, the pulsetemperature dissociation suggested infection with an intracellular pathogen. Hospitalists should recognize this association and be mindful of this often‐subtle clinical finding when faced with diagnostic uncertainty. Second, the patient was exposed to cattle prior to the onset of his illness. The fact that he did not have a direct exposure to animals underscores the infectivity of C burnetti. Finally, elevated alkaline phosphatase and transaminases were suggestive of an infiltrative disease; in the setting of a nonspecific febrile illness, Q fever was an important diagnostic consideration.

The key treatment decision in this case was the initiation and choice of antibiotics. Because of this patient's history of exposure to cattle and lack of a compelling alternative diagnosis, empiric treatment with doxycycline would have been appropriate. Hospitalists must weigh the potential benefit of early treatment of Q fever against the risks associated with antibiotic overuse. In patients presenting with a febrile illness after ungulate exposure, the decision to bet the farm with empiric doxycycline therapy may lead to clinical improvement, obviating a more invasive or extensive diagnostic evaluation.

TEACHING POINTS

1. Acute Q fever typically presents 2 to 3 weeks after ungulate exposure with a febrile illness, pneumonia, and granulomatous hepatitis.
2. Pulsetemperature dissociation is suggestive of infection by intracellular pathogens such as Coxiella, Salmonella, Leptospira, Legionella, and Mycoplasma.
3. Clinicians should consider empiric doxycycline therapy in patients with suspected zoonosis (eg, Q fever, brucellosis, anaplasmosis, leptospirosis, Rocky Mountain spotted fever) while awaiting confirmatory tests, as improvement may obviate invasive testing.

Disclosure: Nothing to report.

A 47‐year‐old paraplegic man presented to our emergency department (ED) with severe pain from his sacral decubitus ulcers. Earlier that day, he had left against medical advice from another area ED. He took no medications but noted that he had been on several medications during recent hospitalizations. He had smoked cocaine that morning. He reported 3 days of watery diarrhea. His triage temperature was 98.2F, his heart rate was 146 beats per minute, and his blood pressure was 155/84 mm Hg. He had multiple foul‐smelling, stage 4 sacral ulcers and a chronic indwelling urinary catheter. Laboratory results included: white blood cell (WBC) count 22,000/mm³ (neutrophils 17,900/mm³), hemoglobin 8.5 g/dL, platelet count 317,000/mm³, creatinine 4.2 mg/dL, and lactate 1.5 mg/dL.

The patient's tachycardia and leukocytosis suggest sepsis. Potential sources include soft tissue infection or osteomyelitis from his sacral ulcers, Clostridium difficile, or a urinary tract infection. Impaired visceral sensation from his spinal cord injury may dampen his response to an intra‐abdominal process, such as mesenteric ischemia or toxic megacolon. Records from other hospitals should be reviewed to assess the acuity of change in his WBC count, hemoglobin, and creatinine. His anemia may be from chronic inflammation (eg, osteomyelitis), renal insufficiency, hemolysis, or occult blood loss, including retroperitoneal and gastrointestinal sources. His kidney injury may be from tubular necrosis in the setting of sepsis or obstructive uropathy related to a neurogenic bladder.

Intravenous vancomycin and piperacillin‐tazobactam were initiated for presumed sepsis. The team requested records from his prior hospitalizations and received only his most recent ED documentation, which revealed that he had received single doses of vancomycin and piperacillin‐tazobactam for a similar presentation. Oral vancomycin and intravenous metronidazole were started when C difficile toxin testing returned positive. He appeared more comfortable and remained normotensive, although his sinus tachycardia persisted at approximately 130 beats per minute. Sixteen hours after admission, the patient went into pulseless electrical activity (PEA) arrest.

Potential contributors to his PEA and cardiovascular collapse are drug use (cocaine), alcohol withdrawal, infection, hypovolemia, myocardial ischemia, or heart failure. Severe hemorrhage, hyperkalemia, or acidosis from acute kidney injury and sepsis could also account for his cardiac arrest. His paraplegia and hospitalization raise the risk of venous thromboembolism, which can lead to PEA from pulmonary embolus and prolonged hypoxia.

Return of spontaneous circulation occurred following 6 minutes of cardiopulmonary resuscitation. Arterial blood gas during bag‐valve mask ventilation with 100% FiO₂ was: pH 7.00, paCO₂ 44 mm Hg, and paO₂ 209 mm Hg. Serum chemistries were: sodium 148 mmol/L, potassium 5.5 mmol/L, chloride 111 mmol/L, bicarbonate 11 mmol/L, blood urea nitrogen 78 mg/dL, creatinine 4.1 mg/dL, glucose 256 mg/dL, calcium 8.4 mg/dL, magnesium 1.7 mg/dL, and phosphorus 5.9 mg/dL. Venous lactate was >11 mmol/L. His WBC count was 28,000/mm³, hematocrit was 4.4%, and platelet count was 196,000/mm³. Hemoglobin was unmeasurable due to interfering substances. An electrocardiogram showed sinus tachycardia with diffuse ST segment depressions. Chest radiograph revealed a properly situated endotracheal tube, normal cardiomediastinal silhouette and right basilar atelectasis.

His profound anemia is the likely cause of his PEA arrest and severe lactic acidosis. Massive hemolysis is most likely given no overt evidence of bleeding to account for the precipitous fall in hematocrit. Hemolysis can result from disorders intrinsic or extrinsic to the red blood cell (RBC). Intrinsic defects are usually congenital and involve the membrane, hemoglobin, or metabolic enzymes within the RBC. Extrinsic hemolysis arises from processes that injure the RBC from the outside: antibodies, infections, and mechanical shearing.

A rapidly declining platelet count is seen in microangiopathic hemolytic conditions such as disseminated intravascular coagulation (DIC) or thrombotic thrombocytopenic purpura (TTP), where platelets are consumed along with RBCs; sepsis makes DIC more likely. Autoimmune hemolytic anemia (AIHA) is sometimes accompanied by immune thrombocytopenia. AIHA arises from antibodies that are idiopathic or produced in response to infection, autoimmune conditions (eg, systemic lupus erythematosus), lymphoproliferative disease, or drugs (eg, ‐lactam antibiotics). The antiphospholipid syndrome can lead to thrombocytopenia, hemolysis, and kidney injury. Devitalized tissue in his sacral ulcers may predispose the patient to infection with Clostridium perfringens, which can elaborate enzymes that trigger massive hemolysis.

