Emergency Medicine

A 22-year old man with no cardiac history presented to our emergency department after 5 days of dyspnea, cough, vomiting, and sharp intermittent epigastric pain. He used marijuana chronically and had inhaled it in unusually high amounts for several days before the onset of his symptoms.

The physical examination was unremarkable. Diagnostic tests including a complete blood cell count, complete metabolic panel, lipase level, urinalysis, and chest radiography showed no notable abnormalities. A urine drug screen revealed marijuana use.

Given this clinical picture, the question was whether cardiac catheterization was needed. Our young, previously healthy patient lacked risk factors for coronary artery disease and did not present with chest pain. Though dyspnea and epigastric pain are angina equivalents, he did not have the profile of patients commonly presenting with angina. Further, acute marijuana intoxication has been reported to be associated with reversible changes affecting the P and T waves and ST segments.^1,2 The likelihood of critical occlusion of the left anterior descending artery in this patient was deemed low.

PSEUDO-WELLENS SYNDROME

Wellens syndrome is characterized by biphasic or deeply inverted T waves in leads V₂ and V₃, normal precordial R-wave progression, and the absence of pathologic Q waves, in addition to a history of angina and minimal or no elevation of cardiac enzymes in a patient with or without ongoing chest pain.^3,4 This ominous syndrome is associated with critical occlusion of the proximal left anterior descending artery whose natural history is anterior myocardial infarction in the next few days. Stress testing is contraindicated, and urgent catheterization is warranted to prevent progression to myocardial infarction, even in patients without known heart disease or multiple cardiac risk factors.⁵

This case shows that acute marijuana intoxication may present with symptoms typical of Wellens syndrome. Because Wellens syndrome is considered highly specific for impending anterior myocardial infarction, urgent cardiac catheterization typically would be recommended. In this age of increasing use and legalization of marijuana, knowledge of the electrocardiographic findings associated with heavy marijuana use may prevent unnecessary cardiac catheterization procedures, especially in patients at low risk.

A 22-year old man with no cardiac history presented to our emergency department after 5 days of dyspnea, cough, vomiting, and sharp intermittent epigastric pain. He used marijuana chronically and had inhaled it in unusually high amounts for several days before the onset of his symptoms.

The physical examination was unremarkable. Diagnostic tests including a complete blood cell count, complete metabolic panel, lipase level, urinalysis, and chest radiography showed no notable abnormalities. A urine drug screen revealed marijuana use.

Given this clinical picture, the question was whether cardiac catheterization was needed. Our young, previously healthy patient lacked risk factors for coronary artery disease and did not present with chest pain. Though dyspnea and epigastric pain are angina equivalents, he did not have the profile of patients commonly presenting with angina. Further, acute marijuana intoxication has been reported to be associated with reversible changes affecting the P and T waves and ST segments.^1,2 The likelihood of critical occlusion of the left anterior descending artery in this patient was deemed low.

PSEUDO-WELLENS SYNDROME

Wellens syndrome is characterized by biphasic or deeply inverted T waves in leads V₂ and V₃, normal precordial R-wave progression, and the absence of pathologic Q waves, in addition to a history of angina and minimal or no elevation of cardiac enzymes in a patient with or without ongoing chest pain.^3,4 This ominous syndrome is associated with critical occlusion of the proximal left anterior descending artery whose natural history is anterior myocardial infarction in the next few days. Stress testing is contraindicated, and urgent catheterization is warranted to prevent progression to myocardial infarction, even in patients without known heart disease or multiple cardiac risk factors.⁵

This case shows that acute marijuana intoxication may present with symptoms typical of Wellens syndrome. Because Wellens syndrome is considered highly specific for impending anterior myocardial infarction, urgent cardiac catheterization typically would be recommended. In this age of increasing use and legalization of marijuana, knowledge of the electrocardiographic findings associated with heavy marijuana use may prevent unnecessary cardiac catheterization procedures, especially in patients at low risk.

A 22-year old man with no cardiac history presented to our emergency department after 5 days of dyspnea, cough, vomiting, and sharp intermittent epigastric pain. He used marijuana chronically and had inhaled it in unusually high amounts for several days before the onset of his symptoms.

The physical examination was unremarkable. Diagnostic tests including a complete blood cell count, complete metabolic panel, lipase level, urinalysis, and chest radiography showed no notable abnormalities. A urine drug screen revealed marijuana use.

Given this clinical picture, the question was whether cardiac catheterization was needed. Our young, previously healthy patient lacked risk factors for coronary artery disease and did not present with chest pain. Though dyspnea and epigastric pain are angina equivalents, he did not have the profile of patients commonly presenting with angina. Further, acute marijuana intoxication has been reported to be associated with reversible changes affecting the P and T waves and ST segments.^1,2 The likelihood of critical occlusion of the left anterior descending artery in this patient was deemed low.

PSEUDO-WELLENS SYNDROME

Wellens syndrome is characterized by biphasic or deeply inverted T waves in leads V₂ and V₃, normal precordial R-wave progression, and the absence of pathologic Q waves, in addition to a history of angina and minimal or no elevation of cardiac enzymes in a patient with or without ongoing chest pain.^3,4 This ominous syndrome is associated with critical occlusion of the proximal left anterior descending artery whose natural history is anterior myocardial infarction in the next few days. Stress testing is contraindicated, and urgent catheterization is warranted to prevent progression to myocardial infarction, even in patients without known heart disease or multiple cardiac risk factors.⁵

This case shows that acute marijuana intoxication may present with symptoms typical of Wellens syndrome. Because Wellens syndrome is considered highly specific for impending anterior myocardial infarction, urgent cardiac catheterization typically would be recommended. In this age of increasing use and legalization of marijuana, knowledge of the electrocardiographic findings associated with heavy marijuana use may prevent unnecessary cardiac catheterization procedures, especially in patients at low risk.

A 42-year-old man presented with a lump on the side of his left hip, which had developed after he fell on his hip while playing basketball about 2 weeks earlier. He was able to continue playing and finished the game. After the game he noticed a lump, which rapidly increased in size. Significant bruising developed afterwards, and the area was mildly painful. The lump did not interfere with his daily activities, but it was annoying.

THE DIFFERENTIAL DIAGNOSIS

Morel-Lavallée lesion is an uncommon condition resulting from shearing trauma and collection of fluid in the space between deep fatty tissue and superficial fascia.⁶ It is usually the result of severe trauma, as in a motor vehicle accident, but it can also result from sports-related trauma, as in our patient.^6–8 Lateral hip, gluteal, and sacral regions are the most common locations for Morel-Lavallée lesions and are often associated with an underlying fracture.^6,9

Morel-Lavallée lesions usually develop hours or days after trauma, although they may develop weeks or even months later.² Symptoms include bulging, pain, and loss of cutaneous sensation over the affected area. Although ultrasonography can be used, magnetic resonance imaging (MRI) is the gold standard for diagnosis and staging.^6,10 If there is concern for fracture, plain radiography should be performed.

Mellado and Bencardino classified Morel-Lavallée lesions into 6 types based on their morphology, presence or absence of a capsule, signal behavior on MRI, and enhancement pattern.¹⁰ The exact rate of infection in patients with Morel-Lavallée lesions is unknown; however, the risk of infection seems to be highest after surgical intervention or aspiration.^5,6

Another potential complication is fluid reaccumulation, which most often occurs with large lesions (> 50 mL) and lesions with a fibrous capsule or pseudocapsule.⁵ Large lesions can compromise adjacent neurovascular structures, particularly in the extremities.⁵ Potential consequences include dermal necrosis, compartment syndrome, and tissue necrosis.⁵

MANAGEMENT APPROACH

Aspiration of a fluid-filled mass is useful in both diagnosis and management of Morel-Lavallée lesions. Treatment includes watchful waiting; compression and pressure wraps; injection of a sclerosing agent (eg, doxycyline, alcohol); needle aspiration; percutaneous drainage with debridement, irrigation, and suction; and incision and evacuation.⁶

The approach to treatment depends on the stage of the lesion and whether an underlying fracture is present. Depending on the amount of blood and lymphatic products and the acuity of the collected fluid (hours to days post-trauma), aspiration with a large-bore needle (eg, 14 to 22 gauge) may or may not be successful.⁷ In general, traumatic serosanguinous fluid collections are less painful and resolve faster than well-formed coagulated hematomas.

Patients who have a large lesion, significant pain, or decreased range of motion should be referred to an orthopedic surgeon.

Our patient was managed conservatively, and his symptoms completely resolved in 2 months.

A 42-year-old man presented with a lump on the side of his left hip, which had developed after he fell on his hip while playing basketball about 2 weeks earlier. He was able to continue playing and finished the game. After the game he noticed a lump, which rapidly increased in size. Significant bruising developed afterwards, and the area was mildly painful. The lump did not interfere with his daily activities, but it was annoying.

THE DIFFERENTIAL DIAGNOSIS

Morel-Lavallée lesion is an uncommon condition resulting from shearing trauma and collection of fluid in the space between deep fatty tissue and superficial fascia.⁶ It is usually the result of severe trauma, as in a motor vehicle accident, but it can also result from sports-related trauma, as in our patient.^6–8 Lateral hip, gluteal, and sacral regions are the most common locations for Morel-Lavallée lesions and are often associated with an underlying fracture.^6,9

Morel-Lavallée lesions usually develop hours or days after trauma, although they may develop weeks or even months later.² Symptoms include bulging, pain, and loss of cutaneous sensation over the affected area. Although ultrasonography can be used, magnetic resonance imaging (MRI) is the gold standard for diagnosis and staging.^6,10 If there is concern for fracture, plain radiography should be performed.

Mellado and Bencardino classified Morel-Lavallée lesions into 6 types based on their morphology, presence or absence of a capsule, signal behavior on MRI, and enhancement pattern.¹⁰ The exact rate of infection in patients with Morel-Lavallée lesions is unknown; however, the risk of infection seems to be highest after surgical intervention or aspiration.^5,6

Another potential complication is fluid reaccumulation, which most often occurs with large lesions (> 50 mL) and lesions with a fibrous capsule or pseudocapsule.⁵ Large lesions can compromise adjacent neurovascular structures, particularly in the extremities.⁵ Potential consequences include dermal necrosis, compartment syndrome, and tissue necrosis.⁵

MANAGEMENT APPROACH

Aspiration of a fluid-filled mass is useful in both diagnosis and management of Morel-Lavallée lesions. Treatment includes watchful waiting; compression and pressure wraps; injection of a sclerosing agent (eg, doxycyline, alcohol); needle aspiration; percutaneous drainage with debridement, irrigation, and suction; and incision and evacuation.⁶

The approach to treatment depends on the stage of the lesion and whether an underlying fracture is present. Depending on the amount of blood and lymphatic products and the acuity of the collected fluid (hours to days post-trauma), aspiration with a large-bore needle (eg, 14 to 22 gauge) may or may not be successful.⁷ In general, traumatic serosanguinous fluid collections are less painful and resolve faster than well-formed coagulated hematomas.

Patients who have a large lesion, significant pain, or decreased range of motion should be referred to an orthopedic surgeon.

Our patient was managed conservatively, and his symptoms completely resolved in 2 months.

A 42-year-old man presented with a lump on the side of his left hip, which had developed after he fell on his hip while playing basketball about 2 weeks earlier. He was able to continue playing and finished the game. After the game he noticed a lump, which rapidly increased in size. Significant bruising developed afterwards, and the area was mildly painful. The lump did not interfere with his daily activities, but it was annoying.

THE DIFFERENTIAL DIAGNOSIS

Morel-Lavallée lesion is an uncommon condition resulting from shearing trauma and collection of fluid in the space between deep fatty tissue and superficial fascia.⁶ It is usually the result of severe trauma, as in a motor vehicle accident, but it can also result from sports-related trauma, as in our patient.^6–8 Lateral hip, gluteal, and sacral regions are the most common locations for Morel-Lavallée lesions and are often associated with an underlying fracture.^6,9

Morel-Lavallée lesions usually develop hours or days after trauma, although they may develop weeks or even months later.² Symptoms include bulging, pain, and loss of cutaneous sensation over the affected area. Although ultrasonography can be used, magnetic resonance imaging (MRI) is the gold standard for diagnosis and staging.^6,10 If there is concern for fracture, plain radiography should be performed.

Mellado and Bencardino classified Morel-Lavallée lesions into 6 types based on their morphology, presence or absence of a capsule, signal behavior on MRI, and enhancement pattern.¹⁰ The exact rate of infection in patients with Morel-Lavallée lesions is unknown; however, the risk of infection seems to be highest after surgical intervention or aspiration.^5,6

Another potential complication is fluid reaccumulation, which most often occurs with large lesions (> 50 mL) and lesions with a fibrous capsule or pseudocapsule.⁵ Large lesions can compromise adjacent neurovascular structures, particularly in the extremities.⁵ Potential consequences include dermal necrosis, compartment syndrome, and tissue necrosis.⁵

MANAGEMENT APPROACH

Aspiration of a fluid-filled mass is useful in both diagnosis and management of Morel-Lavallée lesions. Treatment includes watchful waiting; compression and pressure wraps; injection of a sclerosing agent (eg, doxycyline, alcohol); needle aspiration; percutaneous drainage with debridement, irrigation, and suction; and incision and evacuation.⁶

The approach to treatment depends on the stage of the lesion and whether an underlying fracture is present. Depending on the amount of blood and lymphatic products and the acuity of the collected fluid (hours to days post-trauma), aspiration with a large-bore needle (eg, 14 to 22 gauge) may or may not be successful.⁷ In general, traumatic serosanguinous fluid collections are less painful and resolve faster than well-formed coagulated hematomas.

Patients who have a large lesion, significant pain, or decreased range of motion should be referred to an orthopedic surgeon.

Our patient was managed conservatively, and his symptoms completely resolved in 2 months.

ANSWER

There is significant diastasis of the pubic symphysis, measuring nearly 4 cm. No obvious fractures of the hip or pelvis are seen, but there is mal­alignment of the rami. There is also evidence of a proximal right femur fracture, although this area is not fully imaged.

Such radiographic findings are typically referred to as an open book pelvic fracture. Usually the result of a shear injury, these fractures are not uncommon and carry an increased risk for pelvic vascular ­injury.

Emergent orthopedic and vascular consults were obtained, and the patient was placed in a pelvic binder to help reduce the distraction and tamponade any potential vascular injuries.

ANSWER

There is significant diastasis of the pubic symphysis, measuring nearly 4 cm. No obvious fractures of the hip or pelvis are seen, but there is mal­alignment of the rami. There is also evidence of a proximal right femur fracture, although this area is not fully imaged.

Such radiographic findings are typically referred to as an open book pelvic fracture. Usually the result of a shear injury, these fractures are not uncommon and carry an increased risk for pelvic vascular ­injury.

Emergent orthopedic and vascular consults were obtained, and the patient was placed in a pelvic binder to help reduce the distraction and tamponade any potential vascular injuries.

ANSWER

There is significant diastasis of the pubic symphysis, measuring nearly 4 cm. No obvious fractures of the hip or pelvis are seen, but there is mal­alignment of the rami. There is also evidence of a proximal right femur fracture, although this area is not fully imaged.

Such radiographic findings are typically referred to as an open book pelvic fracture. Usually the result of a shear injury, these fractures are not uncommon and carry an increased risk for pelvic vascular ­injury.

Emergent orthopedic and vascular consults were obtained, and the patient was placed in a pelvic binder to help reduce the distraction and tamponade any potential vascular injuries.

Case

An Asian man in his third decade, with a medical history of hypertension and hyperlipidemia, and who had recently been involved in a motor vehicle collision (MVC), presented to the ED with a chief complaint of severe bilateral upper and lower extremity weakness. The patient noted that the weakness had begun the previous evening and became progressively worse throughout the night, to the point that he was unable to move any of his extremities on the morning of presentation.

Upon arrival at the ED, the patient was awake, alert, and oriented to self, time, and place; he also spoke in full sentences without distress. He denied fever, chills, difficulty breathing, or preceding viral illness. The patient stated that he was not taking any medications and denied a history of alcohol, tobacco, or drug abuse.

Initial vital signs at presentation were: blood pressure, 141/50 mm Hg; heart rate, 90 beats/min; respiratory rate, 16 breaths/min; and temperature, 97.4°F. Oxygen saturation was 100% on room air. On physical examination, the patient was in no acute distress and had a normal mental status. His pupils were normally reactive and his other cranial nerves were normal. Muscle strength in the upper and lower extremities was 1/5 with 1+ reflexes bilaterally, and there was no sensory deficit. The patient was placed on continuous cardiac monitoring with pulse oximetry.

What is the differential diagnosis for acute extremity weakness or paralysis?

The differential diagnosis for acute symmetrical extremity weakness or paralysis is broad and includes conditions of neurological, inflammatory, and toxic/metabolic etiologies.¹ Neurological diagnoses to consider include acute stroke, specifically of the anterior cerebral or middle cerebral artery territories; Guillain-Barré syndrome; myasthenia gravis; spinal cord compression; and tick paralysis. Acute ischemic or hemorrhagic stroke most frequently presents with unilateral upper or lower extremity weakness accompanied by garbled speech and sensory deficits. Patients who have suffered a brainstem or cerebellar stroke commonly present with alterations of consciousness, visual changes, and ataxia. Posterior circulation strokes are also characterized by crossed neurological deficits, such as motor deficits on one side of the body and sensory deficits on the other.

Spinal Cord Pathology. Signs and symptoms of spinal cord compression or inflammation vary widely depending on the level affected. Motor and sensory findings of spinal cord pathology include muscle weakness, spasticity, hyper- or hyporeflexia, and a discrete level below which sensation is absent or reduced.

Guillain-Barré Syndrome. Patients who have Guillain-Barré syndrome (a disease of the myelin sheaths of the peripheral nerves) often present with complaints of numbness or paresthesias in the extremities.² The condition is characterized by progressive symmetric muscle weakness accompanied by absent or depressed deep tendon reflexes and is typically associated with a recent exposure to an infectious agent such as a viral upper respiratory infection, bacterial infection, or vaccine.

Myasthenia Gravis. Myasthenia gravis is a disease of the neuromuscular junction. It presents with weakness in any muscle group, and the muscles are easily fatigued by repetitive use.

Toxic Exposures. Toxins, such as botulinum, ixovotoxin, nicotine, succinylcholine, and tetrodotoxin, are prominent, though less common, causes of muscular weakness or paralysis. Botulinum toxin acts at the neuromuscular junction. Patients with botulism typically present with a gastrointestinal prodrome of nausea, vomiting, and diarrhea followed by cranial nerve dysfunction and descending muscle weakness.³

Tetrodotoxin, nicotine, and curare-like paralytics act at the motor end plate of the neuromuscular junction to produce neuromuscular blockade with subsequent muscular weakness or paralysis. Similarly, ixovotoxin, the toxin responsible for tick paralysis, causes ascending flaccid paralysis by decreasing the release of acetylcholine at the neuromuscular junction.³

Metabolic and Endocrine Disorders. Conditions such as hypokalemia, hypomagnesemia, and periodic paralysis can also present with neurological complaints such as generalized weakness and paresthesias. Of note, it is important to differentiate true neuromuscular weakness from weakness secondary to limited effort.

Case Continuation

Because of the patient’s history of an MVC, cervical cord compression was considered concerning enough to require exclusion through magnetic resonance imaging (MRI) of the cervical spine. However, upon arrival at the MRI suite, the patient became severely tachypneic and tachycardic, and was unable to tolerate lying flat. He was intubated for impending respiratory failure. Laboratory results from blood drawn prior to transport to MRI were reported immediately after the resuscitation and were notable for the following: potassium, <1.5 mEq/L; bicarbonate, 20 mEq/L; creatine kinase, 889 U/L; ethanol, not detected.

What is hypokalemic periodic paralysis?

Hypokalemic periodic paralysis (HypoKPP) is a syndrome of episodic muscle weakness with concomitant hypokalemia. Familial forms of HypoKPP have been attributed to mutations in genes coding for either calcium or sodium channels.

The nonfamilial form of HypoKPP is attributed to hyperthyroidism and is most often seen in Asian men in the second and third decades of life. The disorder is characterized by acute onset hypokalemia and extremity paralysis with simultaneous hyperthyroid state. It is believed that hypokalemia occurs as a result of intracellular shift of potassium from thyroid-induced hormone sensitization of the Na⁺/K⁺-ATPase rather than a depletion of total body potassium. Acute episodes of paralysis are triggered by high-carbohydrate meals, alcohol consumption, emotional stress, and infection. Paralysis can last from 3 to 96 hours and is accompanied by decreased or absent deep tendon reflexes with normal sensation and mental status.

In the nonfamilial form of HypoKPP, signs of thyrotoxicosis are often present and include tachycardia, moist skin, and hyperthermia, but it may be difficult to specifically recognize this etiology given the patient’s grave clinical condition.⁴ Similar to many significant metabolic and electrolyte disturbances, complications of HypoKPP include dysrhythmia, respiratory failure, and sometimes death.⁵

How should HypoKPP be managed in the ED?

Management of HypoKPP begins with careful assessment of the patient’s airway, breathing, and circulation. Once the patient is stabilized, management of consequential effects of hypokalemia, such as respiratory distress and muscular paralysis, should focus on correcting the electrolyte and endocrine derangements.

Propranolol. If the patient exhibits signs of thyrotoxicosis, initial treatment includes propranolol, a nonselective beta-blocker, which both prevents the intracellular shift of potassium and assists in correcting the underlying hyperthyroid and hypermetabolic state. Although there is no standard propranolol dosing protocol for HypoKPP, some authors suggest that an aggressive dose of 2 mg intravenously (IV) every 10 minutes can shorten the patient’s episode of paralysis to 6 hours.⁶

Potassium Chloride. Administration of potassium chloride to raise the serum potassium to life-sustaining concentrations should be done cautiously through IV infusion of standard doses.⁷ In correcting hypokalemia with potassium, care should be taken to avoid overcorrection, which may subsequently result in rebound hyperkalemia as the total body potassium redistributes. Lower doses of potassium (ie, <50 mEq per dose), are preferred to achieve adequate repletion while avoiding rebound hyperkalemia.⁸

Case Conclusion

The results of thyroid studies that had been added on to the original set of laboratory studies revealed profound hyperthyroidism, with an essentially absent concentration of thyroid-stimulating hormone.

Case

An Asian man in his third decade, with a medical history of hypertension and hyperlipidemia, and who had recently been involved in a motor vehicle collision (MVC), presented to the ED with a chief complaint of severe bilateral upper and lower extremity weakness. The patient noted that the weakness had begun the previous evening and became progressively worse throughout the night, to the point that he was unable to move any of his extremities on the morning of presentation.

Upon arrival at the ED, the patient was awake, alert, and oriented to self, time, and place; he also spoke in full sentences without distress. He denied fever, chills, difficulty breathing, or preceding viral illness. The patient stated that he was not taking any medications and denied a history of alcohol, tobacco, or drug abuse.

Initial vital signs at presentation were: blood pressure, 141/50 mm Hg; heart rate, 90 beats/min; respiratory rate, 16 breaths/min; and temperature, 97.4°F. Oxygen saturation was 100% on room air. On physical examination, the patient was in no acute distress and had a normal mental status. His pupils were normally reactive and his other cranial nerves were normal. Muscle strength in the upper and lower extremities was 1/5 with 1+ reflexes bilaterally, and there was no sensory deficit. The patient was placed on continuous cardiac monitoring with pulse oximetry.

What is the differential diagnosis for acute extremity weakness or paralysis?

The differential diagnosis for acute symmetrical extremity weakness or paralysis is broad and includes conditions of neurological, inflammatory, and toxic/metabolic etiologies.¹ Neurological diagnoses to consider include acute stroke, specifically of the anterior cerebral or middle cerebral artery territories; Guillain-Barré syndrome; myasthenia gravis; spinal cord compression; and tick paralysis. Acute ischemic or hemorrhagic stroke most frequently presents with unilateral upper or lower extremity weakness accompanied by garbled speech and sensory deficits. Patients who have suffered a brainstem or cerebellar stroke commonly present with alterations of consciousness, visual changes, and ataxia. Posterior circulation strokes are also characterized by crossed neurological deficits, such as motor deficits on one side of the body and sensory deficits on the other.

Spinal Cord Pathology. Signs and symptoms of spinal cord compression or inflammation vary widely depending on the level affected. Motor and sensory findings of spinal cord pathology include muscle weakness, spasticity, hyper- or hyporeflexia, and a discrete level below which sensation is absent or reduced.

Guillain-Barré Syndrome. Patients who have Guillain-Barré syndrome (a disease of the myelin sheaths of the peripheral nerves) often present with complaints of numbness or paresthesias in the extremities.² The condition is characterized by progressive symmetric muscle weakness accompanied by absent or depressed deep tendon reflexes and is typically associated with a recent exposure to an infectious agent such as a viral upper respiratory infection, bacterial infection, or vaccine.

Myasthenia Gravis. Myasthenia gravis is a disease of the neuromuscular junction. It presents with weakness in any muscle group, and the muscles are easily fatigued by repetitive use.

Toxic Exposures. Toxins, such as botulinum, ixovotoxin, nicotine, succinylcholine, and tetrodotoxin, are prominent, though less common, causes of muscular weakness or paralysis. Botulinum toxin acts at the neuromuscular junction. Patients with botulism typically present with a gastrointestinal prodrome of nausea, vomiting, and diarrhea followed by cranial nerve dysfunction and descending muscle weakness.³

Tetrodotoxin, nicotine, and curare-like paralytics act at the motor end plate of the neuromuscular junction to produce neuromuscular blockade with subsequent muscular weakness or paralysis. Similarly, ixovotoxin, the toxin responsible for tick paralysis, causes ascending flaccid paralysis by decreasing the release of acetylcholine at the neuromuscular junction.³

Metabolic and Endocrine Disorders. Conditions such as hypokalemia, hypomagnesemia, and periodic paralysis can also present with neurological complaints such as generalized weakness and paresthesias. Of note, it is important to differentiate true neuromuscular weakness from weakness secondary to limited effort.

Case Continuation

Because of the patient’s history of an MVC, cervical cord compression was considered concerning enough to require exclusion through magnetic resonance imaging (MRI) of the cervical spine. However, upon arrival at the MRI suite, the patient became severely tachypneic and tachycardic, and was unable to tolerate lying flat. He was intubated for impending respiratory failure. Laboratory results from blood drawn prior to transport to MRI were reported immediately after the resuscitation and were notable for the following: potassium, <1.5 mEq/L; bicarbonate, 20 mEq/L; creatine kinase, 889 U/L; ethanol, not detected.

What is hypokalemic periodic paralysis?

Hypokalemic periodic paralysis (HypoKPP) is a syndrome of episodic muscle weakness with concomitant hypokalemia. Familial forms of HypoKPP have been attributed to mutations in genes coding for either calcium or sodium channels.

