CASE  › Mitchell J, age 62, comes to see you because he’s had a cough with increasing dyspnea for a month. Mr. J has never smoked but has type 2 diabetes mellitus. He also tells you that over the past month, he’s had occasional night sweats and has lost 8 pounds, although he’s not changed his diet. During the past week, he’s noticed blood-tinged sputum. Physical examination reveals a thin, chronically ill appearing man with an oral temperature of 100.6°F and mild tachypnea. You order a complete blood count, chest x-ray, and metabolic profile, administer a tuberculin skin test (TST), and initiate levofloxacin 500 mg/d for a presumed bacterial pneumonia. His lab work reveals mild leukocytosis and hyperglycemia, and the chest x-ray shows a left upper lobe infiltrate. The TST reaction—4 mm 50 hours after placement—was negative.

Mr. J returns a week later and says he feels worse. Your examination reveals worsened tachypnea, with tachycardia and crackles over the left upper lung fields.

How would you proceed with his care?

More people die of tuberculosis (TB) each year than any other infectious disease except human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. In 2013, an estimated 9 million people worldwide developed active TB and 1.5 million died of the disease.¹ Many of these deaths could have been prevented if patients had received a diagnosis and treatment during the latent phase (when the patient was infected, but had no active disease), or as soon as the patient developed active disease. In this article we describe treatment for both latent and active TB.

Before treating latent TB infection, first rule out active TB

Patients with latent tuberculosis infection (LTBI) have a 5% to 10% lifetime risk of developing active TB disease.² Treatment of LTBI can reduce this risk to 1% to 2%.³

Assess patients with latent TB infection for signs of active TB, such as weight loss, unexplained fever, night sweats, or hemoptysis. Although not the focus of this article, diagnosis of LTBI is made by using either a TST, in which the patient receives an intradermal injection of purified protein derivative and the size of the skin induration is measured 48 to 72 hours after administration, or an interferon-gamma release assay (IGRA), which requires a blood draw. After receiving a positive test result for LTBI, the next step is to rule out active TB.⁴ This is necessary because the primary treatment regimen for LTBI involves only one drug, whereas treating active TB with one drug is strongly associated with treatment failure and future resistance to that drug.⁵

To rule out active TB, perform a brief, problem-focused history and physical, and obtain a chest x-ray.⁴ Pertinent findings that suggest active disease include:

• any history of recent weight loss, unexplained fever, night sweats, cough or hemoptysis
• fever or any unexpected lung findings on physical exam
• any parenchymal infiltrates on chest x-ray. (Granulomas and scarring may be signs of previously healed TB infection, but do not indicate active TB.)

Any of these findings should prompt a further investigation to either confirm or definitively rule out active TB disease. In the absence of these findings, the physician may proceed with treatment for LTBI.

Latent TB infection treatment: Isoniazid alone, or another regimen?

The current preferred regimen for most patients with LTBI is 9 months of isoniazid (INH) 5 mg/kg/d (10 mg/kg/d in children) up to a maximum of 300 mg/d. This regimen has been recommended by the Centers for Disease Control and Prevention (CDC), the American Thoracic Society, and the Infectious Diseases Society of America.³ However, there are 3 other CDC-recommended LTBI treatment regimens that include INH, INH plus rifapentine (RPT), or rifampin (RIF) for 6, 3, or 4 months, respectively (TABLE 1).⁶ These other regimens may be considered under certain circumstances. For example, INH and rifapentine might be used to treat an otherwise healthy patient who has had recent exposure to an individual with active, contagious TB.

If the patient is pregnant. INH is a pregnancy category C drug. Treatment for LTBI during pregnancy is generally regarded as safe and should be strongly considered if the patient has risk factors for progression to active TB, such as a recent exposure to someone with active TB.⁷ In otherwise healthy patients, treatment for LTBI may be deferred until after delivery.

Take steps to avoid complications of drug therapy

Drug-induced hepatitis is the primary adverse effect of INH treatment. Risk increases with age, previous hepatic injury, or concomitant use of other hepatotoxic medications. The risk is very small (<0.1%) for healthy children but may be over 10% for adults with multiple risk factors.⁸ Hepatitis is generally preceded by asymptomatic elevation of liver function tests (LFTs), which is much more common than clinical hepatitis.

Baseline LFTs should be obtained in patients who:

• have underlying liver disease, such as hepatitis B or C⁹
• consume ≥2 alcoholic drinks daily or >5 drinks at a time on any occasion
• take other medications with potential hepatotoxicity, such as statins
• have HIV infection¹⁰
• are pregnant or postpartum.