Because automated hemoglobin measurement is performed by spectrophotometry (light absorption and scatter), high concentrations of poorly soluble autoantibodies can increase the turbidity of the sample and preclude the measurement of hemoglobin concentration. This could lead to the report of interfering substances.

Computed tomography of the chest, abdomen, and pelvis did not reveal internal bleeding. Laboratory studies during the resuscitation were: lactate dehydrogenase (LDH) 2,411 U/L (reference range: 88230 U/L), haptoglobin 25 mg/dL (reference range: 36195 mg/dL), and reticulocyte percentage 2.6%. Total bilirubin was 2.4 mg/dL (reference range: 0.11.2 mg/dL), with direct fraction 0.9 mg/dL (reference range: <0.3 mg/dL). Prothrombin time (PT) was 24.9 seconds (reference range: 11.815.2 seconds), international normalized ratio (INR) was 2.3, and activated partial thromboplastin time (aPTT) was 47.3 seconds (reference range: 22.233.0 seconds). Phlebotomy yielded icteric plasma. A peripheral blood smear revealed severe anemia, red cell agglutination, microspherocytes, and hemophagocytosis by neutrophils (Figure 1).

Figure 1

Low haptoglobin, elevated LDH, and hyperbilirubinemia confirm hemolysis. A more robust reticulocytosis is expected in the face of profound anemia, but the patient may also suffer from a concomitant hypoproliferative state (eg, nutritional deficiency). More likely, the rapidity of his decline outpaced the marrow's response, which can be delayed by days.

The most common cause of a combined elevation of the INR/PT and aPTT in a critically ill patient is DIC. Although no schistocytes were detected on the peripheral smear, they can be absent in up to 50% of DIC cases. TTP is associated with hemolytic anemia, kidney injury, and thrombocytopenia, but it generally does not cause coagulopathy.

The combination of red cell agglutination and hemophagocytosis suggests that the RBCs are coated with autoantibodies that cross‐link the cells and make them targets for phagocytosis by neutrophils in the circulation. This is distinct from the hemophagocytic syndrome, a rare immune activation syndrome characterized by macrophage phagocytosis of RBCs in the reticuloendothelial system. The blood smear also shows microspherocytes, which are seen in AIHA and hereditary spherocytosis.

Urinalysis showed large hemoglobin and 11 to 20 red blood cells per high‐power field. Serum creatine phosphokinase was 35 U/dL (reference range: 50388 U/dL). Four units of packed RBCs and 1 unit of fresh‐frozen plasma were transfused. Due to a rising creatinine level and declining urine output, continuous veno‐venous hemofiltration (CVVH) was initiated.

Acute tubular necrosis could result from sepsis, ischemic injury from DIC, hypotension during cardiac arrest, or heme pigment toxicity. Urine sediment should be reviewed for dysmorphic RBCs or RBC casts that would indicate glomerulonephritis (eg, from an underlying autoimmune process associated with AIHA).

Urine hemoglobin that is disproportionate to the degree of hematuria suggests hemoglobinuria, which in turn defines the hemolysis as intravascular. Processes that directly lyse RBCs in circulation via mechanical shearing, activation of complement, infection of the RBC, or enzymatic or oxidative destruction of the membrane cause intravascular hemolysis. Leading considerations include microangiopathy (eg, DIC, TTP), clostridial sepsis, and AIHA.

AIHA can be broadly classified as warm or cold. Warm AIHA is caused by immunoglobulin IgG antibodies that bind most avidly at body temperature. Because warm AIHA does not activate complement, patients present with evidence of extravascular hemolysis that is typically chronic and mild to moderate in severity. It does not typically cause the acute, fulminant, intravascular hemolytic condition seen here.

Cold AIHA is characterized by autoantibodies that bind at lower temperatures and comes in 2 forms: cold agglutinin disease and (rarely) paroxysmal cold hemoglobinuria (PCH). Cold agglutinins are most often IgM antibodies produced in response to infection (Mycoplasma pneumoniae, infectious mononucleosis), drugs, or a hematologic malignancy. These IgM antibodies bind RBCs, causing them to agglutinate, and fix complement (including C3) to the surface of RBCs when blood circulates to cooler parts of the body. This results in complement activation, formation of the membrane attack complex, and intravascular hemolysis when bound and activated complement is present in large numbers. Acute infection can increase the complement available for binding to the surface of RBCs. Through a slightly different mechanism, PCH causes intravascular hemolysis through direct IgG activation of complement fixed to the surface of RBCs. During a hemolytic episode the direct antibody test (DAT) is positive using anti‐C3 and negative for IgG.

Based on the patient's clinical evidence of intravascular hemolysis and a suspected autoimmune etiology, the leading diagnosis at this time is cold AIHA.

Due to coagulopathy and possible cold agglutinin disease, therapeutic hypothermia for neuroprotection was deferred. He continued on vancomycin, piperacillin‐tazobactam, and metronidazole. The DAT and direct IgG were strongly positive (3+), whereas the direct C3 was weakly positive (<1+). His serum free hemoglobin increased from 136.7 mg/dL to 223.8 mg/dL (normal: 0.06.9 mg/dL). His severe metabolic acidosis corrected with CVVH.

The DAT detects IgG or complement adherent to RBCs. This patient has tested positive for both IgG and C3, though much more strongly for IgG, suggesting an unusual ability of the patient's IgG to activate complement. The phenomenon of mixed AIHA, in which the patient has both warm‐ and cold‐reacting antibodies, is rare.

Regarding infections associated with AIHA, there is no cough or rash to suggest M pneumoniae, and there is no sore throat, fever, lymphadenopathy, splenomegaly, or atypical lymphocytosis to suggest infectious mononucleosis. He should be tested for human immunodeficiency virus, which is also associated with AIHA. His leukocytosis may raise suspicion for an underlying hematologic malignancy, but he does not have blasts, dysplastic leukocytes, or lymphocytosis on his peripheral blood smear. Systemic lupus erythematosus can be associated with AIHA, thrombocytopenia, and renal failure, but he lacks the more common clinical manifestations of rash, arthralgias, and fever.