The nonfamilial form of HypoKPP is attributed to hyperthyroidism and is most often seen in Asian men in the second and third decades of life. The disorder is characterized by acute onset hypokalemia and extremity paralysis with simultaneous hyperthyroid state. It is believed that hypokalemia occurs as a result of intracellular shift of potassium from thyroid-induced hormone sensitization of the Na⁺/K⁺-ATPase rather than a depletion of total body potassium. Acute episodes of paralysis are triggered by high-carbohydrate meals, alcohol consumption, emotional stress, and infection. Paralysis can last from 3 to 96 hours and is accompanied by decreased or absent deep tendon reflexes with normal sensation and mental status.

In the nonfamilial form of HypoKPP, signs of thyrotoxicosis are often present and include tachycardia, moist skin, and hyperthermia, but it may be difficult to specifically recognize this etiology given the patient’s grave clinical condition.⁴ Similar to many significant metabolic and electrolyte disturbances, complications of HypoKPP include dysrhythmia, respiratory failure, and sometimes death.⁵

How should HypoKPP be managed in the ED?

Management of HypoKPP begins with careful assessment of the patient’s airway, breathing, and circulation. Once the patient is stabilized, management of consequential effects of hypokalemia, such as respiratory distress and muscular paralysis, should focus on correcting the electrolyte and endocrine derangements.

Propranolol. If the patient exhibits signs of thyrotoxicosis, initial treatment includes propranolol, a nonselective beta-blocker, which both prevents the intracellular shift of potassium and assists in correcting the underlying hyperthyroid and hypermetabolic state. Although there is no standard propranolol dosing protocol for HypoKPP, some authors suggest that an aggressive dose of 2 mg intravenously (IV) every 10 minutes can shorten the patient’s episode of paralysis to 6 hours.⁶

Potassium Chloride. Administration of potassium chloride to raise the serum potassium to life-sustaining concentrations should be done cautiously through IV infusion of standard doses.⁷ In correcting hypokalemia with potassium, care should be taken to avoid overcorrection, which may subsequently result in rebound hyperkalemia as the total body potassium redistributes. Lower doses of potassium (ie, <50 mEq per dose), are preferred to achieve adequate repletion while avoiding rebound hyperkalemia.⁸

Case Conclusion

The results of thyroid studies that had been added on to the original set of laboratory studies revealed profound hyperthyroidism, with an essentially absent concentration of thyroid-stimulating hormone.

Case

An Asian man in his third decade, with a medical history of hypertension and hyperlipidemia, and who had recently been involved in a motor vehicle collision (MVC), presented to the ED with a chief complaint of severe bilateral upper and lower extremity weakness. The patient noted that the weakness had begun the previous evening and became progressively worse throughout the night, to the point that he was unable to move any of his extremities on the morning of presentation.

Upon arrival at the ED, the patient was awake, alert, and oriented to self, time, and place; he also spoke in full sentences without distress. He denied fever, chills, difficulty breathing, or preceding viral illness. The patient stated that he was not taking any medications and denied a history of alcohol, tobacco, or drug abuse.

Initial vital signs at presentation were: blood pressure, 141/50 mm Hg; heart rate, 90 beats/min; respiratory rate, 16 breaths/min; and temperature, 97.4°F. Oxygen saturation was 100% on room air. On physical examination, the patient was in no acute distress and had a normal mental status. His pupils were normally reactive and his other cranial nerves were normal. Muscle strength in the upper and lower extremities was 1/5 with 1+ reflexes bilaterally, and there was no sensory deficit. The patient was placed on continuous cardiac monitoring with pulse oximetry.

What is the differential diagnosis for acute extremity weakness or paralysis?

The differential diagnosis for acute symmetrical extremity weakness or paralysis is broad and includes conditions of neurological, inflammatory, and toxic/metabolic etiologies.¹ Neurological diagnoses to consider include acute stroke, specifically of the anterior cerebral or middle cerebral artery territories; Guillain-Barré syndrome; myasthenia gravis; spinal cord compression; and tick paralysis. Acute ischemic or hemorrhagic stroke most frequently presents with unilateral upper or lower extremity weakness accompanied by garbled speech and sensory deficits. Patients who have suffered a brainstem or cerebellar stroke commonly present with alterations of consciousness, visual changes, and ataxia. Posterior circulation strokes are also characterized by crossed neurological deficits, such as motor deficits on one side of the body and sensory deficits on the other.

Spinal Cord Pathology. Signs and symptoms of spinal cord compression or inflammation vary widely depending on the level affected. Motor and sensory findings of spinal cord pathology include muscle weakness, spasticity, hyper- or hyporeflexia, and a discrete level below which sensation is absent or reduced.

Guillain-Barré Syndrome. Patients who have Guillain-Barré syndrome (a disease of the myelin sheaths of the peripheral nerves) often present with complaints of numbness or paresthesias in the extremities.² The condition is characterized by progressive symmetric muscle weakness accompanied by absent or depressed deep tendon reflexes and is typically associated with a recent exposure to an infectious agent such as a viral upper respiratory infection, bacterial infection, or vaccine.

Myasthenia Gravis. Myasthenia gravis is a disease of the neuromuscular junction. It presents with weakness in any muscle group, and the muscles are easily fatigued by repetitive use.

Toxic Exposures. Toxins, such as botulinum, ixovotoxin, nicotine, succinylcholine, and tetrodotoxin, are prominent, though less common, causes of muscular weakness or paralysis. Botulinum toxin acts at the neuromuscular junction. Patients with botulism typically present with a gastrointestinal prodrome of nausea, vomiting, and diarrhea followed by cranial nerve dysfunction and descending muscle weakness.³

Tetrodotoxin, nicotine, and curare-like paralytics act at the motor end plate of the neuromuscular junction to produce neuromuscular blockade with subsequent muscular weakness or paralysis. Similarly, ixovotoxin, the toxin responsible for tick paralysis, causes ascending flaccid paralysis by decreasing the release of acetylcholine at the neuromuscular junction.³

Metabolic and Endocrine Disorders. Conditions such as hypokalemia, hypomagnesemia, and periodic paralysis can also present with neurological complaints such as generalized weakness and paresthesias. Of note, it is important to differentiate true neuromuscular weakness from weakness secondary to limited effort.

Case Continuation

Because of the patient’s history of an MVC, cervical cord compression was considered concerning enough to require exclusion through magnetic resonance imaging (MRI) of the cervical spine. However, upon arrival at the MRI suite, the patient became severely tachypneic and tachycardic, and was unable to tolerate lying flat. He was intubated for impending respiratory failure. Laboratory results from blood drawn prior to transport to MRI were reported immediately after the resuscitation and were notable for the following: potassium, <1.5 mEq/L; bicarbonate, 20 mEq/L; creatine kinase, 889 U/L; ethanol, not detected.

What is hypokalemic periodic paralysis?

Hypokalemic periodic paralysis (HypoKPP) is a syndrome of episodic muscle weakness with concomitant hypokalemia. Familial forms of HypoKPP have been attributed to mutations in genes coding for either calcium or sodium channels.

The nonfamilial form of HypoKPP is attributed to hyperthyroidism and is most often seen in Asian men in the second and third decades of life. The disorder is characterized by acute onset hypokalemia and extremity paralysis with simultaneous hyperthyroid state. It is believed that hypokalemia occurs as a result of intracellular shift of potassium from thyroid-induced hormone sensitization of the Na⁺/K⁺-ATPase rather than a depletion of total body potassium. Acute episodes of paralysis are triggered by high-carbohydrate meals, alcohol consumption, emotional stress, and infection. Paralysis can last from 3 to 96 hours and is accompanied by decreased or absent deep tendon reflexes with normal sensation and mental status.

In the nonfamilial form of HypoKPP, signs of thyrotoxicosis are often present and include tachycardia, moist skin, and hyperthermia, but it may be difficult to specifically recognize this etiology given the patient’s grave clinical condition.⁴ Similar to many significant metabolic and electrolyte disturbances, complications of HypoKPP include dysrhythmia, respiratory failure, and sometimes death.⁵

How should HypoKPP be managed in the ED?

Management of HypoKPP begins with careful assessment of the patient’s airway, breathing, and circulation. Once the patient is stabilized, management of consequential effects of hypokalemia, such as respiratory distress and muscular paralysis, should focus on correcting the electrolyte and endocrine derangements.

Propranolol. If the patient exhibits signs of thyrotoxicosis, initial treatment includes propranolol, a nonselective beta-blocker, which both prevents the intracellular shift of potassium and assists in correcting the underlying hyperthyroid and hypermetabolic state. Although there is no standard propranolol dosing protocol for HypoKPP, some authors suggest that an aggressive dose of 2 mg intravenously (IV) every 10 minutes can shorten the patient’s episode of paralysis to 6 hours.⁶

Potassium Chloride. Administration of potassium chloride to raise the serum potassium to life-sustaining concentrations should be done cautiously through IV infusion of standard doses.⁷ In correcting hypokalemia with potassium, care should be taken to avoid overcorrection, which may subsequently result in rebound hyperkalemia as the total body potassium redistributes. Lower doses of potassium (ie, <50 mEq per dose), are preferred to achieve adequate repletion while avoiding rebound hyperkalemia.⁸

Case Conclusion

The results of thyroid studies that had been added on to the original set of laboratory studies revealed profound hyperthyroidism, with an essentially absent concentration of thyroid-stimulating hormone.

When a patient presents with suspected venous thromboembolism, ie, deep vein thrombosis or pulmonary embolism, what diagnostic tests are needed to confirm the diagnosis? The clinical signs and symptoms of venous thromboembolism are nonspecific and often difficult to interpret. Therefore, it is essential for clinicians to use a standardized, structured approach to diagnosis that incorporates clinical findings and laboratory testing, as well as judicious use of diagnostic imaging. But while information is important, clinicians must also strive to avoid unnecessary testing, not only to decrease costs, but also to avoid potential harm.

If the diagnosis is confirmed, does the patient need testing for an underlying thrombophilic disorder? Such screening is often considered after a thromboembolic event occurs. However, a growing body of evidence indicates that the results of thrombophilia testing can be misinterpreted and potentially harmful.¹ We need to understand the utility of this testing as well as when and how it should be used. Patients and thrombosis specialists should be involved in deciding whether to perform these tests.

In this article, we provide practical information about how to diagnose venous thromboembolism, including strategies to optimize testing in suspected cases. We also offer guidance on how to decide whether further thrombophilia testing is warranted.

COMMON AND SERIOUS

Venous thromboembolism is a major cause of morbidity and death. Approximately 900,000 cases of pulmonary embolism and deep vein thrombosis occur in the United States each year, causing 60,000 to 300,000 deaths,² with the number of cases projected to double over the next 40 years.³

INITIAL APPROACH: PRETEST PROBABILITY

Given the morbidity and mortality associated with venous thromboembolism, prompt recognition and diagnosis are imperative. Clinical diagnosis alone is insufficient, with confirmed disease found in only 15% to 25% of patients suspected of having venous thromboembolism.^4–8 Therefore, the pretest probability should be coupled with objective testing.

The Wells score shows good discrimination in the outpatient and emergency department settings, but it has been invalidated in the inpatient setting, and thus it should not be used in inpatients.¹⁰

LABORATORY TESTS FOR SUSPECTED VENOUS THROMBOEMBOLISM

Employing an understanding of diagnostic testing is fundamental to identifying patients with venous thromboembolism.

D-dimer is a byproduct of fibrinolysis.

D-dimer testing has very high sensitivity for venous thromboembolism (> 90%) but low specificity (about 50%), and levels can be elevated in a variety of situations such as advanced age, acute inflammation, and cancer.¹⁵ The standard threshold is 500 μg/L, but because the D-dimer level increases with age, some clinicians advocate using an age-adjusted threshold for patients age 50 or older (age in years × 10 μg/L) to increase the diagnostic yield.¹⁶

Of the laboratory tests for D-dimer, the enzyme-linked immunosorbent assay has the highest sensitivity and highest negative predictive value (100%) and may be preferred over the other test methodologies.¹⁷

With its high sensitivity, D-dimer testing is clinically useful for ruling out venous thromboembolism, particularly when the pretest probability is low, but it lacks the specificity required for diagnosing and treating the disease if positive. Thus, it is not useful for ruling in venous thromboembolism. If the patient has a high pretest probability, we can omit D-dimer testing in favor of imaging studies.

Other laboratory tests such as arterial blood gas and brain natriuretic peptide levels have been proposed as markers of pulmonary embolism, but studies suggest they have limited utility in predicting the presence of disease.^18,19

DIAGNOSTIC TESTS FOR DEEP VEIN THROMBOSIS

Ultrasonography

If the pretest probability of deep vein thrombosis is high or a D-dimer test is found to be positive, the next step in evaluation is compression ultrasonography. 

While some guidelines recommend scanning only the proximal leg, many facilities in the United States scan the whole leg, which may reveal distal deep vein thrombosis.²⁰ The clinical significance of isolated distal deep vein thrombosis is unknown, and a selective anticoagulation approach may be used if this condition is discovered. The 2012 and 2016 American College of Chest Physicians (ACCP) guidelines on diagnosis and management of venous thromboembolism address this topic.^20,21

Deep vein thrombosis in the arm should be evaluated in the same manner as in the lower extremities.

Venography

Invasive and therefore no longer often used, venography is considered the gold standard for diagnosing deep vein thrombosis. Computed tomographic (CT) or magnetic resonance (MR) venography is most useful if the patient has aberrant anatomy such as a deformity of the leg, or in situations where the use of ultrasonography is difficult or unreliable, such as in the setting of severe obesity. CT or MR venography may be considered when looking for thrombosis in noncompressible veins of the thorax and abdomen (eg, the subclavian vein, iliac vein, and inferior vena cava) if ultrasonography is negative but clinical suspicion is high. Venous-phase CT angiography is particularly useful in diagnosing deep vein thrombosis in the inferior vena cava and iliac vein when deep vein thrombosis is clinically suspected but cannot be visualized on duplex ultrasonography.

Computed tomography

Imaging is warranted in patients who have a high pretest probability of pulmonary embolism, or in whom the D-dimer assay was positive but the pretest probability was low or moderate.

Once the gold standard, pulmonary angiography is no longer recommended for the initial diagnosis of pulmonary embolism because it is invasive, often unavailable, less sophisticated, and more expensive than noninvasive imaging techniques such as CT angiography. It is still used, however, in catheter-directed thrombolysis.

Thus, multiphasic CT angiography, as guided by pretest probability and the D-dimer level, is the imaging test of choice in the evaluation of pulmonary embolism. It can also offer insight into thrombotic burden and can reveal concurrent or alternative diagnoses (eg, pneumonia).

Ventilation-perfusion scanning

When CT angiography is unavailable or the patient should not be exposed to contrast medium (eg, due to concern for contrast-induced nephropathy or contrast allergy), ventilation-perfusion (V/Q) scanning remains an option for ruling out pulmonary embolism.²²

Anderson et al²³ compared CT angiography and V/Q scanning in a study in 1,417 patients considered likely to have acute pulmonary embolism. Rates of symptomatic pulmonary embolism during 3-month follow-up were similar in patients who initially had negative results on V/Q scanning compared with those who initially had negative results on CT angiography. However, this study used single-detector CT scanners for one-third of the patients. Therefore, the results may have been different if current technology had been used.

Limitations of V/Q scanning include length of time to perform (30–45 minutes), cost, inability to identify other causes of symptoms, and difficulty with interpretation  when other pulmonary pathology is present (eg, lung infiltrate). V/Q scanning is helpful when negative but is often reported based on probability (low, intermediate, or high) and may not provide adequate guidance. Therefore, CT angiography should be used whenever possible for diagnosing pulmonary embolism.

Other tests for pulmonary embolism

Electrocardiography, transthoracic echocardiography, and chest radiography may aid in the search for alternative diagnoses and assess the degree of right heart strain as a sequela of pulmonary embolism, but they do not confirm the diagnosis.

ORDER IMAGING ONLY IF NEEDED

Diagnostic imaging can be optimized by avoiding unnecessary tests that carry both costs and clinical risks.

Most patients in whom acute pulmonary embolism is discovered will not need testing for deep vein thrombosis, as they will receive anticoagulation regardless. Similarly, many patients with acute symptomatic deep vein thrombosis do not need testing for pulmonary embolism with chest CT imaging, as they too will receive anticoagulation regardless.

Therefore, clinicians are encouraged to use diagnostic reasoning while practicing high-value care (including estimating pretest probability and measuring D-dimer when appropriate), ordering additional tests judiciously and only if indicated.

THROMBOEMBOLISM IS CONFIRMED—IS FURTHER TESTING WARRANTED?

Once acute venous thromboembolism is confirmed, key considerations include whether the event was provoked or unprovoked (ie, idiopathic) and whether the patient needs indefinite anticoagulation (eg, after 2 or more unprovoked events).

Was the event provoked or unprovoked?

Even in cases of unprovoked venous thromboembolism, no clear consensus exists as to which patients should be tested for thrombophilia. Experts do advocate, however, that it be done only in highly selected patients and that it be coordinated with the patient, family members, and an expert in this testing. Patients for whom further testing may be considered include those with venous thromboembolism in unusual sites (eg, the cavernous sinus), with warfarin-induced skin necrosis, or with recurrent pregnancy loss.

While screening for malignancy may seem prudent in the case of unexplained venous thromboembolism, the use of CT imaging for this purpose has been found to be of low yield. In one study,²⁴ it was not found to detect additional neoplasms, and it can lead to additional cost and no added benefit for patients.

The American Board of Internal Medicine’s Choosing Wisely campaign strongly recommends consultation with an expert in thrombophilia (eg, a hematologist) before testing.²⁵ Ordering multiple tests in bundles (hypercoagulability panels) is unlikely to alter management, could have a negative clinical impact on patients, and is generally not recommended.

The ‘4 Ps’ approach to testing

• Patient selection
• Pretest counseling
• Proper laboratory interpretation
• Provision of education and advice.

Importantly, testing should be reserved for patients in whom the pretest probability of the thrombophilic disease is moderate to high, such as testing for antiphospholipid antibody syndrome in patients with systemic lupus erythematosus or recurrent miscarriage.

Venous thromboembolism in a patient who is known to have a malignant disease does not typically warrant further thrombophilia testing, as the event was likely a sequela of the malignancy. The evaluation and management of venous thromboembolism with concurrent neoplasm is covered elsewhere.²¹

Thrombophilia testing should be approached the same regardless of whether the venous thromboembolism was diagnosed intentionally or incidentally. First, determine whether the thrombosis was provoked or unprovoked, then order additional tests only if indicated, as recommended. Alternative approaches such as forgoing anticoagulation (but performing serial imaging, if indicated) may be reasonable if the thrombus is deemed clinically irrelevant (eg, nonocclusive, asymptomatic, subsegmental pulmonary embolism in the absence of proximal deep vein thrombosis; isolated distal deep vein thrombosis).^25,27

It is still debatable whether the increasing incidence of asymptomatic pulmonary embolism due to enhanced sensitivity of noninvasive diagnostic imaging warrants a change in diagnostic approach.²⁸

FACTORS TO CONSIDER BEFORE THROMBOPHILIA TESTING

Important factors to consider before testing for thrombophilia are²⁹:

• How will the results affect the anticoagulation plan?
• How may the patient’s clinical status and medications influence the results?
• Has the patient expressed a desire to understand why venous thromboembolism occurred?
• Will the results have a potential impact on the patient’s family members?

How will the results of thrombophilia testing affect anticoagulation management?

Because the goal of any diagnostic test is to find out what type of care the patient needs, clinicians must determine whether knowledge of an underlying thrombophilia will alter the short-term or long-term anticoagulation therapy the patient is receiving for an acute venous thromboembolic event.

As most acute episodes of venous thromboembolism require an initial 3 months of anticoagulation (with the exception of some nonclinically relevant events such as isolated distal deep vein thrombosis without extension on reimaging), testing in the acute setting does not change the short-term management of anticoagulation. Many hospitals have advocated for outpatient-only thrombophilia testing (if testing does occur), as testing in the acute setting may render test results uninterpretable (see What factors can influence thrombophilia testing? below) and can inappropriately affect the long-term management of anticoagulation. We recommend against testing in the inpatient setting.

To determine the duration of anticoagulation, clinicians must balance the risk of recurrent venous thromboembolism and the risk of bleeding. If a patient is at significant risk of bleeding or does not tolerate anticoagulation, clinicians may consider stopping therapy instead of evaluating for thrombophilia. For patients with provoked venous thromboembolism, anticoagulation should generally be limited to 3 months, as the risk of recurrence does not outweigh the risk of bleeding with continued anticoagulation therapy.

Patients with unprovoked venous thromboembolism have a risk of recurrence twice as high as those with provoked venous thromboembolism and generally need a longer duration of anticoagulation.^30,31 Once a patient with an unprovoked venous thromboembolic event has completed the initial 3 months of anticoagulation, a formal risk-benefit evaluation should be performed to determine whether to continue it.

Up to 42% of patients with unprovoked venous thromboembolism may have 1 or more thrombotic disorders, and some clinicians believe that detecting an underlying thrombophilia will aid in decisions regarding duration of therapy.³² However, the risk of recurrent venous thromboembolism in these patients does not differ significantly from that in patients without an underlying thrombophilia.^33–35 As such, it has been suggested that the unprovoked character of the thrombotic event, rather than an underlying thrombophilia, determines the risk of future recurrence and should be used instead of testing to guide the duration of anticoagulation therapy.³²

For more information, see the 2016 ACCP guideline update on antithrombotic therapy for venous thromboembolism.²⁷

What factors can influence the results of thrombophilia testing?

For example, antithrombin is consumed during thrombus formation; therefore, antithrombin levels may be transiently suppressed in acute venous thromboembolism. Moreover, since antithrombin binds to unfractionated heparin, low-molecular-weight heparin, and fondaparinux and mediates their activity as anticoagulants, antithrombin levels may be decreased by heparin therapy.

Similarly, vitamin K antagonists (eg, warfarin) suppress protein C and S activity levels by inhibiting vitamin K epoxide reductase and may falsely indicate a protein C or S deficiency.

Direct oral anticoagulants can cause false-positive results on lupus anticoagulant assays (dilute Russell viper venom time, augmented partial thromboplastin time), raise protein C, protein S, and antithrombin activity levels, and normalize activated protein C resistance assays, leading to missed diagnoses.⁴¹

Since estrogen therapy and pregnancy lead to increases in C4b binding protein, resulting in decreased free protein S, these situations can result in clinicians falsely labeling patients as having congenital protein S deficiency when in fact the patient had a transient reduction in protein S levels.³³

Therefore, to optimize accuracy and interpretation of results, thrombophilia testing should ideally be performed when the patient:

• Is past the acute event and out of the hospital
• Is not pregnant
• Has received the required 3 months of anticoagulation and is off this therapy.

For warfarin, most recommendations say that testing should be performed after the patient has been off therapy for 2 to 6 weeks.⁴² Low-molecular-weight heparins and direct oral anticoagulants should be discontinued for at least 48 to 72 hours, or longer if the patient has kidney impairment, as these medications are renally eliminated.

Genetic tests such as factor V Leiden and prothrombin gene mutation are not affected by these factors and do not require repeat or confirmatory testing.

What if the patient or family wants to understand why an event occurred?

Some experts advocate thrombophilia testing of asymptomatic family members to identify carriers who may need prophylaxis against venous thromboembolism in high-risk situations such as pregnancy, oral contraceptive use, hospitalization, and surgery.²⁹ Asymptomatic family members of a first-degree relative with a history of venous thromboembolism have a 2 times higher risk of an index event.⁴³ Thus, it may be argued that these asymptomatic individuals should receive prophylactic measures in any high-risk situation, based on the family history itself rather than results of thrombophilia testing.

Occasionally, patients and family members want to know the cause of the thrombotic event and want to be tested. In these instances, pretest counseling for the patient and family about the potential implications of testing and shared decision-making between the provider and patient are of utmost importance.²⁹

What is the impact on family members if thrombophilia is diagnosed?

While positive test results can give patients some satisfaction, this knowledge may also cause unnecessary worry, as the patient knows he or she has a hematologic disorder and could possible die of venous thromboembolism.

Thrombophilia testing can have other adverse consequences. For example, while the Genetic Information Nondiscrimination Act of 2008 protects against denial of health insurance benefits based on genetic information, known carriers of thrombophilia may have trouble obtaining life or disability insurance.⁴⁴

Unfortunately, it is not uncommon for thrombophilia testing to be inappropriately performed, interpreted, or followed up. These suboptimal approaches can lead to unnecessary exposure to high-risk therapeutic anticoagulation, excessive durations of therapy, and labeling with an unconfirmed or incorrect diagnosis. Additionally, there are significant costs associated with thrombophilia testing, including the cost of the tests and anticoagulant medications and management of adverse events such as bleeding.

WHAT ARE THE ALTERNATIVES TO THROMBOPHILIA TESTING?

Because discovered thrombophilias (eg, factor V Leiden mutation, prothrombin gene mutation) have not consistently shown a strong correlation with increased recurrence of venous thromboembolism, alternative approaches are emerging to determine the duration of therapy for unprovoked events.

Clinical prediction tools based on patient characteristics and laboratory markers that are more consistently associated with recurrent venous thromboembolism (eg, male sex, persistently elevated D-dimer) have been developed to aid clinicians dealing with this challenging question. Several prediction tools are available:

The “Men Continue and HERDOO2” rule (HERDOO2 = hyperpigmentation, edema, or redness in either leg; D-dimer level ≥ 250 μg/L; obesity with body mass index ≥ 30 kg/m²; or older age, ≥ 65)⁴⁵

The DASH score (D-dimer, age, sex, and hormonal therapy)⁴⁶

The Vienna score,^47,48 at http://cemsiis.meduniwien.ac.at/en/kb/science-research/software/clinical-software/recurrent-vte/.

SUMMARY OF THROMBOPHILIA TESTING RECOMMENDATIONS

Test for thrombophilia only when…

• Discussing with a specialist (eg, hematologist) who has an understanding of thrombophilia
• Using the 4 Ps approach
• A patient requests testing to understand why a thrombotic event occurred, and the patient understands the implications of testing (ie, received counseling) for self and for family
• An expert deems identification of asymptomatic family members important for those who may be carriers of a detected thrombophilia
• The patient with a venous thromboembolic event has completed 3 months of anticoagulation and has been off anticoagulation for the appropriate length of time
• The results will change management.

Forgo thrombophilia testing when…

• A patient has a provoked venous thromboembolic event
• You do not intend to discontinue anticoagulation (ie, anticoagulation is indefinite)
• The patient is in the acute (eg, inpatient) setting
• The patient is on anticoagulants that may render test results uninterpretable
• The patient is pregnant or on oral contraceptives
• Use of alternative patient characteristics and laboratory markers to predict venous thromboembolism recurrence may be an option.

