Cleveland Clinic Journal of Medicine

Opinion about treatment of mall renal masses has changed considerably in the past 2 decades.

Traditionally, the most common treatment was surgical removal of the whole kidney, ie, radical nephrectomy. However, recent studies have shown that many patients who undergo radical nephrectomy develop chronic kidney disease. Furthermore, radical nephrectomy often constitutes over-treatment, as many of these lesions are benign or, if malignant, would follow an indolent course if left alone.

Now that we better understand the biology of small renal masses and are more aware of the morbidity and mortality related to chronic kidney disease, we try to avoid radical nephrectomy whenever possible, favoring nephron-sparing approaches instead.

In this article, we review the current clinical management of small renal masses.

SMALL RENAL MASSES ARE A HETEROGENEOUS GROUP

Small renal masses are defined as solid renal tumors that enhance on computed tomography (CT) and magnetic resonance imaging (MRI) and are suspected of being renal cell carcinomas. They are generally low-stage and relatively small (< 4 cm in diameter) at presentation. Most are now discovered incidentally on CT or MRI done for various abdominal symptoms. From 20,000 to 30,000 new cases are diagnosed each year in the United States, and the rate is increasing by 3% to 4% per year as the use of CT and MRI increases.^1,2

With more small renal masses being detected incidentally, renal cell carcinoma has been going through a stage and size migration—ie, more of these tumors are being discovered in clinical stage T1 (ie, confined to the kidney and measuring less than 7 cm) than in the past. Currently, clinical T1 renal tumors account for 48% to 66% of cases.³

This indicates that the disease is being detected and treated earlier in its course than in the past. However, cancer-specific deaths from renal cell carcinoma have not declined, suggesting that for many of these patients, our traditional practice of aggressive surgical management with radical nephrectomy may not be warranted.⁴

Small renal masses vary in biologic aggressiveness

Recent large surgical series indicate that up to 20% of small renal masses are benign, 55% to 60% are indolent renal cell carcinomas, and only 20% to 25% have potentially aggressive features, defined by high nuclear grade or locally invasive characteristics.^5–7

A relatively strong predictor of the aggressiveness of renal tumors is their size, which directly correlates with the risk of malignant pathology. Of lesions smaller than 1.0 cm, 38% to 46% are benign, dramatically decreasing to 6.3% to 7.1% for lesions larger than 7.0 cm.⁵ Each 1.0-cm increase in tumor diameter correlates with a 16% increase in the risk of malignancy.⁸

Our knowledge of the natural history of small renal masses is limited, being based on small, retrospective series. In these studies, when small renal masses were followed over time, relatively few progressed (ie, metastasized), and there have been no documented reports of disease progression in the absence of demonstrable tumor growth, suggesting a predominance of nonaggressive phenotypes.⁹

In light of these observations, patients with small renal masses should be carefully evaluated to determine if they are candidates for active surveillance as opposed to more aggressive treatment, ie, surgery or thermal ablation.

CT AND MRI ARE THE PREFERRED DIAGNOSTIC STUDIES

In the past, most patients with renal tumors presented with gross hematuria, flank pain, or a palpable abdominal mass. These presentations are now uncommon, as most cases are asymptomatic and are diagnosed incidentally. In a series of 349 small renal masses, microhematuria was found in only 8 cases.¹⁰

Systemic manifestations or paraneoplastic syndromes such as hypercalcemia or hypertension are more common in patients with metastatic renal cell carcinoma than in those with localized tumors. It was because of these varied clinical presentations that renal cell carcinoma was previously known as the “internist’s tumor”; however, small renal masses are better termed the “radiologist’s tumor.”¹¹

High-quality axial imaging with CT or MRI is preferred for evaluating renal cortical neoplasms. Enhancement on CT or MRI is the characteristic finding of a renal lesion that should be suspected of being renal cell carcinoma (Figure 1). Triple-phase CT is ideal, with images taken before contrast is given, immediately after contrast (the early vascular phase), and later (the delayed phase). Alternatively, MRI can be used in patients who are allergic to intravenous contrast or who have moderate renal dysfunction.

Renal tumors with enhancement of more than 15 Hounsfield units (HU) on CT imaging are considered suggestive of renal cell carcinoma, whereas those with less than 10 HU of enhancement are more likely to be benign. Enhancement in the range of 10 to 15 HU is considered equivocal.

Differential diagnosis

By far, most small renal masses are renal cell carcinomas. However, other possibilities include oncocytoma, atypical or fat-poor angiomyolipoma, metanephric adenoma, urothelial carcinoma, metastatic lesions, lymphoma, renal abscess or infarction, mixed epithelial or stromal tumor, pseudotumor, and vascular malformations.

With rare exceptions, dense fat within a renal mass reliably indicates benign angiomyolipoma, and all renal tumors should be reviewed carefully for this feature. Beyond this, no clinical or radiologic feature ensures that a small renal mass is benign.

Imaging’s inability to accurately classify these enhancing renal lesions has led to a renewed interest in renal mass sampling to aid in the evaluation of small renal masses.

RENAL MASS SAMPLING: SAFER, MORE ACCURATE THAN THOUGHT

Renal mass sampling (ie, biopsy) has traditionally had a restricted role in the management of small renal masses, limited specifically to patients with a clinical history suggesting renal lymphoma, carcinoma that had metastasized to the kidney, or primary renal abscess. However, this may be changing, with more interest in it as a way to subtype and stratify select patients with small renal masses, especially potential candidates for active surveillance.

Our thinking about renal mass sampling has changed substantially over the last 2 decades. Previously, it was not routinely performed, because of concern over high false-negative rates (commonly quoted as being as high as 18%) and its potential associated morbidity. A common perception was that a negative biopsy could not be trusted and, therefore, renal mass sampling would not ultimately change patient management. However, many of these false-negative results were actually “noninformative,” ie, cases in which the renal tumor could not be adequately sampled or the pathologist lacked a sufficient specimen to allow for a definitive diagnosis.

Recent evidence suggests that these concerns were exaggerated and that renal mass sampling is more accurate and safer than previously thought. A meta-analysis of studies done before 2001 found that the diagnostic accuracy of renal mass sampling averaged 82%, whereas contemporary series indicate that its accuracy in differentiating benign from malignant tumors is actually greater than 95%.¹² In addition, false-negative rates are now consistently less than 1%.¹³

Furthermore, serious complications requiring clinical intervention or hospitalization occur in fewer than 1% of cases. Seeding of the needle tract with tumor cells, which was another concern, is also exceedingly rare for these small, well-circumscribed renal masses.¹²

Overall morbidity is low with renal mass sampling, which is routinely performed as an outpatient procedure using CT or ultrasono-graphic guidance and local anesthesia.

However, 10% of biopsy results are still noninformative. In this situation, biopsy can be repeated, or the mass can be surgically excised, or the patient can undergo conservative management if he or she is unfit or unwilling to undergo surgery.

The encouraging results with renal mass sampling have led to greater use of it at many centers in the evaluation and risk-stratification of patients with small renal masses. It may be especially useful in patients considering several treatment options.

For example, a 75-year-old patient with modest comorbidities and a 2.0-cm enhancing renal mass could be a candidate for partial nephrectomy, thermal ablation, or active surveillance, and a reasonable argument could be made for each of these options. Renal mass sampling in this instance could be instrumental in guiding this decision, as a tissue diagnosis of high-grade renal cell carcinoma would favor partial nephrectomy, whereas a diagnosis of “oncocytoma neoplasm” would support a more conservative approach.

Older, frail patients with significant comorbidities who are unlikely to be candidates for aggressive surgical management would not need renal mass sampling, as they will ultimately be managed with active surveillance or thermal ablation.

Recent studies have also indicated that molecular profiling through gene expression analysis or proteomic analysis can further improve the accuracy of renal mass sampling.¹⁴ This will likely be the holy grail for this field, allowing for truly rational management (Figure 2).

TREATMENT OPTIONS

Radical nephrectomy: Still the most common treatment

In the past, complete removal of the kidney was standard for nearly all renal masses suspected of being renal cell carcinomas. Partial nephrectomy was generally reserved for patients who had a solitary kidney, bilateral tumors, or preexisting chronic kidney disease.

Although the two procedures provide equivalent oncologic outcomes for clinical T1 lesions, Miller et al¹⁵ reported that, before 2001, only 20% of small renal masses in the United States were managed with partial nephrectomy. That percentage has increased modestly, but radical nephrectomy still predominates.

One explanation for why the radical procedure is done more frequently is that partial nephrectomy is more technically difficult, as it involves renal reconstruction. Furthermore, radical nephrectomy can almost always be performed via a minimally invasive approach, which is inherently appealing to patients and surgeons alike. Laparoscopic radical nephrectomy has been called “the great seductress” because of these considerations.¹⁶ However, total removal of the kidney comes at a great price—loss of renal function.

Over the last decade, various studies have highlighted the association between radical nephrectomy and the subsequent clinical onset of chronic kidney disease, and the potential correlations between chronic kidney disease and cardiovascular events and elevated mortality rates.¹⁷

In a landmark study, Huang et al¹⁸ evaluated the outcomes of 662 patients who had small renal masses, a “normal” serum creatinine concentration (≤ 124 μmol/L [1.4 mg/dL]), and a normal-appearing contralateral kidney who underwent radical or partial nephrectomy. Of these, 26% were found to have preexisting stage 3 chronic kidney disease (glomerular filtration rate < 60 mL/min/1.73 m² as calculated using the Modification of Diet in Renal Disease equation). Additionally, 65% of patients treated with radical nephrectomy were found to have stage 3 chronic kidney disease after surgery vs 20% of patients managed with partial nephrectomy.

The misconception remains that the risk of chronic kidney disease after radical nephrectomy is insignificant, since the risk is low in renal transplant donors.¹⁹ However, renal transplant donors undergo stringent screening to ensure that their general health is good and that their renal function is robust, both of which are not true in many patients with small renal masses, particularly if they are elderly.

The overuse of radical nephrectomy is worrisome in light of the potential implications of chronic kidney disease, such as increased risk of morbid cardiovascular events and elevated mortality rates. Many experts believe that over-treatment of small renal masses may have contributed to the paradoxical increase in overall mortality rates observed with radical nephrectomy in some studies.⁴

Although radical nephrectomy remains an important treatment for locally advanced renal cell carcinoma, it should be performed for small renal masses only if nephron-sparing surgery is not feasible (Table 2).

Over the last 5 years, greater emphasis has been placed on lessening the risk of chronic kidney disease in the management of all urologic conditions, including small renal masses.

The overuse of radical nephrectomy prompted the American Urological Association to commission a panel to provide guidelines for the management of clinical stage T1 renal masses.¹⁷ After an extensive review and rigorous meta-analysis, the panel concluded that partial nephrectomy is the gold standard for most patients (Table 1, Table 2).

Partial nephrectomy involves excision of the tumor with a small margin of normal tissue, preserving as much functional renal parenchyma as possible, followed by closure of the collecting system, suture ligation of any transected vessels, and reapproximation of the capsule. Tumor excision is usually performed during temporary occlusion of the renal vasculature, allowing for a bloodless field. Regional hypothermia (cold ischemia) can also be used to minimize ischemic injury.

Contemporary series have documented that partial and radical nephrectomy have comparable oncologic efficacy for patients with small renal masses.^20,21 Local recurrence rates are only 1% to 2% with partial nephrectomy, and 5- and 10-year cancer-specific survival rates of 96% and 90% have been reported.²²

Furthermore, some studies have shown that patients undergoing partial nephrectomy have higher overall survival rates than those managed with radical nephrectomy—perhaps in part due to greater preservation of renal function and a lower incidence of subsequent chronic kidney disease.^23,24 At Cleveland Clinic, we are now studying the determinants of ultimate renal function after partial nephrectomy in an effort to minimize ischemic injury and optimize this technique.²⁵

Complications. Partial nephrectomy does have a potential downside in that it carries a higher risk of urologic complications such as urine leak and postoperative hemorrhage, which is not surprising because it requires a reconstruction that must heal. In a recent meta-analysis, urologic complications occurred in 6.3% patients who underwent open partial nephrectomy and in 9.0% of patients who underwent laparoscopic partial nephrectomy.¹⁷ Fortunately, most complications associated with partial nephrectomy can be managed with conservative measures.

Postoperative bleeding occurs in about 1% to 2% of patients and is the most serious complication. However, it is typically managed with superselective embolization, which has a high success rate and facilitates renal preservation.

Urine leak occurs in about 3% to 5% of cases and almost always resolves with prolonged drainage, occasionally complemented with a ureteral stent to promote antegrade drainage.

A new refinement, robotic-assisted partial nephrectomy promises to reduce the morbidity of this procedure. This approach takes less time to learn than standard laparoscopic surgery and has expanded the indications for minimally invasive partial nephrectomy, although more-difficult cases are still better done through a traditional, open surgical approach.

Thermal ablation: Another minimally invasive option

Cryoablation and radiofrequency ablation (collectively called thermal ablation) have recently emerged as alternate minimally invasive treatments for small renal masses. They are appealing options for patients with small renal tumors (< 3.5 cm) who have significant comorbidities but still prefer a proactive approach. They can also be considered as salvage procedures in patients with local recurrence after partial nephrectomy or in select patients with multifocal disease.

Both procedures can be performed percutaneously or laparoscopically, offering the potential for rapid convalescence and reduced morbidity.^26,27 A laparoscopic approach is necessary to mobilize the tumor from adjacent organs if they are juxtaposed, whereas a percutaneous approach is less invasive and is better suited for posterior renal masses.²⁸ Renal mass sampling should be performed in these patients before treatment to define the histology and to guide surveillance and should be repeated postoperatively if there is suspicion of local recurrence based on imaging.

Cryoablation destroys tumor cells through rapid cycles of freezing to less than −20°C (−4°F) and thawing, which can be monitored in real time via thermocoupling (ie, a thermometer microprobe strategically placed outside the tumor to ensure that lethal temperatures are extended beyond the edge of the tumor) or via ultrasonography, or both. Treatment is continued until the “ice ball” extends about 1 cm beyond the edge of the tumor.

Initial series reported local tumor control rates in the range of 90% to 95%; however, follow-up was very limited.²⁹ In a more robust single-institution experience,³⁰ renal cryoablation demonstrated 5-year cancer-specific and recurrence-free survival rates of 93% and 83%, respectively, substantially lower than what would be expected with surgical excision in a similar patient population.

Another concern with cryoablation is that options are limited for surgical salvage if the initial treatment fails. Nguyen and Campbell³¹ reported that partial nephrectomy and minimally invasive surgery were often precluded in this situation because of the extensive fibrotic reaction caused by the prior treatment. If cryoablation fails, surgical salvage thus often requires open, radical surgery.

Radiofrequency ablation produces tumor coagulation via protein denaturation and disruption of cell membranes after heating tissues to temperatures above 50°C (122°F) for 4 to 6 minutes.³² One of its disadvantages is that one cannot monitor treatment progress in real time, as there is no identifiable change in tissue appearance analagous to the ice ball that is seen with cryoablation.