Drug‐induced immune hemolytic anemia (DIIHA) can cause both the clinical and serologic profile of an AIHA, as seen here. DIIHA can be distinguished from mixed AIHA if hemolysis abates with discontinuation of an offending drug. His deterioration is temporally associated with drug administration at the time of admission. Cephalosporins and ‐lactams (e.g., piperacillin) are the most common causes of DIIHA, and ‐lactamases such as tazobactam have also been implicated. By exclusion of other causes, DIIHA secondary to piperacillin is most likely responsible for his massive intravascular hemolysis.

Medical records from 2 other hospitals arrived approximately 36 hours after the patient's initial presentation. Three weeks earlier, he had required RBC transfusions for a 6 g/dL hemoglobin reduction after receiving piperacillin‐tazobactam for sepsis. He had been treated with steroids for presumed warm AIHA and dialyzed for acute kidney injury attributed to hemoglobinuria. After 1 week in the intensive care unit, he left against medical advice. Two weeks later he presented to another ED, which immediately preceded his presentation to our hospital.

An antibody screen for drug‐dependent antibodies revealed antipiperacillin antibodies. Antitazobactam antibodies were not tested. Piperacillin‐tazobactam was discontinued, and plasmapheresis was initiated to decrease the amount of piperacillin in the blood. The patient's hemoglobin subsequently remained above 7.0 g/dL without RBC transfusions.

His renal function recovered and he completed antibiotic therapy for C difficile infection and for his pressure ulcers. However, he had sustained severe anoxic brain injury during his cardiac arrest and did not recover neurological function. In accordance with his family's wishes, he was discharged to a long‐term acute care hospital dependent on a ventilator.

COMMENTARY

This case illustrates a dramatic presentation of fulminant intravascular hemolysis secondary to piperacillin. The incidence of DIIHA is estimated to be 1 in 1 million.[1] Historically, methyldopa and high‐dose penicillin have been responsible for the majority of cases,[2] but in recent years complex penicillins, including piperacillin, and second‐ and third‐generation cephalosporins have been implicated.[3, 4] Cases of DIIHA are often underdiagnosed or misdiagnosed, as smoldering or less severe cases may not be recognized or are attributed to other causes.

A positive DAT, suggesting immunoglobulin and/or complement binding to RBCs, is the most reliable laboratory finding in DIIHA.[5] However, a positive DAT does not identify the source of the antigen and may result in misattribution of the immune hemolysis to autoimmunity rather than to a drug. Repeated or continued administration of the offending drug (as in this case) may perpetuate or worsen the hemolysis. Drug‐specific antibody tests may help to confirm the diagnosis, but these tests are complex and take significant time for specialized laboratories to run.

Severe hemolysis should be considered when a patient has a sudden and dramatic drop in his hemoglobin level in the absence of bleeding. Because DIIHA can be rapidly progressive, discontinuing a suspected culprit drug is the most important diagnostic and therapeutic measure. Typically, when an offending drug is stopped, the hemolysis stops as well. The time course over which this occurs depends on the rapidity of drug clearance.[4] Hemodialysis or plasmapheresis may be required in cases where the medication is renally excreted, particularly in cases of concomitant kidney injury. Evidence supporting corticosteroid use in DIIHA is limited, as the offending agent is usually discontinued by the time corticosteroids are initiated.[4]

This patient's DAT confirmed both IgG and complement activation, consistent with DIIHA caused by an immune complexlike reaction. This mechanism involves the antibody binding to a mixed epitope of the drug and a RBC membrane glycoprotein.[6] The offending drug was stopped only when review of his medical records established a clear temporal association between antibiotic administration and prior hemolysis.

The 2009 Health Information Technology for Economic and Clinical Health Act created an electronic health record (EHR) incentive program (meaningful use criteria).[7] By 2012, only 6% of hospitals met all of the stage 2 criteria, which include EHR interoperability across health systems.[8] The patient's preceding hemolytic event was described in records faxed by the outside hospitals, but without EHR interoperability, the treating clinicians did not have timely access to this information. Instead, the familiar manual process of obtaining outside records involving signed forms, phone calls, fax machines, and reams of paper progressed at its usual pace. Real‐time access to health records might have guided providers to select an alternative antibiotic regimen. Instead, a communication breakdown contributed to a catastrophic drug reaction and to this tragic patient outcome.

KEY TEACHING POINTS

1. In a patient presenting with acute hemolysis and a positive DAT, consider DIIHA.
2. Both piperacillin and tazobactam can cause a severe, complement‐mediated immune hemolytic anemia (DIIHA).
3. Drug‐induced antibodies are detected by direct antiglobulin testing, but a complete medication history is the key to diagnosis.
4. Management of drug‐induced hemolytic anemia involves immediate discontinuation of the culprit medication, supportive care, and potentially corticosteroids, plasmapheresis, and/or hemodialysis to expedite removal of the offending agent.
5. EHR interoperability may provide timely access to important health information across different hospitals, expedite health information exchange, and reduce adverse patient outcomes that stem from communication delays.

This case was submitted anonymously to AHRQ WebM&M on July 18, 2014, and was accepted on August 7, 2014. The case and WebM&M commentary were published online on October 26, 2015.[9] This separate commentary on the same case was later submitted to the Journal of Hospital Medicine on September 2, 2015, accepted on November 24, 2015, and published on January 22, 2016. The 2 publications are written by different authors, and although they reference the same case, they make different but valuable points.

A 47‐year‐old paraplegic man presented to our emergency department (ED) with severe pain from his sacral decubitus ulcers. Earlier that day, he had left against medical advice from another area ED. He took no medications but noted that he had been on several medications during recent hospitalizations. He had smoked cocaine that morning. He reported 3 days of watery diarrhea. His triage temperature was 98.2F, his heart rate was 146 beats per minute, and his blood pressure was 155/84 mm Hg. He had multiple foul‐smelling, stage 4 sacral ulcers and a chronic indwelling urinary catheter. Laboratory results included: white blood cell (WBC) count 22,000/mm³ (neutrophils 17,900/mm³), hemoglobin 8.5 g/dL, platelet count 317,000/mm³, creatinine 4.2 mg/dL, and lactate 1.5 mg/dL.