If a patient being considered for INH treatment has not had serologic testing for HIV, hepatitis B, or hepatitis C, these tests should be done prior to initiating INH. LFTs should be monitored every 1 to 2 months during INH therapy for patients who have ≥1 of these conditions and normal baseline LFTs. If baseline transaminases are >3 times the upper limit of normal, treatment for LTBI should probably be withheld, though might be considered in those whose LFTs return to normal after withdrawal of a modifiable risk factor, such as alcohol or a statin medication.

Patients with latent TB infection who are receiving isoniazid should be monitored regularly for signs and symptoms of hepatitis. After beginning LTBI treatment, patients should be monitored regularly for signs and symptoms of hepatitis, including anorexia, nausea, abdominal pain, icterus, and dark urine, and LFTs performed if these develop. If during treatment transaminases increase to >3 times normal in a symptomatic patient (or >5 times normal in an asymptomatic patient), INH should be stopped and generally not resumed, even after LFTs return to normal. (Such patients would be considered to have partially treated LTBI, and their physicians should be alert to signs and symptoms of active TB, such as unexplained fever, weight loss, or blood-tinged sputum, during subsequent patient encounters.)

Peripheral neuropathy is a less common adverse effect of INH. It occurs in up to 2% of patients and is caused by interference with vitamin B6 (pyridoxine) metabolism. It can be prevented by supplementation with pyridoxine 25 to 50 mg/d. Vitamin B6, however, does not prevent INH-induced hepatotoxicity.

Noncompliance is a concern with INH therapy because treatment typically requires a 9-month course of daily medication.¹¹ Patients for whom compliance is likely to be an issue might be considered for a 3-month, 12-dose course of once-weekly, directly-observed therapy (DOT) with INH and RPT administered by a public health agency. (See “Which patients with TB should receive directly observed therapy?” on page 32.^12-14) A randomized, open-label trial involving nearly 8000 patients in 4 low-risk countries found this regimen was as effective as 9 months of self-administered INH.¹⁵ The CDC has published recommendations for using this regimen.¹⁶

Suspect active TB? Don’t wait for cultures to begin Tx

Unlike LTBI, for which the results of diagnostic testing are available within a few days, active TB is diagnosed by culture, which may take as long as 6 to 8 weeks. Don’t wait to receive culture results to initiate treatment in a patient you suspect may have active TB. However, if you suspect your patient has active TB, do not delay treatment while waiting for culture results, or defer treatment for a patient who has a negative acid-fast bacilli (AFB) smear or rapid nucleic acid amplification test.¹⁷ These 2 tests, which are routinely performed during TB cultures, look for other evidence of the presence of TB bacilli; they are not as accurate as cultures, but results are available within days. Likewise, a negative TST or IGRA should not prevent empiric treatment for active TB. Treatment for active TB should be begun empirically based on risk factors and clinical presentation, and can be modified or stopped if cultures are negative, the patient fails to improve, or an alternative diagnosis is found to explain the patient’s symptoms.

Rapid testing for evidence of active TB disease—as well as resistance to medications commonly used to treat TB—can be performed using newer modalities such as MODS (Microscopic-Observation Drug-Susceptibility)^18,19 or Xpert MTB/RIF²⁰ testing. However, these tests are not available in many hospitals, and culture and drug sensitivity testing remain the gold standard.²¹

CASE › Mr. J’s clinical history and chest x-ray findings are highly suggestive of active TB. It was not unreasonable to initially treat him for a bacterial pneumonia, although fluoroquinolones should be used cautiously in this setting, because they are one of the most effective second-line drugs for TB, and using them as a single agent will often invoke drug resistance. Because he failed to respond to treatment for bacterial pneumonia and his presentation suggests TB or another serious cause of nonresponsiveness to standard treatment for community-acquired pneumonia (CAP), you admit him to the hospital.

Treatment for active TB requires multiple drugs in 2 phases

While all family physicians should suspect active TB in appropriate clinical situations and be comfortable with obtaining cultures and initiating empiric treatment, most will want to seek consultation with an infectious disease (ID) specialist especially in the scenarios listed in TABLE 2.^5,22 Delayed or inappropriate treatment of active TB remains a major public health problem and cause of multidrug-resistant TB. Inappropriate treatment has been shown to be associated with a 27-fold increase in treatment failure.²³ TB treatment guidelines are available from the CDC,²⁴ World Health Organization,²⁵ and International Union Against Tuberculosis and Lung Disease.²⁶

In the initial phase of treatment for active TB, patients should begin 4 drugs—INH, RIF, EMB, and PZA—for 2 months. Appropriate treatment requires the use of multiple medications administered in 2 phases. In the initial phase, a patient with suspected TB should begin 4 drugs—usually INH, RIF, ethambutol (EMB), and pyrazinamide (PZA)—for 2 months.^1,2,27 The daily pediatric and adult doses and common adverse effects of these medications are summarized in TABLE 3.²⁸ Although most cases of TB can be adequately treated with 2 drugs to which the organism is susceptible, 4 drugs are used initially while awaiting drug sensitivity test results because of the risk of inadequately treating a strain of drug-resistant TB. Before beginning these medications, a chest x-ray, LFTs, HIV antibody test, hepatitis B and C serologies, a serum creatinine, and complete blood count should be obtained in all patients.⁵ If EMB is prescribed, the patient should also undergo testing for red-green color discrimination, because red-green color vision disturbance is a potential adverse effect of this medication.