OPTIMIZING THE DIAGNOSIS

With the incidence of venous thromboembolism rapidly increasing, optimizing its diagnosis from both a financial and clinical perspective is becoming increasingly important. Clinicians should be familiar with the use of pretest probability scoring for venous thromboembolism, as well as which diagnostic tests are preferred if further workup is indicated. They should strive to minimize or avoid indiscriminate thrombophilia testing, which may lead to increased healthcare costs and patient exposure to potentially harmful anticoagulation.

Testing for thrombophilia should be based on whether a venous thromboembolic event was provoked or unprovoked. Patients with provoked venous thromboembolism or those receiving indefinite anticoagulation therapy should not be tested for thrombophilia. If testing is being considered in a patient with unprovoked venous thromboembolism, a specialist who is able to implement the 4 Ps approach should be consulted to ensure well-informed, shared decision-making with patients and family members.

When a patient presents with suspected venous thromboembolism, ie, deep vein thrombosis or pulmonary embolism, what diagnostic tests are needed to confirm the diagnosis? The clinical signs and symptoms of venous thromboembolism are nonspecific and often difficult to interpret. Therefore, it is essential for clinicians to use a standardized, structured approach to diagnosis that incorporates clinical findings and laboratory testing, as well as judicious use of diagnostic imaging. But while information is important, clinicians must also strive to avoid unnecessary testing, not only to decrease costs, but also to avoid potential harm.

If the diagnosis is confirmed, does the patient need testing for an underlying thrombophilic disorder? Such screening is often considered after a thromboembolic event occurs. However, a growing body of evidence indicates that the results of thrombophilia testing can be misinterpreted and potentially harmful.¹ We need to understand the utility of this testing as well as when and how it should be used. Patients and thrombosis specialists should be involved in deciding whether to perform these tests.

In this article, we provide practical information about how to diagnose venous thromboembolism, including strategies to optimize testing in suspected cases. We also offer guidance on how to decide whether further thrombophilia testing is warranted.

COMMON AND SERIOUS

Venous thromboembolism is a major cause of morbidity and death. Approximately 900,000 cases of pulmonary embolism and deep vein thrombosis occur in the United States each year, causing 60,000 to 300,000 deaths,² with the number of cases projected to double over the next 40 years.³

INITIAL APPROACH: PRETEST PROBABILITY

Given the morbidity and mortality associated with venous thromboembolism, prompt recognition and diagnosis are imperative. Clinical diagnosis alone is insufficient, with confirmed disease found in only 15% to 25% of patients suspected of having venous thromboembolism.^4–8 Therefore, the pretest probability should be coupled with objective testing.

The Wells score shows good discrimination in the outpatient and emergency department settings, but it has been invalidated in the inpatient setting, and thus it should not be used in inpatients.¹⁰

LABORATORY TESTS FOR SUSPECTED VENOUS THROMBOEMBOLISM

Employing an understanding of diagnostic testing is fundamental to identifying patients with venous thromboembolism.

D-dimer is a byproduct of fibrinolysis.

D-dimer testing has very high sensitivity for venous thromboembolism (> 90%) but low specificity (about 50%), and levels can be elevated in a variety of situations such as advanced age, acute inflammation, and cancer.¹⁵ The standard threshold is 500 μg/L, but because the D-dimer level increases with age, some clinicians advocate using an age-adjusted threshold for patients age 50 or older (age in years × 10 μg/L) to increase the diagnostic yield.¹⁶

Of the laboratory tests for D-dimer, the enzyme-linked immunosorbent assay has the highest sensitivity and highest negative predictive value (100%) and may be preferred over the other test methodologies.¹⁷

With its high sensitivity, D-dimer testing is clinically useful for ruling out venous thromboembolism, particularly when the pretest probability is low, but it lacks the specificity required for diagnosing and treating the disease if positive. Thus, it is not useful for ruling in venous thromboembolism. If the patient has a high pretest probability, we can omit D-dimer testing in favor of imaging studies.

Other laboratory tests such as arterial blood gas and brain natriuretic peptide levels have been proposed as markers of pulmonary embolism, but studies suggest they have limited utility in predicting the presence of disease.^18,19

DIAGNOSTIC TESTS FOR DEEP VEIN THROMBOSIS

Ultrasonography

If the pretest probability of deep vein thrombosis is high or a D-dimer test is found to be positive, the next step in evaluation is compression ultrasonography. 

While some guidelines recommend scanning only the proximal leg, many facilities in the United States scan the whole leg, which may reveal distal deep vein thrombosis.²⁰ The clinical significance of isolated distal deep vein thrombosis is unknown, and a selective anticoagulation approach may be used if this condition is discovered. The 2012 and 2016 American College of Chest Physicians (ACCP) guidelines on diagnosis and management of venous thromboembolism address this topic.^20,21

Deep vein thrombosis in the arm should be evaluated in the same manner as in the lower extremities.

Venography

Invasive and therefore no longer often used, venography is considered the gold standard for diagnosing deep vein thrombosis. Computed tomographic (CT) or magnetic resonance (MR) venography is most useful if the patient has aberrant anatomy such as a deformity of the leg, or in situations where the use of ultrasonography is difficult or unreliable, such as in the setting of severe obesity. CT or MR venography may be considered when looking for thrombosis in noncompressible veins of the thorax and abdomen (eg, the subclavian vein, iliac vein, and inferior vena cava) if ultrasonography is negative but clinical suspicion is high. Venous-phase CT angiography is particularly useful in diagnosing deep vein thrombosis in the inferior vena cava and iliac vein when deep vein thrombosis is clinically suspected but cannot be visualized on duplex ultrasonography.

Computed tomography

Imaging is warranted in patients who have a high pretest probability of pulmonary embolism, or in whom the D-dimer assay was positive but the pretest probability was low or moderate.

Once the gold standard, pulmonary angiography is no longer recommended for the initial diagnosis of pulmonary embolism because it is invasive, often unavailable, less sophisticated, and more expensive than noninvasive imaging techniques such as CT angiography. It is still used, however, in catheter-directed thrombolysis.

Thus, multiphasic CT angiography, as guided by pretest probability and the D-dimer level, is the imaging test of choice in the evaluation of pulmonary embolism. It can also offer insight into thrombotic burden and can reveal concurrent or alternative diagnoses (eg, pneumonia).

Ventilation-perfusion scanning

When CT angiography is unavailable or the patient should not be exposed to contrast medium (eg, due to concern for contrast-induced nephropathy or contrast allergy), ventilation-perfusion (V/Q) scanning remains an option for ruling out pulmonary embolism.²²

Anderson et al²³ compared CT angiography and V/Q scanning in a study in 1,417 patients considered likely to have acute pulmonary embolism. Rates of symptomatic pulmonary embolism during 3-month follow-up were similar in patients who initially had negative results on V/Q scanning compared with those who initially had negative results on CT angiography. However, this study used single-detector CT scanners for one-third of the patients. Therefore, the results may have been different if current technology had been used.

Limitations of V/Q scanning include length of time to perform (30–45 minutes), cost, inability to identify other causes of symptoms, and difficulty with interpretation  when other pulmonary pathology is present (eg, lung infiltrate). V/Q scanning is helpful when negative but is often reported based on probability (low, intermediate, or high) and may not provide adequate guidance. Therefore, CT angiography should be used whenever possible for diagnosing pulmonary embolism.

Other tests for pulmonary embolism

Electrocardiography, transthoracic echocardiography, and chest radiography may aid in the search for alternative diagnoses and assess the degree of right heart strain as a sequela of pulmonary embolism, but they do not confirm the diagnosis.

ORDER IMAGING ONLY IF NEEDED

Diagnostic imaging can be optimized by avoiding unnecessary tests that carry both costs and clinical risks.

Most patients in whom acute pulmonary embolism is discovered will not need testing for deep vein thrombosis, as they will receive anticoagulation regardless. Similarly, many patients with acute symptomatic deep vein thrombosis do not need testing for pulmonary embolism with chest CT imaging, as they too will receive anticoagulation regardless.

Therefore, clinicians are encouraged to use diagnostic reasoning while practicing high-value care (including estimating pretest probability and measuring D-dimer when appropriate), ordering additional tests judiciously and only if indicated.

THROMBOEMBOLISM IS CONFIRMED—IS FURTHER TESTING WARRANTED?

Once acute venous thromboembolism is confirmed, key considerations include whether the event was provoked or unprovoked (ie, idiopathic) and whether the patient needs indefinite anticoagulation (eg, after 2 or more unprovoked events).

Was the event provoked or unprovoked?

Even in cases of unprovoked venous thromboembolism, no clear consensus exists as to which patients should be tested for thrombophilia. Experts do advocate, however, that it be done only in highly selected patients and that it be coordinated with the patient, family members, and an expert in this testing. Patients for whom further testing may be considered include those with venous thromboembolism in unusual sites (eg, the cavernous sinus), with warfarin-induced skin necrosis, or with recurrent pregnancy loss.

While screening for malignancy may seem prudent in the case of unexplained venous thromboembolism, the use of CT imaging for this purpose has been found to be of low yield. In one study,²⁴ it was not found to detect additional neoplasms, and it can lead to additional cost and no added benefit for patients.

The American Board of Internal Medicine’s Choosing Wisely campaign strongly recommends consultation with an expert in thrombophilia (eg, a hematologist) before testing.²⁵ Ordering multiple tests in bundles (hypercoagulability panels) is unlikely to alter management, could have a negative clinical impact on patients, and is generally not recommended.

The ‘4 Ps’ approach to testing

• Patient selection
• Pretest counseling
• Proper laboratory interpretation
• Provision of education and advice.

Importantly, testing should be reserved for patients in whom the pretest probability of the thrombophilic disease is moderate to high, such as testing for antiphospholipid antibody syndrome in patients with systemic lupus erythematosus or recurrent miscarriage.

Venous thromboembolism in a patient who is known to have a malignant disease does not typically warrant further thrombophilia testing, as the event was likely a sequela of the malignancy. The evaluation and management of venous thromboembolism with concurrent neoplasm is covered elsewhere.²¹

Thrombophilia testing should be approached the same regardless of whether the venous thromboembolism was diagnosed intentionally or incidentally. First, determine whether the thrombosis was provoked or unprovoked, then order additional tests only if indicated, as recommended. Alternative approaches such as forgoing anticoagulation (but performing serial imaging, if indicated) may be reasonable if the thrombus is deemed clinically irrelevant (eg, nonocclusive, asymptomatic, subsegmental pulmonary embolism in the absence of proximal deep vein thrombosis; isolated distal deep vein thrombosis).^25,27

It is still debatable whether the increasing incidence of asymptomatic pulmonary embolism due to enhanced sensitivity of noninvasive diagnostic imaging warrants a change in diagnostic approach.²⁸

FACTORS TO CONSIDER BEFORE THROMBOPHILIA TESTING

Important factors to consider before testing for thrombophilia are²⁹:

• How will the results affect the anticoagulation plan?
• How may the patient’s clinical status and medications influence the results?
• Has the patient expressed a desire to understand why venous thromboembolism occurred?
• Will the results have a potential impact on the patient’s family members?

How will the results of thrombophilia testing affect anticoagulation management?

Because the goal of any diagnostic test is to find out what type of care the patient needs, clinicians must determine whether knowledge of an underlying thrombophilia will alter the short-term or long-term anticoagulation therapy the patient is receiving for an acute venous thromboembolic event.

As most acute episodes of venous thromboembolism require an initial 3 months of anticoagulation (with the exception of some nonclinically relevant events such as isolated distal deep vein thrombosis without extension on reimaging), testing in the acute setting does not change the short-term management of anticoagulation. Many hospitals have advocated for outpatient-only thrombophilia testing (if testing does occur), as testing in the acute setting may render test results uninterpretable (see What factors can influence thrombophilia testing? below) and can inappropriately affect the long-term management of anticoagulation. We recommend against testing in the inpatient setting.

To determine the duration of anticoagulation, clinicians must balance the risk of recurrent venous thromboembolism and the risk of bleeding. If a patient is at significant risk of bleeding or does not tolerate anticoagulation, clinicians may consider stopping therapy instead of evaluating for thrombophilia. For patients with provoked venous thromboembolism, anticoagulation should generally be limited to 3 months, as the risk of recurrence does not outweigh the risk of bleeding with continued anticoagulation therapy.

Patients with unprovoked venous thromboembolism have a risk of recurrence twice as high as those with provoked venous thromboembolism and generally need a longer duration of anticoagulation.^30,31 Once a patient with an unprovoked venous thromboembolic event has completed the initial 3 months of anticoagulation, a formal risk-benefit evaluation should be performed to determine whether to continue it.

Up to 42% of patients with unprovoked venous thromboembolism may have 1 or more thrombotic disorders, and some clinicians believe that detecting an underlying thrombophilia will aid in decisions regarding duration of therapy.³² However, the risk of recurrent venous thromboembolism in these patients does not differ significantly from that in patients without an underlying thrombophilia.^33–35 As such, it has been suggested that the unprovoked character of the thrombotic event, rather than an underlying thrombophilia, determines the risk of future recurrence and should be used instead of testing to guide the duration of anticoagulation therapy.³²

For more information, see the 2016 ACCP guideline update on antithrombotic therapy for venous thromboembolism.²⁷

What factors can influence the results of thrombophilia testing?

For example, antithrombin is consumed during thrombus formation; therefore, antithrombin levels may be transiently suppressed in acute venous thromboembolism. Moreover, since antithrombin binds to unfractionated heparin, low-molecular-weight heparin, and fondaparinux and mediates their activity as anticoagulants, antithrombin levels may be decreased by heparin therapy.

Similarly, vitamin K antagonists (eg, warfarin) suppress protein C and S activity levels by inhibiting vitamin K epoxide reductase and may falsely indicate a protein C or S deficiency.

Direct oral anticoagulants can cause false-positive results on lupus anticoagulant assays (dilute Russell viper venom time, augmented partial thromboplastin time), raise protein C, protein S, and antithrombin activity levels, and normalize activated protein C resistance assays, leading to missed diagnoses.⁴¹

Since estrogen therapy and pregnancy lead to increases in C4b binding protein, resulting in decreased free protein S, these situations can result in clinicians falsely labeling patients as having congenital protein S deficiency when in fact the patient had a transient reduction in protein S levels.³³

Therefore, to optimize accuracy and interpretation of results, thrombophilia testing should ideally be performed when the patient:

• Is past the acute event and out of the hospital
• Is not pregnant
• Has received the required 3 months of anticoagulation and is off this therapy.

For warfarin, most recommendations say that testing should be performed after the patient has been off therapy for 2 to 6 weeks.⁴² Low-molecular-weight heparins and direct oral anticoagulants should be discontinued for at least 48 to 72 hours, or longer if the patient has kidney impairment, as these medications are renally eliminated.

Genetic tests such as factor V Leiden and prothrombin gene mutation are not affected by these factors and do not require repeat or confirmatory testing.

What if the patient or family wants to understand why an event occurred?

Some experts advocate thrombophilia testing of asymptomatic family members to identify carriers who may need prophylaxis against venous thromboembolism in high-risk situations such as pregnancy, oral contraceptive use, hospitalization, and surgery.²⁹ Asymptomatic family members of a first-degree relative with a history of venous thromboembolism have a 2 times higher risk of an index event.⁴³ Thus, it may be argued that these asymptomatic individuals should receive prophylactic measures in any high-risk situation, based on the family history itself rather than results of thrombophilia testing.

Occasionally, patients and family members want to know the cause of the thrombotic event and want to be tested. In these instances, pretest counseling for the patient and family about the potential implications of testing and shared decision-making between the provider and patient are of utmost importance.²⁹

What is the impact on family members if thrombophilia is diagnosed?

While positive test results can give patients some satisfaction, this knowledge may also cause unnecessary worry, as the patient knows he or she has a hematologic disorder and could possible die of venous thromboembolism.

Thrombophilia testing can have other adverse consequences. For example, while the Genetic Information Nondiscrimination Act of 2008 protects against denial of health insurance benefits based on genetic information, known carriers of thrombophilia may have trouble obtaining life or disability insurance.⁴⁴

Unfortunately, it is not uncommon for thrombophilia testing to be inappropriately performed, interpreted, or followed up. These suboptimal approaches can lead to unnecessary exposure to high-risk therapeutic anticoagulation, excessive durations of therapy, and labeling with an unconfirmed or incorrect diagnosis. Additionally, there are significant costs associated with thrombophilia testing, including the cost of the tests and anticoagulant medications and management of adverse events such as bleeding.

WHAT ARE THE ALTERNATIVES TO THROMBOPHILIA TESTING?

Because discovered thrombophilias (eg, factor V Leiden mutation, prothrombin gene mutation) have not consistently shown a strong correlation with increased recurrence of venous thromboembolism, alternative approaches are emerging to determine the duration of therapy for unprovoked events.

Clinical prediction tools based on patient characteristics and laboratory markers that are more consistently associated with recurrent venous thromboembolism (eg, male sex, persistently elevated D-dimer) have been developed to aid clinicians dealing with this challenging question. Several prediction tools are available:

The “Men Continue and HERDOO2” rule (HERDOO2 = hyperpigmentation, edema, or redness in either leg; D-dimer level ≥ 250 μg/L; obesity with body mass index ≥ 30 kg/m²; or older age, ≥ 65)⁴⁵

The DASH score (D-dimer, age, sex, and hormonal therapy)⁴⁶

The Vienna score,^47,48 at http://cemsiis.meduniwien.ac.at/en/kb/science-research/software/clinical-software/recurrent-vte/.

SUMMARY OF THROMBOPHILIA TESTING RECOMMENDATIONS

Test for thrombophilia only when…

• Discussing with a specialist (eg, hematologist) who has an understanding of thrombophilia
• Using the 4 Ps approach
• A patient requests testing to understand why a thrombotic event occurred, and the patient understands the implications of testing (ie, received counseling) for self and for family
• An expert deems identification of asymptomatic family members important for those who may be carriers of a detected thrombophilia
• The patient with a venous thromboembolic event has completed 3 months of anticoagulation and has been off anticoagulation for the appropriate length of time
• The results will change management.

Forgo thrombophilia testing when…

• A patient has a provoked venous thromboembolic event
• You do not intend to discontinue anticoagulation (ie, anticoagulation is indefinite)
• The patient is in the acute (eg, inpatient) setting
• The patient is on anticoagulants that may render test results uninterpretable
• The patient is pregnant or on oral contraceptives
• Use of alternative patient characteristics and laboratory markers to predict venous thromboembolism recurrence may be an option.

OPTIMIZING THE DIAGNOSIS

With the incidence of venous thromboembolism rapidly increasing, optimizing its diagnosis from both a financial and clinical perspective is becoming increasingly important. Clinicians should be familiar with the use of pretest probability scoring for venous thromboembolism, as well as which diagnostic tests are preferred if further workup is indicated. They should strive to minimize or avoid indiscriminate thrombophilia testing, which may lead to increased healthcare costs and patient exposure to potentially harmful anticoagulation.

Testing for thrombophilia should be based on whether a venous thromboembolic event was provoked or unprovoked. Patients with provoked venous thromboembolism or those receiving indefinite anticoagulation therapy should not be tested for thrombophilia. If testing is being considered in a patient with unprovoked venous thromboembolism, a specialist who is able to implement the 4 Ps approach should be consulted to ensure well-informed, shared decision-making with patients and family members.

When a patient presents with suspected venous thromboembolism, ie, deep vein thrombosis or pulmonary embolism, what diagnostic tests are needed to confirm the diagnosis? The clinical signs and symptoms of venous thromboembolism are nonspecific and often difficult to interpret. Therefore, it is essential for clinicians to use a standardized, structured approach to diagnosis that incorporates clinical findings and laboratory testing, as well as judicious use of diagnostic imaging. But while information is important, clinicians must also strive to avoid unnecessary testing, not only to decrease costs, but also to avoid potential harm.

If the diagnosis is confirmed, does the patient need testing for an underlying thrombophilic disorder? Such screening is often considered after a thromboembolic event occurs. However, a growing body of evidence indicates that the results of thrombophilia testing can be misinterpreted and potentially harmful.¹ We need to understand the utility of this testing as well as when and how it should be used. Patients and thrombosis specialists should be involved in deciding whether to perform these tests.

In this article, we provide practical information about how to diagnose venous thromboembolism, including strategies to optimize testing in suspected cases. We also offer guidance on how to decide whether further thrombophilia testing is warranted.

COMMON AND SERIOUS

Venous thromboembolism is a major cause of morbidity and death. Approximately 900,000 cases of pulmonary embolism and deep vein thrombosis occur in the United States each year, causing 60,000 to 300,000 deaths,² with the number of cases projected to double over the next 40 years.³

INITIAL APPROACH: PRETEST PROBABILITY

Given the morbidity and mortality associated with venous thromboembolism, prompt recognition and diagnosis are imperative. Clinical diagnosis alone is insufficient, with confirmed disease found in only 15% to 25% of patients suspected of having venous thromboembolism.^4–8 Therefore, the pretest probability should be coupled with objective testing.

The Wells score shows good discrimination in the outpatient and emergency department settings, but it has been invalidated in the inpatient setting, and thus it should not be used in inpatients.¹⁰

LABORATORY TESTS FOR SUSPECTED VENOUS THROMBOEMBOLISM

Employing an understanding of diagnostic testing is fundamental to identifying patients with venous thromboembolism.

D-dimer is a byproduct of fibrinolysis.

D-dimer testing has very high sensitivity for venous thromboembolism (> 90%) but low specificity (about 50%), and levels can be elevated in a variety of situations such as advanced age, acute inflammation, and cancer.¹⁵ The standard threshold is 500 μg/L, but because the D-dimer level increases with age, some clinicians advocate using an age-adjusted threshold for patients age 50 or older (age in years × 10 μg/L) to increase the diagnostic yield.¹⁶

Of the laboratory tests for D-dimer, the enzyme-linked immunosorbent assay has the highest sensitivity and highest negative predictive value (100%) and may be preferred over the other test methodologies.¹⁷

With its high sensitivity, D-dimer testing is clinically useful for ruling out venous thromboembolism, particularly when the pretest probability is low, but it lacks the specificity required for diagnosing and treating the disease if positive. Thus, it is not useful for ruling in venous thromboembolism. If the patient has a high pretest probability, we can omit D-dimer testing in favor of imaging studies.

Other laboratory tests such as arterial blood gas and brain natriuretic peptide levels have been proposed as markers of pulmonary embolism, but studies suggest they have limited utility in predicting the presence of disease.^18,19

DIAGNOSTIC TESTS FOR DEEP VEIN THROMBOSIS

Ultrasonography

If the pretest probability of deep vein thrombosis is high or a D-dimer test is found to be positive, the next step in evaluation is compression ultrasonography. 

While some guidelines recommend scanning only the proximal leg, many facilities in the United States scan the whole leg, which may reveal distal deep vein thrombosis.²⁰ The clinical significance of isolated distal deep vein thrombosis is unknown, and a selective anticoagulation approach may be used if this condition is discovered. The 2012 and 2016 American College of Chest Physicians (ACCP) guidelines on diagnosis and management of venous thromboembolism address this topic.^20,21

Deep vein thrombosis in the arm should be evaluated in the same manner as in the lower extremities.

Venography

Invasive and therefore no longer often used, venography is considered the gold standard for diagnosing deep vein thrombosis. Computed tomographic (CT) or magnetic resonance (MR) venography is most useful if the patient has aberrant anatomy such as a deformity of the leg, or in situations where the use of ultrasonography is difficult or unreliable, such as in the setting of severe obesity. CT or MR venography may be considered when looking for thrombosis in noncompressible veins of the thorax and abdomen (eg, the subclavian vein, iliac vein, and inferior vena cava) if ultrasonography is negative but clinical suspicion is high. Venous-phase CT angiography is particularly useful in diagnosing deep vein thrombosis in the inferior vena cava and iliac vein when deep vein thrombosis is clinically suspected but cannot be visualized on duplex ultrasonography.

Computed tomography

Imaging is warranted in patients who have a high pretest probability of pulmonary embolism, or in whom the D-dimer assay was positive but the pretest probability was low or moderate.

Once the gold standard, pulmonary angiography is no longer recommended for the initial diagnosis of pulmonary embolism because it is invasive, often unavailable, less sophisticated, and more expensive than noninvasive imaging techniques such as CT angiography. It is still used, however, in catheter-directed thrombolysis.

Thus, multiphasic CT angiography, as guided by pretest probability and the D-dimer level, is the imaging test of choice in the evaluation of pulmonary embolism. It can also offer insight into thrombotic burden and can reveal concurrent or alternative diagnoses (eg, pneumonia).

Ventilation-perfusion scanning

When CT angiography is unavailable or the patient should not be exposed to contrast medium (eg, due to concern for contrast-induced nephropathy or contrast allergy), ventilation-perfusion (V/Q) scanning remains an option for ruling out pulmonary embolism.²²

Anderson et al²³ compared CT angiography and V/Q scanning in a study in 1,417 patients considered likely to have acute pulmonary embolism. Rates of symptomatic pulmonary embolism during 3-month follow-up were similar in patients who initially had negative results on V/Q scanning compared with those who initially had negative results on CT angiography. However, this study used single-detector CT scanners for one-third of the patients. Therefore, the results may have been different if current technology had been used.

Limitations of V/Q scanning include length of time to perform (30–45 minutes), cost, inability to identify other causes of symptoms, and difficulty with interpretation  when other pulmonary pathology is present (eg, lung infiltrate). V/Q scanning is helpful when negative but is often reported based on probability (low, intermediate, or high) and may not provide adequate guidance. Therefore, CT angiography should be used whenever possible for diagnosing pulmonary embolism.

Other tests for pulmonary embolism

Electrocardiography, transthoracic echocardiography, and chest radiography may aid in the search for alternative diagnoses and assess the degree of right heart strain as a sequela of pulmonary embolism, but they do not confirm the diagnosis.

ORDER IMAGING ONLY IF NEEDED

Diagnostic imaging can be optimized by avoiding unnecessary tests that carry both costs and clinical risks.

Most patients in whom acute pulmonary embolism is discovered will not need testing for deep vein thrombosis, as they will receive anticoagulation regardless. Similarly, many patients with acute symptomatic deep vein thrombosis do not need testing for pulmonary embolism with chest CT imaging, as they too will receive anticoagulation regardless.

Therefore, clinicians are encouraged to use diagnostic reasoning while practicing high-value care (including estimating pretest probability and measuring D-dimer when appropriate), ordering additional tests judiciously and only if indicated.

THROMBOEMBOLISM IS CONFIRMED—IS FURTHER TESTING WARRANTED?

Once acute venous thromboembolism is confirmed, key considerations include whether the event was provoked or unprovoked (ie, idiopathic) and whether the patient needs indefinite anticoagulation (eg, after 2 or more unprovoked events).

Was the event provoked or unprovoked?

Even in cases of unprovoked venous thromboembolism, no clear consensus exists as to which patients should be tested for thrombophilia. Experts do advocate, however, that it be done only in highly selected patients and that it be coordinated with the patient, family members, and an expert in this testing. Patients for whom further testing may be considered include those with venous thromboembolism in unusual sites (eg, the cavernous sinus), with warfarin-induced skin necrosis, or with recurrent pregnancy loss.