The patient's tachycardia and leukocytosis suggest sepsis. Potential sources include soft tissue infection or osteomyelitis from his sacral ulcers, Clostridium difficile, or a urinary tract infection. Impaired visceral sensation from his spinal cord injury may dampen his response to an intra‐abdominal process, such as mesenteric ischemia or toxic megacolon. Records from other hospitals should be reviewed to assess the acuity of change in his WBC count, hemoglobin, and creatinine. His anemia may be from chronic inflammation (eg, osteomyelitis), renal insufficiency, hemolysis, or occult blood loss, including retroperitoneal and gastrointestinal sources. His kidney injury may be from tubular necrosis in the setting of sepsis or obstructive uropathy related to a neurogenic bladder.

Intravenous vancomycin and piperacillin‐tazobactam were initiated for presumed sepsis. The team requested records from his prior hospitalizations and received only his most recent ED documentation, which revealed that he had received single doses of vancomycin and piperacillin‐tazobactam for a similar presentation. Oral vancomycin and intravenous metronidazole were started when C difficile toxin testing returned positive. He appeared more comfortable and remained normotensive, although his sinus tachycardia persisted at approximately 130 beats per minute. Sixteen hours after admission, the patient went into pulseless electrical activity (PEA) arrest.

Potential contributors to his PEA and cardiovascular collapse are drug use (cocaine), alcohol withdrawal, infection, hypovolemia, myocardial ischemia, or heart failure. Severe hemorrhage, hyperkalemia, or acidosis from acute kidney injury and sepsis could also account for his cardiac arrest. His paraplegia and hospitalization raise the risk of venous thromboembolism, which can lead to PEA from pulmonary embolus and prolonged hypoxia.

Return of spontaneous circulation occurred following 6 minutes of cardiopulmonary resuscitation. Arterial blood gas during bag‐valve mask ventilation with 100% FiO₂ was: pH 7.00, paCO₂ 44 mm Hg, and paO₂ 209 mm Hg. Serum chemistries were: sodium 148 mmol/L, potassium 5.5 mmol/L, chloride 111 mmol/L, bicarbonate 11 mmol/L, blood urea nitrogen 78 mg/dL, creatinine 4.1 mg/dL, glucose 256 mg/dL, calcium 8.4 mg/dL, magnesium 1.7 mg/dL, and phosphorus 5.9 mg/dL. Venous lactate was >11 mmol/L. His WBC count was 28,000/mm³, hematocrit was 4.4%, and platelet count was 196,000/mm³. Hemoglobin was unmeasurable due to interfering substances. An electrocardiogram showed sinus tachycardia with diffuse ST segment depressions. Chest radiograph revealed a properly situated endotracheal tube, normal cardiomediastinal silhouette and right basilar atelectasis.

His profound anemia is the likely cause of his PEA arrest and severe lactic acidosis. Massive hemolysis is most likely given no overt evidence of bleeding to account for the precipitous fall in hematocrit. Hemolysis can result from disorders intrinsic or extrinsic to the red blood cell (RBC). Intrinsic defects are usually congenital and involve the membrane, hemoglobin, or metabolic enzymes within the RBC. Extrinsic hemolysis arises from processes that injure the RBC from the outside: antibodies, infections, and mechanical shearing.

A rapidly declining platelet count is seen in microangiopathic hemolytic conditions such as disseminated intravascular coagulation (DIC) or thrombotic thrombocytopenic purpura (TTP), where platelets are consumed along with RBCs; sepsis makes DIC more likely. Autoimmune hemolytic anemia (AIHA) is sometimes accompanied by immune thrombocytopenia. AIHA arises from antibodies that are idiopathic or produced in response to infection, autoimmune conditions (eg, systemic lupus erythematosus), lymphoproliferative disease, or drugs (eg, ‐lactam antibiotics). The antiphospholipid syndrome can lead to thrombocytopenia, hemolysis, and kidney injury. Devitalized tissue in his sacral ulcers may predispose the patient to infection with Clostridium perfringens, which can elaborate enzymes that trigger massive hemolysis.

Because automated hemoglobin measurement is performed by spectrophotometry (light absorption and scatter), high concentrations of poorly soluble autoantibodies can increase the turbidity of the sample and preclude the measurement of hemoglobin concentration. This could lead to the report of interfering substances.

Computed tomography of the chest, abdomen, and pelvis did not reveal internal bleeding. Laboratory studies during the resuscitation were: lactate dehydrogenase (LDH) 2,411 U/L (reference range: 88230 U/L), haptoglobin 25 mg/dL (reference range: 36195 mg/dL), and reticulocyte percentage 2.6%. Total bilirubin was 2.4 mg/dL (reference range: 0.11.2 mg/dL), with direct fraction 0.9 mg/dL (reference range: <0.3 mg/dL). Prothrombin time (PT) was 24.9 seconds (reference range: 11.815.2 seconds), international normalized ratio (INR) was 2.3, and activated partial thromboplastin time (aPTT) was 47.3 seconds (reference range: 22.233.0 seconds). Phlebotomy yielded icteric plasma. A peripheral blood smear revealed severe anemia, red cell agglutination, microspherocytes, and hemophagocytosis by neutrophils (Figure 1).

Figure 1

Low haptoglobin, elevated LDH, and hyperbilirubinemia confirm hemolysis. A more robust reticulocytosis is expected in the face of profound anemia, but the patient may also suffer from a concomitant hypoproliferative state (eg, nutritional deficiency). More likely, the rapidity of his decline outpaced the marrow's response, which can be delayed by days.

The most common cause of a combined elevation of the INR/PT and aPTT in a critically ill patient is DIC. Although no schistocytes were detected on the peripheral smear, they can be absent in up to 50% of DIC cases. TTP is associated with hemolytic anemia, kidney injury, and thrombocytopenia, but it generally does not cause coagulopathy.

The combination of red cell agglutination and hemophagocytosis suggests that the RBCs are coated with autoantibodies that cross‐link the cells and make them targets for phagocytosis by neutrophils in the circulation. This is distinct from the hemophagocytic syndrome, a rare immune activation syndrome characterized by macrophage phagocytosis of RBCs in the reticuloendothelial system. The blood smear also shows microspherocytes, which are seen in AIHA and hereditary spherocytosis.

Urinalysis showed large hemoglobin and 11 to 20 red blood cells per high‐power field. Serum creatine phosphokinase was 35 U/dL (reference range: 50388 U/dL). Four units of packed RBCs and 1 unit of fresh‐frozen plasma were transfused. Due to a rising creatinine level and declining urine output, continuous veno‐venous hemofiltration (CVVH) was initiated.