All 4 drugs may be administered as a single daily dose, and may be taken together.²⁹ They are ordinarily given either daily for 8 weeks, or daily for 2 weeks followed by a twice-weekly schedule for the remaining 6 weeks in higher doses, although the twice-weekly dose of RIF is the same as the daily dose. All are pregnancy category C, although for active TB, the benefit of treatment is almost always greater than the potential harm.

The continuation phase of treatment starts at 8 weeks, when the results of initial cultures and drug sensitivity tests should be available to guide therapy. A second set of cultures and AFB smears is obtained at 8 weeks to document clearing of the initial infection and guide duration of the continuation phase. If the initial culture was positive for Mycobacterium tuberculosis and the organism was sensitive to both INH and RIF, these 2 drugs should be continued for another 4 months (for a total of 6 months of treatment). PZA and EMB may be stopped at 2 months if the organism is sensitive to both INH and RIF. Thus, for most patients with active TB, the standard regimen will be 4 drugs for 2 months, then 2 drugs for 4 months.²

When should the standard treatment regimen be modified?

If a patient with active TB has persistently positive cultures and cavitary disease on an initial chest x-ray, treatment should be extended to 9 months. If the second set of cultures obtained 2 months after beginning drug treatment is positive and there was cavitary disease on the initial chest x-ray, the continuation phase should be extended by 7 months (for a total of 9 months of treatment).³⁰ If a patient has either cavitary disease or persistently positive cultures (but not both), then the length of therapy is determined on an individual basis in consultation with an ID specialist.

Should a patient’s cultures show resistance to any of the first-line drugs, obtain consultation with an ID specialist. Treatment of multidrug-resistant TB (resistant to INH and RIF) and its subset, extensively drug-resistant TB (resistant to INH and RIF, plus any fluoroquinolone, plus either an aminoglycoside or capreomycin) requires prolonged courses of therapy with multiple drugs administered by DOT.^31,32

If at any point during treatment a patient shows clinical deterioration that’s believed to be due to a resurgence of his or her TB disease, obtain a new set of cultures and, in consultation with an ID specialist, add at least 2 drugs to which the patient has not been exposed. Never add only one drug to a failing regimen; active TB always requires 2 drugs to cure, and the patient may have developed resistance to all of the drugs he or she is currently receiving.

If initial cultures are negative for Mycobacterium tuberculosis but the patient responds to treatment, he or she is considered to have “culture-negative TB,” and should generally be continued on INH and RIF for 2 more months after completion of the initial treatment phase (for a total of 4 months of INH and RIF).³³

Remember to report. In the United States, active TB must be reported to your local health department, which can be invaluable in coordinating care and administering DOT.

CASE › In the hospital, Mr. J was placed in respiratory isolation, had prompt sputum cultures for TB, and was started on empiric treatment for active TB with INH, RIF, PZA, and EMB in standard doses. A search for other causes of nonresponsiveness to CAP showed no evidence of malignancy or HIV infection. He improved steadily and was discharged from the hospital after 2 weeks to complete 2 months of 4-drug therapy, with follow-up care coordinated by the local health department, including a home health nurse experienced in administering DOT. Cultures were positive for Mycobacterium tuberculosis sensitive to all drugs tested. After his initial 2 months of 4-drug therapy, he completed 4 months of additional treatment with INH and RIF, given by DOT, and recovered completely. 

CORRESPONDENCE
Jeff Hall, MD, University of South Carolina Department of Family and Preventive Medicine, 3209 Colonial Drive, Columbia, SC 29203; [email protected]

CASE  › Mitchell J, age 62, comes to see you because he’s had a cough with increasing dyspnea for a month. Mr. J has never smoked but has type 2 diabetes mellitus. He also tells you that over the past month, he’s had occasional night sweats and has lost 8 pounds, although he’s not changed his diet. During the past week, he’s noticed blood-tinged sputum. Physical examination reveals a thin, chronically ill appearing man with an oral temperature of 100.6°F and mild tachypnea. You order a complete blood count, chest x-ray, and metabolic profile, administer a tuberculin skin test (TST), and initiate levofloxacin 500 mg/d for a presumed bacterial pneumonia. His lab work reveals mild leukocytosis and hyperglycemia, and the chest x-ray shows a left upper lobe infiltrate. The TST reaction—4 mm 50 hours after placement—was negative.