While screening for malignancy may seem prudent in the case of unexplained venous thromboembolism, the use of CT imaging for this purpose has been found to be of low yield. In one study,²⁴ it was not found to detect additional neoplasms, and it can lead to additional cost and no added benefit for patients.

The American Board of Internal Medicine’s Choosing Wisely campaign strongly recommends consultation with an expert in thrombophilia (eg, a hematologist) before testing.²⁵ Ordering multiple tests in bundles (hypercoagulability panels) is unlikely to alter management, could have a negative clinical impact on patients, and is generally not recommended.

The ‘4 Ps’ approach to testing

• Patient selection
• Pretest counseling
• Proper laboratory interpretation
• Provision of education and advice.

Importantly, testing should be reserved for patients in whom the pretest probability of the thrombophilic disease is moderate to high, such as testing for antiphospholipid antibody syndrome in patients with systemic lupus erythematosus or recurrent miscarriage.

Venous thromboembolism in a patient who is known to have a malignant disease does not typically warrant further thrombophilia testing, as the event was likely a sequela of the malignancy. The evaluation and management of venous thromboembolism with concurrent neoplasm is covered elsewhere.²¹

Thrombophilia testing should be approached the same regardless of whether the venous thromboembolism was diagnosed intentionally or incidentally. First, determine whether the thrombosis was provoked or unprovoked, then order additional tests only if indicated, as recommended. Alternative approaches such as forgoing anticoagulation (but performing serial imaging, if indicated) may be reasonable if the thrombus is deemed clinically irrelevant (eg, nonocclusive, asymptomatic, subsegmental pulmonary embolism in the absence of proximal deep vein thrombosis; isolated distal deep vein thrombosis).^25,27

It is still debatable whether the increasing incidence of asymptomatic pulmonary embolism due to enhanced sensitivity of noninvasive diagnostic imaging warrants a change in diagnostic approach.²⁸

FACTORS TO CONSIDER BEFORE THROMBOPHILIA TESTING

Important factors to consider before testing for thrombophilia are²⁹:

• How will the results affect the anticoagulation plan?
• How may the patient’s clinical status and medications influence the results?
• Has the patient expressed a desire to understand why venous thromboembolism occurred?
• Will the results have a potential impact on the patient’s family members?

How will the results of thrombophilia testing affect anticoagulation management?

Because the goal of any diagnostic test is to find out what type of care the patient needs, clinicians must determine whether knowledge of an underlying thrombophilia will alter the short-term or long-term anticoagulation therapy the patient is receiving for an acute venous thromboembolic event.

As most acute episodes of venous thromboembolism require an initial 3 months of anticoagulation (with the exception of some nonclinically relevant events such as isolated distal deep vein thrombosis without extension on reimaging), testing in the acute setting does not change the short-term management of anticoagulation. Many hospitals have advocated for outpatient-only thrombophilia testing (if testing does occur), as testing in the acute setting may render test results uninterpretable (see What factors can influence thrombophilia testing? below) and can inappropriately affect the long-term management of anticoagulation. We recommend against testing in the inpatient setting.

To determine the duration of anticoagulation, clinicians must balance the risk of recurrent venous thromboembolism and the risk of bleeding. If a patient is at significant risk of bleeding or does not tolerate anticoagulation, clinicians may consider stopping therapy instead of evaluating for thrombophilia. For patients with provoked venous thromboembolism, anticoagulation should generally be limited to 3 months, as the risk of recurrence does not outweigh the risk of bleeding with continued anticoagulation therapy.

Patients with unprovoked venous thromboembolism have a risk of recurrence twice as high as those with provoked venous thromboembolism and generally need a longer duration of anticoagulation.^30,31 Once a patient with an unprovoked venous thromboembolic event has completed the initial 3 months of anticoagulation, a formal risk-benefit evaluation should be performed to determine whether to continue it.

Up to 42% of patients with unprovoked venous thromboembolism may have 1 or more thrombotic disorders, and some clinicians believe that detecting an underlying thrombophilia will aid in decisions regarding duration of therapy.³² However, the risk of recurrent venous thromboembolism in these patients does not differ significantly from that in patients without an underlying thrombophilia.^33–35 As such, it has been suggested that the unprovoked character of the thrombotic event, rather than an underlying thrombophilia, determines the risk of future recurrence and should be used instead of testing to guide the duration of anticoagulation therapy.³²

For more information, see the 2016 ACCP guideline update on antithrombotic therapy for venous thromboembolism.²⁷

What factors can influence the results of thrombophilia testing?

For example, antithrombin is consumed during thrombus formation; therefore, antithrombin levels may be transiently suppressed in acute venous thromboembolism. Moreover, since antithrombin binds to unfractionated heparin, low-molecular-weight heparin, and fondaparinux and mediates their activity as anticoagulants, antithrombin levels may be decreased by heparin therapy.

Similarly, vitamin K antagonists (eg, warfarin) suppress protein C and S activity levels by inhibiting vitamin K epoxide reductase and may falsely indicate a protein C or S deficiency.

Direct oral anticoagulants can cause false-positive results on lupus anticoagulant assays (dilute Russell viper venom time, augmented partial thromboplastin time), raise protein C, protein S, and antithrombin activity levels, and normalize activated protein C resistance assays, leading to missed diagnoses.⁴¹

Since estrogen therapy and pregnancy lead to increases in C4b binding protein, resulting in decreased free protein S, these situations can result in clinicians falsely labeling patients as having congenital protein S deficiency when in fact the patient had a transient reduction in protein S levels.³³

Therefore, to optimize accuracy and interpretation of results, thrombophilia testing should ideally be performed when the patient:

• Is past the acute event and out of the hospital
• Is not pregnant
• Has received the required 3 months of anticoagulation and is off this therapy.

For warfarin, most recommendations say that testing should be performed after the patient has been off therapy for 2 to 6 weeks.⁴² Low-molecular-weight heparins and direct oral anticoagulants should be discontinued for at least 48 to 72 hours, or longer if the patient has kidney impairment, as these medications are renally eliminated.

Genetic tests such as factor V Leiden and prothrombin gene mutation are not affected by these factors and do not require repeat or confirmatory testing.

What if the patient or family wants to understand why an event occurred?

Some experts advocate thrombophilia testing of asymptomatic family members to identify carriers who may need prophylaxis against venous thromboembolism in high-risk situations such as pregnancy, oral contraceptive use, hospitalization, and surgery.²⁹ Asymptomatic family members of a first-degree relative with a history of venous thromboembolism have a 2 times higher risk of an index event.⁴³ Thus, it may be argued that these asymptomatic individuals should receive prophylactic measures in any high-risk situation, based on the family history itself rather than results of thrombophilia testing.

Occasionally, patients and family members want to know the cause of the thrombotic event and want to be tested. In these instances, pretest counseling for the patient and family about the potential implications of testing and shared decision-making between the provider and patient are of utmost importance.²⁹

What is the impact on family members if thrombophilia is diagnosed?

While positive test results can give patients some satisfaction, this knowledge may also cause unnecessary worry, as the patient knows he or she has a hematologic disorder and could possible die of venous thromboembolism.

Thrombophilia testing can have other adverse consequences. For example, while the Genetic Information Nondiscrimination Act of 2008 protects against denial of health insurance benefits based on genetic information, known carriers of thrombophilia may have trouble obtaining life or disability insurance.⁴⁴

Unfortunately, it is not uncommon for thrombophilia testing to be inappropriately performed, interpreted, or followed up. These suboptimal approaches can lead to unnecessary exposure to high-risk therapeutic anticoagulation, excessive durations of therapy, and labeling with an unconfirmed or incorrect diagnosis. Additionally, there are significant costs associated with thrombophilia testing, including the cost of the tests and anticoagulant medications and management of adverse events such as bleeding.

WHAT ARE THE ALTERNATIVES TO THROMBOPHILIA TESTING?

Because discovered thrombophilias (eg, factor V Leiden mutation, prothrombin gene mutation) have not consistently shown a strong correlation with increased recurrence of venous thromboembolism, alternative approaches are emerging to determine the duration of therapy for unprovoked events.

Clinical prediction tools based on patient characteristics and laboratory markers that are more consistently associated with recurrent venous thromboembolism (eg, male sex, persistently elevated D-dimer) have been developed to aid clinicians dealing with this challenging question. Several prediction tools are available:

The “Men Continue and HERDOO2” rule (HERDOO2 = hyperpigmentation, edema, or redness in either leg; D-dimer level ≥ 250 μg/L; obesity with body mass index ≥ 30 kg/m²; or older age, ≥ 65)⁴⁵

The DASH score (D-dimer, age, sex, and hormonal therapy)⁴⁶

The Vienna score,^47,48 at http://cemsiis.meduniwien.ac.at/en/kb/science-research/software/clinical-software/recurrent-vte/.

SUMMARY OF THROMBOPHILIA TESTING RECOMMENDATIONS

Test for thrombophilia only when…

• Discussing with a specialist (eg, hematologist) who has an understanding of thrombophilia
• Using the 4 Ps approach
• A patient requests testing to understand why a thrombotic event occurred, and the patient understands the implications of testing (ie, received counseling) for self and for family
• An expert deems identification of asymptomatic family members important for those who may be carriers of a detected thrombophilia
• The patient with a venous thromboembolic event has completed 3 months of anticoagulation and has been off anticoagulation for the appropriate length of time
• The results will change management.

Forgo thrombophilia testing when…

• A patient has a provoked venous thromboembolic event
• You do not intend to discontinue anticoagulation (ie, anticoagulation is indefinite)
• The patient is in the acute (eg, inpatient) setting
• The patient is on anticoagulants that may render test results uninterpretable
• The patient is pregnant or on oral contraceptives
• Use of alternative patient characteristics and laboratory markers to predict venous thromboembolism recurrence may be an option.

OPTIMIZING THE DIAGNOSIS

With the incidence of venous thromboembolism rapidly increasing, optimizing its diagnosis from both a financial and clinical perspective is becoming increasingly important. Clinicians should be familiar with the use of pretest probability scoring for venous thromboembolism, as well as which diagnostic tests are preferred if further workup is indicated. They should strive to minimize or avoid indiscriminate thrombophilia testing, which may lead to increased healthcare costs and patient exposure to potentially harmful anticoagulation.

Testing for thrombophilia should be based on whether a venous thromboembolic event was provoked or unprovoked. Patients with provoked venous thromboembolism or those receiving indefinite anticoagulation therapy should not be tested for thrombophilia. If testing is being considered in a patient with unprovoked venous thromboembolism, a specialist who is able to implement the 4 Ps approach should be consulted to ensure well-informed, shared decision-making with patients and family members.

Ticks are responsible for most vector-borne infections in the United States. Most infections occur between April and October, when tick populations peak.¹ However, infections can occur year-round.^2,3

Tick bites are often unnoticed because the ticks are small when they are at the infective stage of their life cycle, and their attachment is characteristically painless and often in intertriginous body sites.¹ Therefore, absence of a known tick bite never precludes the diagnosis of a tickborne infection.^1,4,5

Although rural outdoor activities are recognized risk factors, tickborne infections also occur in urban areas.⁶ Thus, the lack of classic epidemiologic clues does not rule out a diagnosis of tickborne infection. 

In most cases, tickborne illnesses present with nonspecific symptoms such as fever, malaise, headache, nausea, and myalgia. Accurate diagnosis of tickborne diseases can be challenging due to the similar clinical manifestations and overlapping geographic distributions of potential tick vectors.¹

This review summarizes the epidemiology, clinical features, treatment, and prevention of the most prevalent non-Lyme tickborne diseases of the United States: Rocky Mountain spotted fever (RMSF), other spotted fever group rickettsial (SFGR) infections, ehrlichiosis, babesiosis, tickborne relapsing fever, Borrelia miyamotoi infection, southern tick-associated rash illness (STARI), tularemia, and tickborne viral infections.

ROCKY MOUNTAIN SPOTTED FEVER

Dermacentor variabilis, the American dog tick, is the major vector in the southern and eastern United States, and D andersoni, the Rocky Mountain wood tick, is the most common vector in the western United States.^4,7,8Rhipicephalus sanguineus, the brown dog tick, has also been found to transmit RMSF in Arizona.^9,10

While most infections in humans are transmitted by tick bite, rare cases of RMSF are contracted through exposure to infective tick hemolymph during tick removal, parenteral inoculation or infectious aerosols in laboratory settings, and blood transfusion.^7,8

RMSF is both the most common and the most likely cause of death among rickettsial infections in the United States.^4,7,8 Most cases occur in children ages 5 to 9.^10,11 The case-fatality rate is over 20% without antimicrobial therapy but less than 1% with timely and appropriate antibiotic treatment.^7,8

Clinical manifestations of Rocky Mountain spotted fever

RMSF is transmitted after only 2 to 20 hours of tick attachment, and symptoms begin 3 to 12 days after inoculation.^1,7,8 Unlike many other species that cause SFGR infection, R rickettsii does not cause an eschar at the site of inoculation.^7,12

The classic triad of RMSF is fever, headache, and a rash. This triad is present in only 3% of early infections, but the prevalence increases to 60% to 70% by 2 weeks after the tick bite.^1,7 Other common initial symptoms include generalized malaise, weakness, and myalgia.^7,8,12 Gastrointestinal symptoms are common, and RMSF can be misdiagnosed as gastroenteritis, particularly in children.⁸

A rash usually occurs. It is due to systemic vasculitis and endothelial injury and often presents 2 to 5 days after the onset of fever, which can delay diagnosis.^7,12,13 It usually progresses from macular to petechial and begins on the ankles, forearms, and wrists, spreading centripetally to the trunk and face and often including the palms and soles.⁷ Large areas of ecchymosis, ulceration, and (uncommonly) gangrene may occur as lesions coalesce.^7,8 The 10% of patients who do not develop a rash (“spotless” fever) tend to have a poorer prognosis due to delayed diagnosis.⁸

Risk factors for severe disease include delay or lack of appropriate treatment, extremes of age, Native American descent, glucose-6-phosphate dehydrogenase deficiency, and immunocompromised states.^1,10,11,13 Complications from the widespread Rickettsia-induced vasculitis may include a septic or toxic shock-like syndrome and neurovascular, cardiac, respiratory, and renal damage.^7,11 Without appropriate therapy, death occurs 7 to 15 days after symptom onset.⁸

Laboratory evaluation may reveal thrombocytopenia and anemia.⁷ Leukocytosis or leukopenia may be present.⁸ Hyponatremia, elevated aminotransferase levels, elevated creatine kinase levels, prolonged coagulation times, and decreased fibrinogen may also be present.^7,8

Diagnosis of Rocky Mountain spotted fever

No diagnostic studies are available for the acute phase of RMSF. Therefore, a high suspicion of RMSF is essential, and treatment should be started as soon as RMSF is suspected. Confirmatory testing can retrospectively validate a clinical diagnosis.^4,7,11

Serologic testing with an immunofluorescence antibody assay remains the principal diagnostic test for RMSF, and paired testing (during the acute and convalescent phases) has a sensitivity of 94%.⁴ A 4-fold or greater increase in antibody titer (with a minimum titer of 1:64) between acute and convalescent samples is considered diagnostic of acute infection.^4,7,8 Serology is often negative early in the disease course.^4,7,8 The assay cross-reacts with other SFGR species, however.^4,8

Amplification of R rickettsii DNA by polymerase chain reaction (PCR) from blood or biopsy sites can be done in some research settings, but its utility is limited because of low sensitivity early in the course of the infection.^4,7

Immunohistochemical staining of a skin biopsy or autopsy specimen is a highly specific diagnostic test performed at a limited number of laboratories, though it has a sensitivity of only 60% to 92%.^4,7,8

Cell culture can also be performed, but only in biosafety level 3 (scale of 1 to 4) laboratories.¹

Treatment of Rocky Mountain spotted fever

Prompt initiation of antibiotic therapy greatly improves prognosis.^1,13,14

Doxycycline for 7 days is the treatment of choice for RMSF, including in pregnant patients with life-threatening disease and in children.^4,7,8,15,16

Tetracycline can also be used.

Chloramphenicol is an alternative treatment for pregnant patients with mild to moderate disease or those patients with a severe hypersensitivity reaction to doxycycline.^{1,4,7,9,15,16} In the United States, chloramphenicol is currently available only in an intravenous formulation.

Fever typically subsides within 24 to 48 hours of starting treatment.^4,8 Failure to clinically improve within 48 hours suggests an alternative diagnosis.^1,4 Long-term complications of severe infection may include hearing loss, blindness, and amputation of digits or extremities due to gangrene.^1,8 Persistence of disease beyond acute infection has not been observed.¹

OTHER SPOTTED FEVER GROUP RICKETTSIAl INFECTIONS

Both infections are characterized by an inoculation eschar. Symptoms include fever, headache, myalgia, and regional lymphadenopathy.¹ Rash (most often maculopapular or vesicopustular) is characteristic of R parkeri, but it is not common in Rickettsia species 364D rickettsiosis.^17,18 Mild thrombocytopenia, leukopenia, and elevated aminotransferase levels are common in R parkeri infection.¹ Both infections appear to be milder than RMSF.

EHRLICHIOSES: EHRLICHIOSIS AND ANAPLASMOSIS

“Ehrlichiosis” is the generic name for infections caused by both the Ehrlichia and Anaplasma genera,^19,20 which are small, gram-negative obligate intracellular bacterial pathogens.²¹ In the United States, infections are most commonly caused by A phagocytophilum, the causative organism of human granulocytic anaplasmosis (HGA) (Table 4), and E chaffeensis, the causative organism of human monocytic ehrlichiosis (HME) (Table 5). The incidence rates of these 2 infections have increased over the past decade, in part due to increased clinical awareness and improved diagnostic capabilities.^3,22,23

E ewingii (Table 6) and E muris-like agent (Table 7) are lesser known causes of human ehrlichiosis in the United States.^20,23–25 Initially, E ewingii was believed to primarily affect immunocompromised patients, but it was later recognized in immunocompetent hosts.²³E muris-like agent was first discovered as a cause of infection in 2009, and cases have been limited to Wisconsin and Minnesota.^24,25

Human granulocytic anaplasmosis. A phagocytophilum is transmitted by Ixodes scapularis (the deer tick or blacklegged tick) in the northeastern and upper-midwestern regions of the United States, and I pacificus (the western blacklegged tick) along the northern Pacific coast.^1,19,20,26 The 6 states accounting for most cases are New York, Connecticut, Massachusetts, Rhode Island, Minnesota, and Wisconsin.²⁷ The white-footed mouse serves as the primary reservoir for A phagocytophilum, and humans are an accidental, “dead-end” host.²¹ Cases have also been reported to be transmitted via blood transfusion and transplacentally.^20,26,28,29

Clinical manifestations of ehrlichiosis

After an incubation time of 5 to 21 days, ehrlichiosis typically presents as a febrile viral-like illness with nonspecific symptoms that include fever, chills, sweats, myalgia, headache, malaise, and cough.^1,26,27,31

Gastrointestinal symptoms, arthralgia, photophobia, and nervous system involvement may also occur.^1,20,29,32 Gastrointestinal symptoms tend to be more common in HME than HGA.²⁰

Rash occurs in up to one-third of patients with HME, but it is rare in HGA.^4,19,20,27 HME presents with more central nervous system involvement (such as meningitis or seizures) than HGA, in which central nervous system involvement is rare.

Severe complications of HME and HGA occur in a minority of cases and may include acute respiratory distress syndrome, renal failure, disseminated intravascular coagulopathy, and spontaneous hemorrhage.¹⁹ In general, HME is more severe than HGA and is more likely to progress to fulminant toxic or septic shocklike syndrome in rare instances.¹⁹

Laboratory tests may reveal leukopenia, lymphopenia, thrombocytopenia, and elevated liver-associated enzyme levels.^1,19,20,26 Anemia and hyponatremia may also be present.^4,30

Diagnosis of ehrlichiosis

The most rapid diagnostic method is examination of Wright- or Giemsa-stained peripheral blood smears for morulae, which are cytoplasmic intravacuolar inclusions of bacteria within leukocytes.²⁰ However, its sensitivity is as low as 20% and declines even further after the first week of infection.^4,20

PCR testing is the most sensitive and rapid tool available during acute infection.^{1,20,26,30,31} However, due to waning of the bacteremic phase, its sensitivity decreases after the first week of infection and after treatment is started.^19,20

Serologic detection of antibodies with an indirect immunofluorescence assay is the most frequently used test for diagnosis of ehr­lichiosis, and paired serology demonstrating seroconversion (at least a 4-fold increase in titer, with a minimal titer of 1:64) is most sensitive (82% to 100%).^4,19,20,26 Cross-reactivity can occur, so testing for antibodies to both A phagocytophilum and E chaffeensis might assist in a more accurate diagnosis in areas where tick vectors overlap.^4,19,20,26

HGA and HME can be isolated through cell culture in blood or cerebrospinal fluid. However, this is labor-intensive and performed in only a few specialized laboratories.^{4,19,20,27,31}

Treatment of ehrlichiosis

If ehrlichiosis is suspected, treatment should not be delayed; the disease can be life-threatening and the ability to diagnose acute infection is often limited.^20,26,32

Doxycycline is the treatment of choice, even in pregnant patients with severe infection and in children.^1,19,26,27 Antibiotics are given for 5 to 10 days and continued for at least 3 days after the fever subsides.^{19,20,26,27,30} In HGA, a 10-day course of doxycycline is recommended to also provide the appropriate length of treatment for Borrelia burgdorferi.^1,31

Rifampin is an alternative for those with severe tetracycline allergy, as well as those with mild to moderate infection during pregnancy.^{1,20,26,29–32}

Fever typically resolves within 24 to 48 hours of starting treatment, and persistence of fever over 48 hours after starting antibiotics suggests an alternative diagnosis or possible coinfection.^{1,4,19,20,26,27,30,32}

Persistence of chronic A phagocytophilum or E chaffeensis infection in humans beyond 2 months has not been demonstrated.^20,26,30,33 Therefore, antibiotic treatment beyond the acute stage of infection is not indicated.³⁰ Long-term prognosis is favorable, and patients are expected to make a full recovery.^26,30

BABESIOSIS

Babesiosis occurs in the northeastern and upper midwestern states, with most cases reported in Massachusetts, Connecticut, Rhode Island, New York, New Jersey, Minnesota, and Wisconsin.^{31,32,34–36} Outbreaks have also been documented in Washington, California, and Missouri.^31,32,35 The spread mimics that of Lyme disease, though it can be slower.^34,36–39

Most cases in the Northeast and upper Midwest are caused by Babesia microti, while Babesia duncani has sporadically caused disease along the Pacific coast and Babesia divergens has been found in the Midwest and Northwest.^34,36,39

Though babesiosis is usually a tickborne illness, it can also be transmitted through blood transfusion and, rarely, transplacental spread.^{31,32,34,36,39–41} The I scapularis tick is the host vector for Babesia microti, and transmission of disease requires 24 to 72 hours of attachment to a host.^34,35 The primary reservoir for Babesia microti is the white-footed mouse, and humans are accidental hosts.^{32,34–36,39}

Clinical manifestations of babesiosis

Babesia species cause illness by lysing erythrocytes, with resultant cytokine release.³⁴

Symptoms typically appear 1 to 4 weeks after inoculation, after which most cases present as a viral-like illness with gradual onset of fever, chills, sweats, fatigue, malaise, headache, arthralgia, myalgia, nausea, anorexia, and nonproductive cough.^{32,34–36,39}

Physical findings may include splenomegaly, hepatomegaly, jaundice, petechiae, and ecchymosis.^{32,34–36,39} Rash is seldom present and is not a characteristic feature of babesiosis.^35,36

Laboratory features may include thrombocytopenia, hemolytic anemia, and elevated liver enzyme levels.^32,34,36,39

Severe disease can occur in elderly, immunocompromised, or splenectomized individuals and can be life-threatening.^34,39 Complications of severe infection can include acute respiratory distress syndrome, diffuse intravascular coagulation, and liver or renal failure.^{31,32,34–36,39} Splenic infarction or rupture may occur at lower levels of parasitemia in those without other manifestations of severe disease.³¹ The course can be prolonged and relapsing despite standard antibiotic therapy, typically in the setting of severe immunocompromise.^32,34,42,43 Death occurs in up to 10% of severe cases.³⁴

Diagnosis of babesiosis

Babesiosis should be considered if a patient presents with a febrile illness and nonspecific symptoms and comes from an endemic area or has received a blood transfusion within 6 months.^34,35

The diagnosis of babesiosis is most commonly made by finding the intraerythrocytic ring form of the organism (trophozoite) on Giemsa- or Wright-stained thin blood smears.^34,36,39Babesia can be distinguished from Plasmodia (the agent of malaria) by the rare presence of tetrads of merozoites arranged in a cross-like pattern (the Maltese cross); the absence of hemozoin (brownish deposits) in the ring form; and the occasional presence of extracellular ring forms.^34,36

The level of parasitemia (representing the number of parasites per microliter of blood) is generally between 1% and 10%, although it can be as high as 80%.^36,39 Because parasitemia is often low early in disease (< 1%), multiple blood smears should be examined.^34–36,39

Several real-time PCR assays are available to detect low-grade Babesia microti parasitemia in patients with negative blood smears during early infection.³¹ These assays have high diagnostic sensitivity and specificity and do not cross-react with other Babesia or Plasmodium species.^34–36,39

Paired serology (immunoglobulin G) can confirm infection, although antibody may be absent early in the course of illness.^{31,34–36,39}

Treatment of babesiosis

Current guidelines recommend antimicrobial therapy only for patients with symptoms and positive test results for Babesia.³² Treatment of asymptomatic patients should additionally be considered if parasitemia (not positive PCR or serology) persists for 3 months or longer.^{32,34–36,39}

For mild to moderate babesiosis, the combination of oral atovaquone and azithromycin for 7 to 10 days has similar efficacy and a lower incidence of adverse effects than clindamycin plus quinine.^31,32,34,44 For immunocompromised patients, higher doses of azithromycin can be used.^31,32

For severe babesiosis or those with risk factors for severe disease, intravenous clindamycin and oral quinine are recommended for 7 to 10 days based on expert opinion.^{31,32,34–36,39,43} Adverse effects of this regimen include diarrhea, tinnitus, and hearing deficits.^35,39 If necessary, intravenous quinidine can be used, but the patient should receive cardiac monitoring for possible prolongation of the QT interval.^34,39 As quinine therapy is often interrupted due to the above side effects, alternative regimens such as intravenous azithromycin or clindamycin in combination with oral atovaquone should be considered for severe cases.³¹ However, these regimens are not well studied.³¹

Partial or complete exchange transfusion of whole blood or packed red blood cells should be considered in patients with a high level of parasitemia (≥ 10%), severe anemia (hemoglobin < 10 g/dL), or renal, hepatic, or pulmonary compromise.^{31,32,34–36,39} In critically ill patients, parasitemia should be monitored daily until it has decreased to less than 5%.^32,34,39

Generally, symptoms improve within 48 hours of antimicrobial therapy initiation; however, parasitemia may take up to 3 months to resolve.^32,34,39 In severely immunocompromised patients, babesiosis may persist or relapse despite appropriate therapy.^34,39,42,43 In these cases, at least 6 weeks of antimicrobial therapy is recommended, including 2 weeks of therapy after Babesia organisms are no longer seen on blood smear.^{31,33,36,39,42}

TICKBORNE RELAPSING FEVER

The illness is transmitted by either ticks or body lice. The tick-borne illness is caused by spirochetes of the genus Borrelia and transmitted to humans by the bite of an infected Ornithodoros soft tick.⁴⁵ Approximately 70% of reported cases in the United States occur in California, Washington, and Colorado.⁴⁶ Most cases are caused by Borrelia hermsii and are linked to sleeping in rodent-infested cabins in mountainous areas.⁴⁶ Remarkably, tick-borne borreliae are transmitted within about 30 seconds of tick attachment.^47,48

The hallmark of tickborne relapsing fever is febrile episodes lasting 3 to 5 days, with relapses after 5 to 7 days of apparent recovery.⁴⁹ If untreated, several episodes of fever and nonspecific symptoms will occur before illness resolves spontaneously. Overall mortality rates are very low (< 5%).⁵⁰

Laboratory confirmation of tickborne relapsing fever is made by detecting spirochetes in a blood smear during a febrile episode or serologic antibody confirmation. However, serologic testing is unhelpful in the acute setting and can yield false-positive results with prior exposure to other Borrelia species (eg, Lyme disease) or other spirochetes. Serologic antibody testing with a 4-fold increase between acute and convalescent samples or PCR can aid in diagnosis, though the latter is available only in research settings.⁴⁷

The preferred treatment regimen for adults is an oral tetracycline for 10 days. Erythromycin is recommended when tetracyclines are contraindicated.⁵¹

When starting treatment, all patients should be monitored closely for the Jarisch-Herxheimer reaction (rigors, hypotension, and high fevers), which develops in over 50% of cases as a result of rapid spirochetal killing and massive cytokine release.⁵²

BORRELIA MIYAMOTOI INFECTION

The most common clinical manifestations are similar to other tickborne relapsing fever infections, although a true “relapsing fever” itself is not usually present.⁵³ The characteristic erythema migrans rash often found in Lyme disease is typically absent in B miyamotoi infection; however, when present, it should prompt investigation into coinfection.⁵⁴ Cases of meningoencephalitis have been reported in immunosuppressed hosts.⁵⁵

There is currently no validated test available for diagnosis of B miyamotoi; however, PCR and serology are available in a few specialized laboratories.^31,53

The treatment of choice is doxycycline for 2 to 4 weeks. Amoxicillin and ceftriaxone also appear effective.⁵³

SOUTHERN TICK-ASSOCIATED RASH ILLNESS

Infection can present similarly to Lyme disease with an erythema migrans-like rash and associated flulike symptoms, although systemic symptoms and multiple erythema migrans lesions are less likely with STARI. Also, the erythema migrans-like lesions tend to be smaller and more likely to have central clearing than those in Lyme disease.⁵⁷ Nevertheless, it is difficult to distinguish the 2 illnesses, especially in mid-Atlantic states such as Maryland or Virginia, where both diseases coexist. The most reliable method of distinguishing STARI from Lyme disease is demonstrating that the patient was bitten by a Lone Star tick rather than an Ixodes tick. Numerous questions remain unanswered about the causative organism, pathophysiology, definitive diagnosis, geographic range of illness, and most effective treatment for STARI.