Although the outcomes of radiofrequency ablation are less robust than those of cryoablation, most studies suggest that local control is achieved in 80% to 90% of cases based on radiographic loss of enhancement after treatment.^17,30,33 A recent meta-analysis comparing these treatments found that lesions treated with radiofrequency ablation had a significantly higher rate of local tumor progression than those treated with cryoablation (12.3% vs 4.7%, P < .0001).³⁴ Both of these local recurrence rates are substantially higher than that seen after surgical excision, despite much shorter follow-up after thermal ablation.

Tempered enthusiasm. Because thermal ablation has been developed relatively recently, its long-term outcomes and treatment efficacy have not been well established, and current studies have confirmed higher local recurrence rates with thermal ablation than with surgical excision (Table 1). Furthermore, there are significant deficiencies in the literature about thermal ablation, including limited follow-up, lack of pathologic confirmation, and controversies regarding histologic or radiologic definitions of success (Table 2).

Although current enthusiasm for thermal ablation has been tempered by suboptimal results, further refinement in technique and acknowledgment of its limitations will help to define appropriate candidates for these treatments.

Active surveillance for select patients

In select patients with extensive medical comorbidities or short life expectancy, the risks associated with proactive management may outweigh the benefits, especially considering the indolent nature of many small renal masses. In such patients, active surveillance is reasonable.

A recent meta-analysis found that most small enhancing renal masses grew relatively slowly (median 0.28 cm/year) and posed a low risk of metastasis (1%–2%).^17,22 Furthermore, almost all renal lesions that progressed to metastatic disease demonstrated rapid radiographic growth, suggesting that the radiographic growth of a renal mass under active surveillance may serve as an indicator for aggressive behavior.³⁵

Unfortunately, the growth rates of small renal masses do not reliably predict malignancy, and one study reported that 83% of tumors without demonstrable growth were malignant.³⁶

Studies of active surveillance to date have had several other important limitations. Many did not incorporate pathologic confirmation, so that about 20% of the tumors were actually benign, thus artificially reducing the risk of adverse outcomes.^5,22,37 Furthermore, the follow-up has been short, with most studies including data for only 2 to 3 years, which is clearly inadequate for this type of malignancy.^37,38 Finally, most series had significant selection bias towards small, homogenous masses. In general, small renal masses that appear to be more aggressive are treated and thus excluded from these surveillance populations (Table 2).

Another concern about active surveillance is the small but real risk of tumor progression to metastatic disease, rendering these patients incurable even with new, targeted molecular therapies. Additionally, some patients may lose their window of opportunity for nephron-sparing surgery if significant tumor growth occurs during observation, rendering partial nephrectomy unfeasible. Therefore, active surveillance is not advisable for young, otherwise healthy patients (Table 2).

In the future, advances in renal mass sampling with molecular profiling may help determine which renal lesions are less biologically aggressive and, thereby, help identify appropriate candidates for observation (Figure 2).

Opinion about treatment of mall renal masses has changed considerably in the past 2 decades.

Traditionally, the most common treatment was surgical removal of the whole kidney, ie, radical nephrectomy. However, recent studies have shown that many patients who undergo radical nephrectomy develop chronic kidney disease. Furthermore, radical nephrectomy often constitutes over-treatment, as many of these lesions are benign or, if malignant, would follow an indolent course if left alone.

Now that we better understand the biology of small renal masses and are more aware of the morbidity and mortality related to chronic kidney disease, we try to avoid radical nephrectomy whenever possible, favoring nephron-sparing approaches instead.

In this article, we review the current clinical management of small renal masses.

SMALL RENAL MASSES ARE A HETEROGENEOUS GROUP

Small renal masses are defined as solid renal tumors that enhance on computed tomography (CT) and magnetic resonance imaging (MRI) and are suspected of being renal cell carcinomas. They are generally low-stage and relatively small (< 4 cm in diameter) at presentation. Most are now discovered incidentally on CT or MRI done for various abdominal symptoms. From 20,000 to 30,000 new cases are diagnosed each year in the United States, and the rate is increasing by 3% to 4% per year as the use of CT and MRI increases.^1,2

With more small renal masses being detected incidentally, renal cell carcinoma has been going through a stage and size migration—ie, more of these tumors are being discovered in clinical stage T1 (ie, confined to the kidney and measuring less than 7 cm) than in the past. Currently, clinical T1 renal tumors account for 48% to 66% of cases.³

This indicates that the disease is being detected and treated earlier in its course than in the past. However, cancer-specific deaths from renal cell carcinoma have not declined, suggesting that for many of these patients, our traditional practice of aggressive surgical management with radical nephrectomy may not be warranted.⁴

Small renal masses vary in biologic aggressiveness

Recent large surgical series indicate that up to 20% of small renal masses are benign, 55% to 60% are indolent renal cell carcinomas, and only 20% to 25% have potentially aggressive features, defined by high nuclear grade or locally invasive characteristics.^5–7

A relatively strong predictor of the aggressiveness of renal tumors is their size, which directly correlates with the risk of malignant pathology. Of lesions smaller than 1.0 cm, 38% to 46% are benign, dramatically decreasing to 6.3% to 7.1% for lesions larger than 7.0 cm.⁵ Each 1.0-cm increase in tumor diameter correlates with a 16% increase in the risk of malignancy.⁸

Our knowledge of the natural history of small renal masses is limited, being based on small, retrospective series. In these studies, when small renal masses were followed over time, relatively few progressed (ie, metastasized), and there have been no documented reports of disease progression in the absence of demonstrable tumor growth, suggesting a predominance of nonaggressive phenotypes.⁹

In light of these observations, patients with small renal masses should be carefully evaluated to determine if they are candidates for active surveillance as opposed to more aggressive treatment, ie, surgery or thermal ablation.

CT AND MRI ARE THE PREFERRED DIAGNOSTIC STUDIES

In the past, most patients with renal tumors presented with gross hematuria, flank pain, or a palpable abdominal mass. These presentations are now uncommon, as most cases are asymptomatic and are diagnosed incidentally. In a series of 349 small renal masses, microhematuria was found in only 8 cases.¹⁰

Systemic manifestations or paraneoplastic syndromes such as hypercalcemia or hypertension are more common in patients with metastatic renal cell carcinoma than in those with localized tumors. It was because of these varied clinical presentations that renal cell carcinoma was previously known as the “internist’s tumor”; however, small renal masses are better termed the “radiologist’s tumor.”¹¹

High-quality axial imaging with CT or MRI is preferred for evaluating renal cortical neoplasms. Enhancement on CT or MRI is the characteristic finding of a renal lesion that should be suspected of being renal cell carcinoma (Figure 1). Triple-phase CT is ideal, with images taken before contrast is given, immediately after contrast (the early vascular phase), and later (the delayed phase). Alternatively, MRI can be used in patients who are allergic to intravenous contrast or who have moderate renal dysfunction.

Renal tumors with enhancement of more than 15 Hounsfield units (HU) on CT imaging are considered suggestive of renal cell carcinoma, whereas those with less than 10 HU of enhancement are more likely to be benign. Enhancement in the range of 10 to 15 HU is considered equivocal.

Differential diagnosis

By far, most small renal masses are renal cell carcinomas. However, other possibilities include oncocytoma, atypical or fat-poor angiomyolipoma, metanephric adenoma, urothelial carcinoma, metastatic lesions, lymphoma, renal abscess or infarction, mixed epithelial or stromal tumor, pseudotumor, and vascular malformations.

With rare exceptions, dense fat within a renal mass reliably indicates benign angiomyolipoma, and all renal tumors should be reviewed carefully for this feature. Beyond this, no clinical or radiologic feature ensures that a small renal mass is benign.

Imaging’s inability to accurately classify these enhancing renal lesions has led to a renewed interest in renal mass sampling to aid in the evaluation of small renal masses.

RENAL MASS SAMPLING: SAFER, MORE ACCURATE THAN THOUGHT

Renal mass sampling (ie, biopsy) has traditionally had a restricted role in the management of small renal masses, limited specifically to patients with a clinical history suggesting renal lymphoma, carcinoma that had metastasized to the kidney, or primary renal abscess. However, this may be changing, with more interest in it as a way to subtype and stratify select patients with small renal masses, especially potential candidates for active surveillance.

Our thinking about renal mass sampling has changed substantially over the last 2 decades. Previously, it was not routinely performed, because of concern over high false-negative rates (commonly quoted as being as high as 18%) and its potential associated morbidity. A common perception was that a negative biopsy could not be trusted and, therefore, renal mass sampling would not ultimately change patient management. However, many of these false-negative results were actually “noninformative,” ie, cases in which the renal tumor could not be adequately sampled or the pathologist lacked a sufficient specimen to allow for a definitive diagnosis.

Recent evidence suggests that these concerns were exaggerated and that renal mass sampling is more accurate and safer than previously thought. A meta-analysis of studies done before 2001 found that the diagnostic accuracy of renal mass sampling averaged 82%, whereas contemporary series indicate that its accuracy in differentiating benign from malignant tumors is actually greater than 95%.¹² In addition, false-negative rates are now consistently less than 1%.¹³

Furthermore, serious complications requiring clinical intervention or hospitalization occur in fewer than 1% of cases. Seeding of the needle tract with tumor cells, which was another concern, is also exceedingly rare for these small, well-circumscribed renal masses.¹²

Overall morbidity is low with renal mass sampling, which is routinely performed as an outpatient procedure using CT or ultrasono-graphic guidance and local anesthesia.

However, 10% of biopsy results are still noninformative. In this situation, biopsy can be repeated, or the mass can be surgically excised, or the patient can undergo conservative management if he or she is unfit or unwilling to undergo surgery.

The encouraging results with renal mass sampling have led to greater use of it at many centers in the evaluation and risk-stratification of patients with small renal masses. It may be especially useful in patients considering several treatment options.

For example, a 75-year-old patient with modest comorbidities and a 2.0-cm enhancing renal mass could be a candidate for partial nephrectomy, thermal ablation, or active surveillance, and a reasonable argument could be made for each of these options. Renal mass sampling in this instance could be instrumental in guiding this decision, as a tissue diagnosis of high-grade renal cell carcinoma would favor partial nephrectomy, whereas a diagnosis of “oncocytoma neoplasm” would support a more conservative approach.

Older, frail patients with significant comorbidities who are unlikely to be candidates for aggressive surgical management would not need renal mass sampling, as they will ultimately be managed with active surveillance or thermal ablation.

Recent studies have also indicated that molecular profiling through gene expression analysis or proteomic analysis can further improve the accuracy of renal mass sampling.¹⁴ This will likely be the holy grail for this field, allowing for truly rational management (Figure 2).

TREATMENT OPTIONS

Radical nephrectomy: Still the most common treatment

In the past, complete removal of the kidney was standard for nearly all renal masses suspected of being renal cell carcinomas. Partial nephrectomy was generally reserved for patients who had a solitary kidney, bilateral tumors, or preexisting chronic kidney disease.

Although the two procedures provide equivalent oncologic outcomes for clinical T1 lesions, Miller et al¹⁵ reported that, before 2001, only 20% of small renal masses in the United States were managed with partial nephrectomy. That percentage has increased modestly, but radical nephrectomy still predominates.

One explanation for why the radical procedure is done more frequently is that partial nephrectomy is more technically difficult, as it involves renal reconstruction. Furthermore, radical nephrectomy can almost always be performed via a minimally invasive approach, which is inherently appealing to patients and surgeons alike. Laparoscopic radical nephrectomy has been called “the great seductress” because of these considerations.¹⁶ However, total removal of the kidney comes at a great price—loss of renal function.

Over the last decade, various studies have highlighted the association between radical nephrectomy and the subsequent clinical onset of chronic kidney disease, and the potential correlations between chronic kidney disease and cardiovascular events and elevated mortality rates.¹⁷

In a landmark study, Huang et al¹⁸ evaluated the outcomes of 662 patients who had small renal masses, a “normal” serum creatinine concentration (≤ 124 μmol/L [1.4 mg/dL]), and a normal-appearing contralateral kidney who underwent radical or partial nephrectomy. Of these, 26% were found to have preexisting stage 3 chronic kidney disease (glomerular filtration rate < 60 mL/min/1.73 m² as calculated using the Modification of Diet in Renal Disease equation). Additionally, 65% of patients treated with radical nephrectomy were found to have stage 3 chronic kidney disease after surgery vs 20% of patients managed with partial nephrectomy.

The misconception remains that the risk of chronic kidney disease after radical nephrectomy is insignificant, since the risk is low in renal transplant donors.¹⁹ However, renal transplant donors undergo stringent screening to ensure that their general health is good and that their renal function is robust, both of which are not true in many patients with small renal masses, particularly if they are elderly.

The overuse of radical nephrectomy is worrisome in light of the potential implications of chronic kidney disease, such as increased risk of morbid cardiovascular events and elevated mortality rates. Many experts believe that over-treatment of small renal masses may have contributed to the paradoxical increase in overall mortality rates observed with radical nephrectomy in some studies.⁴

Although radical nephrectomy remains an important treatment for locally advanced renal cell carcinoma, it should be performed for small renal masses only if nephron-sparing surgery is not feasible (Table 2).

Over the last 5 years, greater emphasis has been placed on lessening the risk of chronic kidney disease in the management of all urologic conditions, including small renal masses.

The overuse of radical nephrectomy prompted the American Urological Association to commission a panel to provide guidelines for the management of clinical stage T1 renal masses.¹⁷ After an extensive review and rigorous meta-analysis, the panel concluded that partial nephrectomy is the gold standard for most patients (Table 1, Table 2).

Partial nephrectomy involves excision of the tumor with a small margin of normal tissue, preserving as much functional renal parenchyma as possible, followed by closure of the collecting system, suture ligation of any transected vessels, and reapproximation of the capsule. Tumor excision is usually performed during temporary occlusion of the renal vasculature, allowing for a bloodless field. Regional hypothermia (cold ischemia) can also be used to minimize ischemic injury.

Contemporary series have documented that partial and radical nephrectomy have comparable oncologic efficacy for patients with small renal masses.^20,21 Local recurrence rates are only 1% to 2% with partial nephrectomy, and 5- and 10-year cancer-specific survival rates of 96% and 90% have been reported.²²

Furthermore, some studies have shown that patients undergoing partial nephrectomy have higher overall survival rates than those managed with radical nephrectomy—perhaps in part due to greater preservation of renal function and a lower incidence of subsequent chronic kidney disease.^23,24 At Cleveland Clinic, we are now studying the determinants of ultimate renal function after partial nephrectomy in an effort to minimize ischemic injury and optimize this technique.²⁵

Complications. Partial nephrectomy does have a potential downside in that it carries a higher risk of urologic complications such as urine leak and postoperative hemorrhage, which is not surprising because it requires a reconstruction that must heal. In a recent meta-analysis, urologic complications occurred in 6.3% patients who underwent open partial nephrectomy and in 9.0% of patients who underwent laparoscopic partial nephrectomy.¹⁷ Fortunately, most complications associated with partial nephrectomy can be managed with conservative measures.

Postoperative bleeding occurs in about 1% to 2% of patients and is the most serious complication. However, it is typically managed with superselective embolization, which has a high success rate and facilitates renal preservation.

Urine leak occurs in about 3% to 5% of cases and almost always resolves with prolonged drainage, occasionally complemented with a ureteral stent to promote antegrade drainage.