Mr. J returns a week later and says he feels worse. Your examination reveals worsened tachypnea, with tachycardia and crackles over the left upper lung fields.

How would you proceed with his care?

More people die of tuberculosis (TB) each year than any other infectious disease except human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. In 2013, an estimated 9 million people worldwide developed active TB and 1.5 million died of the disease.¹ Many of these deaths could have been prevented if patients had received a diagnosis and treatment during the latent phase (when the patient was infected, but had no active disease), or as soon as the patient developed active disease. In this article we describe treatment for both latent and active TB.

Before treating latent TB infection, first rule out active TB

Patients with latent tuberculosis infection (LTBI) have a 5% to 10% lifetime risk of developing active TB disease.² Treatment of LTBI can reduce this risk to 1% to 2%.³

Assess patients with latent TB infection for signs of active TB, such as weight loss, unexplained fever, night sweats, or hemoptysis. Although not the focus of this article, diagnosis of LTBI is made by using either a TST, in which the patient receives an intradermal injection of purified protein derivative and the size of the skin induration is measured 48 to 72 hours after administration, or an interferon-gamma release assay (IGRA), which requires a blood draw. After receiving a positive test result for LTBI, the next step is to rule out active TB.⁴ This is necessary because the primary treatment regimen for LTBI involves only one drug, whereas treating active TB with one drug is strongly associated with treatment failure and future resistance to that drug.⁵

To rule out active TB, perform a brief, problem-focused history and physical, and obtain a chest x-ray.⁴ Pertinent findings that suggest active disease include:

• any history of recent weight loss, unexplained fever, night sweats, cough or hemoptysis
• fever or any unexpected lung findings on physical exam
• any parenchymal infiltrates on chest x-ray. (Granulomas and scarring may be signs of previously healed TB infection, but do not indicate active TB.)

Any of these findings should prompt a further investigation to either confirm or definitively rule out active TB disease. In the absence of these findings, the physician may proceed with treatment for LTBI.

Latent TB infection treatment: Isoniazid alone, or another regimen?

The current preferred regimen for most patients with LTBI is 9 months of isoniazid (INH) 5 mg/kg/d (10 mg/kg/d in children) up to a maximum of 300 mg/d. This regimen has been recommended by the Centers for Disease Control and Prevention (CDC), the American Thoracic Society, and the Infectious Diseases Society of America.³ However, there are 3 other CDC-recommended LTBI treatment regimens that include INH, INH plus rifapentine (RPT), or rifampin (RIF) for 6, 3, or 4 months, respectively (TABLE 1).⁶ These other regimens may be considered under certain circumstances. For example, INH and rifapentine might be used to treat an otherwise healthy patient who has had recent exposure to an individual with active, contagious TB.

If the patient is pregnant. INH is a pregnancy category C drug. Treatment for LTBI during pregnancy is generally regarded as safe and should be strongly considered if the patient has risk factors for progression to active TB, such as a recent exposure to someone with active TB.⁷ In otherwise healthy patients, treatment for LTBI may be deferred until after delivery.

Take steps to avoid complications of drug therapy

Drug-induced hepatitis is the primary adverse effect of INH treatment. Risk increases with age, previous hepatic injury, or concomitant use of other hepatotoxic medications. The risk is very small (<0.1%) for healthy children but may be over 10% for adults with multiple risk factors.⁸ Hepatitis is generally preceded by asymptomatic elevation of liver function tests (LFTs), which is much more common than clinical hepatitis.

Baseline LFTs should be obtained in patients who:

• have underlying liver disease, such as hepatitis B or C⁹
• consume ≥2 alcoholic drinks daily or >5 drinks at a time on any occasion
• take other medications with potential hepatotoxicity, such as statins
• have HIV infection¹⁰
• are pregnant or postpartum.

If a patient being considered for INH treatment has not had serologic testing for HIV, hepatitis B, or hepatitis C, these tests should be done prior to initiating INH. LFTs should be monitored every 1 to 2 months during INH therapy for patients who have ≥1 of these conditions and normal baseline LFTs. If baseline transaminases are >3 times the upper limit of normal, treatment for LTBI should probably be withheld, though might be considered in those whose LFTs return to normal after withdrawal of a modifiable risk factor, such as alcohol or a statin medication.

Patients with latent TB infection who are receiving isoniazid should be monitored regularly for signs and symptoms of hepatitis. After beginning LTBI treatment, patients should be monitored regularly for signs and symptoms of hepatitis, including anorexia, nausea, abdominal pain, icterus, and dark urine, and LFTs performed if these develop. If during treatment transaminases increase to >3 times normal in a symptomatic patient (or >5 times normal in an asymptomatic patient), INH should be stopped and generally not resumed, even after LFTs return to normal. (Such patients would be considered to have partially treated LTBI, and their physicians should be alert to signs and symptoms of active TB, such as unexplained fever, weight loss, or blood-tinged sputum, during subsequent patient encounters.)