Most reported cases have responded promptly to doxycycline, though it is not known whether antibiotic treatment is necessary.⁵⁸

TULAREMIA

Ticks are thought to be the most important vectors, and most cases occur in the south-central United States.⁵⁹ The geographic distribution of disease is gradually shifting northward due to spread of the major tick vectors, A americanum, D variabilis, and D andersoni. Approximately 100 to 200 cases of tularemia are diagnosed each year in the United States, with most concentrated in Kansas, Oklahoma, Missouri, and Arkansas.⁶⁰

Humans can acquire F tularensis by several routes, and the route of infection ultimately dictates the clinical syndrome. Ulceroglandular and glandular forms of the disease are the most common in the United States, and both frequently result from a tick bite. A few days after tick exposure, an erythematous, often painful papuloulcerative lesion with a central eschar manifests at the site of the tick bite. Additional symptoms may include fever, chills, headache, myalgia, malaise, and suppurative lymphadenitis.⁶¹

Diagnosis can be made by identifying F tularensis in blood, fluid, or tissue culture performed under biosafety level 3 conditions; however, serology is used in most cases.⁶²

Streptomycin and gentamicin are considered drugs of choice and should be continued for at least 10 days. For relatively mild disease, oral doxycycline or ciprofloxacin can be considered for at least 14 days, although the latter is not approved for treatment.^59,63

TICKBORNE VIRAL INFECTIONS

Powassan virus, an uncommon flavivirus, is found in the Great Lakes region and northeast United States. In the Great Lakes region, I cookei ticks transmit the traditional lineage of this virus. However, more recent cases have been identified in the Northeast and Midwest, where Powassan virus lineage II (or deer tick virus) is transmitted by I scapularis.^31,64

The classic presentation is a viral encephalitis. Rash (most often maculopapular) and gastrointestinal symptoms have been reported as well. A high index of suspicion is needed for diagnosis because clinical features and laboratory findings resemble those of other arboviral infections.

Treatment for Powassan viral encephalitis is supportive, although corticosteroids have been used with some success.⁶⁴ While asymptomatic infection has been documented, the reported mortality rate of Powassan virus encephalitis is 10% to 15%, and focal neurologic deficits can persist among survivors.⁶⁵

Clinical and laboratory features appear to be very similar to those of the ehrlichioses.¹ A clinical diagnosis should be considered in patients with A americanum exposure, fever, and cytopenias who lack PCR or serologic evidence for ehrlichiosis infection or who fail to respond to doxycycline therapy.²⁴

COINFECTION

Some tick vectors transmit more than 1 type of infection, and therefore, coinfection with multiple pathogens may occur. For example, I scapularis transmits Borrelia burgdorferi (Lyme disease), HGA, Babesia microti, B miyamotoi, E muris-like agent, and Powassan virus lineage II, while A americanum transmits HME and Heartland virus.^{24,26,31,34,36,67} Coinfection may increase the severity of disease, often due to a delay in diagnosis, though more research is needed to understand the clinical manifestations of coinfection.^31,35,67

PREVENTION

Unfortunately, there are no available human vaccines for tickborne illnesses in the United States, and the effectiveness of single-dose prophylaxis with doxycycline for non-Lyme infections has not been evaluated.^4,7,26

Illness is best prevented by minimizing skin exposure to ticks, use of tick repellents containing DEET, use of long-legged and long-sleeved clothing impregnated with an acaricide such as permethrin, and conducting timely body checks for ticks after potential exposure.^1,31,32 Light-colored clothing is suggested, since it allows for better visibility of crawling ticks.^4,32 Bathing or showering within 2 hours of tick exposure helps prevent attachment of ticks.^4,31,68 If camping outside, use of a bed net is recommended.⁶⁸

Ticks are most easily removed by grasping the head of the tick as close to the skin surface as possible with fine-tipped tweezers.^32,68 Removing or crushing ticks with bare hands should be avoided to prevent potential contamination, and hands should be washed thoroughly after tick removal.^1,4

Blood donors are screened for a history of symptomatic tickborne disease; however, asymp­tomatic donors who are not identified at screening pose the greatest risk to the blood supply. Babesia microti is the most common reported transfusion-transmitted parasite in the United States, and transmission of R rickettsii, A phagocytophilum, and E ewingii have also been reported infrequently.^28,40,69 Currently, no test is approved to screen blood for tickborne illnesses, though such a test would help prevent transmission of tickborne illnesses by blood transfusion in areas where these diseases are endemic.^40,41

TAKE-HOME POINTS

Tickborne illnesses are increasing throughout the United States as a result of vector expansion and changes in human ecology.

It is essential that primary care clinicians consider tickborne illnesses in the differential diagnosis for any patient presenting with a fever and constitutional symptoms when the cause of symptoms is unclear and tick exposure is possible or known.

All the diseases discussed are nationally notifiable conditions, and confirmed cases should be reported.

Knowledge of the geographic locations of potential exposure is paramount to determining which tickborne infections to consider, and the absence of a tick bite history should not exclude the diagnosis in the correct clinical presentation.

In addition, it is important to recognize the limitations of diagnostic testing for many tickborne infections; empiric treatment is most often warranted before confirming the diagnosis.

Tick avoidance is the most effective way to prevent these often severe infections.

Ticks are responsible for most vector-borne infections in the United States. Most infections occur between April and October, when tick populations peak.¹ However, infections can occur year-round.^2,3

Tick bites are often unnoticed because the ticks are small when they are at the infective stage of their life cycle, and their attachment is characteristically painless and often in intertriginous body sites.¹ Therefore, absence of a known tick bite never precludes the diagnosis of a tickborne infection.^1,4,5

Although rural outdoor activities are recognized risk factors, tickborne infections also occur in urban areas.⁶ Thus, the lack of classic epidemiologic clues does not rule out a diagnosis of tickborne infection. 

In most cases, tickborne illnesses present with nonspecific symptoms such as fever, malaise, headache, nausea, and myalgia. Accurate diagnosis of tickborne diseases can be challenging due to the similar clinical manifestations and overlapping geographic distributions of potential tick vectors.¹

This review summarizes the epidemiology, clinical features, treatment, and prevention of the most prevalent non-Lyme tickborne diseases of the United States: Rocky Mountain spotted fever (RMSF), other spotted fever group rickettsial (SFGR) infections, ehrlichiosis, babesiosis, tickborne relapsing fever, Borrelia miyamotoi infection, southern tick-associated rash illness (STARI), tularemia, and tickborne viral infections.

ROCKY MOUNTAIN SPOTTED FEVER

Dermacentor variabilis, the American dog tick, is the major vector in the southern and eastern United States, and D andersoni, the Rocky Mountain wood tick, is the most common vector in the western United States.^4,7,8Rhipicephalus sanguineus, the brown dog tick, has also been found to transmit RMSF in Arizona.^9,10

While most infections in humans are transmitted by tick bite, rare cases of RMSF are contracted through exposure to infective tick hemolymph during tick removal, parenteral inoculation or infectious aerosols in laboratory settings, and blood transfusion.^7,8

RMSF is both the most common and the most likely cause of death among rickettsial infections in the United States.^4,7,8 Most cases occur in children ages 5 to 9.^10,11 The case-fatality rate is over 20% without antimicrobial therapy but less than 1% with timely and appropriate antibiotic treatment.^7,8

Clinical manifestations of Rocky Mountain spotted fever

RMSF is transmitted after only 2 to 20 hours of tick attachment, and symptoms begin 3 to 12 days after inoculation.^1,7,8 Unlike many other species that cause SFGR infection, R rickettsii does not cause an eschar at the site of inoculation.^7,12

The classic triad of RMSF is fever, headache, and a rash. This triad is present in only 3% of early infections, but the prevalence increases to 60% to 70% by 2 weeks after the tick bite.^1,7 Other common initial symptoms include generalized malaise, weakness, and myalgia.^7,8,12 Gastrointestinal symptoms are common, and RMSF can be misdiagnosed as gastroenteritis, particularly in children.⁸

A rash usually occurs. It is due to systemic vasculitis and endothelial injury and often presents 2 to 5 days after the onset of fever, which can delay diagnosis.^7,12,13 It usually progresses from macular to petechial and begins on the ankles, forearms, and wrists, spreading centripetally to the trunk and face and often including the palms and soles.⁷ Large areas of ecchymosis, ulceration, and (uncommonly) gangrene may occur as lesions coalesce.^7,8 The 10% of patients who do not develop a rash (“spotless” fever) tend to have a poorer prognosis due to delayed diagnosis.⁸

Risk factors for severe disease include delay or lack of appropriate treatment, extremes of age, Native American descent, glucose-6-phosphate dehydrogenase deficiency, and immunocompromised states.^1,10,11,13 Complications from the widespread Rickettsia-induced vasculitis may include a septic or toxic shock-like syndrome and neurovascular, cardiac, respiratory, and renal damage.^7,11 Without appropriate therapy, death occurs 7 to 15 days after symptom onset.⁸

Laboratory evaluation may reveal thrombocytopenia and anemia.⁷ Leukocytosis or leukopenia may be present.⁸ Hyponatremia, elevated aminotransferase levels, elevated creatine kinase levels, prolonged coagulation times, and decreased fibrinogen may also be present.^7,8

Diagnosis of Rocky Mountain spotted fever

No diagnostic studies are available for the acute phase of RMSF. Therefore, a high suspicion of RMSF is essential, and treatment should be started as soon as RMSF is suspected. Confirmatory testing can retrospectively validate a clinical diagnosis.^4,7,11

Serologic testing with an immunofluorescence antibody assay remains the principal diagnostic test for RMSF, and paired testing (during the acute and convalescent phases) has a sensitivity of 94%.⁴ A 4-fold or greater increase in antibody titer (with a minimum titer of 1:64) between acute and convalescent samples is considered diagnostic of acute infection.^4,7,8 Serology is often negative early in the disease course.^4,7,8 The assay cross-reacts with other SFGR species, however.^4,8

Amplification of R rickettsii DNA by polymerase chain reaction (PCR) from blood or biopsy sites can be done in some research settings, but its utility is limited because of low sensitivity early in the course of the infection.^4,7

Immunohistochemical staining of a skin biopsy or autopsy specimen is a highly specific diagnostic test performed at a limited number of laboratories, though it has a sensitivity of only 60% to 92%.^4,7,8

Cell culture can also be performed, but only in biosafety level 3 (scale of 1 to 4) laboratories.¹

Treatment of Rocky Mountain spotted fever

Prompt initiation of antibiotic therapy greatly improves prognosis.^1,13,14

Doxycycline for 7 days is the treatment of choice for RMSF, including in pregnant patients with life-threatening disease and in children.^4,7,8,15,16

Tetracycline can also be used.

Chloramphenicol is an alternative treatment for pregnant patients with mild to moderate disease or those patients with a severe hypersensitivity reaction to doxycycline.^{1,4,7,9,15,16} In the United States, chloramphenicol is currently available only in an intravenous formulation.

Fever typically subsides within 24 to 48 hours of starting treatment.^4,8 Failure to clinically improve within 48 hours suggests an alternative diagnosis.^1,4 Long-term complications of severe infection may include hearing loss, blindness, and amputation of digits or extremities due to gangrene.^1,8 Persistence of disease beyond acute infection has not been observed.¹

OTHER SPOTTED FEVER GROUP RICKETTSIAl INFECTIONS

Both infections are characterized by an inoculation eschar. Symptoms include fever, headache, myalgia, and regional lymphadenopathy.¹ Rash (most often maculopapular or vesicopustular) is characteristic of R parkeri, but it is not common in Rickettsia species 364D rickettsiosis.^17,18 Mild thrombocytopenia, leukopenia, and elevated aminotransferase levels are common in R parkeri infection.¹ Both infections appear to be milder than RMSF.

EHRLICHIOSES: EHRLICHIOSIS AND ANAPLASMOSIS

“Ehrlichiosis” is the generic name for infections caused by both the Ehrlichia and Anaplasma genera,^19,20 which are small, gram-negative obligate intracellular bacterial pathogens.²¹ In the United States, infections are most commonly caused by A phagocytophilum, the causative organism of human granulocytic anaplasmosis (HGA) (Table 4), and E chaffeensis, the causative organism of human monocytic ehrlichiosis (HME) (Table 5). The incidence rates of these 2 infections have increased over the past decade, in part due to increased clinical awareness and improved diagnostic capabilities.^3,22,23

E ewingii (Table 6) and E muris-like agent (Table 7) are lesser known causes of human ehrlichiosis in the United States.^20,23–25 Initially, E ewingii was believed to primarily affect immunocompromised patients, but it was later recognized in immunocompetent hosts.²³E muris-like agent was first discovered as a cause of infection in 2009, and cases have been limited to Wisconsin and Minnesota.^24,25

Human granulocytic anaplasmosis. A phagocytophilum is transmitted by Ixodes scapularis (the deer tick or blacklegged tick) in the northeastern and upper-midwestern regions of the United States, and I pacificus (the western blacklegged tick) along the northern Pacific coast.^1,19,20,26 The 6 states accounting for most cases are New York, Connecticut, Massachusetts, Rhode Island, Minnesota, and Wisconsin.²⁷ The white-footed mouse serves as the primary reservoir for A phagocytophilum, and humans are an accidental, “dead-end” host.²¹ Cases have also been reported to be transmitted via blood transfusion and transplacentally.^20,26,28,29

Clinical manifestations of ehrlichiosis

After an incubation time of 5 to 21 days, ehrlichiosis typically presents as a febrile viral-like illness with nonspecific symptoms that include fever, chills, sweats, myalgia, headache, malaise, and cough.^1,26,27,31

Gastrointestinal symptoms, arthralgia, photophobia, and nervous system involvement may also occur.^1,20,29,32 Gastrointestinal symptoms tend to be more common in HME than HGA.²⁰

Rash occurs in up to one-third of patients with HME, but it is rare in HGA.^4,19,20,27 HME presents with more central nervous system involvement (such as meningitis or seizures) than HGA, in which central nervous system involvement is rare.

Severe complications of HME and HGA occur in a minority of cases and may include acute respiratory distress syndrome, renal failure, disseminated intravascular coagulopathy, and spontaneous hemorrhage.¹⁹ In general, HME is more severe than HGA and is more likely to progress to fulminant toxic or septic shocklike syndrome in rare instances.¹⁹

Laboratory tests may reveal leukopenia, lymphopenia, thrombocytopenia, and elevated liver-associated enzyme levels.^1,19,20,26 Anemia and hyponatremia may also be present.^4,30

Diagnosis of ehrlichiosis

The most rapid diagnostic method is examination of Wright- or Giemsa-stained peripheral blood smears for morulae, which are cytoplasmic intravacuolar inclusions of bacteria within leukocytes.²⁰ However, its sensitivity is as low as 20% and declines even further after the first week of infection.^4,20

PCR testing is the most sensitive and rapid tool available during acute infection.^{1,20,26,30,31} However, due to waning of the bacteremic phase, its sensitivity decreases after the first week of infection and after treatment is started.^19,20

Serologic detection of antibodies with an indirect immunofluorescence assay is the most frequently used test for diagnosis of ehr­lichiosis, and paired serology demonstrating seroconversion (at least a 4-fold increase in titer, with a minimal titer of 1:64) is most sensitive (82% to 100%).^4,19,20,26 Cross-reactivity can occur, so testing for antibodies to both A phagocytophilum and E chaffeensis might assist in a more accurate diagnosis in areas where tick vectors overlap.^4,19,20,26

HGA and HME can be isolated through cell culture in blood or cerebrospinal fluid. However, this is labor-intensive and performed in only a few specialized laboratories.^{4,19,20,27,31}

Treatment of ehrlichiosis

If ehrlichiosis is suspected, treatment should not be delayed; the disease can be life-threatening and the ability to diagnose acute infection is often limited.^20,26,32

Doxycycline is the treatment of choice, even in pregnant patients with severe infection and in children.^1,19,26,27 Antibiotics are given for 5 to 10 days and continued for at least 3 days after the fever subsides.^{19,20,26,27,30} In HGA, a 10-day course of doxycycline is recommended to also provide the appropriate length of treatment for Borrelia burgdorferi.^1,31

Rifampin is an alternative for those with severe tetracycline allergy, as well as those with mild to moderate infection during pregnancy.^{1,20,26,29–32}

Fever typically resolves within 24 to 48 hours of starting treatment, and persistence of fever over 48 hours after starting antibiotics suggests an alternative diagnosis or possible coinfection.^{1,4,19,20,26,27,30,32}

Persistence of chronic A phagocytophilum or E chaffeensis infection in humans beyond 2 months has not been demonstrated.^20,26,30,33 Therefore, antibiotic treatment beyond the acute stage of infection is not indicated.³⁰ Long-term prognosis is favorable, and patients are expected to make a full recovery.^26,30

BABESIOSIS

Babesiosis occurs in the northeastern and upper midwestern states, with most cases reported in Massachusetts, Connecticut, Rhode Island, New York, New Jersey, Minnesota, and Wisconsin.^{31,32,34–36} Outbreaks have also been documented in Washington, California, and Missouri.^31,32,35 The spread mimics that of Lyme disease, though it can be slower.^34,36–39

Most cases in the Northeast and upper Midwest are caused by Babesia microti, while Babesia duncani has sporadically caused disease along the Pacific coast and Babesia divergens has been found in the Midwest and Northwest.^34,36,39

Though babesiosis is usually a tickborne illness, it can also be transmitted through blood transfusion and, rarely, transplacental spread.^{31,32,34,36,39–41} The I scapularis tick is the host vector for Babesia microti, and transmission of disease requires 24 to 72 hours of attachment to a host.^34,35 The primary reservoir for Babesia microti is the white-footed mouse, and humans are accidental hosts.^{32,34–36,39}

Clinical manifestations of babesiosis

Babesia species cause illness by lysing erythrocytes, with resultant cytokine release.³⁴

Symptoms typically appear 1 to 4 weeks after inoculation, after which most cases present as a viral-like illness with gradual onset of fever, chills, sweats, fatigue, malaise, headache, arthralgia, myalgia, nausea, anorexia, and nonproductive cough.^{32,34–36,39}

Physical findings may include splenomegaly, hepatomegaly, jaundice, petechiae, and ecchymosis.^{32,34–36,39} Rash is seldom present and is not a characteristic feature of babesiosis.^35,36

Laboratory features may include thrombocytopenia, hemolytic anemia, and elevated liver enzyme levels.^32,34,36,39

Severe disease can occur in elderly, immunocompromised, or splenectomized individuals and can be life-threatening.^34,39 Complications of severe infection can include acute respiratory distress syndrome, diffuse intravascular coagulation, and liver or renal failure.^{31,32,34–36,39} Splenic infarction or rupture may occur at lower levels of parasitemia in those without other manifestations of severe disease.³¹ The course can be prolonged and relapsing despite standard antibiotic therapy, typically in the setting of severe immunocompromise.^32,34,42,43 Death occurs in up to 10% of severe cases.³⁴

Diagnosis of babesiosis

Babesiosis should be considered if a patient presents with a febrile illness and nonspecific symptoms and comes from an endemic area or has received a blood transfusion within 6 months.^34,35

The diagnosis of babesiosis is most commonly made by finding the intraerythrocytic ring form of the organism (trophozoite) on Giemsa- or Wright-stained thin blood smears.^34,36,39Babesia can be distinguished from Plasmodia (the agent of malaria) by the rare presence of tetrads of merozoites arranged in a cross-like pattern (the Maltese cross); the absence of hemozoin (brownish deposits) in the ring form; and the occasional presence of extracellular ring forms.^34,36

The level of parasitemia (representing the number of parasites per microliter of blood) is generally between 1% and 10%, although it can be as high as 80%.^36,39 Because parasitemia is often low early in disease (< 1%), multiple blood smears should be examined.^34–36,39

Several real-time PCR assays are available to detect low-grade Babesia microti parasitemia in patients with negative blood smears during early infection.³¹ These assays have high diagnostic sensitivity and specificity and do not cross-react with other Babesia or Plasmodium species.^34–36,39

Paired serology (immunoglobulin G) can confirm infection, although antibody may be absent early in the course of illness.^{31,34–36,39}

Treatment of babesiosis

Current guidelines recommend antimicrobial therapy only for patients with symptoms and positive test results for Babesia.³² Treatment of asymptomatic patients should additionally be considered if parasitemia (not positive PCR or serology) persists for 3 months or longer.^{32,34–36,39}

For mild to moderate babesiosis, the combination of oral atovaquone and azithromycin for 7 to 10 days has similar efficacy and a lower incidence of adverse effects than clindamycin plus quinine.^31,32,34,44 For immunocompromised patients, higher doses of azithromycin can be used.^31,32

For severe babesiosis or those with risk factors for severe disease, intravenous clindamycin and oral quinine are recommended for 7 to 10 days based on expert opinion.^{31,32,34–36,39,43} Adverse effects of this regimen include diarrhea, tinnitus, and hearing deficits.^35,39 If necessary, intravenous quinidine can be used, but the patient should receive cardiac monitoring for possible prolongation of the QT interval.^34,39 As quinine therapy is often interrupted due to the above side effects, alternative regimens such as intravenous azithromycin or clindamycin in combination with oral atovaquone should be considered for severe cases.³¹ However, these regimens are not well studied.³¹

Partial or complete exchange transfusion of whole blood or packed red blood cells should be considered in patients with a high level of parasitemia (≥ 10%), severe anemia (hemoglobin < 10 g/dL), or renal, hepatic, or pulmonary compromise.^{31,32,34–36,39} In critically ill patients, parasitemia should be monitored daily until it has decreased to less than 5%.^32,34,39

Generally, symptoms improve within 48 hours of antimicrobial therapy initiation; however, parasitemia may take up to 3 months to resolve.^32,34,39 In severely immunocompromised patients, babesiosis may persist or relapse despite appropriate therapy.^34,39,42,43 In these cases, at least 6 weeks of antimicrobial therapy is recommended, including 2 weeks of therapy after Babesia organisms are no longer seen on blood smear.^{31,33,36,39,42}

TICKBORNE RELAPSING FEVER

The illness is transmitted by either ticks or body lice. The tick-borne illness is caused by spirochetes of the genus Borrelia and transmitted to humans by the bite of an infected Ornithodoros soft tick.⁴⁵ Approximately 70% of reported cases in the United States occur in California, Washington, and Colorado.⁴⁶ Most cases are caused by Borrelia hermsii and are linked to sleeping in rodent-infested cabins in mountainous areas.⁴⁶ Remarkably, tick-borne borreliae are transmitted within about 30 seconds of tick attachment.^47,48

The hallmark of tickborne relapsing fever is febrile episodes lasting 3 to 5 days, with relapses after 5 to 7 days of apparent recovery.⁴⁹ If untreated, several episodes of fever and nonspecific symptoms will occur before illness resolves spontaneously. Overall mortality rates are very low (< 5%).⁵⁰

Laboratory confirmation of tickborne relapsing fever is made by detecting spirochetes in a blood smear during a febrile episode or serologic antibody confirmation. However, serologic testing is unhelpful in the acute setting and can yield false-positive results with prior exposure to other Borrelia species (eg, Lyme disease) or other spirochetes. Serologic antibody testing with a 4-fold increase between acute and convalescent samples or PCR can aid in diagnosis, though the latter is available only in research settings.⁴⁷

The preferred treatment regimen for adults is an oral tetracycline for 10 days. Erythromycin is recommended when tetracyclines are contraindicated.⁵¹

When starting treatment, all patients should be monitored closely for the Jarisch-Herxheimer reaction (rigors, hypotension, and high fevers), which develops in over 50% of cases as a result of rapid spirochetal killing and massive cytokine release.⁵²

BORRELIA MIYAMOTOI INFECTION

The most common clinical manifestations are similar to other tickborne relapsing fever infections, although a true “relapsing fever” itself is not usually present.⁵³ The characteristic erythema migrans rash often found in Lyme disease is typically absent in B miyamotoi infection; however, when present, it should prompt investigation into coinfection.⁵⁴ Cases of meningoencephalitis have been reported in immunosuppressed hosts.⁵⁵

There is currently no validated test available for diagnosis of B miyamotoi; however, PCR and serology are available in a few specialized laboratories.^31,53

The treatment of choice is doxycycline for 2 to 4 weeks. Amoxicillin and ceftriaxone also appear effective.⁵³

SOUTHERN TICK-ASSOCIATED RASH ILLNESS

Infection can present similarly to Lyme disease with an erythema migrans-like rash and associated flulike symptoms, although systemic symptoms and multiple erythema migrans lesions are less likely with STARI. Also, the erythema migrans-like lesions tend to be smaller and more likely to have central clearing than those in Lyme disease.⁵⁷ Nevertheless, it is difficult to distinguish the 2 illnesses, especially in mid-Atlantic states such as Maryland or Virginia, where both diseases coexist. The most reliable method of distinguishing STARI from Lyme disease is demonstrating that the patient was bitten by a Lone Star tick rather than an Ixodes tick. Numerous questions remain unanswered about the causative organism, pathophysiology, definitive diagnosis, geographic range of illness, and most effective treatment for STARI.