Acute tubular necrosis could result from sepsis, ischemic injury from DIC, hypotension during cardiac arrest, or heme pigment toxicity. Urine sediment should be reviewed for dysmorphic RBCs or RBC casts that would indicate glomerulonephritis (eg, from an underlying autoimmune process associated with AIHA).

Urine hemoglobin that is disproportionate to the degree of hematuria suggests hemoglobinuria, which in turn defines the hemolysis as intravascular. Processes that directly lyse RBCs in circulation via mechanical shearing, activation of complement, infection of the RBC, or enzymatic or oxidative destruction of the membrane cause intravascular hemolysis. Leading considerations include microangiopathy (eg, DIC, TTP), clostridial sepsis, and AIHA.

AIHA can be broadly classified as warm or cold. Warm AIHA is caused by immunoglobulin IgG antibodies that bind most avidly at body temperature. Because warm AIHA does not activate complement, patients present with evidence of extravascular hemolysis that is typically chronic and mild to moderate in severity. It does not typically cause the acute, fulminant, intravascular hemolytic condition seen here.

Cold AIHA is characterized by autoantibodies that bind at lower temperatures and comes in 2 forms: cold agglutinin disease and (rarely) paroxysmal cold hemoglobinuria (PCH). Cold agglutinins are most often IgM antibodies produced in response to infection (Mycoplasma pneumoniae, infectious mononucleosis), drugs, or a hematologic malignancy. These IgM antibodies bind RBCs, causing them to agglutinate, and fix complement (including C3) to the surface of RBCs when blood circulates to cooler parts of the body. This results in complement activation, formation of the membrane attack complex, and intravascular hemolysis when bound and activated complement is present in large numbers. Acute infection can increase the complement available for binding to the surface of RBCs. Through a slightly different mechanism, PCH causes intravascular hemolysis through direct IgG activation of complement fixed to the surface of RBCs. During a hemolytic episode the direct antibody test (DAT) is positive using anti‐C3 and negative for IgG.

Based on the patient's clinical evidence of intravascular hemolysis and a suspected autoimmune etiology, the leading diagnosis at this time is cold AIHA.

Due to coagulopathy and possible cold agglutinin disease, therapeutic hypothermia for neuroprotection was deferred. He continued on vancomycin, piperacillin‐tazobactam, and metronidazole. The DAT and direct IgG were strongly positive (3+), whereas the direct C3 was weakly positive (<1+). His serum free hemoglobin increased from 136.7 mg/dL to 223.8 mg/dL (normal: 0.06.9 mg/dL). His severe metabolic acidosis corrected with CVVH.

The DAT detects IgG or complement adherent to RBCs. This patient has tested positive for both IgG and C3, though much more strongly for IgG, suggesting an unusual ability of the patient's IgG to activate complement. The phenomenon of mixed AIHA, in which the patient has both warm‐ and cold‐reacting antibodies, is rare.

Regarding infections associated with AIHA, there is no cough or rash to suggest M pneumoniae, and there is no sore throat, fever, lymphadenopathy, splenomegaly, or atypical lymphocytosis to suggest infectious mononucleosis. He should be tested for human immunodeficiency virus, which is also associated with AIHA. His leukocytosis may raise suspicion for an underlying hematologic malignancy, but he does not have blasts, dysplastic leukocytes, or lymphocytosis on his peripheral blood smear. Systemic lupus erythematosus can be associated with AIHA, thrombocytopenia, and renal failure, but he lacks the more common clinical manifestations of rash, arthralgias, and fever.

Drug‐induced immune hemolytic anemia (DIIHA) can cause both the clinical and serologic profile of an AIHA, as seen here. DIIHA can be distinguished from mixed AIHA if hemolysis abates with discontinuation of an offending drug. His deterioration is temporally associated with drug administration at the time of admission. Cephalosporins and ‐lactams (e.g., piperacillin) are the most common causes of DIIHA, and ‐lactamases such as tazobactam have also been implicated. By exclusion of other causes, DIIHA secondary to piperacillin is most likely responsible for his massive intravascular hemolysis.

Medical records from 2 other hospitals arrived approximately 36 hours after the patient's initial presentation. Three weeks earlier, he had required RBC transfusions for a 6 g/dL hemoglobin reduction after receiving piperacillin‐tazobactam for sepsis. He had been treated with steroids for presumed warm AIHA and dialyzed for acute kidney injury attributed to hemoglobinuria. After 1 week in the intensive care unit, he left against medical advice. Two weeks later he presented to another ED, which immediately preceded his presentation to our hospital.

An antibody screen for drug‐dependent antibodies revealed antipiperacillin antibodies. Antitazobactam antibodies were not tested. Piperacillin‐tazobactam was discontinued, and plasmapheresis was initiated to decrease the amount of piperacillin in the blood. The patient's hemoglobin subsequently remained above 7.0 g/dL without RBC transfusions.

His renal function recovered and he completed antibiotic therapy for C difficile infection and for his pressure ulcers. However, he had sustained severe anoxic brain injury during his cardiac arrest and did not recover neurological function. In accordance with his family's wishes, he was discharged to a long‐term acute care hospital dependent on a ventilator.

COMMENTARY

This case illustrates a dramatic presentation of fulminant intravascular hemolysis secondary to piperacillin. The incidence of DIIHA is estimated to be 1 in 1 million.[1] Historically, methyldopa and high‐dose penicillin have been responsible for the majority of cases,[2] but in recent years complex penicillins, including piperacillin, and second‐ and third‐generation cephalosporins have been implicated.[3, 4] Cases of DIIHA are often underdiagnosed or misdiagnosed, as smoldering or less severe cases may not be recognized or are attributed to other causes.

A positive DAT, suggesting immunoglobulin and/or complement binding to RBCs, is the most reliable laboratory finding in DIIHA.[5] However, a positive DAT does not identify the source of the antigen and may result in misattribution of the immune hemolysis to autoimmunity rather than to a drug. Repeated or continued administration of the offending drug (as in this case) may perpetuate or worsen the hemolysis. Drug‐specific antibody tests may help to confirm the diagnosis, but these tests are complex and take significant time for specialized laboratories to run.