Peripheral neuropathy is a less common adverse effect of INH. It occurs in up to 2% of patients and is caused by interference with vitamin B6 (pyridoxine) metabolism. It can be prevented by supplementation with pyridoxine 25 to 50 mg/d. Vitamin B6, however, does not prevent INH-induced hepatotoxicity.

Noncompliance is a concern with INH therapy because treatment typically requires a 9-month course of daily medication.¹¹ Patients for whom compliance is likely to be an issue might be considered for a 3-month, 12-dose course of once-weekly, directly-observed therapy (DOT) with INH and RPT administered by a public health agency. (See “Which patients with TB should receive directly observed therapy?” on page 32.^12-14) A randomized, open-label trial involving nearly 8000 patients in 4 low-risk countries found this regimen was as effective as 9 months of self-administered INH.¹⁵ The CDC has published recommendations for using this regimen.¹⁶

Suspect active TB? Don’t wait for cultures to begin Tx

Unlike LTBI, for which the results of diagnostic testing are available within a few days, active TB is diagnosed by culture, which may take as long as 6 to 8 weeks. Don’t wait to receive culture results to initiate treatment in a patient you suspect may have active TB. However, if you suspect your patient has active TB, do not delay treatment while waiting for culture results, or defer treatment for a patient who has a negative acid-fast bacilli (AFB) smear or rapid nucleic acid amplification test.¹⁷ These 2 tests, which are routinely performed during TB cultures, look for other evidence of the presence of TB bacilli; they are not as accurate as cultures, but results are available within days. Likewise, a negative TST or IGRA should not prevent empiric treatment for active TB. Treatment for active TB should be begun empirically based on risk factors and clinical presentation, and can be modified or stopped if cultures are negative, the patient fails to improve, or an alternative diagnosis is found to explain the patient’s symptoms.

Rapid testing for evidence of active TB disease—as well as resistance to medications commonly used to treat TB—can be performed using newer modalities such as MODS (Microscopic-Observation Drug-Susceptibility)^18,19 or Xpert MTB/RIF²⁰ testing. However, these tests are not available in many hospitals, and culture and drug sensitivity testing remain the gold standard.²¹

CASE › Mr. J’s clinical history and chest x-ray findings are highly suggestive of active TB. It was not unreasonable to initially treat him for a bacterial pneumonia, although fluoroquinolones should be used cautiously in this setting, because they are one of the most effective second-line drugs for TB, and using them as a single agent will often invoke drug resistance. Because he failed to respond to treatment for bacterial pneumonia and his presentation suggests TB or another serious cause of nonresponsiveness to standard treatment for community-acquired pneumonia (CAP), you admit him to the hospital.

Treatment for active TB requires multiple drugs in 2 phases

While all family physicians should suspect active TB in appropriate clinical situations and be comfortable with obtaining cultures and initiating empiric treatment, most will want to seek consultation with an infectious disease (ID) specialist especially in the scenarios listed in TABLE 2.^5,22 Delayed or inappropriate treatment of active TB remains a major public health problem and cause of multidrug-resistant TB. Inappropriate treatment has been shown to be associated with a 27-fold increase in treatment failure.²³ TB treatment guidelines are available from the CDC,²⁴ World Health Organization,²⁵ and International Union Against Tuberculosis and Lung Disease.²⁶

In the initial phase of treatment for active TB, patients should begin 4 drugs—INH, RIF, EMB, and PZA—for 2 months. Appropriate treatment requires the use of multiple medications administered in 2 phases. In the initial phase, a patient with suspected TB should begin 4 drugs—usually INH, RIF, ethambutol (EMB), and pyrazinamide (PZA)—for 2 months.^1,2,27 The daily pediatric and adult doses and common adverse effects of these medications are summarized in TABLE 3.²⁸ Although most cases of TB can be adequately treated with 2 drugs to which the organism is susceptible, 4 drugs are used initially while awaiting drug sensitivity test results because of the risk of inadequately treating a strain of drug-resistant TB. Before beginning these medications, a chest x-ray, LFTs, HIV antibody test, hepatitis B and C serologies, a serum creatinine, and complete blood count should be obtained in all patients.⁵ If EMB is prescribed, the patient should also undergo testing for red-green color discrimination, because red-green color vision disturbance is a potential adverse effect of this medication.

All 4 drugs may be administered as a single daily dose, and may be taken together.²⁹ They are ordinarily given either daily for 8 weeks, or daily for 2 weeks followed by a twice-weekly schedule for the remaining 6 weeks in higher doses, although the twice-weekly dose of RIF is the same as the daily dose. All are pregnancy category C, although for active TB, the benefit of treatment is almost always greater than the potential harm.