A new refinement, robotic-assisted partial nephrectomy promises to reduce the morbidity of this procedure. This approach takes less time to learn than standard laparoscopic surgery and has expanded the indications for minimally invasive partial nephrectomy, although more-difficult cases are still better done through a traditional, open surgical approach.

Thermal ablation: Another minimally invasive option

Cryoablation and radiofrequency ablation (collectively called thermal ablation) have recently emerged as alternate minimally invasive treatments for small renal masses. They are appealing options for patients with small renal tumors (< 3.5 cm) who have significant comorbidities but still prefer a proactive approach. They can also be considered as salvage procedures in patients with local recurrence after partial nephrectomy or in select patients with multifocal disease.

Both procedures can be performed percutaneously or laparoscopically, offering the potential for rapid convalescence and reduced morbidity.^26,27 A laparoscopic approach is necessary to mobilize the tumor from adjacent organs if they are juxtaposed, whereas a percutaneous approach is less invasive and is better suited for posterior renal masses.²⁸ Renal mass sampling should be performed in these patients before treatment to define the histology and to guide surveillance and should be repeated postoperatively if there is suspicion of local recurrence based on imaging.

Cryoablation destroys tumor cells through rapid cycles of freezing to less than −20°C (−4°F) and thawing, which can be monitored in real time via thermocoupling (ie, a thermometer microprobe strategically placed outside the tumor to ensure that lethal temperatures are extended beyond the edge of the tumor) or via ultrasonography, or both. Treatment is continued until the “ice ball” extends about 1 cm beyond the edge of the tumor.

Initial series reported local tumor control rates in the range of 90% to 95%; however, follow-up was very limited.²⁹ In a more robust single-institution experience,³⁰ renal cryoablation demonstrated 5-year cancer-specific and recurrence-free survival rates of 93% and 83%, respectively, substantially lower than what would be expected with surgical excision in a similar patient population.

Another concern with cryoablation is that options are limited for surgical salvage if the initial treatment fails. Nguyen and Campbell³¹ reported that partial nephrectomy and minimally invasive surgery were often precluded in this situation because of the extensive fibrotic reaction caused by the prior treatment. If cryoablation fails, surgical salvage thus often requires open, radical surgery.

Radiofrequency ablation produces tumor coagulation via protein denaturation and disruption of cell membranes after heating tissues to temperatures above 50°C (122°F) for 4 to 6 minutes.³² One of its disadvantages is that one cannot monitor treatment progress in real time, as there is no identifiable change in tissue appearance analagous to the ice ball that is seen with cryoablation.

Although the outcomes of radiofrequency ablation are less robust than those of cryoablation, most studies suggest that local control is achieved in 80% to 90% of cases based on radiographic loss of enhancement after treatment.^17,30,33 A recent meta-analysis comparing these treatments found that lesions treated with radiofrequency ablation had a significantly higher rate of local tumor progression than those treated with cryoablation (12.3% vs 4.7%, P < .0001).³⁴ Both of these local recurrence rates are substantially higher than that seen after surgical excision, despite much shorter follow-up after thermal ablation.

Tempered enthusiasm. Because thermal ablation has been developed relatively recently, its long-term outcomes and treatment efficacy have not been well established, and current studies have confirmed higher local recurrence rates with thermal ablation than with surgical excision (Table 1). Furthermore, there are significant deficiencies in the literature about thermal ablation, including limited follow-up, lack of pathologic confirmation, and controversies regarding histologic or radiologic definitions of success (Table 2).

Although current enthusiasm for thermal ablation has been tempered by suboptimal results, further refinement in technique and acknowledgment of its limitations will help to define appropriate candidates for these treatments.

Active surveillance for select patients

In select patients with extensive medical comorbidities or short life expectancy, the risks associated with proactive management may outweigh the benefits, especially considering the indolent nature of many small renal masses. In such patients, active surveillance is reasonable.

A recent meta-analysis found that most small enhancing renal masses grew relatively slowly (median 0.28 cm/year) and posed a low risk of metastasis (1%–2%).^17,22 Furthermore, almost all renal lesions that progressed to metastatic disease demonstrated rapid radiographic growth, suggesting that the radiographic growth of a renal mass under active surveillance may serve as an indicator for aggressive behavior.³⁵

Unfortunately, the growth rates of small renal masses do not reliably predict malignancy, and one study reported that 83% of tumors without demonstrable growth were malignant.³⁶

Studies of active surveillance to date have had several other important limitations. Many did not incorporate pathologic confirmation, so that about 20% of the tumors were actually benign, thus artificially reducing the risk of adverse outcomes.^5,22,37 Furthermore, the follow-up has been short, with most studies including data for only 2 to 3 years, which is clearly inadequate for this type of malignancy.^37,38 Finally, most series had significant selection bias towards small, homogenous masses. In general, small renal masses that appear to be more aggressive are treated and thus excluded from these surveillance populations (Table 2).

Another concern about active surveillance is the small but real risk of tumor progression to metastatic disease, rendering these patients incurable even with new, targeted molecular therapies. Additionally, some patients may lose their window of opportunity for nephron-sparing surgery if significant tumor growth occurs during observation, rendering partial nephrectomy unfeasible. Therefore, active surveillance is not advisable for young, otherwise healthy patients (Table 2).

In the future, advances in renal mass sampling with molecular profiling may help determine which renal lesions are less biologically aggressive and, thereby, help identify appropriate candidates for observation (Figure 2).

Opinion about treatment of mall renal masses has changed considerably in the past 2 decades.

Traditionally, the most common treatment was surgical removal of the whole kidney, ie, radical nephrectomy. However, recent studies have shown that many patients who undergo radical nephrectomy develop chronic kidney disease. Furthermore, radical nephrectomy often constitutes over-treatment, as many of these lesions are benign or, if malignant, would follow an indolent course if left alone.

Now that we better understand the biology of small renal masses and are more aware of the morbidity and mortality related to chronic kidney disease, we try to avoid radical nephrectomy whenever possible, favoring nephron-sparing approaches instead.

In this article, we review the current clinical management of small renal masses.

SMALL RENAL MASSES ARE A HETEROGENEOUS GROUP

Small renal masses are defined as solid renal tumors that enhance on computed tomography (CT) and magnetic resonance imaging (MRI) and are suspected of being renal cell carcinomas. They are generally low-stage and relatively small (< 4 cm in diameter) at presentation. Most are now discovered incidentally on CT or MRI done for various abdominal symptoms. From 20,000 to 30,000 new cases are diagnosed each year in the United States, and the rate is increasing by 3% to 4% per year as the use of CT and MRI increases.^1,2

With more small renal masses being detected incidentally, renal cell carcinoma has been going through a stage and size migration—ie, more of these tumors are being discovered in clinical stage T1 (ie, confined to the kidney and measuring less than 7 cm) than in the past. Currently, clinical T1 renal tumors account for 48% to 66% of cases.³

This indicates that the disease is being detected and treated earlier in its course than in the past. However, cancer-specific deaths from renal cell carcinoma have not declined, suggesting that for many of these patients, our traditional practice of aggressive surgical management with radical nephrectomy may not be warranted.⁴

Small renal masses vary in biologic aggressiveness

Recent large surgical series indicate that up to 20% of small renal masses are benign, 55% to 60% are indolent renal cell carcinomas, and only 20% to 25% have potentially aggressive features, defined by high nuclear grade or locally invasive characteristics.^5–7

A relatively strong predictor of the aggressiveness of renal tumors is their size, which directly correlates with the risk of malignant pathology. Of lesions smaller than 1.0 cm, 38% to 46% are benign, dramatically decreasing to 6.3% to 7.1% for lesions larger than 7.0 cm.⁵ Each 1.0-cm increase in tumor diameter correlates with a 16% increase in the risk of malignancy.⁸

Our knowledge of the natural history of small renal masses is limited, being based on small, retrospective series. In these studies, when small renal masses were followed over time, relatively few progressed (ie, metastasized), and there have been no documented reports of disease progression in the absence of demonstrable tumor growth, suggesting a predominance of nonaggressive phenotypes.⁹

In light of these observations, patients with small renal masses should be carefully evaluated to determine if they are candidates for active surveillance as opposed to more aggressive treatment, ie, surgery or thermal ablation.

CT AND MRI ARE THE PREFERRED DIAGNOSTIC STUDIES

In the past, most patients with renal tumors presented with gross hematuria, flank pain, or a palpable abdominal mass. These presentations are now uncommon, as most cases are asymptomatic and are diagnosed incidentally. In a series of 349 small renal masses, microhematuria was found in only 8 cases.¹⁰

Systemic manifestations or paraneoplastic syndromes such as hypercalcemia or hypertension are more common in patients with metastatic renal cell carcinoma than in those with localized tumors. It was because of these varied clinical presentations that renal cell carcinoma was previously known as the “internist’s tumor”; however, small renal masses are better termed the “radiologist’s tumor.”¹¹

High-quality axial imaging with CT or MRI is preferred for evaluating renal cortical neoplasms. Enhancement on CT or MRI is the characteristic finding of a renal lesion that should be suspected of being renal cell carcinoma (Figure 1). Triple-phase CT is ideal, with images taken before contrast is given, immediately after contrast (the early vascular phase), and later (the delayed phase). Alternatively, MRI can be used in patients who are allergic to intravenous contrast or who have moderate renal dysfunction.

Renal tumors with enhancement of more than 15 Hounsfield units (HU) on CT imaging are considered suggestive of renal cell carcinoma, whereas those with less than 10 HU of enhancement are more likely to be benign. Enhancement in the range of 10 to 15 HU is considered equivocal.

Differential diagnosis

By far, most small renal masses are renal cell carcinomas. However, other possibilities include oncocytoma, atypical or fat-poor angiomyolipoma, metanephric adenoma, urothelial carcinoma, metastatic lesions, lymphoma, renal abscess or infarction, mixed epithelial or stromal tumor, pseudotumor, and vascular malformations.

With rare exceptions, dense fat within a renal mass reliably indicates benign angiomyolipoma, and all renal tumors should be reviewed carefully for this feature. Beyond this, no clinical or radiologic feature ensures that a small renal mass is benign.

Imaging’s inability to accurately classify these enhancing renal lesions has led to a renewed interest in renal mass sampling to aid in the evaluation of small renal masses.

RENAL MASS SAMPLING: SAFER, MORE ACCURATE THAN THOUGHT

Renal mass sampling (ie, biopsy) has traditionally had a restricted role in the management of small renal masses, limited specifically to patients with a clinical history suggesting renal lymphoma, carcinoma that had metastasized to the kidney, or primary renal abscess. However, this may be changing, with more interest in it as a way to subtype and stratify select patients with small renal masses, especially potential candidates for active surveillance.

Our thinking about renal mass sampling has changed substantially over the last 2 decades. Previously, it was not routinely performed, because of concern over high false-negative rates (commonly quoted as being as high as 18%) and its potential associated morbidity. A common perception was that a negative biopsy could not be trusted and, therefore, renal mass sampling would not ultimately change patient management. However, many of these false-negative results were actually “noninformative,” ie, cases in which the renal tumor could not be adequately sampled or the pathologist lacked a sufficient specimen to allow for a definitive diagnosis.

Recent evidence suggests that these concerns were exaggerated and that renal mass sampling is more accurate and safer than previously thought. A meta-analysis of studies done before 2001 found that the diagnostic accuracy of renal mass sampling averaged 82%, whereas contemporary series indicate that its accuracy in differentiating benign from malignant tumors is actually greater than 95%.¹² In addition, false-negative rates are now consistently less than 1%.¹³

Furthermore, serious complications requiring clinical intervention or hospitalization occur in fewer than 1% of cases. Seeding of the needle tract with tumor cells, which was another concern, is also exceedingly rare for these small, well-circumscribed renal masses.¹²

Overall morbidity is low with renal mass sampling, which is routinely performed as an outpatient procedure using CT or ultrasono-graphic guidance and local anesthesia.

However, 10% of biopsy results are still noninformative. In this situation, biopsy can be repeated, or the mass can be surgically excised, or the patient can undergo conservative management if he or she is unfit or unwilling to undergo surgery.

The encouraging results with renal mass sampling have led to greater use of it at many centers in the evaluation and risk-stratification of patients with small renal masses. It may be especially useful in patients considering several treatment options.

For example, a 75-year-old patient with modest comorbidities and a 2.0-cm enhancing renal mass could be a candidate for partial nephrectomy, thermal ablation, or active surveillance, and a reasonable argument could be made for each of these options. Renal mass sampling in this instance could be instrumental in guiding this decision, as a tissue diagnosis of high-grade renal cell carcinoma would favor partial nephrectomy, whereas a diagnosis of “oncocytoma neoplasm” would support a more conservative approach.

Older, frail patients with significant comorbidities who are unlikely to be candidates for aggressive surgical management would not need renal mass sampling, as they will ultimately be managed with active surveillance or thermal ablation.

Recent studies have also indicated that molecular profiling through gene expression analysis or proteomic analysis can further improve the accuracy of renal mass sampling.¹⁴ This will likely be the holy grail for this field, allowing for truly rational management (Figure 2).

TREATMENT OPTIONS

Radical nephrectomy: Still the most common treatment

In the past, complete removal of the kidney was standard for nearly all renal masses suspected of being renal cell carcinomas. Partial nephrectomy was generally reserved for patients who had a solitary kidney, bilateral tumors, or preexisting chronic kidney disease.

Although the two procedures provide equivalent oncologic outcomes for clinical T1 lesions, Miller et al¹⁵ reported that, before 2001, only 20% of small renal masses in the United States were managed with partial nephrectomy. That percentage has increased modestly, but radical nephrectomy still predominates.

One explanation for why the radical procedure is done more frequently is that partial nephrectomy is more technically difficult, as it involves renal reconstruction. Furthermore, radical nephrectomy can almost always be performed via a minimally invasive approach, which is inherently appealing to patients and surgeons alike. Laparoscopic radical nephrectomy has been called “the great seductress” because of these considerations.¹⁶ However, total removal of the kidney comes at a great price—loss of renal function.

Over the last decade, various studies have highlighted the association between radical nephrectomy and the subsequent clinical onset of chronic kidney disease, and the potential correlations between chronic kidney disease and cardiovascular events and elevated mortality rates.¹⁷

In a landmark study, Huang et al¹⁸ evaluated the outcomes of 662 patients who had small renal masses, a “normal” serum creatinine concentration (≤ 124 μmol/L [1.4 mg/dL]), and a normal-appearing contralateral kidney who underwent radical or partial nephrectomy. Of these, 26% were found to have preexisting stage 3 chronic kidney disease (glomerular filtration rate < 60 mL/min/1.73 m² as calculated using the Modification of Diet in Renal Disease equation). Additionally, 65% of patients treated with radical nephrectomy were found to have stage 3 chronic kidney disease after surgery vs 20% of patients managed with partial nephrectomy.

The misconception remains that the risk of chronic kidney disease after radical nephrectomy is insignificant, since the risk is low in renal transplant donors.¹⁹ However, renal transplant donors undergo stringent screening to ensure that their general health is good and that their renal function is robust, both of which are not true in many patients with small renal masses, particularly if they are elderly.