Severe hemolysis should be considered when a patient has a sudden and dramatic drop in his hemoglobin level in the absence of bleeding. Because DIIHA can be rapidly progressive, discontinuing a suspected culprit drug is the most important diagnostic and therapeutic measure. Typically, when an offending drug is stopped, the hemolysis stops as well. The time course over which this occurs depends on the rapidity of drug clearance.[4] Hemodialysis or plasmapheresis may be required in cases where the medication is renally excreted, particularly in cases of concomitant kidney injury. Evidence supporting corticosteroid use in DIIHA is limited, as the offending agent is usually discontinued by the time corticosteroids are initiated.[4]

This patient's DAT confirmed both IgG and complement activation, consistent with DIIHA caused by an immune complexlike reaction. This mechanism involves the antibody binding to a mixed epitope of the drug and a RBC membrane glycoprotein.[6] The offending drug was stopped only when review of his medical records established a clear temporal association between antibiotic administration and prior hemolysis.

The 2009 Health Information Technology for Economic and Clinical Health Act created an electronic health record (EHR) incentive program (meaningful use criteria).[7] By 2012, only 6% of hospitals met all of the stage 2 criteria, which include EHR interoperability across health systems.[8] The patient's preceding hemolytic event was described in records faxed by the outside hospitals, but without EHR interoperability, the treating clinicians did not have timely access to this information. Instead, the familiar manual process of obtaining outside records involving signed forms, phone calls, fax machines, and reams of paper progressed at its usual pace. Real‐time access to health records might have guided providers to select an alternative antibiotic regimen. Instead, a communication breakdown contributed to a catastrophic drug reaction and to this tragic patient outcome.

KEY TEACHING POINTS

1. In a patient presenting with acute hemolysis and a positive DAT, consider DIIHA.
2. Both piperacillin and tazobactam can cause a severe, complement‐mediated immune hemolytic anemia (DIIHA).
3. Drug‐induced antibodies are detected by direct antiglobulin testing, but a complete medication history is the key to diagnosis.
4. Management of drug‐induced hemolytic anemia involves immediate discontinuation of the culprit medication, supportive care, and potentially corticosteroids, plasmapheresis, and/or hemodialysis to expedite removal of the offending agent.
5. EHR interoperability may provide timely access to important health information across different hospitals, expedite health information exchange, and reduce adverse patient outcomes that stem from communication delays.

This case was submitted anonymously to AHRQ WebM&M on July 18, 2014, and was accepted on August 7, 2014. The case and WebM&M commentary were published online on October 26, 2015.[9] This separate commentary on the same case was later submitted to the Journal of Hospital Medicine on September 2, 2015, accepted on November 24, 2015, and published on January 22, 2016. The 2 publications are written by different authors, and although they reference the same case, they make different but valuable points.

A 47‐year‐old paraplegic man presented to our emergency department (ED) with severe pain from his sacral decubitus ulcers. Earlier that day, he had left against medical advice from another area ED. He took no medications but noted that he had been on several medications during recent hospitalizations. He had smoked cocaine that morning. He reported 3 days of watery diarrhea. His triage temperature was 98.2F, his heart rate was 146 beats per minute, and his blood pressure was 155/84 mm Hg. He had multiple foul‐smelling, stage 4 sacral ulcers and a chronic indwelling urinary catheter. Laboratory results included: white blood cell (WBC) count 22,000/mm³ (neutrophils 17,900/mm³), hemoglobin 8.5 g/dL, platelet count 317,000/mm³, creatinine 4.2 mg/dL, and lactate 1.5 mg/dL.

The patient's tachycardia and leukocytosis suggest sepsis. Potential sources include soft tissue infection or osteomyelitis from his sacral ulcers, Clostridium difficile, or a urinary tract infection. Impaired visceral sensation from his spinal cord injury may dampen his response to an intra‐abdominal process, such as mesenteric ischemia or toxic megacolon. Records from other hospitals should be reviewed to assess the acuity of change in his WBC count, hemoglobin, and creatinine. His anemia may be from chronic inflammation (eg, osteomyelitis), renal insufficiency, hemolysis, or occult blood loss, including retroperitoneal and gastrointestinal sources. His kidney injury may be from tubular necrosis in the setting of sepsis or obstructive uropathy related to a neurogenic bladder.

Intravenous vancomycin and piperacillin‐tazobactam were initiated for presumed sepsis. The team requested records from his prior hospitalizations and received only his most recent ED documentation, which revealed that he had received single doses of vancomycin and piperacillin‐tazobactam for a similar presentation. Oral vancomycin and intravenous metronidazole were started when C difficile toxin testing returned positive. He appeared more comfortable and remained normotensive, although his sinus tachycardia persisted at approximately 130 beats per minute. Sixteen hours after admission, the patient went into pulseless electrical activity (PEA) arrest.

Potential contributors to his PEA and cardiovascular collapse are drug use (cocaine), alcohol withdrawal, infection, hypovolemia, myocardial ischemia, or heart failure. Severe hemorrhage, hyperkalemia, or acidosis from acute kidney injury and sepsis could also account for his cardiac arrest. His paraplegia and hospitalization raise the risk of venous thromboembolism, which can lead to PEA from pulmonary embolus and prolonged hypoxia.

Return of spontaneous circulation occurred following 6 minutes of cardiopulmonary resuscitation. Arterial blood gas during bag‐valve mask ventilation with 100% FiO₂ was: pH 7.00, paCO₂ 44 mm Hg, and paO₂ 209 mm Hg. Serum chemistries were: sodium 148 mmol/L, potassium 5.5 mmol/L, chloride 111 mmol/L, bicarbonate 11 mmol/L, blood urea nitrogen 78 mg/dL, creatinine 4.1 mg/dL, glucose 256 mg/dL, calcium 8.4 mg/dL, magnesium 1.7 mg/dL, and phosphorus 5.9 mg/dL. Venous lactate was >11 mmol/L. His WBC count was 28,000/mm³, hematocrit was 4.4%, and platelet count was 196,000/mm³. Hemoglobin was unmeasurable due to interfering substances. An electrocardiogram showed sinus tachycardia with diffuse ST segment depressions. Chest radiograph revealed a properly situated endotracheal tube, normal cardiomediastinal silhouette and right basilar atelectasis.