The continuation phase of treatment starts at 8 weeks, when the results of initial cultures and drug sensitivity tests should be available to guide therapy. A second set of cultures and AFB smears is obtained at 8 weeks to document clearing of the initial infection and guide duration of the continuation phase. If the initial culture was positive for Mycobacterium tuberculosis and the organism was sensitive to both INH and RIF, these 2 drugs should be continued for another 4 months (for a total of 6 months of treatment). PZA and EMB may be stopped at 2 months if the organism is sensitive to both INH and RIF. Thus, for most patients with active TB, the standard regimen will be 4 drugs for 2 months, then 2 drugs for 4 months.²

When should the standard treatment regimen be modified?

If a patient with active TB has persistently positive cultures and cavitary disease on an initial chest x-ray, treatment should be extended to 9 months. If the second set of cultures obtained 2 months after beginning drug treatment is positive and there was cavitary disease on the initial chest x-ray, the continuation phase should be extended by 7 months (for a total of 9 months of treatment).³⁰ If a patient has either cavitary disease or persistently positive cultures (but not both), then the length of therapy is determined on an individual basis in consultation with an ID specialist.

Should a patient’s cultures show resistance to any of the first-line drugs, obtain consultation with an ID specialist. Treatment of multidrug-resistant TB (resistant to INH and RIF) and its subset, extensively drug-resistant TB (resistant to INH and RIF, plus any fluoroquinolone, plus either an aminoglycoside or capreomycin) requires prolonged courses of therapy with multiple drugs administered by DOT.^31,32

If at any point during treatment a patient shows clinical deterioration that’s believed to be due to a resurgence of his or her TB disease, obtain a new set of cultures and, in consultation with an ID specialist, add at least 2 drugs to which the patient has not been exposed. Never add only one drug to a failing regimen; active TB always requires 2 drugs to cure, and the patient may have developed resistance to all of the drugs he or she is currently receiving.

If initial cultures are negative for Mycobacterium tuberculosis but the patient responds to treatment, he or she is considered to have “culture-negative TB,” and should generally be continued on INH and RIF for 2 more months after completion of the initial treatment phase (for a total of 4 months of INH and RIF).³³

Remember to report. In the United States, active TB must be reported to your local health department, which can be invaluable in coordinating care and administering DOT.

CASE › In the hospital, Mr. J was placed in respiratory isolation, had prompt sputum cultures for TB, and was started on empiric treatment for active TB with INH, RIF, PZA, and EMB in standard doses. A search for other causes of nonresponsiveness to CAP showed no evidence of malignancy or HIV infection. He improved steadily and was discharged from the hospital after 2 weeks to complete 2 months of 4-drug therapy, with follow-up care coordinated by the local health department, including a home health nurse experienced in administering DOT. Cultures were positive for Mycobacterium tuberculosis sensitive to all drugs tested. After his initial 2 months of 4-drug therapy, he completed 4 months of additional treatment with INH and RIF, given by DOT, and recovered completely. 

CORRESPONDENCE
Jeff Hall, MD, University of South Carolina Department of Family and Preventive Medicine, 3209 Colonial Drive, Columbia, SC 29203; [email protected]

CASE  › Mitchell J, age 62, comes to see you because he’s had a cough with increasing dyspnea for a month. Mr. J has never smoked but has type 2 diabetes mellitus. He also tells you that over the past month, he’s had occasional night sweats and has lost 8 pounds, although he’s not changed his diet. During the past week, he’s noticed blood-tinged sputum. Physical examination reveals a thin, chronically ill appearing man with an oral temperature of 100.6°F and mild tachypnea. You order a complete blood count, chest x-ray, and metabolic profile, administer a tuberculin skin test (TST), and initiate levofloxacin 500 mg/d for a presumed bacterial pneumonia. His lab work reveals mild leukocytosis and hyperglycemia, and the chest x-ray shows a left upper lobe infiltrate. The TST reaction—4 mm 50 hours after placement—was negative.

Mr. J returns a week later and says he feels worse. Your examination reveals worsened tachypnea, with tachycardia and crackles over the left upper lung fields.

How would you proceed with his care?

More people die of tuberculosis (TB) each year than any other infectious disease except human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. In 2013, an estimated 9 million people worldwide developed active TB and 1.5 million died of the disease.¹ Many of these deaths could have been prevented if patients had received a diagnosis and treatment during the latent phase (when the patient was infected, but had no active disease), or as soon as the patient developed active disease. In this article we describe treatment for both latent and active TB.