The overuse of radical nephrectomy is worrisome in light of the potential implications of chronic kidney disease, such as increased risk of morbid cardiovascular events and elevated mortality rates. Many experts believe that over-treatment of small renal masses may have contributed to the paradoxical increase in overall mortality rates observed with radical nephrectomy in some studies.⁴

Although radical nephrectomy remains an important treatment for locally advanced renal cell carcinoma, it should be performed for small renal masses only if nephron-sparing surgery is not feasible (Table 2).

Over the last 5 years, greater emphasis has been placed on lessening the risk of chronic kidney disease in the management of all urologic conditions, including small renal masses.

The overuse of radical nephrectomy prompted the American Urological Association to commission a panel to provide guidelines for the management of clinical stage T1 renal masses.¹⁷ After an extensive review and rigorous meta-analysis, the panel concluded that partial nephrectomy is the gold standard for most patients (Table 1, Table 2).

Partial nephrectomy involves excision of the tumor with a small margin of normal tissue, preserving as much functional renal parenchyma as possible, followed by closure of the collecting system, suture ligation of any transected vessels, and reapproximation of the capsule. Tumor excision is usually performed during temporary occlusion of the renal vasculature, allowing for a bloodless field. Regional hypothermia (cold ischemia) can also be used to minimize ischemic injury.

Contemporary series have documented that partial and radical nephrectomy have comparable oncologic efficacy for patients with small renal masses.^20,21 Local recurrence rates are only 1% to 2% with partial nephrectomy, and 5- and 10-year cancer-specific survival rates of 96% and 90% have been reported.²²

Furthermore, some studies have shown that patients undergoing partial nephrectomy have higher overall survival rates than those managed with radical nephrectomy—perhaps in part due to greater preservation of renal function and a lower incidence of subsequent chronic kidney disease.^23,24 At Cleveland Clinic, we are now studying the determinants of ultimate renal function after partial nephrectomy in an effort to minimize ischemic injury and optimize this technique.²⁵

Complications. Partial nephrectomy does have a potential downside in that it carries a higher risk of urologic complications such as urine leak and postoperative hemorrhage, which is not surprising because it requires a reconstruction that must heal. In a recent meta-analysis, urologic complications occurred in 6.3% patients who underwent open partial nephrectomy and in 9.0% of patients who underwent laparoscopic partial nephrectomy.¹⁷ Fortunately, most complications associated with partial nephrectomy can be managed with conservative measures.

Postoperative bleeding occurs in about 1% to 2% of patients and is the most serious complication. However, it is typically managed with superselective embolization, which has a high success rate and facilitates renal preservation.

Urine leak occurs in about 3% to 5% of cases and almost always resolves with prolonged drainage, occasionally complemented with a ureteral stent to promote antegrade drainage.

A new refinement, robotic-assisted partial nephrectomy promises to reduce the morbidity of this procedure. This approach takes less time to learn than standard laparoscopic surgery and has expanded the indications for minimally invasive partial nephrectomy, although more-difficult cases are still better done through a traditional, open surgical approach.

Thermal ablation: Another minimally invasive option

Cryoablation and radiofrequency ablation (collectively called thermal ablation) have recently emerged as alternate minimally invasive treatments for small renal masses. They are appealing options for patients with small renal tumors (< 3.5 cm) who have significant comorbidities but still prefer a proactive approach. They can also be considered as salvage procedures in patients with local recurrence after partial nephrectomy or in select patients with multifocal disease.

Both procedures can be performed percutaneously or laparoscopically, offering the potential for rapid convalescence and reduced morbidity.^26,27 A laparoscopic approach is necessary to mobilize the tumor from adjacent organs if they are juxtaposed, whereas a percutaneous approach is less invasive and is better suited for posterior renal masses.²⁸ Renal mass sampling should be performed in these patients before treatment to define the histology and to guide surveillance and should be repeated postoperatively if there is suspicion of local recurrence based on imaging.

Cryoablation destroys tumor cells through rapid cycles of freezing to less than −20°C (−4°F) and thawing, which can be monitored in real time via thermocoupling (ie, a thermometer microprobe strategically placed outside the tumor to ensure that lethal temperatures are extended beyond the edge of the tumor) or via ultrasonography, or both. Treatment is continued until the “ice ball” extends about 1 cm beyond the edge of the tumor.

Initial series reported local tumor control rates in the range of 90% to 95%; however, follow-up was very limited.²⁹ In a more robust single-institution experience,³⁰ renal cryoablation demonstrated 5-year cancer-specific and recurrence-free survival rates of 93% and 83%, respectively, substantially lower than what would be expected with surgical excision in a similar patient population.

Another concern with cryoablation is that options are limited for surgical salvage if the initial treatment fails. Nguyen and Campbell³¹ reported that partial nephrectomy and minimally invasive surgery were often precluded in this situation because of the extensive fibrotic reaction caused by the prior treatment. If cryoablation fails, surgical salvage thus often requires open, radical surgery.

Radiofrequency ablation produces tumor coagulation via protein denaturation and disruption of cell membranes after heating tissues to temperatures above 50°C (122°F) for 4 to 6 minutes.³² One of its disadvantages is that one cannot monitor treatment progress in real time, as there is no identifiable change in tissue appearance analagous to the ice ball that is seen with cryoablation.

Although the outcomes of radiofrequency ablation are less robust than those of cryoablation, most studies suggest that local control is achieved in 80% to 90% of cases based on radiographic loss of enhancement after treatment.^17,30,33 A recent meta-analysis comparing these treatments found that lesions treated with radiofrequency ablation had a significantly higher rate of local tumor progression than those treated with cryoablation (12.3% vs 4.7%, P < .0001).³⁴ Both of these local recurrence rates are substantially higher than that seen after surgical excision, despite much shorter follow-up after thermal ablation.

Tempered enthusiasm. Because thermal ablation has been developed relatively recently, its long-term outcomes and treatment efficacy have not been well established, and current studies have confirmed higher local recurrence rates with thermal ablation than with surgical excision (Table 1). Furthermore, there are significant deficiencies in the literature about thermal ablation, including limited follow-up, lack of pathologic confirmation, and controversies regarding histologic or radiologic definitions of success (Table 2).

Although current enthusiasm for thermal ablation has been tempered by suboptimal results, further refinement in technique and acknowledgment of its limitations will help to define appropriate candidates for these treatments.

Active surveillance for select patients

In select patients with extensive medical comorbidities or short life expectancy, the risks associated with proactive management may outweigh the benefits, especially considering the indolent nature of many small renal masses. In such patients, active surveillance is reasonable.

A recent meta-analysis found that most small enhancing renal masses grew relatively slowly (median 0.28 cm/year) and posed a low risk of metastasis (1%–2%).^17,22 Furthermore, almost all renal lesions that progressed to metastatic disease demonstrated rapid radiographic growth, suggesting that the radiographic growth of a renal mass under active surveillance may serve as an indicator for aggressive behavior.³⁵

Unfortunately, the growth rates of small renal masses do not reliably predict malignancy, and one study reported that 83% of tumors without demonstrable growth were malignant.³⁶

Studies of active surveillance to date have had several other important limitations. Many did not incorporate pathologic confirmation, so that about 20% of the tumors were actually benign, thus artificially reducing the risk of adverse outcomes.^5,22,37 Furthermore, the follow-up has been short, with most studies including data for only 2 to 3 years, which is clearly inadequate for this type of malignancy.^37,38 Finally, most series had significant selection bias towards small, homogenous masses. In general, small renal masses that appear to be more aggressive are treated and thus excluded from these surveillance populations (Table 2).

Another concern about active surveillance is the small but real risk of tumor progression to metastatic disease, rendering these patients incurable even with new, targeted molecular therapies. Additionally, some patients may lose their window of opportunity for nephron-sparing surgery if significant tumor growth occurs during observation, rendering partial nephrectomy unfeasible. Therefore, active surveillance is not advisable for young, otherwise healthy patients (Table 2).

In the future, advances in renal mass sampling with molecular profiling may help determine which renal lesions are less biologically aggressive and, thereby, help identify appropriate candidates for observation (Figure 2).

A 49-year-old woman presents with a cough that has persisted for 3 weeks.

Two weeks ago, she was seen in the outpatient clinic for a nonproductive cough, rhinorrhea, sneezing, and a sore throat. At that time, she described coughing spells that were occasionally accompanied by posttussive chest pain and vomiting. The cough was worse at night and was occasionally associated with wheezing. She reported no fevers, chills, rigors, night sweats, or dyspnea. She said she has tried over-the-counter cough suppressants, antihistamines, and decongestants, but they provided no relief. Since she had a history of well-controlled asthma, she was diagnosed with an asthma exacerbation and was given prednisone 20 mg to take orally every day for 5 days, to be followed by an inhaled corticosteroid until her symptoms resolved.

Now, she has returned because her symptoms have persisted despite treatment, and she is seeking a second medical opinion. Her paroxysmal cough has become more frequent and more severe.

In addition to asthma, she has a history of allergic rhinitis. Her current medications include the over-the-counter histamine H1 antagonist cetirizine (Zyrtec), a fluticasone-salmeterol inhaler (Advair), and an albuterol inhaler (Proventil HFA). She reports having had mild asthma exacerbations in the past during the winter, which were managed well with her albuterol inhaler.

She has never smoked; she drinks alcohol socially. She has not traveled outside the United States during the past several months. She is married and has two children, ages 25 and 23. She lives at home with only her husband, and he has not been sick. However, she works at a greeting card store, and two of her coworkers have similar upper respiratory symptoms, although they have only a mild cough.

Her immunizations are not up-to-date. She last received the tetanus-diphtheria toxoid (Td) vaccine 12 years ago, and she never received the pediatric tetanus, diphtheria, and acellular pertussis (Tdap) vaccine. She generally receives the influenza vaccine annually, and she received it about 6 weeks before this presentation.

She is not in distress, but she has paroxysms of severe coughing throughout her examination. Her pulse is 100 beats per minute, respiratory rate 18, and blood pressure 130/86 mm Hg. Her oropharynx is clear. The pulmonary examination reveals poor inspiratory effort due to coughing but is otherwise normal. The rest of the examination is normal, as is her chest radiograph.

WHAT DOES SHE HAVE?

1. Which of the following would best explain her symptoms?

• Asthma
• Postviral cough
• Pertussis
• Chronic bronchitis
• Pneumonia
• Gastroesophageal reflux disease

Asthma is a reasonable consideration, given her medical history, her occasional wheezing, and her nonproductive cough that is worse at night. However, asthma typically responds well to corticosteroid therapy. She has already received a course of prednisone, but her symptoms have not improved.

Postviral cough could also be considered in this patient. However, postviral cough does not typically occur in paroxysms, nor does it lead to posttussive vomiting. It is also generally regarded as a diagnosis of exclusion.

Pertussis (whooping cough) should be suspected in this patient, given the time course of her symptoms, the paroxysmal cough, and the posttussive vomiting. In addition, at her job she interacts with hundreds of people a day, increasing her risk of exposure to respiratory tract pathogens, including Bordetella pertussis.

Chronic bronchitis is defined by cough (typically productive) lasting at least 3 months per year for at least 2 consecutive years, which does not fit the time course for this patient. It is vastly more common in smokers.

Pneumonia typically presents with a cough that can be productive or nonproductive, but also with fever, chills, and radiologic evidence of a pulmonary infiltrate or consolidation. This woman has none of these.

Gastroesophageal reflux disease is one of the most common causes of chronic cough, with symptoms typically worse at night. However, it is generally associated with symptoms such as heartburn, a sour taste in the mouth, or regurgitation, which our patient did not report.

Thus, pertussis is the most likely diagnosis.

PERTUSSIS IS ON THE RISE

Pertussis is an acute and highly contagious disease caused by infection of the respiratory tract by B pertussis, a small, aerobic, gramnegative, pleomorphic coccobacillus that produces a number of antigenic and biologically active products, including pertussis toxin, filamentous hemagglutinin, agglutinogens, and tracheal cytotoxin. Transmitted by aerosolized droplets, it attaches to the ciliated epithelial cells of the lower respiratory tract, paralyzes the cilia via toxins, and causes inflammation, thus interfering with the clearing of respiratory secretions.

The incidence of pertussis is on the rise. In 2005, 25,827 cases were reported in the United States, the highest number since 1959.¹ Pertussis is now epidemic in California. At the time of this writing, the number of confirmed, probable, and suspected cases in California was 9,477 (including 10 infant deaths) for the year 2010—the most cases reported in the past 65 years.^2,3

In 2010, outbreaks were also reported in Michigan, Texas, Ohio, upstate New York, and Arizona.⁴ The overall incidence of pertussis is likely even higher than what is reported, since many cases go unrecognized or unreported.

Pertussis is transmitted person-to-person, primarily through aerosolized droplets from coughing or sneezing or by direct contact with secretions from the respiratory tract of infected persons. It is highly contagious, with secondary attack rates of up to 80% in susceptible people.

A three-stage clinical course

The clinical definition of pertussis used by the US Centers for Disease Control and Prevention (CDC) and the Council of State and Territorial Epidemiologists is an acute cough illness lasting at least 2 weeks, with paroxysms of coughing, an inspiratory “whoop,” or posttussive vomiting without another apparent cause.⁵

The clinical course of the illness is traditionally divided into three stages:

The catarrhal phase typically lasts 1 to 2 weeks and is clinically indistinguishable from a viral upper respiratory infection. It is characterized by the insidious onset of malaise, coryza, sneezing, low-grade fever, and a mild cough that gradually becomes severe.⁶

The paroxysmal phase normally lasts 1 to 6 weeks but may persist for up to 10 weeks. The diagnosis of pertussis is usually suspected during this phase. The classic features of this phase are bursts or paroxysms of numerous, rapid coughs. These are followed by a long inspiratory effort usually accompanied by a characteristic high-pitched whoop, most notably observed in infants and children. Infants and children may appear very ill and distressed during this time and may become cyanotic, but cyanosis is uncommon in adults and adolescents. The paroxysms may also be followed by exhaustion and posttussive vomiting. In some cases, the cough is not paroxysmal, but rather simply persistent. The coughing attacks tend to occur more often at night, with an average of 15 attacks per 24 hours. During the first 1 to 2 weeks of this stage, the attacks generally increase in frequency, remain at the same intensity level for 2 to 3 weeks, and then gradually decrease over 1 to 2 weeks.^1,7

The convalescent phase can have a variable course, ranging from weeks to months, with an average duration of 2 to 3 weeks. During this stage, the paroxysms of coughing become less frequent and gradually resolve. Paroxysms often recur with subsequent respiratory infections.

In infants and young children, pertussis tends to follow these stages in a predictable sequence. Adolescents and adults, however, tend to go through the stages without being as ill and typically do not exhibit the characteristic whoop.

TESTING FOR PERTUSSIS

2. Which would be the test of choice to confirm pertussis in this patient?

• Bacterial culture of nasopharyngeal secretions
• Polymerase chain reaction (PCR) testing of nasopharyngeal secretions
• Direct fluorescent antibody testing of nasopharyngeal secretions
• Enzyme-linked immunosorbent assay (ELISA) serologic testing

Establishing the diagnosis of pertussis is often rather challenging.