Most reported cases have responded promptly to doxycycline, though it is not known whether antibiotic treatment is necessary.⁵⁸

TULAREMIA

Ticks are thought to be the most important vectors, and most cases occur in the south-central United States.⁵⁹ The geographic distribution of disease is gradually shifting northward due to spread of the major tick vectors, A americanum, D variabilis, and D andersoni. Approximately 100 to 200 cases of tularemia are diagnosed each year in the United States, with most concentrated in Kansas, Oklahoma, Missouri, and Arkansas.⁶⁰

Humans can acquire F tularensis by several routes, and the route of infection ultimately dictates the clinical syndrome. Ulceroglandular and glandular forms of the disease are the most common in the United States, and both frequently result from a tick bite. A few days after tick exposure, an erythematous, often painful papuloulcerative lesion with a central eschar manifests at the site of the tick bite. Additional symptoms may include fever, chills, headache, myalgia, malaise, and suppurative lymphadenitis.⁶¹

Diagnosis can be made by identifying F tularensis in blood, fluid, or tissue culture performed under biosafety level 3 conditions; however, serology is used in most cases.⁶²

Streptomycin and gentamicin are considered drugs of choice and should be continued for at least 10 days. For relatively mild disease, oral doxycycline or ciprofloxacin can be considered for at least 14 days, although the latter is not approved for treatment.^59,63

TICKBORNE VIRAL INFECTIONS

Powassan virus, an uncommon flavivirus, is found in the Great Lakes region and northeast United States. In the Great Lakes region, I cookei ticks transmit the traditional lineage of this virus. However, more recent cases have been identified in the Northeast and Midwest, where Powassan virus lineage II (or deer tick virus) is transmitted by I scapularis.^31,64

The classic presentation is a viral encephalitis. Rash (most often maculopapular) and gastrointestinal symptoms have been reported as well. A high index of suspicion is needed for diagnosis because clinical features and laboratory findings resemble those of other arboviral infections.

Treatment for Powassan viral encephalitis is supportive, although corticosteroids have been used with some success.⁶⁴ While asymptomatic infection has been documented, the reported mortality rate of Powassan virus encephalitis is 10% to 15%, and focal neurologic deficits can persist among survivors.⁶⁵

Clinical and laboratory features appear to be very similar to those of the ehrlichioses.¹ A clinical diagnosis should be considered in patients with A americanum exposure, fever, and cytopenias who lack PCR or serologic evidence for ehrlichiosis infection or who fail to respond to doxycycline therapy.²⁴

COINFECTION

Some tick vectors transmit more than 1 type of infection, and therefore, coinfection with multiple pathogens may occur. For example, I scapularis transmits Borrelia burgdorferi (Lyme disease), HGA, Babesia microti, B miyamotoi, E muris-like agent, and Powassan virus lineage II, while A americanum transmits HME and Heartland virus.^{24,26,31,34,36,67} Coinfection may increase the severity of disease, often due to a delay in diagnosis, though more research is needed to understand the clinical manifestations of coinfection.^31,35,67

PREVENTION

Unfortunately, there are no available human vaccines for tickborne illnesses in the United States, and the effectiveness of single-dose prophylaxis with doxycycline for non-Lyme infections has not been evaluated.^4,7,26

Illness is best prevented by minimizing skin exposure to ticks, use of tick repellents containing DEET, use of long-legged and long-sleeved clothing impregnated with an acaricide such as permethrin, and conducting timely body checks for ticks after potential exposure.^1,31,32 Light-colored clothing is suggested, since it allows for better visibility of crawling ticks.^4,32 Bathing or showering within 2 hours of tick exposure helps prevent attachment of ticks.^4,31,68 If camping outside, use of a bed net is recommended.⁶⁸

Ticks are most easily removed by grasping the head of the tick as close to the skin surface as possible with fine-tipped tweezers.^32,68 Removing or crushing ticks with bare hands should be avoided to prevent potential contamination, and hands should be washed thoroughly after tick removal.^1,4

Blood donors are screened for a history of symptomatic tickborne disease; however, asymp­tomatic donors who are not identified at screening pose the greatest risk to the blood supply. Babesia microti is the most common reported transfusion-transmitted parasite in the United States, and transmission of R rickettsii, A phagocytophilum, and E ewingii have also been reported infrequently.^28,40,69 Currently, no test is approved to screen blood for tickborne illnesses, though such a test would help prevent transmission of tickborne illnesses by blood transfusion in areas where these diseases are endemic.^40,41

TAKE-HOME POINTS

Tickborne illnesses are increasing throughout the United States as a result of vector expansion and changes in human ecology.

It is essential that primary care clinicians consider tickborne illnesses in the differential diagnosis for any patient presenting with a fever and constitutional symptoms when the cause of symptoms is unclear and tick exposure is possible or known.

All the diseases discussed are nationally notifiable conditions, and confirmed cases should be reported.

Knowledge of the geographic locations of potential exposure is paramount to determining which tickborne infections to consider, and the absence of a tick bite history should not exclude the diagnosis in the correct clinical presentation.

In addition, it is important to recognize the limitations of diagnostic testing for many tickborne infections; empiric treatment is most often warranted before confirming the diagnosis.

Tick avoidance is the most effective way to prevent these often severe infections.

Ticks are responsible for most vector-borne infections in the United States. Most infections occur between April and October, when tick populations peak.¹ However, infections can occur year-round.^2,3

Tick bites are often unnoticed because the ticks are small when they are at the infective stage of their life cycle, and their attachment is characteristically painless and often in intertriginous body sites.¹ Therefore, absence of a known tick bite never precludes the diagnosis of a tickborne infection.^1,4,5

Although rural outdoor activities are recognized risk factors, tickborne infections also occur in urban areas.⁶ Thus, the lack of classic epidemiologic clues does not rule out a diagnosis of tickborne infection. 

In most cases, tickborne illnesses present with nonspecific symptoms such as fever, malaise, headache, nausea, and myalgia. Accurate diagnosis of tickborne diseases can be challenging due to the similar clinical manifestations and overlapping geographic distributions of potential tick vectors.¹

This review summarizes the epidemiology, clinical features, treatment, and prevention of the most prevalent non-Lyme tickborne diseases of the United States: Rocky Mountain spotted fever (RMSF), other spotted fever group rickettsial (SFGR) infections, ehrlichiosis, babesiosis, tickborne relapsing fever, Borrelia miyamotoi infection, southern tick-associated rash illness (STARI), tularemia, and tickborne viral infections.

ROCKY MOUNTAIN SPOTTED FEVER

Dermacentor variabilis, the American dog tick, is the major vector in the southern and eastern United States, and D andersoni, the Rocky Mountain wood tick, is the most common vector in the western United States.^4,7,8Rhipicephalus sanguineus, the brown dog tick, has also been found to transmit RMSF in Arizona.^9,10

While most infections in humans are transmitted by tick bite, rare cases of RMSF are contracted through exposure to infective tick hemolymph during tick removal, parenteral inoculation or infectious aerosols in laboratory settings, and blood transfusion.^7,8

RMSF is both the most common and the most likely cause of death among rickettsial infections in the United States.^4,7,8 Most cases occur in children ages 5 to 9.^10,11 The case-fatality rate is over 20% without antimicrobial therapy but less than 1% with timely and appropriate antibiotic treatment.^7,8

Clinical manifestations of Rocky Mountain spotted fever

RMSF is transmitted after only 2 to 20 hours of tick attachment, and symptoms begin 3 to 12 days after inoculation.^1,7,8 Unlike many other species that cause SFGR infection, R rickettsii does not cause an eschar at the site of inoculation.^7,12

The classic triad of RMSF is fever, headache, and a rash. This triad is present in only 3% of early infections, but the prevalence increases to 60% to 70% by 2 weeks after the tick bite.^1,7 Other common initial symptoms include generalized malaise, weakness, and myalgia.^7,8,12 Gastrointestinal symptoms are common, and RMSF can be misdiagnosed as gastroenteritis, particularly in children.⁸

A rash usually occurs. It is due to systemic vasculitis and endothelial injury and often presents 2 to 5 days after the onset of fever, which can delay diagnosis.^7,12,13 It usually progresses from macular to petechial and begins on the ankles, forearms, and wrists, spreading centripetally to the trunk and face and often including the palms and soles.⁷ Large areas of ecchymosis, ulceration, and (uncommonly) gangrene may occur as lesions coalesce.^7,8 The 10% of patients who do not develop a rash (“spotless” fever) tend to have a poorer prognosis due to delayed diagnosis.⁸

Risk factors for severe disease include delay or lack of appropriate treatment, extremes of age, Native American descent, glucose-6-phosphate dehydrogenase deficiency, and immunocompromised states.^1,10,11,13 Complications from the widespread Rickettsia-induced vasculitis may include a septic or toxic shock-like syndrome and neurovascular, cardiac, respiratory, and renal damage.^7,11 Without appropriate therapy, death occurs 7 to 15 days after symptom onset.⁸

Laboratory evaluation may reveal thrombocytopenia and anemia.⁷ Leukocytosis or leukopenia may be present.⁸ Hyponatremia, elevated aminotransferase levels, elevated creatine kinase levels, prolonged coagulation times, and decreased fibrinogen may also be present.^7,8

Diagnosis of Rocky Mountain spotted fever

No diagnostic studies are available for the acute phase of RMSF. Therefore, a high suspicion of RMSF is essential, and treatment should be started as soon as RMSF is suspected. Confirmatory testing can retrospectively validate a clinical diagnosis.^4,7,11

Serologic testing with an immunofluorescence antibody assay remains the principal diagnostic test for RMSF, and paired testing (during the acute and convalescent phases) has a sensitivity of 94%.⁴ A 4-fold or greater increase in antibody titer (with a minimum titer of 1:64) between acute and convalescent samples is considered diagnostic of acute infection.^4,7,8 Serology is often negative early in the disease course.^4,7,8 The assay cross-reacts with other SFGR species, however.^4,8

Amplification of R rickettsii DNA by polymerase chain reaction (PCR) from blood or biopsy sites can be done in some research settings, but its utility is limited because of low sensitivity early in the course of the infection.^4,7

Immunohistochemical staining of a skin biopsy or autopsy specimen is a highly specific diagnostic test performed at a limited number of laboratories, though it has a sensitivity of only 60% to 92%.^4,7,8

Cell culture can also be performed, but only in biosafety level 3 (scale of 1 to 4) laboratories.¹

Treatment of Rocky Mountain spotted fever

Prompt initiation of antibiotic therapy greatly improves prognosis.^1,13,14

Doxycycline for 7 days is the treatment of choice for RMSF, including in pregnant patients with life-threatening disease and in children.^4,7,8,15,16

Tetracycline can also be used.

Chloramphenicol is an alternative treatment for pregnant patients with mild to moderate disease or those patients with a severe hypersensitivity reaction to doxycycline.^{1,4,7,9,15,16} In the United States, chloramphenicol is currently available only in an intravenous formulation.

Fever typically subsides within 24 to 48 hours of starting treatment.^4,8 Failure to clinically improve within 48 hours suggests an alternative diagnosis.^1,4 Long-term complications of severe infection may include hearing loss, blindness, and amputation of digits or extremities due to gangrene.^1,8 Persistence of disease beyond acute infection has not been observed.¹

OTHER SPOTTED FEVER GROUP RICKETTSIAl INFECTIONS

Both infections are characterized by an inoculation eschar. Symptoms include fever, headache, myalgia, and regional lymphadenopathy.¹ Rash (most often maculopapular or vesicopustular) is characteristic of R parkeri, but it is not common in Rickettsia species 364D rickettsiosis.^17,18 Mild thrombocytopenia, leukopenia, and elevated aminotransferase levels are common in R parkeri infection.¹ Both infections appear to be milder than RMSF.

EHRLICHIOSES: EHRLICHIOSIS AND ANAPLASMOSIS

“Ehrlichiosis” is the generic name for infections caused by both the Ehrlichia and Anaplasma genera,^19,20 which are small, gram-negative obligate intracellular bacterial pathogens.²¹ In the United States, infections are most commonly caused by A phagocytophilum, the causative organism of human granulocytic anaplasmosis (HGA) (Table 4), and E chaffeensis, the causative organism of human monocytic ehrlichiosis (HME) (Table 5). The incidence rates of these 2 infections have increased over the past decade, in part due to increased clinical awareness and improved diagnostic capabilities.^3,22,23

E ewingii (Table 6) and E muris-like agent (Table 7) are lesser known causes of human ehrlichiosis in the United States.^20,23–25 Initially, E ewingii was believed to primarily affect immunocompromised patients, but it was later recognized in immunocompetent hosts.²³E muris-like agent was first discovered as a cause of infection in 2009, and cases have been limited to Wisconsin and Minnesota.^24,25

Human granulocytic anaplasmosis. A phagocytophilum is transmitted by Ixodes scapularis (the deer tick or blacklegged tick) in the northeastern and upper-midwestern regions of the United States, and I pacificus (the western blacklegged tick) along the northern Pacific coast.^1,19,20,26 The 6 states accounting for most cases are New York, Connecticut, Massachusetts, Rhode Island, Minnesota, and Wisconsin.²⁷ The white-footed mouse serves as the primary reservoir for A phagocytophilum, and humans are an accidental, “dead-end” host.²¹ Cases have also been reported to be transmitted via blood transfusion and transplacentally.^20,26,28,29

Clinical manifestations of ehrlichiosis

After an incubation time of 5 to 21 days, ehrlichiosis typically presents as a febrile viral-like illness with nonspecific symptoms that include fever, chills, sweats, myalgia, headache, malaise, and cough.^1,26,27,31

Gastrointestinal symptoms, arthralgia, photophobia, and nervous system involvement may also occur.^1,20,29,32 Gastrointestinal symptoms tend to be more common in HME than HGA.²⁰

Rash occurs in up to one-third of patients with HME, but it is rare in HGA.^4,19,20,27 HME presents with more central nervous system involvement (such as meningitis or seizures) than HGA, in which central nervous system involvement is rare.

Severe complications of HME and HGA occur in a minority of cases and may include acute respiratory distress syndrome, renal failure, disseminated intravascular coagulopathy, and spontaneous hemorrhage.¹⁹ In general, HME is more severe than HGA and is more likely to progress to fulminant toxic or septic shocklike syndrome in rare instances.¹⁹

Laboratory tests may reveal leukopenia, lymphopenia, thrombocytopenia, and elevated liver-associated enzyme levels.^1,19,20,26 Anemia and hyponatremia may also be present.^4,30

Diagnosis of ehrlichiosis

The most rapid diagnostic method is examination of Wright- or Giemsa-stained peripheral blood smears for morulae, which are cytoplasmic intravacuolar inclusions of bacteria within leukocytes.²⁰ However, its sensitivity is as low as 20% and declines even further after the first week of infection.^4,20

PCR testing is the most sensitive and rapid tool available during acute infection.^{1,20,26,30,31} However, due to waning of the bacteremic phase, its sensitivity decreases after the first week of infection and after treatment is started.^19,20

Serologic detection of antibodies with an indirect immunofluorescence assay is the most frequently used test for diagnosis of ehr­lichiosis, and paired serology demonstrating seroconversion (at least a 4-fold increase in titer, with a minimal titer of 1:64) is most sensitive (82% to 100%).^4,19,20,26 Cross-reactivity can occur, so testing for antibodies to both A phagocytophilum and E chaffeensis might assist in a more accurate diagnosis in areas where tick vectors overlap.^4,19,20,26

HGA and HME can be isolated through cell culture in blood or cerebrospinal fluid. However, this is labor-intensive and performed in only a few specialized laboratories.^{4,19,20,27,31}

Treatment of ehrlichiosis

If ehrlichiosis is suspected, treatment should not be delayed; the disease can be life-threatening and the ability to diagnose acute infection is often limited.^20,26,32

Doxycycline is the treatment of choice, even in pregnant patients with severe infection and in children.^1,19,26,27 Antibiotics are given for 5 to 10 days and continued for at least 3 days after the fever subsides.^{19,20,26,27,30} In HGA, a 10-day course of doxycycline is recommended to also provide the appropriate length of treatment for Borrelia burgdorferi.^1,31

Rifampin is an alternative for those with severe tetracycline allergy, as well as those with mild to moderate infection during pregnancy.^{1,20,26,29–32}

Fever typically resolves within 24 to 48 hours of starting treatment, and persistence of fever over 48 hours after starting antibiotics suggests an alternative diagnosis or possible coinfection.^{1,4,19,20,26,27,30,32}

Persistence of chronic A phagocytophilum or E chaffeensis infection in humans beyond 2 months has not been demonstrated.^20,26,30,33 Therefore, antibiotic treatment beyond the acute stage of infection is not indicated.³⁰ Long-term prognosis is favorable, and patients are expected to make a full recovery.^26,30

BABESIOSIS

Babesiosis occurs in the northeastern and upper midwestern states, with most cases reported in Massachusetts, Connecticut, Rhode Island, New York, New Jersey, Minnesota, and Wisconsin.^{31,32,34–36} Outbreaks have also been documented in Washington, California, and Missouri.^31,32,35 The spread mimics that of Lyme disease, though it can be slower.^34,36–39

Most cases in the Northeast and upper Midwest are caused by Babesia microti, while Babesia duncani has sporadically caused disease along the Pacific coast and Babesia divergens has been found in the Midwest and Northwest.^34,36,39

Though babesiosis is usually a tickborne illness, it can also be transmitted through blood transfusion and, rarely, transplacental spread.^{31,32,34,36,39–41} The I scapularis tick is the host vector for Babesia microti, and transmission of disease requires 24 to 72 hours of attachment to a host.^34,35 The primary reservoir for Babesia microti is the white-footed mouse, and humans are accidental hosts.^{32,34–36,39}

Clinical manifestations of babesiosis

Babesia species cause illness by lysing erythrocytes, with resultant cytokine release.³⁴

Symptoms typically appear 1 to 4 weeks after inoculation, after which most cases present as a viral-like illness with gradual onset of fever, chills, sweats, fatigue, malaise, headache, arthralgia, myalgia, nausea, anorexia, and nonproductive cough.^{32,34–36,39}

Physical findings may include splenomegaly, hepatomegaly, jaundice, petechiae, and ecchymosis.^{32,34–36,39} Rash is seldom present and is not a characteristic feature of babesiosis.^35,36

Laboratory features may include thrombocytopenia, hemolytic anemia, and elevated liver enzyme levels.^32,34,36,39

Severe disease can occur in elderly, immunocompromised, or splenectomized individuals and can be life-threatening.^34,39 Complications of severe infection can include acute respiratory distress syndrome, diffuse intravascular coagulation, and liver or renal failure.^{31,32,34–36,39} Splenic infarction or rupture may occur at lower levels of parasitemia in those without other manifestations of severe disease.³¹ The course can be prolonged and relapsing despite standard antibiotic therapy, typically in the setting of severe immunocompromise.^32,34,42,43 Death occurs in up to 10% of severe cases.³⁴

Diagnosis of babesiosis

Babesiosis should be considered if a patient presents with a febrile illness and nonspecific symptoms and comes from an endemic area or has received a blood transfusion within 6 months.^34,35

The diagnosis of babesiosis is most commonly made by finding the intraerythrocytic ring form of the organism (trophozoite) on Giemsa- or Wright-stained thin blood smears.^34,36,39Babesia can be distinguished from Plasmodia (the agent of malaria) by the rare presence of tetrads of merozoites arranged in a cross-like pattern (the Maltese cross); the absence of hemozoin (brownish deposits) in the ring form; and the occasional presence of extracellular ring forms.^34,36

The level of parasitemia (representing the number of parasites per microliter of blood) is generally between 1% and 10%, although it can be as high as 80%.^36,39 Because parasitemia is often low early in disease (< 1%), multiple blood smears should be examined.^34–36,39

Several real-time PCR assays are available to detect low-grade Babesia microti parasitemia in patients with negative blood smears during early infection.³¹ These assays have high diagnostic sensitivity and specificity and do not cross-react with other Babesia or Plasmodium species.^34–36,39

Paired serology (immunoglobulin G) can confirm infection, although antibody may be absent early in the course of illness.^{31,34–36,39}

Treatment of babesiosis

Current guidelines recommend antimicrobial therapy only for patients with symptoms and positive test results for Babesia.³² Treatment of asymptomatic patients should additionally be considered if parasitemia (not positive PCR or serology) persists for 3 months or longer.^{32,34–36,39}

For mild to moderate babesiosis, the combination of oral atovaquone and azithromycin for 7 to 10 days has similar efficacy and a lower incidence of adverse effects than clindamycin plus quinine.^31,32,34,44 For immunocompromised patients, higher doses of azithromycin can be used.^31,32

For severe babesiosis or those with risk factors for severe disease, intravenous clindamycin and oral quinine are recommended for 7 to 10 days based on expert opinion.^{31,32,34–36,39,43} Adverse effects of this regimen include diarrhea, tinnitus, and hearing deficits.^35,39 If necessary, intravenous quinidine can be used, but the patient should receive cardiac monitoring for possible prolongation of the QT interval.^34,39 As quinine therapy is often interrupted due to the above side effects, alternative regimens such as intravenous azithromycin or clindamycin in combination with oral atovaquone should be considered for severe cases.³¹ However, these regimens are not well studied.³¹

Partial or complete exchange transfusion of whole blood or packed red blood cells should be considered in patients with a high level of parasitemia (≥ 10%), severe anemia (hemoglobin < 10 g/dL), or renal, hepatic, or pulmonary compromise.^{31,32,34–36,39} In critically ill patients, parasitemia should be monitored daily until it has decreased to less than 5%.^32,34,39

Generally, symptoms improve within 48 hours of antimicrobial therapy initiation; however, parasitemia may take up to 3 months to resolve.^32,34,39 In severely immunocompromised patients, babesiosis may persist or relapse despite appropriate therapy.^34,39,42,43 In these cases, at least 6 weeks of antimicrobial therapy is recommended, including 2 weeks of therapy after Babesia organisms are no longer seen on blood smear.^{31,33,36,39,42}

TICKBORNE RELAPSING FEVER

The illness is transmitted by either ticks or body lice. The tick-borne illness is caused by spirochetes of the genus Borrelia and transmitted to humans by the bite of an infected Ornithodoros soft tick.⁴⁵ Approximately 70% of reported cases in the United States occur in California, Washington, and Colorado.⁴⁶ Most cases are caused by Borrelia hermsii and are linked to sleeping in rodent-infested cabins in mountainous areas.⁴⁶ Remarkably, tick-borne borreliae are transmitted within about 30 seconds of tick attachment.^47,48

The hallmark of tickborne relapsing fever is febrile episodes lasting 3 to 5 days, with relapses after 5 to 7 days of apparent recovery.⁴⁹ If untreated, several episodes of fever and nonspecific symptoms will occur before illness resolves spontaneously. Overall mortality rates are very low (< 5%).⁵⁰

Laboratory confirmation of tickborne relapsing fever is made by detecting spirochetes in a blood smear during a febrile episode or serologic antibody confirmation. However, serologic testing is unhelpful in the acute setting and can yield false-positive results with prior exposure to other Borrelia species (eg, Lyme disease) or other spirochetes. Serologic antibody testing with a 4-fold increase between acute and convalescent samples or PCR can aid in diagnosis, though the latter is available only in research settings.⁴⁷

The preferred treatment regimen for adults is an oral tetracycline for 10 days. Erythromycin is recommended when tetracyclines are contraindicated.⁵¹

When starting treatment, all patients should be monitored closely for the Jarisch-Herxheimer reaction (rigors, hypotension, and high fevers), which develops in over 50% of cases as a result of rapid spirochetal killing and massive cytokine release.⁵²

BORRELIA MIYAMOTOI INFECTION

The most common clinical manifestations are similar to other tickborne relapsing fever infections, although a true “relapsing fever” itself is not usually present.⁵³ The characteristic erythema migrans rash often found in Lyme disease is typically absent in B miyamotoi infection; however, when present, it should prompt investigation into coinfection.⁵⁴ Cases of meningoencephalitis have been reported in immunosuppressed hosts.⁵⁵

There is currently no validated test available for diagnosis of B miyamotoi; however, PCR and serology are available in a few specialized laboratories.^31,53

The treatment of choice is doxycycline for 2 to 4 weeks. Amoxicillin and ceftriaxone also appear effective.⁵³

SOUTHERN TICK-ASSOCIATED RASH ILLNESS

Infection can present similarly to Lyme disease with an erythema migrans-like rash and associated flulike symptoms, although systemic symptoms and multiple erythema migrans lesions are less likely with STARI. Also, the erythema migrans-like lesions tend to be smaller and more likely to have central clearing than those in Lyme disease.⁵⁷ Nevertheless, it is difficult to distinguish the 2 illnesses, especially in mid-Atlantic states such as Maryland or Virginia, where both diseases coexist. The most reliable method of distinguishing STARI from Lyme disease is demonstrating that the patient was bitten by a Lone Star tick rather than an Ixodes tick. Numerous questions remain unanswered about the causative organism, pathophysiology, definitive diagnosis, geographic range of illness, and most effective treatment for STARI.