His profound anemia is the likely cause of his PEA arrest and severe lactic acidosis. Massive hemolysis is most likely given no overt evidence of bleeding to account for the precipitous fall in hematocrit. Hemolysis can result from disorders intrinsic or extrinsic to the red blood cell (RBC). Intrinsic defects are usually congenital and involve the membrane, hemoglobin, or metabolic enzymes within the RBC. Extrinsic hemolysis arises from processes that injure the RBC from the outside: antibodies, infections, and mechanical shearing.

A rapidly declining platelet count is seen in microangiopathic hemolytic conditions such as disseminated intravascular coagulation (DIC) or thrombotic thrombocytopenic purpura (TTP), where platelets are consumed along with RBCs; sepsis makes DIC more likely. Autoimmune hemolytic anemia (AIHA) is sometimes accompanied by immune thrombocytopenia. AIHA arises from antibodies that are idiopathic or produced in response to infection, autoimmune conditions (eg, systemic lupus erythematosus), lymphoproliferative disease, or drugs (eg, ‐lactam antibiotics). The antiphospholipid syndrome can lead to thrombocytopenia, hemolysis, and kidney injury. Devitalized tissue in his sacral ulcers may predispose the patient to infection with Clostridium perfringens, which can elaborate enzymes that trigger massive hemolysis.

Because automated hemoglobin measurement is performed by spectrophotometry (light absorption and scatter), high concentrations of poorly soluble autoantibodies can increase the turbidity of the sample and preclude the measurement of hemoglobin concentration. This could lead to the report of interfering substances.

Computed tomography of the chest, abdomen, and pelvis did not reveal internal bleeding. Laboratory studies during the resuscitation were: lactate dehydrogenase (LDH) 2,411 U/L (reference range: 88230 U/L), haptoglobin 25 mg/dL (reference range: 36195 mg/dL), and reticulocyte percentage 2.6%. Total bilirubin was 2.4 mg/dL (reference range: 0.11.2 mg/dL), with direct fraction 0.9 mg/dL (reference range: <0.3 mg/dL). Prothrombin time (PT) was 24.9 seconds (reference range: 11.815.2 seconds), international normalized ratio (INR) was 2.3, and activated partial thromboplastin time (aPTT) was 47.3 seconds (reference range: 22.233.0 seconds). Phlebotomy yielded icteric plasma. A peripheral blood smear revealed severe anemia, red cell agglutination, microspherocytes, and hemophagocytosis by neutrophils (Figure 1).

Figure 1

Low haptoglobin, elevated LDH, and hyperbilirubinemia confirm hemolysis. A more robust reticulocytosis is expected in the face of profound anemia, but the patient may also suffer from a concomitant hypoproliferative state (eg, nutritional deficiency). More likely, the rapidity of his decline outpaced the marrow's response, which can be delayed by days.

The most common cause of a combined elevation of the INR/PT and aPTT in a critically ill patient is DIC. Although no schistocytes were detected on the peripheral smear, they can be absent in up to 50% of DIC cases. TTP is associated with hemolytic anemia, kidney injury, and thrombocytopenia, but it generally does not cause coagulopathy.

The combination of red cell agglutination and hemophagocytosis suggests that the RBCs are coated with autoantibodies that cross‐link the cells and make them targets for phagocytosis by neutrophils in the circulation. This is distinct from the hemophagocytic syndrome, a rare immune activation syndrome characterized by macrophage phagocytosis of RBCs in the reticuloendothelial system. The blood smear also shows microspherocytes, which are seen in AIHA and hereditary spherocytosis.

Urinalysis showed large hemoglobin and 11 to 20 red blood cells per high‐power field. Serum creatine phosphokinase was 35 U/dL (reference range: 50388 U/dL). Four units of packed RBCs and 1 unit of fresh‐frozen plasma were transfused. Due to a rising creatinine level and declining urine output, continuous veno‐venous hemofiltration (CVVH) was initiated.

Acute tubular necrosis could result from sepsis, ischemic injury from DIC, hypotension during cardiac arrest, or heme pigment toxicity. Urine sediment should be reviewed for dysmorphic RBCs or RBC casts that would indicate glomerulonephritis (eg, from an underlying autoimmune process associated with AIHA).

Urine hemoglobin that is disproportionate to the degree of hematuria suggests hemoglobinuria, which in turn defines the hemolysis as intravascular. Processes that directly lyse RBCs in circulation via mechanical shearing, activation of complement, infection of the RBC, or enzymatic or oxidative destruction of the membrane cause intravascular hemolysis. Leading considerations include microangiopathy (eg, DIC, TTP), clostridial sepsis, and AIHA.

AIHA can be broadly classified as warm or cold. Warm AIHA is caused by immunoglobulin IgG antibodies that bind most avidly at body temperature. Because warm AIHA does not activate complement, patients present with evidence of extravascular hemolysis that is typically chronic and mild to moderate in severity. It does not typically cause the acute, fulminant, intravascular hemolytic condition seen here.

Cold AIHA is characterized by autoantibodies that bind at lower temperatures and comes in 2 forms: cold agglutinin disease and (rarely) paroxysmal cold hemoglobinuria (PCH). Cold agglutinins are most often IgM antibodies produced in response to infection (Mycoplasma pneumoniae, infectious mononucleosis), drugs, or a hematologic malignancy. These IgM antibodies bind RBCs, causing them to agglutinate, and fix complement (including C3) to the surface of RBCs when blood circulates to cooler parts of the body. This results in complement activation, formation of the membrane attack complex, and intravascular hemolysis when bound and activated complement is present in large numbers. Acute infection can increase the complement available for binding to the surface of RBCs. Through a slightly different mechanism, PCH causes intravascular hemolysis through direct IgG activation of complement fixed to the surface of RBCs. During a hemolytic episode the direct antibody test (DAT) is positive using anti‐C3 and negative for IgG.

Based on the patient's clinical evidence of intravascular hemolysis and a suspected autoimmune etiology, the leading diagnosis at this time is cold AIHA.

Due to coagulopathy and possible cold agglutinin disease, therapeutic hypothermia for neuroprotection was deferred. He continued on vancomycin, piperacillin‐tazobactam, and metronidazole. The DAT and direct IgG were strongly positive (3+), whereas the direct C3 was weakly positive (<1+). His serum free hemoglobin increased from 136.7 mg/dL to 223.8 mg/dL (normal: 0.06.9 mg/dL). His severe metabolic acidosis corrected with CVVH.