Bacterial culture: Very specific, but slow and not so sensitive

Bacterial culture is still the gold standard for diagnosing pertussis, as a positive culture for B pertussis is 100% specific.⁵

However, this test has drawbacks. Its sensitivity has a wide range (15% to 80%) and depends very much on the time from the onset of symptoms to the time the culture specimen is collected. The yield drops off significantly after 1 week, and after 3 weeks the test has a sensitivity of only 1% to 3%.⁸ Therefore, for our patient, who has had symptoms for 3 weeks already, bacterial culture would not be the best test. In addition, the results are usually not known for 7 to 14 days, which is too slow to be useful in managing acute cases.

For swabbing, a Dacron swab is inserted through the nostril to the posterior pharynx and is left in place for 10 seconds to maximize the yield of the specimen. Recovery rates for B pertussis are low if the throat or the anterior nasal passage is swabbed instead of the posterior pharynx.⁹

Nasopharyngeal aspiration is a more complicated procedure, requiring a suction device to trap the mucus, but it may provide higher yields than swabbing.¹⁰ In this method, the specimen is obtained by inserting a small tube (eg, an infant feeding tube) connected to a mucus trap into the nostril back to the posterior pharynx.

Often, direct inoculation of medium for B pertussis is not possible. In such cases, clinical specimens are placed in Regan Lowe transport medium (half-strength charcoal agar supplemented with horse blood and cephalexin).^11,12

Polymerase chain reaction testing: Faster, more sensitive, but less specific

PCR testing of nasopharyngeal specimens is now being used instead of bacterial culture to diagnose pertussis in many situations. Alternatively, nasopharyngeal aspirate (or secretions collected with two Dacron swabs) can be obtained and divided at the time of collection and the specimens sent for both culture and PCR testing. Because bacterial culture is time-consuming and has poor sensitivity, the CDC states that a positive PCR test, along with the clinical symptoms and epidemiologic information, is sufficient for diagnosis.⁵

PCR testing can detect B pertussis with greater sensitivity and more rapidly than bacterial culture.^12–14 Its sensitivity ranges from 61% to 99%, its specificity ranges from 88% to 98%,^12,15,16 and its results can be available in 2 to 24 hours.¹²

PCR testing’s advantage in terms of sensitivity is especially pronounced in the later stages of the disease (as in our patient), when clinical suspicion of pertussis typically arises. It can be used effectively for up to 4 weeks from the onset of cough.¹⁴ Our patient, who presented nearly 3 weeks after the onset of symptoms, underwent nasopharyngeal sampling for PCR testing.

However, PCR testing is not as specific for B pertussis as is bacterial culture, since other Bordetella species can cause positive results on PCR testing. Also, as with culture, a negative test does not reliably rule out the disease, especially if the sample is collected late in the course.

Therefore, basing the diagnosis on PCR testing alone without the proper clinical context is not advised: pertussis outbreaks have been mistakenly declared on the basis of false-positive PCR test results. Three so-called “pertussis outbreaks” in three different states from 2004 to 2006¹⁷ were largely the result of overdiagnosis based on equivocal or false-positive PCR test results without the appropriate clinical circumstances. Retrospective review of these pseudo-outbreaks revealed that few cases actually met the CDC’s diagnostic criteria.¹⁷ Many patients were not tested (by any method) for pertussis and were treated as having probable cases of pertussis on the basis of their symptoms. Patients who were tested and who had a positive PCR test did not meet the clinical definition of pertussis according to the Council of State and Territorial Epidemiologists.¹⁷

Since PCR testing varies in sensitivity and specificity, obtaining culture confirmation of pertussis for at least one suspicious case is recommended any time an outbreak is suspected. This is necessary for monitoring for continued presence of the agent among cases of disease, recruitment of isolates for epidemiologic studies, and surveillance for antibiotic resistance.

The CDC does not recommend direct fluorescence antibody testing to diagnose pertussis. This test is commercially available and is sometimes used to screen patients for B pertussis infection, but it lacks sensitivity and specificity for this organism. Cross-reaction with normal nasopharyngeal flora can lead to a false-positive result.¹⁸ In addition, the interpretation of the test is subjective, so the sensitivity and specificity are quite variable: the sensitivity is reported as 52% to 65%, while the specificity can vary from 15% to 99%.

Enzyme-linked immunosorbent assay

ELISA testing has been used in epidemiologic studies to measure serum antibodies to B pertussis. Many serologic tests exist, but none is commercially available. Many of these tests are used by the CDC and state health departments to help confirm the diagnosis, especially during outbreaks. Generally, serologic tests are more useful for diagnosis in later phases of the disease. Currently used ELISA tests use both paired and single serology techniques measuring elevated immunoglobulin G serum antibody concentrations against an array of antigens, including pertussis toxin, filamentous hemagglutinin, pertactin, and fimbrae. As a result, a range of sensitivities (33%–95%) and specificities (72%–100%) has been reported.^12,14,19

TREATING PERTUSSIS

Our patient’s PCR test result comes back positive. In view of her symptoms and this result, we decide to treat her empirically for pertussis, even though she has had no known contact with anyone with the disease and there is currently no outbreak of it in the community.

3. According to the most recent evidence, which of the following would be the treatment of choice for pertussis in this patient?

• Azithromycin (Zithromax)
• Amoxicillin (Moxatag)
• Levofloxacin (Levaquin)
• Sulfamethoxazole-trimethoprim (Bactrim)
• Supportive measures (hydration, humidifier, antitussives, antihistamines, decongestants)

Azithromycin and the other macrolide antibiotics erythromycin and clarithromycin are first-line therapies for pertussis in adolescents and adults. If given during the catarrhal phase, they can reduce the duration and severity of symptoms and lessen the period of communicability.^20,21 After the catarrhal phase, however, it is uncertain whether antibiotics change the clinical course of pertussis, as the data are conflicting.^20–22

Factors to consider when selecting a macrolide antibiotic are tolerability, the potential for adverse events and drug interactions, ease of compliance, and cost. All three macrolides are equally effective against pertussis, but azithromycin and clarithromycin are generally better tolerated and are associated with milder and less frequent side effects than erythromycin, including lower rates of gastrointestinal side effects.

Erythromycin and clarithromycin inhibit the cytochrome P450 enzyme system, specifically CYP3A4, and can interact with a great many commonly prescribed drugs metabolized by this enzyme. Therefore, azithromycin may be a better choice for patients already taking other medications, like our patient.

Azithromycin and clarithromycin have longer half-lives and achieve higher tissue concentrations than erythromycin, allowing for less-frequent dosing (daily for azithromycin and twice daily for clarithromycin) and shorter treatment duration (5 days for azithromycin and 7 days for clarithromycin).

An advantage of erythromycin, though, is its lower cost. The cost of a recommended course of erythromycin treatment for pertussis (ie, 500 mg every 6 hours for 14 days) is roughly $20, compared with $75 for azithromycin.

Amoxicillin is not effective in clearing B pertussis from the nasopharynx and thus is not a reasonable option for the treatment of pertussis.²³

Levofloxacin is also not recommended for the treatment of pertussis.

Sulfamethoxazole-trimethoprim is a second-line agent for pertussis. It is effective in eradicating B pertussis from the nasopharynx²⁰ and is generally used as an alternative to the macrolide agents in patients who cannot tolerate or have contraindications to macrolides. Sulfamethoxazole-trimethoprim can also be an option for patients infected with rare macrolide-resistant strains of B pertussis.

Supportive measures by themselves are reasonable for patients with pertussis beyond the catarrhal phase, since antibiotics are typically not effective at that stage of the disease.

From 80% to 90% of patients with untreated pertussis spontaneously clear the bacteria from the nasopharynx within 3 to 4 weeks from the onset of cough symptoms.²⁰ However, supportive measures, including antitussives (both over-the-counter and prescription), tend to have very little effect on the severity or duration of the illness, especially when used past the early stage of the illness.

POSTEXPOSURE CHEMOPROPHYLAXIS FOR CLOSE CONTACTS

Postexposure chemoprophylaxis should be given to close contacts of patients who have pertussis to help prevent secondary cases.²² The CDC defines a close contact as someone who has had face-to-face exposure within 3 feet of a symptomatic patient within 21 days after the onset of symptoms in the patient. Close contacts should be treated with antibiotic regimens similar to those used in confirmed cases of pertussis.

In our patient’s case, the diagnosis of pertussis was reported to the Ohio Department of Health. Shortly afterward, the department contacted the patient and obtained information about her close contacts. These people were then contacted and encouraged to complete a course of antibiotics for postexposure chemoprophylaxis, given the high secondary attack rates.

PERTUSSIS VACCINES

4. Which of the following vaccines could have reduced our patient’s chance of contracting the disease or reduced the severity or time course of the illness?

• DTaP
• Tdap
• Whole-cell pertussis vaccine
• No vaccine would have reduced her risk

It is important to prevent pertussis, given its associated morbidities and its generally poor response to drug therapy. Continued vigilance is imperative to maintain high levels of vaccine coverage, including the timely completion of the pertussis vaccination schedule.

The two vaccines in current use in the United States to produce immunity to pertussis—DTaP and Tdap—also confer immunity to diphtheria and tetanus. DTaP is used for children under 7 years of age, and Tdap is for ages 10 to 64. Thus, our patient should have received a series of DTaP injections as an infant and small child, and a Tdap booster at age 11 or 12 years and every 10 years after that.

The upper case “D,” “T,” and “P” in the abbreviations signifies full-strength doses and the lower case “d,” “t,” and “p” indicate that the doses of those components have been reduced. The “a” in both vaccines stands for “acellular”: ie, the pertussis component does not contain cellular elements.

The current recommendation for initial pertussis vaccination consists of a primary series of DTaP. DTaP vaccination is recommended for infants at 2 months of age, then again at 4 months of age, and again at 6 months of age. A fourth dose is given between the ages of 15 and 18 months, and a fifth dose is given between the ages of 4 to 6 years. If the fourth dose was given after age 4, then no fifth dose is needed.²⁰

Tdap as a booster

The booster vaccine for adolescents and adults is Tdap. In 2005, two Tdap vaccines were licensed in the United States: Adacel for people ages 11 to 64 years, and Boostrix for people ages 10 to 18 years.

The CDC’s Advisory Committee on Immunization Practices (ACIP) recommends a booster dose of Tdap at age 11 or 12 years. Every 10 years thereafter, a booster of tetanus and diphtheria toxoid (Td) vaccine is recommended, except that one of the Td doses can be replaced by Tdap if the patient hasn’t received Tdap yet.

For adults ages 19 to 64, the ACIP currently recommends routine use of a single booster dose of Tdap to replace a single dose of Td if they received the last dose of toxoid vaccine 10 or more years earlier. If the previous dose of Td was given within the past 10 years, a single dose of Tdap is appropriate to protect patients against pertussis. This is especially true for patients at increased risk of pertussis or its complications, as well as for health care professionals and adults who have close contact with infants, such as new parents, grandparents, and child-care providers. The minimum interval since the last Td vaccination is ideally 2 years, although shorter intervals can be used for control of pertussis outbreaks and for those who have close contact with infants.²⁴

In 2010, the ACIP decided that, for those ages 65 and older, a single dose of Tdap vaccine may be given in place of Td if the patient has not previously received Tdap, regardless of how much time has elapsed since the last vaccination with a Td-containing vaccine.²⁵ Data from the Vaccine Adverse Event Reporting System suggest that Tdap vaccine in this age group is as safe as the Td vaccine.²⁵

Subsequent tetanus vaccine doses, in the form of Td, should be given at 10-year intervals throughout adulthood. Administration of Tdap at 10-year intervals appears to be highly immunogenic and well tolerated,²⁵ suggesting that it is possible that Tdap will become part of routine booster dosing instead of Td, pending further study.

Tdap is not contraindicated in pregnant women. Ideally, women should be vaccinated with Tdap before becoming pregnant if they have not previously received it. If the pregnant woman is not at risk of acquiring or transmitting pertussis during pregnancy, the ACIP recommends deferring Tdap vaccination until the immediate postpartum period.

Adults who require a vaccine containing tetanus toxoid for wound management should receive Tdap instead of Td if they have never received Tdap. Adults who have never received vaccine containing tetanus and diphtheria toxoid should receive a series of three vaccinations. The preferred schedule is a dose of Tdap, followed by a dose of Td more than 4 weeks later, and a second dose of Td 6 to 12 months later, though Tdap can be substituted for Td for any one of the three doses in the series. Adults with a history of pertussis generally should receive Tdap according to routine recommendations.

Tdap is contraindicated in people with a history of serious allergic reaction to any component of the Tdap vaccine or with a history of encephalopathy not attributable to an identifiable cause within 7 days of receiving a pertussis vaccine. Tdap is relatively contraindicated and should be deferred in people with current moderate to severe acute illness, current unstable neurologic condition, or a history of Arthus hypersensitivity reaction to a tetanus-toxoid-containing vaccine within the past 10 years, and in people who have developed Guillain-Barré syndrome, within 6 weeks of receiving a tetanus-toxoid–containing vaccine.

Tdap is generally well tolerated. Adverse effects are typically mild and may include localized pain, redness, and swelling; low-grade fever; headache; fatigue; and, less commonly, gastrointestinal upset, myalgia, arthralgia, rash, and swollen glands.

Whole-cell pertussis vaccine is no longer available in the United States

Whole-cell pertussis vaccine provides good protection against pertussis, with 70% to 90% efficacy after three doses. It is less expensive-than acellular formulations and therefore is used in many parts of the world where cost is an issue. It is no longer available in the United States, however, due to high rates of local reactions such as redness, swelling, and pain at the injection site.

The importance of staying up-to-date with booster shots

Booster vaccination for pertussis in adolescents and adults is critical, since the largest recent outbreaks have occurred in these groups.²¹ The high rate of outbreaks is presumably the result of waning immunity from childhood immunizations and of high interpersonal contact rates. Vaccination has been shown to reduce the chance of contracting the disease and to reduce the severity and time course of the illness.²¹

Adolescents and adults are an important reservoir for potentially serious infections in infants who are either unvaccinated or whose vaccination schedule has not been completed. These infants are at risk of severe illness, including pneumonia, seizures, encephalopathy, and apnea, or even death. Adults and teens can also suffer complications from pertussis, although these tend to be less serious, especially in those who have been vaccinated. Complications in teens and adults are often caused by malaise and the cough itself, including weight loss (33%), urinary stress incontinence (28%), syncope (6%), rib fractures from severe coughing (4%), and pneumonia (2%).²⁶ Thus, it is important that adolescents and adults stay up-to-date with pertussis vaccination.

CASE CONTINUED

Our patient was treated with a short (5-day) course of azithromycin 500 mg daily. It did not improve her symptoms very much, but this was not unexpected, given her late presentation and duration of symptoms. Her cough persisted for about 2 months afterwards, but it improved with time and with supportive care at home.

CONTINUED CHALLENGES

Pertussis is a reemerging disease with an increased incidence over the past 30 years, and even more so over the past 10 years. Unfortunately, treatments are not very effective, especially since the disease is often diagnosed late in the course.