Most reported cases have responded promptly to doxycycline, though it is not known whether antibiotic treatment is necessary.⁵⁸

TULAREMIA

Ticks are thought to be the most important vectors, and most cases occur in the south-central United States.⁵⁹ The geographic distribution of disease is gradually shifting northward due to spread of the major tick vectors, A americanum, D variabilis, and D andersoni. Approximately 100 to 200 cases of tularemia are diagnosed each year in the United States, with most concentrated in Kansas, Oklahoma, Missouri, and Arkansas.⁶⁰

Humans can acquire F tularensis by several routes, and the route of infection ultimately dictates the clinical syndrome. Ulceroglandular and glandular forms of the disease are the most common in the United States, and both frequently result from a tick bite. A few days after tick exposure, an erythematous, often painful papuloulcerative lesion with a central eschar manifests at the site of the tick bite. Additional symptoms may include fever, chills, headache, myalgia, malaise, and suppurative lymphadenitis.⁶¹

Diagnosis can be made by identifying F tularensis in blood, fluid, or tissue culture performed under biosafety level 3 conditions; however, serology is used in most cases.⁶²

Streptomycin and gentamicin are considered drugs of choice and should be continued for at least 10 days. For relatively mild disease, oral doxycycline or ciprofloxacin can be considered for at least 14 days, although the latter is not approved for treatment.^59,63

TICKBORNE VIRAL INFECTIONS

Powassan virus, an uncommon flavivirus, is found in the Great Lakes region and northeast United States. In the Great Lakes region, I cookei ticks transmit the traditional lineage of this virus. However, more recent cases have been identified in the Northeast and Midwest, where Powassan virus lineage II (or deer tick virus) is transmitted by I scapularis.^31,64

The classic presentation is a viral encephalitis. Rash (most often maculopapular) and gastrointestinal symptoms have been reported as well. A high index of suspicion is needed for diagnosis because clinical features and laboratory findings resemble those of other arboviral infections.

Treatment for Powassan viral encephalitis is supportive, although corticosteroids have been used with some success.⁶⁴ While asymptomatic infection has been documented, the reported mortality rate of Powassan virus encephalitis is 10% to 15%, and focal neurologic deficits can persist among survivors.⁶⁵

Clinical and laboratory features appear to be very similar to those of the ehrlichioses.¹ A clinical diagnosis should be considered in patients with A americanum exposure, fever, and cytopenias who lack PCR or serologic evidence for ehrlichiosis infection or who fail to respond to doxycycline therapy.²⁴

COINFECTION

Some tick vectors transmit more than 1 type of infection, and therefore, coinfection with multiple pathogens may occur. For example, I scapularis transmits Borrelia burgdorferi (Lyme disease), HGA, Babesia microti, B miyamotoi, E muris-like agent, and Powassan virus lineage II, while A americanum transmits HME and Heartland virus.^{24,26,31,34,36,67} Coinfection may increase the severity of disease, often due to a delay in diagnosis, though more research is needed to understand the clinical manifestations of coinfection.^31,35,67

PREVENTION

Unfortunately, there are no available human vaccines for tickborne illnesses in the United States, and the effectiveness of single-dose prophylaxis with doxycycline for non-Lyme infections has not been evaluated.^4,7,26

Illness is best prevented by minimizing skin exposure to ticks, use of tick repellents containing DEET, use of long-legged and long-sleeved clothing impregnated with an acaricide such as permethrin, and conducting timely body checks for ticks after potential exposure.^1,31,32 Light-colored clothing is suggested, since it allows for better visibility of crawling ticks.^4,32 Bathing or showering within 2 hours of tick exposure helps prevent attachment of ticks.^4,31,68 If camping outside, use of a bed net is recommended.⁶⁸

Ticks are most easily removed by grasping the head of the tick as close to the skin surface as possible with fine-tipped tweezers.^32,68 Removing or crushing ticks with bare hands should be avoided to prevent potential contamination, and hands should be washed thoroughly after tick removal.^1,4

Blood donors are screened for a history of symptomatic tickborne disease; however, asymp­tomatic donors who are not identified at screening pose the greatest risk to the blood supply. Babesia microti is the most common reported transfusion-transmitted parasite in the United States, and transmission of R rickettsii, A phagocytophilum, and E ewingii have also been reported infrequently.^28,40,69 Currently, no test is approved to screen blood for tickborne illnesses, though such a test would help prevent transmission of tickborne illnesses by blood transfusion in areas where these diseases are endemic.^40,41

TAKE-HOME POINTS

Tickborne illnesses are increasing throughout the United States as a result of vector expansion and changes in human ecology.

It is essential that primary care clinicians consider tickborne illnesses in the differential diagnosis for any patient presenting with a fever and constitutional symptoms when the cause of symptoms is unclear and tick exposure is possible or known.

All the diseases discussed are nationally notifiable conditions, and confirmed cases should be reported.

Knowledge of the geographic locations of potential exposure is paramount to determining which tickborne infections to consider, and the absence of a tick bite history should not exclude the diagnosis in the correct clinical presentation.

In addition, it is important to recognize the limitations of diagnostic testing for many tickborne infections; empiric treatment is most often warranted before confirming the diagnosis.

Tick avoidance is the most effective way to prevent these often severe infections.

As summer is upon us, we enter the peak of tick season. Most reported cases of tickborne disease occur from April to October, and in this issue, Eickhoff and Blaylock offer a timely review of less common (non-Lyme disease) but significant tickborne infections.

In areas endemic for infection with Rickettsia rickettsii, the organism responsible for Rocky Mountain spotted fever (RMSF), physicians and many patients are keenly aware of the signs and symptoms of the disease and are quick to offer and accept empiric antibiotic (doxycycline) therapy. Empiric therapy at the first suspicion of RMSF is appropriate, as untreated infection carries a 20% death rate. Vigilance for early Lyme disease (caused by Borrelia burgdorferi) is also high in true endemic areas, likely because of public awareness and concern for various documented—and some touted but unproven—associated morbidities.

Other tickborne infections are likely underrecognized by physicians who are not experts in infectious disease, and thus are not treated early. There are many reasons for this, including the relative infrequency of severe disease, the nonspecific clinical signs of early infection, and the spreading of infections to geographic areas where they are traditionally not considered endemic.

Additional features likely contribute to delayed diagnosis. Surveys of patients with documented RMSF or Lyme disease show that a large proportion of infections occur in patients who have no history of camping or hiking. Most people are not even aware that they have been harboring a feeding tick, as many ticks are quite small and attachment is painless. Because some ticks survive more than a year, they may stay alive in clothes and closets throughout the winter months and occasionally cause nonseasonal infections.

Geography and entomology matter; the matching of a specific tick vector to a specific disease is tight. With the slow migration of some tick species along with their nonhuman animal hosts into new territories due to temperature changes and urbanization, some diseases are appearing in areas of the country where they had not been previously diagnosed. We must be aware of these changes, and the US Centers for Disease Control and Prevention (CDC) offers useful updated infection maps on their website.

The diagnosis of acute infection is often delayed because of late consideration of the possibility of the disease. In addition, some tests are serologic and require the passage of time before a diagnostic result is obtained. But an increasing and distinct problem is the overdiagnosis and long-term treatment of some patients whose infection is undocumented, perpetuating concern over the unproven entity of chronic infection, the most prevalent being the diagnosis and treatment of “chronic Lyme disease.” Close attention must be paid to the manner of diagnosis and the specific tests used to purportedly confirm the diagnosis of infection. This has been an ongoing challenge in managing patients with chronic fatigue and malaise, a vexing and significant clinical problem without a ready solution in patients who have undergone an extensive evaluation. It is obviously tempting for patients to grasp at any “diagnostic” answer. But chronic and repeated therapy for nonexistent infection is not benign. The CDC has published lists of tests for Lyme disease in particular that are considered to have inadequately established accuracy and clinical utility; these include lymphocyte transformation tests, quantitative CD57 lymphocyte assays, and urinary antigen “capture assays.”

Recognizing and treating acute tickborne infections is crucial, as in distinguishing them from their mimics, which include some systemic autoimmune diseases. But we should not allow the fear of undertreatment of early infection to morph into unwarranted overtreatment of nonexistent chronic infection, just as we should not prematurely assume that ongoing symptoms of fatigue and malaise after a presumed tickborne infection are from the psychologically crippling fear of ongoing morbidity. Periodic reappraisal of the patient and his or her symptoms is warranted.

As summer is upon us, we enter the peak of tick season. Most reported cases of tickborne disease occur from April to October, and in this issue, Eickhoff and Blaylock offer a timely review of less common (non-Lyme disease) but significant tickborne infections.

In areas endemic for infection with Rickettsia rickettsii, the organism responsible for Rocky Mountain spotted fever (RMSF), physicians and many patients are keenly aware of the signs and symptoms of the disease and are quick to offer and accept empiric antibiotic (doxycycline) therapy. Empiric therapy at the first suspicion of RMSF is appropriate, as untreated infection carries a 20% death rate. Vigilance for early Lyme disease (caused by Borrelia burgdorferi) is also high in true endemic areas, likely because of public awareness and concern for various documented—and some touted but unproven—associated morbidities.

Other tickborne infections are likely underrecognized by physicians who are not experts in infectious disease, and thus are not treated early. There are many reasons for this, including the relative infrequency of severe disease, the nonspecific clinical signs of early infection, and the spreading of infections to geographic areas where they are traditionally not considered endemic.

Additional features likely contribute to delayed diagnosis. Surveys of patients with documented RMSF or Lyme disease show that a large proportion of infections occur in patients who have no history of camping or hiking. Most people are not even aware that they have been harboring a feeding tick, as many ticks are quite small and attachment is painless. Because some ticks survive more than a year, they may stay alive in clothes and closets throughout the winter months and occasionally cause nonseasonal infections.

Geography and entomology matter; the matching of a specific tick vector to a specific disease is tight. With the slow migration of some tick species along with their nonhuman animal hosts into new territories due to temperature changes and urbanization, some diseases are appearing in areas of the country where they had not been previously diagnosed. We must be aware of these changes, and the US Centers for Disease Control and Prevention (CDC) offers useful updated infection maps on their website.

The diagnosis of acute infection is often delayed because of late consideration of the possibility of the disease. In addition, some tests are serologic and require the passage of time before a diagnostic result is obtained. But an increasing and distinct problem is the overdiagnosis and long-term treatment of some patients whose infection is undocumented, perpetuating concern over the unproven entity of chronic infection, the most prevalent being the diagnosis and treatment of “chronic Lyme disease.” Close attention must be paid to the manner of diagnosis and the specific tests used to purportedly confirm the diagnosis of infection. This has been an ongoing challenge in managing patients with chronic fatigue and malaise, a vexing and significant clinical problem without a ready solution in patients who have undergone an extensive evaluation. It is obviously tempting for patients to grasp at any “diagnostic” answer. But chronic and repeated therapy for nonexistent infection is not benign. The CDC has published lists of tests for Lyme disease in particular that are considered to have inadequately established accuracy and clinical utility; these include lymphocyte transformation tests, quantitative CD57 lymphocyte assays, and urinary antigen “capture assays.”

Recognizing and treating acute tickborne infections is crucial, as in distinguishing them from their mimics, which include some systemic autoimmune diseases. But we should not allow the fear of undertreatment of early infection to morph into unwarranted overtreatment of nonexistent chronic infection, just as we should not prematurely assume that ongoing symptoms of fatigue and malaise after a presumed tickborne infection are from the psychologically crippling fear of ongoing morbidity. Periodic reappraisal of the patient and his or her symptoms is warranted.

As summer is upon us, we enter the peak of tick season. Most reported cases of tickborne disease occur from April to October, and in this issue, Eickhoff and Blaylock offer a timely review of less common (non-Lyme disease) but significant tickborne infections.

In areas endemic for infection with Rickettsia rickettsii, the organism responsible for Rocky Mountain spotted fever (RMSF), physicians and many patients are keenly aware of the signs and symptoms of the disease and are quick to offer and accept empiric antibiotic (doxycycline) therapy. Empiric therapy at the first suspicion of RMSF is appropriate, as untreated infection carries a 20% death rate. Vigilance for early Lyme disease (caused by Borrelia burgdorferi) is also high in true endemic areas, likely because of public awareness and concern for various documented—and some touted but unproven—associated morbidities.

Other tickborne infections are likely underrecognized by physicians who are not experts in infectious disease, and thus are not treated early. There are many reasons for this, including the relative infrequency of severe disease, the nonspecific clinical signs of early infection, and the spreading of infections to geographic areas where they are traditionally not considered endemic.

Additional features likely contribute to delayed diagnosis. Surveys of patients with documented RMSF or Lyme disease show that a large proportion of infections occur in patients who have no history of camping or hiking. Most people are not even aware that they have been harboring a feeding tick, as many ticks are quite small and attachment is painless. Because some ticks survive more than a year, they may stay alive in clothes and closets throughout the winter months and occasionally cause nonseasonal infections.

Geography and entomology matter; the matching of a specific tick vector to a specific disease is tight. With the slow migration of some tick species along with their nonhuman animal hosts into new territories due to temperature changes and urbanization, some diseases are appearing in areas of the country where they had not been previously diagnosed. We must be aware of these changes, and the US Centers for Disease Control and Prevention (CDC) offers useful updated infection maps on their website.

The diagnosis of acute infection is often delayed because of late consideration of the possibility of the disease. In addition, some tests are serologic and require the passage of time before a diagnostic result is obtained. But an increasing and distinct problem is the overdiagnosis and long-term treatment of some patients whose infection is undocumented, perpetuating concern over the unproven entity of chronic infection, the most prevalent being the diagnosis and treatment of “chronic Lyme disease.” Close attention must be paid to the manner of diagnosis and the specific tests used to purportedly confirm the diagnosis of infection. This has been an ongoing challenge in managing patients with chronic fatigue and malaise, a vexing and significant clinical problem without a ready solution in patients who have undergone an extensive evaluation. It is obviously tempting for patients to grasp at any “diagnostic” answer. But chronic and repeated therapy for nonexistent infection is not benign. The CDC has published lists of tests for Lyme disease in particular that are considered to have inadequately established accuracy and clinical utility; these include lymphocyte transformation tests, quantitative CD57 lymphocyte assays, and urinary antigen “capture assays.”

Recognizing and treating acute tickborne infections is crucial, as in distinguishing them from their mimics, which include some systemic autoimmune diseases. But we should not allow the fear of undertreatment of early infection to morph into unwarranted overtreatment of nonexistent chronic infection, just as we should not prematurely assume that ongoing symptoms of fatigue and malaise after a presumed tickborne infection are from the psychologically crippling fear of ongoing morbidity. Periodic reappraisal of the patient and his or her symptoms is warranted.

ANSWER

The radiograph demonstrates no acute fractures or pneumothorax. Of note is a right upper lobe infiltrate, which is a rounded cavitary lesion measuring approximately 4 cm. The differential includes pulmonary malignancy, active or previous pulmonary infection (eg, tuberculosis), or pneumatocele. Further evaluation with CT and a pulmonary consultation was coordinated.

ANSWER

The radiograph demonstrates no acute fractures or pneumothorax. Of note is a right upper lobe infiltrate, which is a rounded cavitary lesion measuring approximately 4 cm. The differential includes pulmonary malignancy, active or previous pulmonary infection (eg, tuberculosis), or pneumatocele. Further evaluation with CT and a pulmonary consultation was coordinated.

ANSWER

The radiograph demonstrates no acute fractures or pneumothorax. Of note is a right upper lobe infiltrate, which is a rounded cavitary lesion measuring approximately 4 cm. The differential includes pulmonary malignancy, active or previous pulmonary infection (eg, tuberculosis), or pneumatocele. Further evaluation with CT and a pulmonary consultation was coordinated.

It could happen. You are on a plane, perhaps on your way to a medical conference or a well-deserved vacation, when the flight attendant asks you to help a passenger experiencing an in-flight medical emergency. What is your role in this situation?

FLIGHT ATTENDANTS USED TO BE NURSES

Before World War II, nearly all American flight attendants were nurses, who could address most medical issues that arose during flights.¹ Airlines eliminated this preferential hiring practice to support the war effort. Traveling healthcare providers thereafter often volunteered to assist when in-flight medical issues arose, but aircraft carried minimal medical equipment and volunteers’ liability was uncertain.

In 1998, Congress passed the Aviation Medical Assistance Act (AMAA), which provides liability protection for on-board healthcare providers who render medical assistance. It also required the Federal Aviation Administration (FAA) to improve its standards for in-flight medical equipment.^2,3

HOW OFTEN DO EMERGENCIES ARISE?

How often medical events occur during flight is difficult to estimate because airlines are not mandated to report such issues.⁴ Based on data from a ground-based communications center that provides medical consultation service to airlines, medical events occur in approximately 1 in every 604 flights.⁵ This is likely an underestimate, as many medical events may be handled on board without involving a ground-based consultation center.

The most common emergencies are syncope or presyncope, representing 37.4% of consultations, followed by respiratory symptoms (12.1%), nausea or vomiting (9.5%), cardiac symptoms (7.7%), seizures (5.8%), and abdominal pain (4.1%).⁵ Very few in-flight medical emergencies progress to death; the reported mortality rate is 0.3%.⁵

CABIN PRESSURES ARE RELATIVELY LOW

The cabins of commercial airliners are pressurized, but the pressure is still lower than on the ground. The cabin pressure in flight is equivalent to that at an altitude of 6,000 to 8,000 feet,^6,7 ie, about 23 or 24 mm Hg, compared with about 30 mm Hg at sea level. At this pressure, passengers have a partial pressure of arterial oxygen (Pao₂) of 60 mm Hg (normal at sea level is > 80).⁸

This reduced oxygen pressure is typically not clinically meaningful in healthy people. However, people with underlying pulmonary or cardiac illness may be starting further to the left on the oxygen dissociation curve before gaining altitude, putting them at risk for acute exacerbations of underlying medical conditions. Many patients who rely on supplemental oxygen, such as those with chronic obstructive pulmonary disease, are advised to increase their oxygen support during flight.⁹

Boyle’s law says that the volume of a gas is inversely proportional to its pressure. As the pressure drops in the cabin after takeoff, air trapped in an enclosed space—eg, in some patient’s bodies—can increase in volume up to 30%,¹⁰ which can have medical ramifications. Clinically significant pneumothorax during flight has been reported.^11–13 Partially because of these volumetric changes, patients who have undergone abdominal surgery are advised to avoid flying for at least 2 weeks after their procedure.^10,14 Patients who have had recent ocular or intracranial surgery may also be at risk of in-flight complications.¹⁵

IN-FLIGHT MEDICAL RESOURCES

The limited medical supplies available on aircraft often challenge healthcare providers who offer to respond to in-flight medical events. However, several important medical resources are available.

Medical kits and defibrillators

FAA regulations require airlines based in the United States to carry basic first aid supplies such as bandages and splints.³ Airlines are also required to carry a medical kit containing the items listed in Table 1.

The FAA-mandated kit does not cover every circumstance that may arise. Although in-flight pediatric events occasionally occur,¹⁶ many of the available medications are inappropriate for young children. The FAA does not require sedative or antipsychotic agents, which could be useful for passengers who have acute psychiatric episodes. Obstetric supplies are absent. On international carriers, the contents of medical kits are highly variable,¹⁷ as are the names used for some medications.

The FAA requires at least 1 automated external defibrillator (AED) to be available on each commercial aircraft.³ The timely use of AEDs greatly improves survivability after out-of-hospital cardiac arrest.^18,19 One study involving a major US airline found a 40% survival rate to hospital discharge in patients who received in-flight defibrillation.²⁰ Without this intervention, very few of the patients would have been expected to survive. In addition to being clinically effective, placing AEDs aboard commercial aircraft is a cost-effective public health intervention.²¹

Most major airlines can contact ground-based medical consultation services during flight.¹⁰ These centers are staffed with healthcare providers who can provide flight crews with advice on how to handle medical events in real time. Healthcare providers can likewise discuss specific medical issues with these services if they respond to an in-flight medical event. Ground-based call centers can also communicate with prehospital providers should a flight need to be diverted.

Other on-board providers

Some medical events require the involvement of more than one medical provider. Other physicians, nurses, and prehospital providers are often also on board.²² Responding physicians can also request the assistance of these other healthcare providers. Flight attendants in the United States are required to be trained in cardiopulmonary resuscitation (CPR).²³

Flight diversion

Critically ill patients or those with time-sensitive medical emergencies may require the aircraft to divert from its intended destination. As may be expected, medical emergencies suspected to involve the cardiovascular, neurologic, or respiratory system have been shown to most likely result in aircraft diversion.^5,24 Approximately 7% of in-flight medical events in which a ground-based medical consultation service is contacted result in diversion.⁵

While an on-board responding physician can make a recommendation to divert based on the patient’s acute medical status, only the captain can make the ultimate decision.⁴ On-board healthcare providers should clearly state that a patient might benefit from an unscheduled landing if that is truly their assessment. In addition to communicating their clinical concerns with the flight crew, the responding physician may also be able to discuss the situation with the airline’s ground-based consultation service. On-board physicians can make important contributions to the assessment of illness severity and triage decisions.

MEDICOLEGAL ISSUES

No legal duty to assist

US healthcare providers are not legally required to respond to on-board medical emergencies on US-based airlines. Canada and the United Kingdom also do not require providers to render assistance. But the General Medical Council (the regulatory body for UK doctors) states that doctors have an ethical duty to respond in the event of a medical emergency, including one on board an aircraft. Other countries, notably Australia and some in the European Union, require healthcare professionals to respond to on-board medical emergencies.¹⁰

Regardless of potential legal duties to assist, healthcare providers are arguably ethically obliged to render assistance if they can.

Aviation Medical Assistance Act

The extent of an American healthcare provider’s liability risk for assisting in a medical emergency on a plane registered in the United States is limited by statute. The 1998 AMAA provides liability protection for on-board medical providers who are asked to assist during an in-flight medical emergency. This statute covers all US-certified air carriers on domestic flights and would likely be held to apply to US aircraft in foreign airspace because of the general rule that the law of the country where the air carrier is registered applies to in-flight events.

Under the AMAA, providers asked to assist with in-flight medical emergencies are not liable for malpractice as long as their actions are not “grossly” negligent or intended to cause the patient harm.²⁵ This is distinguishable from a standard malpractice liability scenario, in which the plaintiff only needs to show ordinary negligence. In a traditional healthcare setting, a provider has to act within the “standard of care” when assessing and treating a patient. If the provider deviates from the standard of care, such as by making an error in judgment or diagnosis, the provider is legally negligent. Under traditional malpractice law, even if a provider is minimally negligent, he or she is liable for any damages resulting from that negligence. Under a gross negligence standard, providers are protected from liability unless they demonstrate flagrant disregard for the patient’s health and safety.

Postflight issues

A provider who undertakes care should continue to provide care until it is no longer necessary, either because the patient recovers or the responsibility has been transferred to another provider. At the point of transfer, the healthcare provider’s relationship with the patient terminates.

The provider should document the encounter, typically using airline-specific documentation. The responding physician needs to be mindful of the patient’s privacy, refraining from discussing the event with others without the patient’s authorization.²⁶

Healthcare providers who wish to respond to in-flight medical emergencies must first determine if they are sufficiently capable of providing care. During a flight, providers do not expect to be on duty and so may have consumed alcoholic beverages to an extent that would potentially render them unsuitable to respond. When it is appropriate to become involved in a medical emergency during flight, the healthcare provider should state his or her qualifications to the passenger and to flight personnel.

If circumstances allow, the volunteer provider should obtain the patient’s consent for evaluation and treatment.¹⁰ Additionally, with the multilingual nature of commercial air travel, especially on international flights, the provider may need to enlist a translator’s assistance.

Providers may find it preferable to treat passengers in their seats.²⁷ Given the confined space in an aircraft, keeping ill passengers out of the aisle allows others to move about the cabin. If it becomes necessary to move the patient, a location should be sought that minimally interferes with other passengers’ needs.

If a passenger has critical medical needs, in-flight medical volunteers can recommend flight diversion, which should also be discussed with ground-based medical staff. However, as emphasized earlier, the captain makes the ultimate decision to divert, taking into account other operational factors that affect the safety of the aircraft and its occupants. In-flight medical care providers should perform only the treatments they are qualified to provide and should operate within their scope of training.

After the aircraft lands, if the passenger must be transported to a hospital, providers should supply prehospital personnel with a requisite transfer-of-care communication. In-flight medical providers who have performed a significant medical intervention might find it appropriate to accompany the patient to the hospital.

SPECIFIC CONDITIONS

The list of possible acute medical issues that occur aboard aircraft is extensive. Here are a few of them.

Trauma

Passengers may experience injuries during flight, for example during periods of heavy air turbulence. Responding physicians should assess for potential life-threatening injuries, keeping in mind that some passengers may be at higher risk. For example, if a passenger on anticoagulation experiences a blunt head injury, this would raise suspicion for possible intracranial hemorrhage, and frequent reassessment of neurologic status may be necessary. If an extremity fracture is suspected, the physician should splint the affected limb. Analgesia may be provided from the medical kit, if appropriate.

Gastrointestinal issues

Acute gastrointestinal issues such as nausea and vomiting are often reported to ground-based medical consultation services.⁵ Responding on-board providers must consider if the passenger is simply experiencing gastrointestinal upset from a benign condition such as gastroenteritis or has a more serious condition. For some patients, vomiting may be a symptom of a myocardial infarction.²⁸ Bilious emesis with abdominal distention may be associated with small-bowel obstruction. While antiemetics are not included in the FAA-mandated medical kit, providers can initiate intravenous fluid therapy for passengers who show signs of hypovolemia.

Cardiac arrest

Although cardiac arrest during flight is rare,⁵ medical providers should nonetheless be prepared to handle it. Upon recognition of cardiac arrest, the provider should immediately begin cardiopulmonary resuscitation and use the on-board AED to defibrillate a potentially shockable rhythm. Flight attendants are trained in cardiopulmonary resuscitation and therefore may assist with resuscitation efforts. If the patient is resuscitated, the responding physician should recommend diversion of the flight.

In the event of a severe life-threatening allergic reaction, the FAA-mandated emergency medical kit contains both diphenhydramine and epinephrine. For an adult experiencing anaphylaxis, a responding on-board physician can administer diphenhydramine 50 mg and epinephrine 0.3 mg (using the 1:1000 formulation), both intramuscularly. For patients with bronchospasm, a metered-dose inhaler of albuterol can be given. As anaphylaxis is an acute and potentially lethal condition, diversion of the aircraft would also be appropriate.²⁹

Myocardial infarction

When acute myocardial infarction is suspected, it is appropriate for the provider to give aspirin, with important exceptions for patients who are experiencing an acute hemorrhage or who have an aspirin allergy.³⁰ Supplemental oxygen should likewise be provided if the responding physician suspects compromised oxygenation. As acute myocardial infarction is also a time-sensitive condition, the clinician who suspects this diagnosis should recommend diversion of the aircraft.