Before treating latent TB infection, first rule out active TB

Patients with latent tuberculosis infection (LTBI) have a 5% to 10% lifetime risk of developing active TB disease.² Treatment of LTBI can reduce this risk to 1% to 2%.³

Assess patients with latent TB infection for signs of active TB, such as weight loss, unexplained fever, night sweats, or hemoptysis. Although not the focus of this article, diagnosis of LTBI is made by using either a TST, in which the patient receives an intradermal injection of purified protein derivative and the size of the skin induration is measured 48 to 72 hours after administration, or an interferon-gamma release assay (IGRA), which requires a blood draw. After receiving a positive test result for LTBI, the next step is to rule out active TB.⁴ This is necessary because the primary treatment regimen for LTBI involves only one drug, whereas treating active TB with one drug is strongly associated with treatment failure and future resistance to that drug.⁵

To rule out active TB, perform a brief, problem-focused history and physical, and obtain a chest x-ray.⁴ Pertinent findings that suggest active disease include:

• any history of recent weight loss, unexplained fever, night sweats, cough or hemoptysis
• fever or any unexpected lung findings on physical exam
• any parenchymal infiltrates on chest x-ray. (Granulomas and scarring may be signs of previously healed TB infection, but do not indicate active TB.)

Any of these findings should prompt a further investigation to either confirm or definitively rule out active TB disease. In the absence of these findings, the physician may proceed with treatment for LTBI.

Latent TB infection treatment: Isoniazid alone, or another regimen?

The current preferred regimen for most patients with LTBI is 9 months of isoniazid (INH) 5 mg/kg/d (10 mg/kg/d in children) up to a maximum of 300 mg/d. This regimen has been recommended by the Centers for Disease Control and Prevention (CDC), the American Thoracic Society, and the Infectious Diseases Society of America.³ However, there are 3 other CDC-recommended LTBI treatment regimens that include INH, INH plus rifapentine (RPT), or rifampin (RIF) for 6, 3, or 4 months, respectively (TABLE 1).⁶ These other regimens may be considered under certain circumstances. For example, INH and rifapentine might be used to treat an otherwise healthy patient who has had recent exposure to an individual with active, contagious TB.

If the patient is pregnant. INH is a pregnancy category C drug. Treatment for LTBI during pregnancy is generally regarded as safe and should be strongly considered if the patient has risk factors for progression to active TB, such as a recent exposure to someone with active TB.⁷ In otherwise healthy patients, treatment for LTBI may be deferred until after delivery.

Take steps to avoid complications of drug therapy

Drug-induced hepatitis is the primary adverse effect of INH treatment. Risk increases with age, previous hepatic injury, or concomitant use of other hepatotoxic medications. The risk is very small (<0.1%) for healthy children but may be over 10% for adults with multiple risk factors.⁸ Hepatitis is generally preceded by asymptomatic elevation of liver function tests (LFTs), which is much more common than clinical hepatitis.

Baseline LFTs should be obtained in patients who:

• have underlying liver disease, such as hepatitis B or C⁹
• consume ≥2 alcoholic drinks daily or >5 drinks at a time on any occasion
• take other medications with potential hepatotoxicity, such as statins
• have HIV infection¹⁰
• are pregnant or postpartum.

If a patient being considered for INH treatment has not had serologic testing for HIV, hepatitis B, or hepatitis C, these tests should be done prior to initiating INH. LFTs should be monitored every 1 to 2 months during INH therapy for patients who have ≥1 of these conditions and normal baseline LFTs. If baseline transaminases are >3 times the upper limit of normal, treatment for LTBI should probably be withheld, though might be considered in those whose LFTs return to normal after withdrawal of a modifiable risk factor, such as alcohol or a statin medication.

Patients with latent TB infection who are receiving isoniazid should be monitored regularly for signs and symptoms of hepatitis. After beginning LTBI treatment, patients should be monitored regularly for signs and symptoms of hepatitis, including anorexia, nausea, abdominal pain, icterus, and dark urine, and LFTs performed if these develop. If during treatment transaminases increase to >3 times normal in a symptomatic patient (or >5 times normal in an asymptomatic patient), INH should be stopped and generally not resumed, even after LFTs return to normal. (Such patients would be considered to have partially treated LTBI, and their physicians should be alert to signs and symptoms of active TB, such as unexplained fever, weight loss, or blood-tinged sputum, during subsequent patient encounters.)

Peripheral neuropathy is a less common adverse effect of INH. It occurs in up to 2% of patients and is caused by interference with vitamin B6 (pyridoxine) metabolism. It can be prevented by supplementation with pyridoxine 25 to 50 mg/d. Vitamin B6, however, does not prevent INH-induced hepatotoxicity.