We are fortunate to have a vaccine that can prevent pertussis, yet pertussis persists, in large part because of waning immunity from childhood vaccination. The duration of immunity from childhood vaccination is not yet clear. Many adolescents and adults do not follow up on these booster vaccines, thus increasing their susceptibility to pertussis. Consequently, they can transmit the disease to children who are not fully immunized. Prevention by maintaining active immunity is the key to controlling this terrible disease.

A 49-year-old woman presents with a cough that has persisted for 3 weeks.

Two weeks ago, she was seen in the outpatient clinic for a nonproductive cough, rhinorrhea, sneezing, and a sore throat. At that time, she described coughing spells that were occasionally accompanied by posttussive chest pain and vomiting. The cough was worse at night and was occasionally associated with wheezing. She reported no fevers, chills, rigors, night sweats, or dyspnea. She said she has tried over-the-counter cough suppressants, antihistamines, and decongestants, but they provided no relief. Since she had a history of well-controlled asthma, she was diagnosed with an asthma exacerbation and was given prednisone 20 mg to take orally every day for 5 days, to be followed by an inhaled corticosteroid until her symptoms resolved.

Now, she has returned because her symptoms have persisted despite treatment, and she is seeking a second medical opinion. Her paroxysmal cough has become more frequent and more severe.

In addition to asthma, she has a history of allergic rhinitis. Her current medications include the over-the-counter histamine H1 antagonist cetirizine (Zyrtec), a fluticasone-salmeterol inhaler (Advair), and an albuterol inhaler (Proventil HFA). She reports having had mild asthma exacerbations in the past during the winter, which were managed well with her albuterol inhaler.

She has never smoked; she drinks alcohol socially. She has not traveled outside the United States during the past several months. She is married and has two children, ages 25 and 23. She lives at home with only her husband, and he has not been sick. However, she works at a greeting card store, and two of her coworkers have similar upper respiratory symptoms, although they have only a mild cough.

Her immunizations are not up-to-date. She last received the tetanus-diphtheria toxoid (Td) vaccine 12 years ago, and she never received the pediatric tetanus, diphtheria, and acellular pertussis (Tdap) vaccine. She generally receives the influenza vaccine annually, and she received it about 6 weeks before this presentation.

She is not in distress, but she has paroxysms of severe coughing throughout her examination. Her pulse is 100 beats per minute, respiratory rate 18, and blood pressure 130/86 mm Hg. Her oropharynx is clear. The pulmonary examination reveals poor inspiratory effort due to coughing but is otherwise normal. The rest of the examination is normal, as is her chest radiograph.

WHAT DOES SHE HAVE?

1. Which of the following would best explain her symptoms?

• Asthma
• Postviral cough
• Pertussis
• Chronic bronchitis
• Pneumonia
• Gastroesophageal reflux disease

Asthma is a reasonable consideration, given her medical history, her occasional wheezing, and her nonproductive cough that is worse at night. However, asthma typically responds well to corticosteroid therapy. She has already received a course of prednisone, but her symptoms have not improved.

Postviral cough could also be considered in this patient. However, postviral cough does not typically occur in paroxysms, nor does it lead to posttussive vomiting. It is also generally regarded as a diagnosis of exclusion.

Pertussis (whooping cough) should be suspected in this patient, given the time course of her symptoms, the paroxysmal cough, and the posttussive vomiting. In addition, at her job she interacts with hundreds of people a day, increasing her risk of exposure to respiratory tract pathogens, including Bordetella pertussis.

Chronic bronchitis is defined by cough (typically productive) lasting at least 3 months per year for at least 2 consecutive years, which does not fit the time course for this patient. It is vastly more common in smokers.

Pneumonia typically presents with a cough that can be productive or nonproductive, but also with fever, chills, and radiologic evidence of a pulmonary infiltrate or consolidation. This woman has none of these.

Gastroesophageal reflux disease is one of the most common causes of chronic cough, with symptoms typically worse at night. However, it is generally associated with symptoms such as heartburn, a sour taste in the mouth, or regurgitation, which our patient did not report.

Thus, pertussis is the most likely diagnosis.

PERTUSSIS IS ON THE RISE

Pertussis is an acute and highly contagious disease caused by infection of the respiratory tract by B pertussis, a small, aerobic, gramnegative, pleomorphic coccobacillus that produces a number of antigenic and biologically active products, including pertussis toxin, filamentous hemagglutinin, agglutinogens, and tracheal cytotoxin. Transmitted by aerosolized droplets, it attaches to the ciliated epithelial cells of the lower respiratory tract, paralyzes the cilia via toxins, and causes inflammation, thus interfering with the clearing of respiratory secretions.

The incidence of pertussis is on the rise. In 2005, 25,827 cases were reported in the United States, the highest number since 1959.¹ Pertussis is now epidemic in California. At the time of this writing, the number of confirmed, probable, and suspected cases in California was 9,477 (including 10 infant deaths) for the year 2010—the most cases reported in the past 65 years.^2,3

In 2010, outbreaks were also reported in Michigan, Texas, Ohio, upstate New York, and Arizona.⁴ The overall incidence of pertussis is likely even higher than what is reported, since many cases go unrecognized or unreported.

Pertussis is transmitted person-to-person, primarily through aerosolized droplets from coughing or sneezing or by direct contact with secretions from the respiratory tract of infected persons. It is highly contagious, with secondary attack rates of up to 80% in susceptible people.

A three-stage clinical course

The clinical definition of pertussis used by the US Centers for Disease Control and Prevention (CDC) and the Council of State and Territorial Epidemiologists is an acute cough illness lasting at least 2 weeks, with paroxysms of coughing, an inspiratory “whoop,” or posttussive vomiting without another apparent cause.⁵

The clinical course of the illness is traditionally divided into three stages:

The catarrhal phase typically lasts 1 to 2 weeks and is clinically indistinguishable from a viral upper respiratory infection. It is characterized by the insidious onset of malaise, coryza, sneezing, low-grade fever, and a mild cough that gradually becomes severe.⁶

The paroxysmal phase normally lasts 1 to 6 weeks but may persist for up to 10 weeks. The diagnosis of pertussis is usually suspected during this phase. The classic features of this phase are bursts or paroxysms of numerous, rapid coughs. These are followed by a long inspiratory effort usually accompanied by a characteristic high-pitched whoop, most notably observed in infants and children. Infants and children may appear very ill and distressed during this time and may become cyanotic, but cyanosis is uncommon in adults and adolescents. The paroxysms may also be followed by exhaustion and posttussive vomiting. In some cases, the cough is not paroxysmal, but rather simply persistent. The coughing attacks tend to occur more often at night, with an average of 15 attacks per 24 hours. During the first 1 to 2 weeks of this stage, the attacks generally increase in frequency, remain at the same intensity level for 2 to 3 weeks, and then gradually decrease over 1 to 2 weeks.^1,7

The convalescent phase can have a variable course, ranging from weeks to months, with an average duration of 2 to 3 weeks. During this stage, the paroxysms of coughing become less frequent and gradually resolve. Paroxysms often recur with subsequent respiratory infections.

In infants and young children, pertussis tends to follow these stages in a predictable sequence. Adolescents and adults, however, tend to go through the stages without being as ill and typically do not exhibit the characteristic whoop.

TESTING FOR PERTUSSIS

2. Which would be the test of choice to confirm pertussis in this patient?

• Bacterial culture of nasopharyngeal secretions
• Polymerase chain reaction (PCR) testing of nasopharyngeal secretions
• Direct fluorescent antibody testing of nasopharyngeal secretions
• Enzyme-linked immunosorbent assay (ELISA) serologic testing

Establishing the diagnosis of pertussis is often rather challenging.

Bacterial culture: Very specific, but slow and not so sensitive

Bacterial culture is still the gold standard for diagnosing pertussis, as a positive culture for B pertussis is 100% specific.⁵

However, this test has drawbacks. Its sensitivity has a wide range (15% to 80%) and depends very much on the time from the onset of symptoms to the time the culture specimen is collected. The yield drops off significantly after 1 week, and after 3 weeks the test has a sensitivity of only 1% to 3%.⁸ Therefore, for our patient, who has had symptoms for 3 weeks already, bacterial culture would not be the best test. In addition, the results are usually not known for 7 to 14 days, which is too slow to be useful in managing acute cases.

For swabbing, a Dacron swab is inserted through the nostril to the posterior pharynx and is left in place for 10 seconds to maximize the yield of the specimen. Recovery rates for B pertussis are low if the throat or the anterior nasal passage is swabbed instead of the posterior pharynx.⁹

Nasopharyngeal aspiration is a more complicated procedure, requiring a suction device to trap the mucus, but it may provide higher yields than swabbing.¹⁰ In this method, the specimen is obtained by inserting a small tube (eg, an infant feeding tube) connected to a mucus trap into the nostril back to the posterior pharynx.

Often, direct inoculation of medium for B pertussis is not possible. In such cases, clinical specimens are placed in Regan Lowe transport medium (half-strength charcoal agar supplemented with horse blood and cephalexin).^11,12

Polymerase chain reaction testing: Faster, more sensitive, but less specific

PCR testing of nasopharyngeal specimens is now being used instead of bacterial culture to diagnose pertussis in many situations. Alternatively, nasopharyngeal aspirate (or secretions collected with two Dacron swabs) can be obtained and divided at the time of collection and the specimens sent for both culture and PCR testing. Because bacterial culture is time-consuming and has poor sensitivity, the CDC states that a positive PCR test, along with the clinical symptoms and epidemiologic information, is sufficient for diagnosis.⁵

PCR testing can detect B pertussis with greater sensitivity and more rapidly than bacterial culture.^12–14 Its sensitivity ranges from 61% to 99%, its specificity ranges from 88% to 98%,^12,15,16 and its results can be available in 2 to 24 hours.¹²

PCR testing’s advantage in terms of sensitivity is especially pronounced in the later stages of the disease (as in our patient), when clinical suspicion of pertussis typically arises. It can be used effectively for up to 4 weeks from the onset of cough.¹⁴ Our patient, who presented nearly 3 weeks after the onset of symptoms, underwent nasopharyngeal sampling for PCR testing.

However, PCR testing is not as specific for B pertussis as is bacterial culture, since other Bordetella species can cause positive results on PCR testing. Also, as with culture, a negative test does not reliably rule out the disease, especially if the sample is collected late in the course.

Therefore, basing the diagnosis on PCR testing alone without the proper clinical context is not advised: pertussis outbreaks have been mistakenly declared on the basis of false-positive PCR test results. Three so-called “pertussis outbreaks” in three different states from 2004 to 2006¹⁷ were largely the result of overdiagnosis based on equivocal or false-positive PCR test results without the appropriate clinical circumstances. Retrospective review of these pseudo-outbreaks revealed that few cases actually met the CDC’s diagnostic criteria.¹⁷ Many patients were not tested (by any method) for pertussis and were treated as having probable cases of pertussis on the basis of their symptoms. Patients who were tested and who had a positive PCR test did not meet the clinical definition of pertussis according to the Council of State and Territorial Epidemiologists.¹⁷

Since PCR testing varies in sensitivity and specificity, obtaining culture confirmation of pertussis for at least one suspicious case is recommended any time an outbreak is suspected. This is necessary for monitoring for continued presence of the agent among cases of disease, recruitment of isolates for epidemiologic studies, and surveillance for antibiotic resistance.

The CDC does not recommend direct fluorescence antibody testing to diagnose pertussis. This test is commercially available and is sometimes used to screen patients for B pertussis infection, but it lacks sensitivity and specificity for this organism. Cross-reaction with normal nasopharyngeal flora can lead to a false-positive result.¹⁸ In addition, the interpretation of the test is subjective, so the sensitivity and specificity are quite variable: the sensitivity is reported as 52% to 65%, while the specificity can vary from 15% to 99%.

Enzyme-linked immunosorbent assay

ELISA testing has been used in epidemiologic studies to measure serum antibodies to B pertussis. Many serologic tests exist, but none is commercially available. Many of these tests are used by the CDC and state health departments to help confirm the diagnosis, especially during outbreaks. Generally, serologic tests are more useful for diagnosis in later phases of the disease. Currently used ELISA tests use both paired and single serology techniques measuring elevated immunoglobulin G serum antibody concentrations against an array of antigens, including pertussis toxin, filamentous hemagglutinin, pertactin, and fimbrae. As a result, a range of sensitivities (33%–95%) and specificities (72%–100%) has been reported.^12,14,19

TREATING PERTUSSIS

Our patient’s PCR test result comes back positive. In view of her symptoms and this result, we decide to treat her empirically for pertussis, even though she has had no known contact with anyone with the disease and there is currently no outbreak of it in the community.

3. According to the most recent evidence, which of the following would be the treatment of choice for pertussis in this patient?

• Azithromycin (Zithromax)
• Amoxicillin (Moxatag)
• Levofloxacin (Levaquin)
• Sulfamethoxazole-trimethoprim (Bactrim)
• Supportive measures (hydration, humidifier, antitussives, antihistamines, decongestants)

Azithromycin and the other macrolide antibiotics erythromycin and clarithromycin are first-line therapies for pertussis in adolescents and adults. If given during the catarrhal phase, they can reduce the duration and severity of symptoms and lessen the period of communicability.^20,21 After the catarrhal phase, however, it is uncertain whether antibiotics change the clinical course of pertussis, as the data are conflicting.^20–22

Factors to consider when selecting a macrolide antibiotic are tolerability, the potential for adverse events and drug interactions, ease of compliance, and cost. All three macrolides are equally effective against pertussis, but azithromycin and clarithromycin are generally better tolerated and are associated with milder and less frequent side effects than erythromycin, including lower rates of gastrointestinal side effects.

Erythromycin and clarithromycin inhibit the cytochrome P450 enzyme system, specifically CYP3A4, and can interact with a great many commonly prescribed drugs metabolized by this enzyme. Therefore, azithromycin may be a better choice for patients already taking other medications, like our patient.

Azithromycin and clarithromycin have longer half-lives and achieve higher tissue concentrations than erythromycin, allowing for less-frequent dosing (daily for azithromycin and twice daily for clarithromycin) and shorter treatment duration (5 days for azithromycin and 7 days for clarithromycin).

An advantage of erythromycin, though, is its lower cost. The cost of a recommended course of erythromycin treatment for pertussis (ie, 500 mg every 6 hours for 14 days) is roughly $20, compared with $75 for azithromycin.

Amoxicillin is not effective in clearing B pertussis from the nasopharynx and thus is not a reasonable option for the treatment of pertussis.²³

Levofloxacin is also not recommended for the treatment of pertussis.

Sulfamethoxazole-trimethoprim is a second-line agent for pertussis. It is effective in eradicating B pertussis from the nasopharynx²⁰ and is generally used as an alternative to the macrolide agents in patients who cannot tolerate or have contraindications to macrolides. Sulfamethoxazole-trimethoprim can also be an option for patients infected with rare macrolide-resistant strains of B pertussis.

Supportive measures by themselves are reasonable for patients with pertussis beyond the catarrhal phase, since antibiotics are typically not effective at that stage of the disease.

From 80% to 90% of patients with untreated pertussis spontaneously clear the bacteria from the nasopharynx within 3 to 4 weeks from the onset of cough symptoms.²⁰ However, supportive measures, including antitussives (both over-the-counter and prescription), tend to have very little effect on the severity or duration of the illness, especially when used past the early stage of the illness.