Acute psychiatric issues

While approximately 2.4% of on-board medical events are attributed to psychiatric issues,⁵ there are few tools at the clinician’s disposal in the FAA-mandated emergency medical kit. Antipsychotics and sedatives are not included. The responding physician may need to attempt verbal de-escalation of aggressive behavior. If the safety of the flight is compromised, the application of improvised physical restraints may be appropriate.

Altered mental status

The differential diagnosis for altered mental status is extensive. The on-board physician should try to identify reversible and potentially lethal conditions and determine the potential need for aircraft diversion.

If possible, a blood sugar level should be measured (although the FAA-mandated kit does not contain a glucometer). It may be appropriate to empirically give intravenous dextrose to patients strongly suspected of having hypoglycemia.

If respiratory or cerebrovascular compromise is suspected, supplemental oxygen should be provided.

Unless a reversible cause of altered mental status is identified and treated successfully, it will likely be appropriate to recommend diversion of the aircraft.

Acknowledgment: The authors acknowledge Linda J. Kesselring, MS, ELS, the technical editor/writer in the Department of Emergency Medicine University of Maryland School of Medicine, for her contributions as copy editor of a previous version of this manuscript.

It could happen. You are on a plane, perhaps on your way to a medical conference or a well-deserved vacation, when the flight attendant asks you to help a passenger experiencing an in-flight medical emergency. What is your role in this situation?

FLIGHT ATTENDANTS USED TO BE NURSES

Before World War II, nearly all American flight attendants were nurses, who could address most medical issues that arose during flights.¹ Airlines eliminated this preferential hiring practice to support the war effort. Traveling healthcare providers thereafter often volunteered to assist when in-flight medical issues arose, but aircraft carried minimal medical equipment and volunteers’ liability was uncertain.

In 1998, Congress passed the Aviation Medical Assistance Act (AMAA), which provides liability protection for on-board healthcare providers who render medical assistance. It also required the Federal Aviation Administration (FAA) to improve its standards for in-flight medical equipment.^2,3

HOW OFTEN DO EMERGENCIES ARISE?

How often medical events occur during flight is difficult to estimate because airlines are not mandated to report such issues.⁴ Based on data from a ground-based communications center that provides medical consultation service to airlines, medical events occur in approximately 1 in every 604 flights.⁵ This is likely an underestimate, as many medical events may be handled on board without involving a ground-based consultation center.

The most common emergencies are syncope or presyncope, representing 37.4% of consultations, followed by respiratory symptoms (12.1%), nausea or vomiting (9.5%), cardiac symptoms (7.7%), seizures (5.8%), and abdominal pain (4.1%).⁵ Very few in-flight medical emergencies progress to death; the reported mortality rate is 0.3%.⁵

CABIN PRESSURES ARE RELATIVELY LOW

The cabins of commercial airliners are pressurized, but the pressure is still lower than on the ground. The cabin pressure in flight is equivalent to that at an altitude of 6,000 to 8,000 feet,^6,7 ie, about 23 or 24 mm Hg, compared with about 30 mm Hg at sea level. At this pressure, passengers have a partial pressure of arterial oxygen (Pao₂) of 60 mm Hg (normal at sea level is > 80).⁸

This reduced oxygen pressure is typically not clinically meaningful in healthy people. However, people with underlying pulmonary or cardiac illness may be starting further to the left on the oxygen dissociation curve before gaining altitude, putting them at risk for acute exacerbations of underlying medical conditions. Many patients who rely on supplemental oxygen, such as those with chronic obstructive pulmonary disease, are advised to increase their oxygen support during flight.⁹

Boyle’s law says that the volume of a gas is inversely proportional to its pressure. As the pressure drops in the cabin after takeoff, air trapped in an enclosed space—eg, in some patient’s bodies—can increase in volume up to 30%,¹⁰ which can have medical ramifications. Clinically significant pneumothorax during flight has been reported.^11–13 Partially because of these volumetric changes, patients who have undergone abdominal surgery are advised to avoid flying for at least 2 weeks after their procedure.^10,14 Patients who have had recent ocular or intracranial surgery may also be at risk of in-flight complications.¹⁵

IN-FLIGHT MEDICAL RESOURCES

The limited medical supplies available on aircraft often challenge healthcare providers who offer to respond to in-flight medical events. However, several important medical resources are available.

Medical kits and defibrillators

FAA regulations require airlines based in the United States to carry basic first aid supplies such as bandages and splints.³ Airlines are also required to carry a medical kit containing the items listed in Table 1.

The FAA-mandated kit does not cover every circumstance that may arise. Although in-flight pediatric events occasionally occur,¹⁶ many of the available medications are inappropriate for young children. The FAA does not require sedative or antipsychotic agents, which could be useful for passengers who have acute psychiatric episodes. Obstetric supplies are absent. On international carriers, the contents of medical kits are highly variable,¹⁷ as are the names used for some medications.

The FAA requires at least 1 automated external defibrillator (AED) to be available on each commercial aircraft.³ The timely use of AEDs greatly improves survivability after out-of-hospital cardiac arrest.^18,19 One study involving a major US airline found a 40% survival rate to hospital discharge in patients who received in-flight defibrillation.²⁰ Without this intervention, very few of the patients would have been expected to survive. In addition to being clinically effective, placing AEDs aboard commercial aircraft is a cost-effective public health intervention.²¹

Most major airlines can contact ground-based medical consultation services during flight.¹⁰ These centers are staffed with healthcare providers who can provide flight crews with advice on how to handle medical events in real time. Healthcare providers can likewise discuss specific medical issues with these services if they respond to an in-flight medical event. Ground-based call centers can also communicate with prehospital providers should a flight need to be diverted.

Other on-board providers

Some medical events require the involvement of more than one medical provider. Other physicians, nurses, and prehospital providers are often also on board.²² Responding physicians can also request the assistance of these other healthcare providers. Flight attendants in the United States are required to be trained in cardiopulmonary resuscitation (CPR).²³

Flight diversion

Critically ill patients or those with time-sensitive medical emergencies may require the aircraft to divert from its intended destination. As may be expected, medical emergencies suspected to involve the cardiovascular, neurologic, or respiratory system have been shown to most likely result in aircraft diversion.^5,24 Approximately 7% of in-flight medical events in which a ground-based medical consultation service is contacted result in diversion.⁵

While an on-board responding physician can make a recommendation to divert based on the patient’s acute medical status, only the captain can make the ultimate decision.⁴ On-board healthcare providers should clearly state that a patient might benefit from an unscheduled landing if that is truly their assessment. In addition to communicating their clinical concerns with the flight crew, the responding physician may also be able to discuss the situation with the airline’s ground-based consultation service. On-board physicians can make important contributions to the assessment of illness severity and triage decisions.

MEDICOLEGAL ISSUES

No legal duty to assist

US healthcare providers are not legally required to respond to on-board medical emergencies on US-based airlines. Canada and the United Kingdom also do not require providers to render assistance. But the General Medical Council (the regulatory body for UK doctors) states that doctors have an ethical duty to respond in the event of a medical emergency, including one on board an aircraft. Other countries, notably Australia and some in the European Union, require healthcare professionals to respond to on-board medical emergencies.¹⁰

Regardless of potential legal duties to assist, healthcare providers are arguably ethically obliged to render assistance if they can.

Aviation Medical Assistance Act

The extent of an American healthcare provider’s liability risk for assisting in a medical emergency on a plane registered in the United States is limited by statute. The 1998 AMAA provides liability protection for on-board medical providers who are asked to assist during an in-flight medical emergency. This statute covers all US-certified air carriers on domestic flights and would likely be held to apply to US aircraft in foreign airspace because of the general rule that the law of the country where the air carrier is registered applies to in-flight events.

Under the AMAA, providers asked to assist with in-flight medical emergencies are not liable for malpractice as long as their actions are not “grossly” negligent or intended to cause the patient harm.²⁵ This is distinguishable from a standard malpractice liability scenario, in which the plaintiff only needs to show ordinary negligence. In a traditional healthcare setting, a provider has to act within the “standard of care” when assessing and treating a patient. If the provider deviates from the standard of care, such as by making an error in judgment or diagnosis, the provider is legally negligent. Under traditional malpractice law, even if a provider is minimally negligent, he or she is liable for any damages resulting from that negligence. Under a gross negligence standard, providers are protected from liability unless they demonstrate flagrant disregard for the patient’s health and safety.

Postflight issues

A provider who undertakes care should continue to provide care until it is no longer necessary, either because the patient recovers or the responsibility has been transferred to another provider. At the point of transfer, the healthcare provider’s relationship with the patient terminates.

The provider should document the encounter, typically using airline-specific documentation. The responding physician needs to be mindful of the patient’s privacy, refraining from discussing the event with others without the patient’s authorization.²⁶

Healthcare providers who wish to respond to in-flight medical emergencies must first determine if they are sufficiently capable of providing care. During a flight, providers do not expect to be on duty and so may have consumed alcoholic beverages to an extent that would potentially render them unsuitable to respond. When it is appropriate to become involved in a medical emergency during flight, the healthcare provider should state his or her qualifications to the passenger and to flight personnel.

If circumstances allow, the volunteer provider should obtain the patient’s consent for evaluation and treatment.¹⁰ Additionally, with the multilingual nature of commercial air travel, especially on international flights, the provider may need to enlist a translator’s assistance.

Providers may find it preferable to treat passengers in their seats.²⁷ Given the confined space in an aircraft, keeping ill passengers out of the aisle allows others to move about the cabin. If it becomes necessary to move the patient, a location should be sought that minimally interferes with other passengers’ needs.

If a passenger has critical medical needs, in-flight medical volunteers can recommend flight diversion, which should also be discussed with ground-based medical staff. However, as emphasized earlier, the captain makes the ultimate decision to divert, taking into account other operational factors that affect the safety of the aircraft and its occupants. In-flight medical care providers should perform only the treatments they are qualified to provide and should operate within their scope of training.

After the aircraft lands, if the passenger must be transported to a hospital, providers should supply prehospital personnel with a requisite transfer-of-care communication. In-flight medical providers who have performed a significant medical intervention might find it appropriate to accompany the patient to the hospital.

SPECIFIC CONDITIONS

The list of possible acute medical issues that occur aboard aircraft is extensive. Here are a few of them.

Trauma

Passengers may experience injuries during flight, for example during periods of heavy air turbulence. Responding physicians should assess for potential life-threatening injuries, keeping in mind that some passengers may be at higher risk. For example, if a passenger on anticoagulation experiences a blunt head injury, this would raise suspicion for possible intracranial hemorrhage, and frequent reassessment of neurologic status may be necessary. If an extremity fracture is suspected, the physician should splint the affected limb. Analgesia may be provided from the medical kit, if appropriate.

Gastrointestinal issues

Acute gastrointestinal issues such as nausea and vomiting are often reported to ground-based medical consultation services.⁵ Responding on-board providers must consider if the passenger is simply experiencing gastrointestinal upset from a benign condition such as gastroenteritis or has a more serious condition. For some patients, vomiting may be a symptom of a myocardial infarction.²⁸ Bilious emesis with abdominal distention may be associated with small-bowel obstruction. While antiemetics are not included in the FAA-mandated medical kit, providers can initiate intravenous fluid therapy for passengers who show signs of hypovolemia.

Cardiac arrest

Although cardiac arrest during flight is rare,⁵ medical providers should nonetheless be prepared to handle it. Upon recognition of cardiac arrest, the provider should immediately begin cardiopulmonary resuscitation and use the on-board AED to defibrillate a potentially shockable rhythm. Flight attendants are trained in cardiopulmonary resuscitation and therefore may assist with resuscitation efforts. If the patient is resuscitated, the responding physician should recommend diversion of the flight.

In the event of a severe life-threatening allergic reaction, the FAA-mandated emergency medical kit contains both diphenhydramine and epinephrine. For an adult experiencing anaphylaxis, a responding on-board physician can administer diphenhydramine 50 mg and epinephrine 0.3 mg (using the 1:1000 formulation), both intramuscularly. For patients with bronchospasm, a metered-dose inhaler of albuterol can be given. As anaphylaxis is an acute and potentially lethal condition, diversion of the aircraft would also be appropriate.²⁹

Myocardial infarction

When acute myocardial infarction is suspected, it is appropriate for the provider to give aspirin, with important exceptions for patients who are experiencing an acute hemorrhage or who have an aspirin allergy.³⁰ Supplemental oxygen should likewise be provided if the responding physician suspects compromised oxygenation. As acute myocardial infarction is also a time-sensitive condition, the clinician who suspects this diagnosis should recommend diversion of the aircraft.

Acute psychiatric issues

While approximately 2.4% of on-board medical events are attributed to psychiatric issues,⁵ there are few tools at the clinician’s disposal in the FAA-mandated emergency medical kit. Antipsychotics and sedatives are not included. The responding physician may need to attempt verbal de-escalation of aggressive behavior. If the safety of the flight is compromised, the application of improvised physical restraints may be appropriate.

Altered mental status

The differential diagnosis for altered mental status is extensive. The on-board physician should try to identify reversible and potentially lethal conditions and determine the potential need for aircraft diversion.

If possible, a blood sugar level should be measured (although the FAA-mandated kit does not contain a glucometer). It may be appropriate to empirically give intravenous dextrose to patients strongly suspected of having hypoglycemia.

If respiratory or cerebrovascular compromise is suspected, supplemental oxygen should be provided.

Unless a reversible cause of altered mental status is identified and treated successfully, it will likely be appropriate to recommend diversion of the aircraft.

Acknowledgment: The authors acknowledge Linda J. Kesselring, MS, ELS, the technical editor/writer in the Department of Emergency Medicine University of Maryland School of Medicine, for her contributions as copy editor of a previous version of this manuscript.

It could happen. You are on a plane, perhaps on your way to a medical conference or a well-deserved vacation, when the flight attendant asks you to help a passenger experiencing an in-flight medical emergency. What is your role in this situation?

FLIGHT ATTENDANTS USED TO BE NURSES

Before World War II, nearly all American flight attendants were nurses, who could address most medical issues that arose during flights.¹ Airlines eliminated this preferential hiring practice to support the war effort. Traveling healthcare providers thereafter often volunteered to assist when in-flight medical issues arose, but aircraft carried minimal medical equipment and volunteers’ liability was uncertain.

In 1998, Congress passed the Aviation Medical Assistance Act (AMAA), which provides liability protection for on-board healthcare providers who render medical assistance. It also required the Federal Aviation Administration (FAA) to improve its standards for in-flight medical equipment.^2,3

HOW OFTEN DO EMERGENCIES ARISE?

How often medical events occur during flight is difficult to estimate because airlines are not mandated to report such issues.⁴ Based on data from a ground-based communications center that provides medical consultation service to airlines, medical events occur in approximately 1 in every 604 flights.⁵ This is likely an underestimate, as many medical events may be handled on board without involving a ground-based consultation center.

The most common emergencies are syncope or presyncope, representing 37.4% of consultations, followed by respiratory symptoms (12.1%), nausea or vomiting (9.5%), cardiac symptoms (7.7%), seizures (5.8%), and abdominal pain (4.1%).⁵ Very few in-flight medical emergencies progress to death; the reported mortality rate is 0.3%.⁵

CABIN PRESSURES ARE RELATIVELY LOW

The cabins of commercial airliners are pressurized, but the pressure is still lower than on the ground. The cabin pressure in flight is equivalent to that at an altitude of 6,000 to 8,000 feet,^6,7 ie, about 23 or 24 mm Hg, compared with about 30 mm Hg at sea level. At this pressure, passengers have a partial pressure of arterial oxygen (Pao₂) of 60 mm Hg (normal at sea level is > 80).⁸

This reduced oxygen pressure is typically not clinically meaningful in healthy people. However, people with underlying pulmonary or cardiac illness may be starting further to the left on the oxygen dissociation curve before gaining altitude, putting them at risk for acute exacerbations of underlying medical conditions. Many patients who rely on supplemental oxygen, such as those with chronic obstructive pulmonary disease, are advised to increase their oxygen support during flight.⁹

Boyle’s law says that the volume of a gas is inversely proportional to its pressure. As the pressure drops in the cabin after takeoff, air trapped in an enclosed space—eg, in some patient’s bodies—can increase in volume up to 30%,¹⁰ which can have medical ramifications. Clinically significant pneumothorax during flight has been reported.^11–13 Partially because of these volumetric changes, patients who have undergone abdominal surgery are advised to avoid flying for at least 2 weeks after their procedure.^10,14 Patients who have had recent ocular or intracranial surgery may also be at risk of in-flight complications.¹⁵

IN-FLIGHT MEDICAL RESOURCES

The limited medical supplies available on aircraft often challenge healthcare providers who offer to respond to in-flight medical events. However, several important medical resources are available.

Medical kits and defibrillators

FAA regulations require airlines based in the United States to carry basic first aid supplies such as bandages and splints.³ Airlines are also required to carry a medical kit containing the items listed in Table 1.

The FAA-mandated kit does not cover every circumstance that may arise. Although in-flight pediatric events occasionally occur,¹⁶ many of the available medications are inappropriate for young children. The FAA does not require sedative or antipsychotic agents, which could be useful for passengers who have acute psychiatric episodes. Obstetric supplies are absent. On international carriers, the contents of medical kits are highly variable,¹⁷ as are the names used for some medications.

The FAA requires at least 1 automated external defibrillator (AED) to be available on each commercial aircraft.³ The timely use of AEDs greatly improves survivability after out-of-hospital cardiac arrest.^18,19 One study involving a major US airline found a 40% survival rate to hospital discharge in patients who received in-flight defibrillation.²⁰ Without this intervention, very few of the patients would have been expected to survive. In addition to being clinically effective, placing AEDs aboard commercial aircraft is a cost-effective public health intervention.²¹

Most major airlines can contact ground-based medical consultation services during flight.¹⁰ These centers are staffed with healthcare providers who can provide flight crews with advice on how to handle medical events in real time. Healthcare providers can likewise discuss specific medical issues with these services if they respond to an in-flight medical event. Ground-based call centers can also communicate with prehospital providers should a flight need to be diverted.

Other on-board providers

Some medical events require the involvement of more than one medical provider. Other physicians, nurses, and prehospital providers are often also on board.²² Responding physicians can also request the assistance of these other healthcare providers. Flight attendants in the United States are required to be trained in cardiopulmonary resuscitation (CPR).²³

Flight diversion

Critically ill patients or those with time-sensitive medical emergencies may require the aircraft to divert from its intended destination. As may be expected, medical emergencies suspected to involve the cardiovascular, neurologic, or respiratory system have been shown to most likely result in aircraft diversion.^5,24 Approximately 7% of in-flight medical events in which a ground-based medical consultation service is contacted result in diversion.⁵

While an on-board responding physician can make a recommendation to divert based on the patient’s acute medical status, only the captain can make the ultimate decision.⁴ On-board healthcare providers should clearly state that a patient might benefit from an unscheduled landing if that is truly their assessment. In addition to communicating their clinical concerns with the flight crew, the responding physician may also be able to discuss the situation with the airline’s ground-based consultation service. On-board physicians can make important contributions to the assessment of illness severity and triage decisions.

MEDICOLEGAL ISSUES

No legal duty to assist

US healthcare providers are not legally required to respond to on-board medical emergencies on US-based airlines. Canada and the United Kingdom also do not require providers to render assistance. But the General Medical Council (the regulatory body for UK doctors) states that doctors have an ethical duty to respond in the event of a medical emergency, including one on board an aircraft. Other countries, notably Australia and some in the European Union, require healthcare professionals to respond to on-board medical emergencies.¹⁰

Regardless of potential legal duties to assist, healthcare providers are arguably ethically obliged to render assistance if they can.

Aviation Medical Assistance Act

The extent of an American healthcare provider’s liability risk for assisting in a medical emergency on a plane registered in the United States is limited by statute. The 1998 AMAA provides liability protection for on-board medical providers who are asked to assist during an in-flight medical emergency. This statute covers all US-certified air carriers on domestic flights and would likely be held to apply to US aircraft in foreign airspace because of the general rule that the law of the country where the air carrier is registered applies to in-flight events.

Under the AMAA, providers asked to assist with in-flight medical emergencies are not liable for malpractice as long as their actions are not “grossly” negligent or intended to cause the patient harm.²⁵ This is distinguishable from a standard malpractice liability scenario, in which the plaintiff only needs to show ordinary negligence. In a traditional healthcare setting, a provider has to act within the “standard of care” when assessing and treating a patient. If the provider deviates from the standard of care, such as by making an error in judgment or diagnosis, the provider is legally negligent. Under traditional malpractice law, even if a provider is minimally negligent, he or she is liable for any damages resulting from that negligence. Under a gross negligence standard, providers are protected from liability unless they demonstrate flagrant disregard for the patient’s health and safety.

Postflight issues

A provider who undertakes care should continue to provide care until it is no longer necessary, either because the patient recovers or the responsibility has been transferred to another provider. At the point of transfer, the healthcare provider’s relationship with the patient terminates.

The provider should document the encounter, typically using airline-specific documentation. The responding physician needs to be mindful of the patient’s privacy, refraining from discussing the event with others without the patient’s authorization.²⁶

Healthcare providers who wish to respond to in-flight medical emergencies must first determine if they are sufficiently capable of providing care. During a flight, providers do not expect to be on duty and so may have consumed alcoholic beverages to an extent that would potentially render them unsuitable to respond. When it is appropriate to become involved in a medical emergency during flight, the healthcare provider should state his or her qualifications to the passenger and to flight personnel.

If circumstances allow, the volunteer provider should obtain the patient’s consent for evaluation and treatment.¹⁰ Additionally, with the multilingual nature of commercial air travel, especially on international flights, the provider may need to enlist a translator’s assistance.

Providers may find it preferable to treat passengers in their seats.²⁷ Given the confined space in an aircraft, keeping ill passengers out of the aisle allows others to move about the cabin. If it becomes necessary to move the patient, a location should be sought that minimally interferes with other passengers’ needs.

If a passenger has critical medical needs, in-flight medical volunteers can recommend flight diversion, which should also be discussed with ground-based medical staff. However, as emphasized earlier, the captain makes the ultimate decision to divert, taking into account other operational factors that affect the safety of the aircraft and its occupants. In-flight medical care providers should perform only the treatments they are qualified to provide and should operate within their scope of training.

After the aircraft lands, if the passenger must be transported to a hospital, providers should supply prehospital personnel with a requisite transfer-of-care communication. In-flight medical providers who have performed a significant medical intervention might find it appropriate to accompany the patient to the hospital.

SPECIFIC CONDITIONS

The list of possible acute medical issues that occur aboard aircraft is extensive. Here are a few of them.

Trauma

Passengers may experience injuries during flight, for example during periods of heavy air turbulence. Responding physicians should assess for potential life-threatening injuries, keeping in mind that some passengers may be at higher risk. For example, if a passenger on anticoagulation experiences a blunt head injury, this would raise suspicion for possible intracranial hemorrhage, and frequent reassessment of neurologic status may be necessary. If an extremity fracture is suspected, the physician should splint the affected limb. Analgesia may be provided from the medical kit, if appropriate.

Gastrointestinal issues

Acute gastrointestinal issues such as nausea and vomiting are often reported to ground-based medical consultation services.⁵ Responding on-board providers must consider if the passenger is simply experiencing gastrointestinal upset from a benign condition such as gastroenteritis or has a more serious condition. For some patients, vomiting may be a symptom of a myocardial infarction.²⁸ Bilious emesis with abdominal distention may be associated with small-bowel obstruction. While antiemetics are not included in the FAA-mandated medical kit, providers can initiate intravenous fluid therapy for passengers who show signs of hypovolemia.

Cardiac arrest

Although cardiac arrest during flight is rare,⁵ medical providers should nonetheless be prepared to handle it. Upon recognition of cardiac arrest, the provider should immediately begin cardiopulmonary resuscitation and use the on-board AED to defibrillate a potentially shockable rhythm. Flight attendants are trained in cardiopulmonary resuscitation and therefore may assist with resuscitation efforts. If the patient is resuscitated, the responding physician should recommend diversion of the flight.

In the event of a severe life-threatening allergic reaction, the FAA-mandated emergency medical kit contains both diphenhydramine and epinephrine. For an adult experiencing anaphylaxis, a responding on-board physician can administer diphenhydramine 50 mg and epinephrine 0.3 mg (using the 1:1000 formulation), both intramuscularly. For patients with bronchospasm, a metered-dose inhaler of albuterol can be given. As anaphylaxis is an acute and potentially lethal condition, diversion of the aircraft would also be appropriate.²⁹

Myocardial infarction

When acute myocardial infarction is suspected, it is appropriate for the provider to give aspirin, with important exceptions for patients who are experiencing an acute hemorrhage or who have an aspirin allergy.³⁰ Supplemental oxygen should likewise be provided if the responding physician suspects compromised oxygenation. As acute myocardial infarction is also a time-sensitive condition, the clinician who suspects this diagnosis should recommend diversion of the aircraft.

Acute psychiatric issues

While approximately 2.4% of on-board medical events are attributed to psychiatric issues,⁵ there are few tools at the clinician’s disposal in the FAA-mandated emergency medical kit. Antipsychotics and sedatives are not included. The responding physician may need to attempt verbal de-escalation of aggressive behavior. If the safety of the flight is compromised, the application of improvised physical restraints may be appropriate.

Altered mental status

The differential diagnosis for altered mental status is extensive. The on-board physician should try to identify reversible and potentially lethal conditions and determine the potential need for aircraft diversion.

If possible, a blood sugar level should be measured (although the FAA-mandated kit does not contain a glucometer). It may be appropriate to empirically give intravenous dextrose to patients strongly suspected of having hypoglycemia.

If respiratory or cerebrovascular compromise is suspected, supplemental oxygen should be provided.

Unless a reversible cause of altered mental status is identified and treated successfully, it will likely be appropriate to recommend diversion of the aircraft.

Acknowledgment: The authors acknowledge Linda J. Kesselring, MS, ELS, the technical editor/writer in the Department of Emergency Medicine University of Maryland School of Medicine, for her contributions as copy editor of a previous version of this manuscript.

ANSWER

The radiograph shows a large, hyperdense mass within the left hilum. A second hyperdense mass is seen within the left upper lobe. Both are concerning for neoplastic processes and warrant further evaluation with contrast-enhanced CT.

Although thorough work-up and biopsy is needed, the presumptive diagnosis is a primary lung mass with likely metastasis to the brain.

ANSWER

The radiograph shows a large, hyperdense mass within the left hilum. A second hyperdense mass is seen within the left upper lobe. Both are concerning for neoplastic processes and warrant further evaluation with contrast-enhanced CT.

Although thorough work-up and biopsy is needed, the presumptive diagnosis is a primary lung mass with likely metastasis to the brain.

ANSWER

The radiograph shows a large, hyperdense mass within the left hilum. A second hyperdense mass is seen within the left upper lobe. Both are concerning for neoplastic processes and warrant further evaluation with contrast-enhanced CT.

Although thorough work-up and biopsy is needed, the presumptive diagnosis is a primary lung mass with likely metastasis to the brain.