The DAT detects IgG or complement adherent to RBCs. This patient has tested positive for both IgG and C3, though much more strongly for IgG, suggesting an unusual ability of the patient's IgG to activate complement. The phenomenon of mixed AIHA, in which the patient has both warm‐ and cold‐reacting antibodies, is rare.

Regarding infections associated with AIHA, there is no cough or rash to suggest M pneumoniae, and there is no sore throat, fever, lymphadenopathy, splenomegaly, or atypical lymphocytosis to suggest infectious mononucleosis. He should be tested for human immunodeficiency virus, which is also associated with AIHA. His leukocytosis may raise suspicion for an underlying hematologic malignancy, but he does not have blasts, dysplastic leukocytes, or lymphocytosis on his peripheral blood smear. Systemic lupus erythematosus can be associated with AIHA, thrombocytopenia, and renal failure, but he lacks the more common clinical manifestations of rash, arthralgias, and fever.

Drug‐induced immune hemolytic anemia (DIIHA) can cause both the clinical and serologic profile of an AIHA, as seen here. DIIHA can be distinguished from mixed AIHA if hemolysis abates with discontinuation of an offending drug. His deterioration is temporally associated with drug administration at the time of admission. Cephalosporins and ‐lactams (e.g., piperacillin) are the most common causes of DIIHA, and ‐lactamases such as tazobactam have also been implicated. By exclusion of other causes, DIIHA secondary to piperacillin is most likely responsible for his massive intravascular hemolysis.

Medical records from 2 other hospitals arrived approximately 36 hours after the patient's initial presentation. Three weeks earlier, he had required RBC transfusions for a 6 g/dL hemoglobin reduction after receiving piperacillin‐tazobactam for sepsis. He had been treated with steroids for presumed warm AIHA and dialyzed for acute kidney injury attributed to hemoglobinuria. After 1 week in the intensive care unit, he left against medical advice. Two weeks later he presented to another ED, which immediately preceded his presentation to our hospital.

An antibody screen for drug‐dependent antibodies revealed antipiperacillin antibodies. Antitazobactam antibodies were not tested. Piperacillin‐tazobactam was discontinued, and plasmapheresis was initiated to decrease the amount of piperacillin in the blood. The patient's hemoglobin subsequently remained above 7.0 g/dL without RBC transfusions.

His renal function recovered and he completed antibiotic therapy for C difficile infection and for his pressure ulcers. However, he had sustained severe anoxic brain injury during his cardiac arrest and did not recover neurological function. In accordance with his family's wishes, he was discharged to a long‐term acute care hospital dependent on a ventilator.

COMMENTARY

This case illustrates a dramatic presentation of fulminant intravascular hemolysis secondary to piperacillin. The incidence of DIIHA is estimated to be 1 in 1 million.[1] Historically, methyldopa and high‐dose penicillin have been responsible for the majority of cases,[2] but in recent years complex penicillins, including piperacillin, and second‐ and third‐generation cephalosporins have been implicated.[3, 4] Cases of DIIHA are often underdiagnosed or misdiagnosed, as smoldering or less severe cases may not be recognized or are attributed to other causes.

A positive DAT, suggesting immunoglobulin and/or complement binding to RBCs, is the most reliable laboratory finding in DIIHA.[5] However, a positive DAT does not identify the source of the antigen and may result in misattribution of the immune hemolysis to autoimmunity rather than to a drug. Repeated or continued administration of the offending drug (as in this case) may perpetuate or worsen the hemolysis. Drug‐specific antibody tests may help to confirm the diagnosis, but these tests are complex and take significant time for specialized laboratories to run.

Severe hemolysis should be considered when a patient has a sudden and dramatic drop in his hemoglobin level in the absence of bleeding. Because DIIHA can be rapidly progressive, discontinuing a suspected culprit drug is the most important diagnostic and therapeutic measure. Typically, when an offending drug is stopped, the hemolysis stops as well. The time course over which this occurs depends on the rapidity of drug clearance.[4] Hemodialysis or plasmapheresis may be required in cases where the medication is renally excreted, particularly in cases of concomitant kidney injury. Evidence supporting corticosteroid use in DIIHA is limited, as the offending agent is usually discontinued by the time corticosteroids are initiated.[4]

This patient's DAT confirmed both IgG and complement activation, consistent with DIIHA caused by an immune complexlike reaction. This mechanism involves the antibody binding to a mixed epitope of the drug and a RBC membrane glycoprotein.[6] The offending drug was stopped only when review of his medical records established a clear temporal association between antibiotic administration and prior hemolysis.

The 2009 Health Information Technology for Economic and Clinical Health Act created an electronic health record (EHR) incentive program (meaningful use criteria).[7] By 2012, only 6% of hospitals met all of the stage 2 criteria, which include EHR interoperability across health systems.[8] The patient's preceding hemolytic event was described in records faxed by the outside hospitals, but without EHR interoperability, the treating clinicians did not have timely access to this information. Instead, the familiar manual process of obtaining outside records involving signed forms, phone calls, fax machines, and reams of paper progressed at its usual pace. Real‐time access to health records might have guided providers to select an alternative antibiotic regimen. Instead, a communication breakdown contributed to a catastrophic drug reaction and to this tragic patient outcome.

KEY TEACHING POINTS

1. In a patient presenting with acute hemolysis and a positive DAT, consider DIIHA.
2. Both piperacillin and tazobactam can cause a severe, complement‐mediated immune hemolytic anemia (DIIHA).
3. Drug‐induced antibodies are detected by direct antiglobulin testing, but a complete medication history is the key to diagnosis.
4. Management of drug‐induced hemolytic anemia involves immediate discontinuation of the culprit medication, supportive care, and potentially corticosteroids, plasmapheresis, and/or hemodialysis to expedite removal of the offending agent.
5. EHR interoperability may provide timely access to important health information across different hospitals, expedite health information exchange, and reduce adverse patient outcomes that stem from communication delays.

This case was submitted anonymously to AHRQ WebM&M on July 18, 2014, and was accepted on August 7, 2014. The case and WebM&M commentary were published online on October 26, 2015.[9] This separate commentary on the same case was later submitted to the Journal of Hospital Medicine on September 2, 2015, accepted on November 24, 2015, and published on January 22, 2016. The 2 publications are written by different authors, and although they reference the same case, they make different but valuable points.