POSTEXPOSURE CHEMOPROPHYLAXIS FOR CLOSE CONTACTS

Postexposure chemoprophylaxis should be given to close contacts of patients who have pertussis to help prevent secondary cases.²² The CDC defines a close contact as someone who has had face-to-face exposure within 3 feet of a symptomatic patient within 21 days after the onset of symptoms in the patient. Close contacts should be treated with antibiotic regimens similar to those used in confirmed cases of pertussis.

In our patient’s case, the diagnosis of pertussis was reported to the Ohio Department of Health. Shortly afterward, the department contacted the patient and obtained information about her close contacts. These people were then contacted and encouraged to complete a course of antibiotics for postexposure chemoprophylaxis, given the high secondary attack rates.

PERTUSSIS VACCINES

4. Which of the following vaccines could have reduced our patient’s chance of contracting the disease or reduced the severity or time course of the illness?

• DTaP
• Tdap
• Whole-cell pertussis vaccine
• No vaccine would have reduced her risk

It is important to prevent pertussis, given its associated morbidities and its generally poor response to drug therapy. Continued vigilance is imperative to maintain high levels of vaccine coverage, including the timely completion of the pertussis vaccination schedule.

The two vaccines in current use in the United States to produce immunity to pertussis—DTaP and Tdap—also confer immunity to diphtheria and tetanus. DTaP is used for children under 7 years of age, and Tdap is for ages 10 to 64. Thus, our patient should have received a series of DTaP injections as an infant and small child, and a Tdap booster at age 11 or 12 years and every 10 years after that.

The upper case “D,” “T,” and “P” in the abbreviations signifies full-strength doses and the lower case “d,” “t,” and “p” indicate that the doses of those components have been reduced. The “a” in both vaccines stands for “acellular”: ie, the pertussis component does not contain cellular elements.

The current recommendation for initial pertussis vaccination consists of a primary series of DTaP. DTaP vaccination is recommended for infants at 2 months of age, then again at 4 months of age, and again at 6 months of age. A fourth dose is given between the ages of 15 and 18 months, and a fifth dose is given between the ages of 4 to 6 years. If the fourth dose was given after age 4, then no fifth dose is needed.²⁰

Tdap as a booster

The booster vaccine for adolescents and adults is Tdap. In 2005, two Tdap vaccines were licensed in the United States: Adacel for people ages 11 to 64 years, and Boostrix for people ages 10 to 18 years.

The CDC’s Advisory Committee on Immunization Practices (ACIP) recommends a booster dose of Tdap at age 11 or 12 years. Every 10 years thereafter, a booster of tetanus and diphtheria toxoid (Td) vaccine is recommended, except that one of the Td doses can be replaced by Tdap if the patient hasn’t received Tdap yet.

For adults ages 19 to 64, the ACIP currently recommends routine use of a single booster dose of Tdap to replace a single dose of Td if they received the last dose of toxoid vaccine 10 or more years earlier. If the previous dose of Td was given within the past 10 years, a single dose of Tdap is appropriate to protect patients against pertussis. This is especially true for patients at increased risk of pertussis or its complications, as well as for health care professionals and adults who have close contact with infants, such as new parents, grandparents, and child-care providers. The minimum interval since the last Td vaccination is ideally 2 years, although shorter intervals can be used for control of pertussis outbreaks and for those who have close contact with infants.²⁴

In 2010, the ACIP decided that, for those ages 65 and older, a single dose of Tdap vaccine may be given in place of Td if the patient has not previously received Tdap, regardless of how much time has elapsed since the last vaccination with a Td-containing vaccine.²⁵ Data from the Vaccine Adverse Event Reporting System suggest that Tdap vaccine in this age group is as safe as the Td vaccine.²⁵

Subsequent tetanus vaccine doses, in the form of Td, should be given at 10-year intervals throughout adulthood. Administration of Tdap at 10-year intervals appears to be highly immunogenic and well tolerated,²⁵ suggesting that it is possible that Tdap will become part of routine booster dosing instead of Td, pending further study.

Tdap is not contraindicated in pregnant women. Ideally, women should be vaccinated with Tdap before becoming pregnant if they have not previously received it. If the pregnant woman is not at risk of acquiring or transmitting pertussis during pregnancy, the ACIP recommends deferring Tdap vaccination until the immediate postpartum period.

Adults who require a vaccine containing tetanus toxoid for wound management should receive Tdap instead of Td if they have never received Tdap. Adults who have never received vaccine containing tetanus and diphtheria toxoid should receive a series of three vaccinations. The preferred schedule is a dose of Tdap, followed by a dose of Td more than 4 weeks later, and a second dose of Td 6 to 12 months later, though Tdap can be substituted for Td for any one of the three doses in the series. Adults with a history of pertussis generally should receive Tdap according to routine recommendations.

Tdap is contraindicated in people with a history of serious allergic reaction to any component of the Tdap vaccine or with a history of encephalopathy not attributable to an identifiable cause within 7 days of receiving a pertussis vaccine. Tdap is relatively contraindicated and should be deferred in people with current moderate to severe acute illness, current unstable neurologic condition, or a history of Arthus hypersensitivity reaction to a tetanus-toxoid-containing vaccine within the past 10 years, and in people who have developed Guillain-Barré syndrome, within 6 weeks of receiving a tetanus-toxoid–containing vaccine.

Tdap is generally well tolerated. Adverse effects are typically mild and may include localized pain, redness, and swelling; low-grade fever; headache; fatigue; and, less commonly, gastrointestinal upset, myalgia, arthralgia, rash, and swollen glands.

Whole-cell pertussis vaccine is no longer available in the United States

Whole-cell pertussis vaccine provides good protection against pertussis, with 70% to 90% efficacy after three doses. It is less expensive-than acellular formulations and therefore is used in many parts of the world where cost is an issue. It is no longer available in the United States, however, due to high rates of local reactions such as redness, swelling, and pain at the injection site.

The importance of staying up-to-date with booster shots

Booster vaccination for pertussis in adolescents and adults is critical, since the largest recent outbreaks have occurred in these groups.²¹ The high rate of outbreaks is presumably the result of waning immunity from childhood immunizations and of high interpersonal contact rates. Vaccination has been shown to reduce the chance of contracting the disease and to reduce the severity and time course of the illness.²¹

Adolescents and adults are an important reservoir for potentially serious infections in infants who are either unvaccinated or whose vaccination schedule has not been completed. These infants are at risk of severe illness, including pneumonia, seizures, encephalopathy, and apnea, or even death. Adults and teens can also suffer complications from pertussis, although these tend to be less serious, especially in those who have been vaccinated. Complications in teens and adults are often caused by malaise and the cough itself, including weight loss (33%), urinary stress incontinence (28%), syncope (6%), rib fractures from severe coughing (4%), and pneumonia (2%).²⁶ Thus, it is important that adolescents and adults stay up-to-date with pertussis vaccination.

CASE CONTINUED

Our patient was treated with a short (5-day) course of azithromycin 500 mg daily. It did not improve her symptoms very much, but this was not unexpected, given her late presentation and duration of symptoms. Her cough persisted for about 2 months afterwards, but it improved with time and with supportive care at home.

CONTINUED CHALLENGES

Pertussis is a reemerging disease with an increased incidence over the past 30 years, and even more so over the past 10 years. Unfortunately, treatments are not very effective, especially since the disease is often diagnosed late in the course.

We are fortunate to have a vaccine that can prevent pertussis, yet pertussis persists, in large part because of waning immunity from childhood vaccination. The duration of immunity from childhood vaccination is not yet clear. Many adolescents and adults do not follow up on these booster vaccines, thus increasing their susceptibility to pertussis. Consequently, they can transmit the disease to children who are not fully immunized. Prevention by maintaining active immunity is the key to controlling this terrible disease.

A 49-year-old woman presents with a cough that has persisted for 3 weeks.

Two weeks ago, she was seen in the outpatient clinic for a nonproductive cough, rhinorrhea, sneezing, and a sore throat. At that time, she described coughing spells that were occasionally accompanied by posttussive chest pain and vomiting. The cough was worse at night and was occasionally associated with wheezing. She reported no fevers, chills, rigors, night sweats, or dyspnea. She said she has tried over-the-counter cough suppressants, antihistamines, and decongestants, but they provided no relief. Since she had a history of well-controlled asthma, she was diagnosed with an asthma exacerbation and was given prednisone 20 mg to take orally every day for 5 days, to be followed by an inhaled corticosteroid until her symptoms resolved.

Now, she has returned because her symptoms have persisted despite treatment, and she is seeking a second medical opinion. Her paroxysmal cough has become more frequent and more severe.

In addition to asthma, she has a history of allergic rhinitis. Her current medications include the over-the-counter histamine H1 antagonist cetirizine (Zyrtec), a fluticasone-salmeterol inhaler (Advair), and an albuterol inhaler (Proventil HFA). She reports having had mild asthma exacerbations in the past during the winter, which were managed well with her albuterol inhaler.

She has never smoked; she drinks alcohol socially. She has not traveled outside the United States during the past several months. She is married and has two children, ages 25 and 23. She lives at home with only her husband, and he has not been sick. However, she works at a greeting card store, and two of her coworkers have similar upper respiratory symptoms, although they have only a mild cough.

Her immunizations are not up-to-date. She last received the tetanus-diphtheria toxoid (Td) vaccine 12 years ago, and she never received the pediatric tetanus, diphtheria, and acellular pertussis (Tdap) vaccine. She generally receives the influenza vaccine annually, and she received it about 6 weeks before this presentation.

She is not in distress, but she has paroxysms of severe coughing throughout her examination. Her pulse is 100 beats per minute, respiratory rate 18, and blood pressure 130/86 mm Hg. Her oropharynx is clear. The pulmonary examination reveals poor inspiratory effort due to coughing but is otherwise normal. The rest of the examination is normal, as is her chest radiograph.

WHAT DOES SHE HAVE?

1. Which of the following would best explain her symptoms?

• Asthma
• Postviral cough
• Pertussis
• Chronic bronchitis
• Pneumonia
• Gastroesophageal reflux disease

Asthma is a reasonable consideration, given her medical history, her occasional wheezing, and her nonproductive cough that is worse at night. However, asthma typically responds well to corticosteroid therapy. She has already received a course of prednisone, but her symptoms have not improved.

Postviral cough could also be considered in this patient. However, postviral cough does not typically occur in paroxysms, nor does it lead to posttussive vomiting. It is also generally regarded as a diagnosis of exclusion.

Pertussis (whooping cough) should be suspected in this patient, given the time course of her symptoms, the paroxysmal cough, and the posttussive vomiting. In addition, at her job she interacts with hundreds of people a day, increasing her risk of exposure to respiratory tract pathogens, including Bordetella pertussis.

Chronic bronchitis is defined by cough (typically productive) lasting at least 3 months per year for at least 2 consecutive years, which does not fit the time course for this patient. It is vastly more common in smokers.

Pneumonia typically presents with a cough that can be productive or nonproductive, but also with fever, chills, and radiologic evidence of a pulmonary infiltrate or consolidation. This woman has none of these.

Gastroesophageal reflux disease is one of the most common causes of chronic cough, with symptoms typically worse at night. However, it is generally associated with symptoms such as heartburn, a sour taste in the mouth, or regurgitation, which our patient did not report.

Thus, pertussis is the most likely diagnosis.

PERTUSSIS IS ON THE RISE

Pertussis is an acute and highly contagious disease caused by infection of the respiratory tract by B pertussis, a small, aerobic, gramnegative, pleomorphic coccobacillus that produces a number of antigenic and biologically active products, including pertussis toxin, filamentous hemagglutinin, agglutinogens, and tracheal cytotoxin. Transmitted by aerosolized droplets, it attaches to the ciliated epithelial cells of the lower respiratory tract, paralyzes the cilia via toxins, and causes inflammation, thus interfering with the clearing of respiratory secretions.

The incidence of pertussis is on the rise. In 2005, 25,827 cases were reported in the United States, the highest number since 1959.¹ Pertussis is now epidemic in California. At the time of this writing, the number of confirmed, probable, and suspected cases in California was 9,477 (including 10 infant deaths) for the year 2010—the most cases reported in the past 65 years.^2,3

In 2010, outbreaks were also reported in Michigan, Texas, Ohio, upstate New York, and Arizona.⁴ The overall incidence of pertussis is likely even higher than what is reported, since many cases go unrecognized or unreported.

Pertussis is transmitted person-to-person, primarily through aerosolized droplets from coughing or sneezing or by direct contact with secretions from the respiratory tract of infected persons. It is highly contagious, with secondary attack rates of up to 80% in susceptible people.

A three-stage clinical course

The clinical definition of pertussis used by the US Centers for Disease Control and Prevention (CDC) and the Council of State and Territorial Epidemiologists is an acute cough illness lasting at least 2 weeks, with paroxysms of coughing, an inspiratory “whoop,” or posttussive vomiting without another apparent cause.⁵

The clinical course of the illness is traditionally divided into three stages:

The catarrhal phase typically lasts 1 to 2 weeks and is clinically indistinguishable from a viral upper respiratory infection. It is characterized by the insidious onset of malaise, coryza, sneezing, low-grade fever, and a mild cough that gradually becomes severe.⁶

The paroxysmal phase normally lasts 1 to 6 weeks but may persist for up to 10 weeks. The diagnosis of pertussis is usually suspected during this phase. The classic features of this phase are bursts or paroxysms of numerous, rapid coughs. These are followed by a long inspiratory effort usually accompanied by a characteristic high-pitched whoop, most notably observed in infants and children. Infants and children may appear very ill and distressed during this time and may become cyanotic, but cyanosis is uncommon in adults and adolescents. The paroxysms may also be followed by exhaustion and posttussive vomiting. In some cases, the cough is not paroxysmal, but rather simply persistent. The coughing attacks tend to occur more often at night, with an average of 15 attacks per 24 hours. During the first 1 to 2 weeks of this stage, the attacks generally increase in frequency, remain at the same intensity level for 2 to 3 weeks, and then gradually decrease over 1 to 2 weeks.^1,7

The convalescent phase can have a variable course, ranging from weeks to months, with an average duration of 2 to 3 weeks. During this stage, the paroxysms of coughing become less frequent and gradually resolve. Paroxysms often recur with subsequent respiratory infections.

In infants and young children, pertussis tends to follow these stages in a predictable sequence. Adolescents and adults, however, tend to go through the stages without being as ill and typically do not exhibit the characteristic whoop.

TESTING FOR PERTUSSIS

2. Which would be the test of choice to confirm pertussis in this patient?

• Bacterial culture of nasopharyngeal secretions
• Polymerase chain reaction (PCR) testing of nasopharyngeal secretions
• Direct fluorescent antibody testing of nasopharyngeal secretions
• Enzyme-linked immunosorbent assay (ELISA) serologic testing

Establishing the diagnosis of pertussis is often rather challenging.

Bacterial culture: Very specific, but slow and not so sensitive

Bacterial culture is still the gold standard for diagnosing pertussis, as a positive culture for B pertussis is 100% specific.⁵

However, this test has drawbacks. Its sensitivity has a wide range (15% to 80%) and depends very much on the time from the onset of symptoms to the time the culture specimen is collected. The yield drops off significantly after 1 week, and after 3 weeks the test has a sensitivity of only 1% to 3%.⁸ Therefore, for our patient, who has had symptoms for 3 weeks already, bacterial culture would not be the best test. In addition, the results are usually not known for 7 to 14 days, which is too slow to be useful in managing acute cases.

For swabbing, a Dacron swab is inserted through the nostril to the posterior pharynx and is left in place for 10 seconds to maximize the yield of the specimen. Recovery rates for B pertussis are low if the throat or the anterior nasal passage is swabbed instead of the posterior pharynx.⁹

Nasopharyngeal aspiration is a more complicated procedure, requiring a suction device to trap the mucus, but it may provide higher yields than swabbing.¹⁰ In this method, the specimen is obtained by inserting a small tube (eg, an infant feeding tube) connected to a mucus trap into the nostril back to the posterior pharynx.

Often, direct inoculation of medium for B pertussis is not possible. In such cases, clinical specimens are placed in Regan Lowe transport medium (half-strength charcoal agar supplemented with horse blood and cephalexin).^11,12

Polymerase chain reaction testing: Faster, more sensitive, but less specific

PCR testing of nasopharyngeal specimens is now being used instead of bacterial culture to diagnose pertussis in many situations. Alternatively, nasopharyngeal aspirate (or secretions collected with two Dacron swabs) can be obtained and divided at the time of collection and the specimens sent for both culture and PCR testing. Because bacterial culture is time-consuming and has poor sensitivity, the CDC states that a positive PCR test, along with the clinical symptoms and epidemiologic information, is sufficient for diagnosis.⁵

PCR testing can detect B pertussis with greater sensitivity and more rapidly than bacterial culture.^12–14 Its sensitivity ranges from 61% to 99%, its specificity ranges from 88% to 98%,^12,15,16 and its results can be available in 2 to 24 hours.¹²

PCR testing’s advantage in terms of sensitivity is especially pronounced in the later stages of the disease (as in our patient), when clinical suspicion of pertussis typically arises. It can be used effectively for up to 4 weeks from the onset of cough.¹⁴ Our patient, who presented nearly 3 weeks after the onset of symptoms, underwent nasopharyngeal sampling for PCR testing.

However, PCR testing is not as specific for B pertussis as is bacterial culture, since other Bordetella species can cause positive results on PCR testing. Also, as with culture, a negative test does not reliably rule out the disease, especially if the sample is collected late in the course.

Therefore, basing the diagnosis on PCR testing alone without the proper clinical context is not advised: pertussis outbreaks have been mistakenly declared on the basis of false-positive PCR test results. Three so-called “pertussis outbreaks” in three different states from 2004 to 2006¹⁷ were largely the result of overdiagnosis based on equivocal or false-positive PCR test results without the appropriate clinical circumstances. Retrospective review of these pseudo-outbreaks revealed that few cases actually met the CDC’s diagnostic criteria.¹⁷ Many patients were not tested (by any method) for pertussis and were treated as having probable cases of pertussis on the basis of their symptoms. Patients who were tested and who had a positive PCR test did not meet the clinical definition of pertussis according to the Council of State and Territorial Epidemiologists.¹⁷

Since PCR testing varies in sensitivity and specificity, obtaining culture confirmation of pertussis for at least one suspicious case is recommended any time an outbreak is suspected. This is necessary for monitoring for continued presence of the agent among cases of disease, recruitment of isolates for epidemiologic studies, and surveillance for antibiotic resistance.

The CDC does not recommend direct fluorescence antibody testing to diagnose pertussis. This test is commercially available and is sometimes used to screen patients for B pertussis infection, but it lacks sensitivity and specificity for this organism. Cross-reaction with normal nasopharyngeal flora can lead to a false-positive result.¹⁸ In addition, the interpretation of the test is subjective, so the sensitivity and specificity are quite variable: the sensitivity is reported as 52% to 65%, while the specificity can vary from 15% to 99%.

Enzyme-linked immunosorbent assay

ELISA testing has been used in epidemiologic studies to measure serum antibodies to B pertussis. Many serologic tests exist, but none is commercially available. Many of these tests are used by the CDC and state health departments to help confirm the diagnosis, especially during outbreaks. Generally, serologic tests are more useful for diagnosis in later phases of the disease. Currently used ELISA tests use both paired and single serology techniques measuring elevated immunoglobulin G serum antibody concentrations against an array of antigens, including pertussis toxin, filamentous hemagglutinin, pertactin, and fimbrae. As a result, a range of sensitivities (33%–95%) and specificities (72%–100%) has been reported.^12,14,19

TREATING PERTUSSIS

Our patient’s PCR test result comes back positive. In view of her symptoms and this result, we decide to treat her empirically for pertussis, even though she has had no known contact with anyone with the disease and there is currently no outbreak of it in the community.

3. According to the most recent evidence, which of the following would be the treatment of choice for pertussis in this patient?

• Azithromycin (Zithromax)
• Amoxicillin (Moxatag)
• Levofloxacin (Levaquin)
• Sulfamethoxazole-trimethoprim (Bactrim)
• Supportive measures (hydration, humidifier, antitussives, antihistamines, decongestants)

Azithromycin and the other macrolide antibiotics erythromycin and clarithromycin are first-line therapies for pertussis in adolescents and adults. If given during the catarrhal phase, they can reduce the duration and severity of symptoms and lessen the period of communicability.^20,21 After the catarrhal phase, however, it is uncertain whether antibiotics change the clinical course of pertussis, as the data are conflicting.^20–22

Factors to consider when selecting a macrolide antibiotic are tolerability, the potential for adverse events and drug interactions, ease of compliance, and cost. All three macrolides are equally effective against pertussis, but azithromycin and clarithromycin are generally better tolerated and are associated with milder and less frequent side effects than erythromycin, including lower rates of gastrointestinal side effects.

Erythromycin and clarithromycin inhibit the cytochrome P450 enzyme system, specifically CYP3A4, and can interact with a great many commonly prescribed drugs metabolized by this enzyme. Therefore, azithromycin may be a better choice for patients already taking other medications, like our patient.

Azithromycin and clarithromycin have longer half-lives and achieve higher tissue concentrations than erythromycin, allowing for less-frequent dosing (daily for azithromycin and twice daily for clarithromycin) and shorter treatment duration (5 days for azithromycin and 7 days for clarithromycin).

An advantage of erythromycin, though, is its lower cost. The cost of a recommended course of erythromycin treatment for pertussis (ie, 500 mg every 6 hours for 14 days) is roughly $20, compared with $75 for azithromycin.

Amoxicillin is not effective in clearing B pertussis from the nasopharynx and thus is not a reasonable option for the treatment of pertussis.²³

Levofloxacin is also not recommended for the treatment of pertussis.

Sulfamethoxazole-trimethoprim is a second-line agent for pertussis. It is effective in eradicating B pertussis from the nasopharynx²⁰ and is generally used as an alternative to the macrolide agents in patients who cannot tolerate or have contraindications to macrolides. Sulfamethoxazole-trimethoprim can also be an option for patients infected with rare macrolide-resistant strains of B pertussis.

Supportive measures by themselves are reasonable for patients with pertussis beyond the catarrhal phase, since antibiotics are typically not effective at that stage of the disease.

From 80% to 90% of patients with untreated pertussis spontaneously clear the bacteria from the nasopharynx within 3 to 4 weeks from the onset of cough symptoms.²⁰ However, supportive measures, including antitussives (both over-the-counter and prescription), tend to have very little effect on the severity or duration of the illness, especially when used past the early stage of the illness.

POSTEXPOSURE CHEMOPROPHYLAXIS FOR CLOSE CONTACTS

Postexposure chemoprophylaxis should be given to close contacts of patients who have pertussis to help prevent secondary cases.²² The CDC defines a close contact as someone who has had face-to-face exposure within 3 feet of a symptomatic patient within 21 days after the onset of symptoms in the patient. Close contacts should be treated with antibiotic regimens similar to those used in confirmed cases of pertussis.

In our patient’s case, the diagnosis of pertussis was reported to the Ohio Department of Health. Shortly afterward, the department contacted the patient and obtained information about her close contacts. These people were then contacted and encouraged to complete a course of antibiotics for postexposure chemoprophylaxis, given the high secondary attack rates.

PERTUSSIS VACCINES

4. Which of the following vaccines could have reduced our patient’s chance of contracting the disease or reduced the severity or time course of the illness?

• DTaP
• Tdap
• Whole-cell pertussis vaccine
• No vaccine would have reduced her risk

It is important to prevent pertussis, given its associated morbidities and its generally poor response to drug therapy. Continued vigilance is imperative to maintain high levels of vaccine coverage, including the timely completion of the pertussis vaccination schedule.

The two vaccines in current use in the United States to produce immunity to pertussis—DTaP and Tdap—also confer immunity to diphtheria and tetanus. DTaP is used for children under 7 years of age, and Tdap is for ages 10 to 64. Thus, our patient should have received a series of DTaP injections as an infant and small child, and a Tdap booster at age 11 or 12 years and every 10 years after that.

The upper case “D,” “T,” and “P” in the abbreviations signifies full-strength doses and the lower case “d,” “t,” and “p” indicate that the doses of those components have been reduced. The “a” in both vaccines stands for “acellular”: ie, the pertussis component does not contain cellular elements.

The current recommendation for initial pertussis vaccination consists of a primary series of DTaP. DTaP vaccination is recommended for infants at 2 months of age, then again at 4 months of age, and again at 6 months of age. A fourth dose is given between the ages of 15 and 18 months, and a fifth dose is given between the ages of 4 to 6 years. If the fourth dose was given after age 4, then no fifth dose is needed.²⁰

Tdap as a booster

The booster vaccine for adolescents and adults is Tdap. In 2005, two Tdap vaccines were licensed in the United States: Adacel for people ages 11 to 64 years, and Boostrix for people ages 10 to 18 years.

The CDC’s Advisory Committee on Immunization Practices (ACIP) recommends a booster dose of Tdap at age 11 or 12 years. Every 10 years thereafter, a booster of tetanus and diphtheria toxoid (Td) vaccine is recommended, except that one of the Td doses can be replaced by Tdap if the patient hasn’t received Tdap yet.

For adults ages 19 to 64, the ACIP currently recommends routine use of a single booster dose of Tdap to replace a single dose of Td if they received the last dose of toxoid vaccine 10 or more years earlier. If the previous dose of Td was given within the past 10 years, a single dose of Tdap is appropriate to protect patients against pertussis. This is especially true for patients at increased risk of pertussis or its complications, as well as for health care professionals and adults who have close contact with infants, such as new parents, grandparents, and child-care providers. The minimum interval since the last Td vaccination is ideally 2 years, although shorter intervals can be used for control of pertussis outbreaks and for those who have close contact with infants.²⁴

In 2010, the ACIP decided that, for those ages 65 and older, a single dose of Tdap vaccine may be given in place of Td if the patient has not previously received Tdap, regardless of how much time has elapsed since the last vaccination with a Td-containing vaccine.²⁵ Data from the Vaccine Adverse Event Reporting System suggest that Tdap vaccine in this age group is as safe as the Td vaccine.²⁵

Subsequent tetanus vaccine doses, in the form of Td, should be given at 10-year intervals throughout adulthood. Administration of Tdap at 10-year intervals appears to be highly immunogenic and well tolerated,²⁵ suggesting that it is possible that Tdap will become part of routine booster dosing instead of Td, pending further study.

Tdap is not contraindicated in pregnant women. Ideally, women should be vaccinated with Tdap before becoming pregnant if they have not previously received it. If the pregnant woman is not at risk of acquiring or transmitting pertussis during pregnancy, the ACIP recommends deferring Tdap vaccination until the immediate postpartum period.

Adults who require a vaccine containing tetanus toxoid for wound management should receive Tdap instead of Td if they have never received Tdap. Adults who have never received vaccine containing tetanus and diphtheria toxoid should receive a series of three vaccinations. The preferred schedule is a dose of Tdap, followed by a dose of Td more than 4 weeks later, and a second dose of Td 6 to 12 months later, though Tdap can be substituted for Td for any one of the three doses in the series. Adults with a history of pertussis generally should receive Tdap according to routine recommendations.

Tdap is contraindicated in people with a history of serious allergic reaction to any component of the Tdap vaccine or with a history of encephalopathy not attributable to an identifiable cause within 7 days of receiving a pertussis vaccine. Tdap is relatively contraindicated and should be deferred in people with current moderate to severe acute illness, current unstable neurologic condition, or a history of Arthus hypersensitivity reaction to a tetanus-toxoid-containing vaccine within the past 10 years, and in people who have developed Guillain-Barré syndrome, within 6 weeks of receiving a tetanus-toxoid–containing vaccine.

Tdap is generally well tolerated. Adverse effects are typically mild and may include localized pain, redness, and swelling; low-grade fever; headache; fatigue; and, less commonly, gastrointestinal upset, myalgia, arthralgia, rash, and swollen glands.

Whole-cell pertussis vaccine is no longer available in the United States

Whole-cell pertussis vaccine provides good protection against pertussis, with 70% to 90% efficacy after three doses. It is less expensive-than acellular formulations and therefore is used in many parts of the world where cost is an issue. It is no longer available in the United States, however, due to high rates of local reactions such as redness, swelling, and pain at the injection site.

The importance of staying up-to-date with booster shots

Booster vaccination for pertussis in adolescents and adults is critical, since the largest recent outbreaks have occurred in these groups.²¹ The high rate of outbreaks is presumably the result of waning immunity from childhood immunizations and of high interpersonal contact rates. Vaccination has been shown to reduce the chance of contracting the disease and to reduce the severity and time course of the illness.²¹

Adolescents and adults are an important reservoir for potentially serious infections in infants who are either unvaccinated or whose vaccination schedule has not been completed. These infants are at risk of severe illness, including pneumonia, seizures, encephalopathy, and apnea, or even death. Adults and teens can also suffer complications from pertussis, although these tend to be less serious, especially in those who have been vaccinated. Complications in teens and adults are often caused by malaise and the cough itself, including weight loss (33%), urinary stress incontinence (28%), syncope (6%), rib fractures from severe coughing (4%), and pneumonia (2%).²⁶ Thus, it is important that adolescents and adults stay up-to-date with pertussis vaccination.

CASE CONTINUED

Our patient was treated with a short (5-day) course of azithromycin 500 mg daily. It did not improve her symptoms very much, but this was not unexpected, given her late presentation and duration of symptoms. Her cough persisted for about 2 months afterwards, but it improved with time and with supportive care at home.

CONTINUED CHALLENGES

Pertussis is a reemerging disease with an increased incidence over the past 30 years, and even more so over the past 10 years. Unfortunately, treatments are not very effective, especially since the disease is often diagnosed late in the course.

We are fortunate to have a vaccine that can prevent pertussis, yet pertussis persists, in large part because of waning immunity from childhood vaccination. The duration of immunity from childhood vaccination is not yet clear. Many adolescents and adults do not follow up on these booster vaccines, thus increasing their susceptibility to pertussis. Consequently, they can transmit the disease to children who are not fully immunized. Prevention by maintaining active immunity is the key to controlling this terrible disease.