Noncompliance is a concern with INH therapy because treatment typically requires a 9-month course of daily medication.¹¹ Patients for whom compliance is likely to be an issue might be considered for a 3-month, 12-dose course of once-weekly, directly-observed therapy (DOT) with INH and RPT administered by a public health agency. (See “Which patients with TB should receive directly observed therapy?” on page 32.^12-14) A randomized, open-label trial involving nearly 8000 patients in 4 low-risk countries found this regimen was as effective as 9 months of self-administered INH.¹⁵ The CDC has published recommendations for using this regimen.¹⁶

Suspect active TB? Don’t wait for cultures to begin Tx

Unlike LTBI, for which the results of diagnostic testing are available within a few days, active TB is diagnosed by culture, which may take as long as 6 to 8 weeks. Don’t wait to receive culture results to initiate treatment in a patient you suspect may have active TB. However, if you suspect your patient has active TB, do not delay treatment while waiting for culture results, or defer treatment for a patient who has a negative acid-fast bacilli (AFB) smear or rapid nucleic acid amplification test.¹⁷ These 2 tests, which are routinely performed during TB cultures, look for other evidence of the presence of TB bacilli; they are not as accurate as cultures, but results are available within days. Likewise, a negative TST or IGRA should not prevent empiric treatment for active TB. Treatment for active TB should be begun empirically based on risk factors and clinical presentation, and can be modified or stopped if cultures are negative, the patient fails to improve, or an alternative diagnosis is found to explain the patient’s symptoms.

Rapid testing for evidence of active TB disease—as well as resistance to medications commonly used to treat TB—can be performed using newer modalities such as MODS (Microscopic-Observation Drug-Susceptibility)^18,19 or Xpert MTB/RIF²⁰ testing. However, these tests are not available in many hospitals, and culture and drug sensitivity testing remain the gold standard.²¹

CASE › Mr. J’s clinical history and chest x-ray findings are highly suggestive of active TB. It was not unreasonable to initially treat him for a bacterial pneumonia, although fluoroquinolones should be used cautiously in this setting, because they are one of the most effective second-line drugs for TB, and using them as a single agent will often invoke drug resistance. Because he failed to respond to treatment for bacterial pneumonia and his presentation suggests TB or another serious cause of nonresponsiveness to standard treatment for community-acquired pneumonia (CAP), you admit him to the hospital.

Treatment for active TB requires multiple drugs in 2 phases

While all family physicians should suspect active TB in appropriate clinical situations and be comfortable with obtaining cultures and initiating empiric treatment, most will want to seek consultation with an infectious disease (ID) specialist especially in the scenarios listed in TABLE 2.^5,22 Delayed or inappropriate treatment of active TB remains a major public health problem and cause of multidrug-resistant TB. Inappropriate treatment has been shown to be associated with a 27-fold increase in treatment failure.²³ TB treatment guidelines are available from the CDC,²⁴ World Health Organization,²⁵ and International Union Against Tuberculosis and Lung Disease.²⁶

In the initial phase of treatment for active TB, patients should begin 4 drugs—INH, RIF, EMB, and PZA—for 2 months. Appropriate treatment requires the use of multiple medications administered in 2 phases. In the initial phase, a patient with suspected TB should begin 4 drugs—usually INH, RIF, ethambutol (EMB), and pyrazinamide (PZA)—for 2 months.^1,2,27 The daily pediatric and adult doses and common adverse effects of these medications are summarized in TABLE 3.²⁸ Although most cases of TB can be adequately treated with 2 drugs to which the organism is susceptible, 4 drugs are used initially while awaiting drug sensitivity test results because of the risk of inadequately treating a strain of drug-resistant TB. Before beginning these medications, a chest x-ray, LFTs, HIV antibody test, hepatitis B and C serologies, a serum creatinine, and complete blood count should be obtained in all patients.⁵ If EMB is prescribed, the patient should also undergo testing for red-green color discrimination, because red-green color vision disturbance is a potential adverse effect of this medication.

All 4 drugs may be administered as a single daily dose, and may be taken together.²⁹ They are ordinarily given either daily for 8 weeks, or daily for 2 weeks followed by a twice-weekly schedule for the remaining 6 weeks in higher doses, although the twice-weekly dose of RIF is the same as the daily dose. All are pregnancy category C, although for active TB, the benefit of treatment is almost always greater than the potential harm.

The continuation phase of treatment starts at 8 weeks, when the results of initial cultures and drug sensitivity tests should be available to guide therapy. A second set of cultures and AFB smears is obtained at 8 weeks to document clearing of the initial infection and guide duration of the continuation phase. If the initial culture was positive for Mycobacterium tuberculosis and the organism was sensitive to both INH and RIF, these 2 drugs should be continued for another 4 months (for a total of 6 months of treatment). PZA and EMB may be stopped at 2 months if the organism is sensitive to both INH and RIF. Thus, for most patients with active TB, the standard regimen will be 4 drugs for 2 months, then 2 drugs for 4 months.²

When should the standard treatment regimen be modified?

If a patient with active TB has persistently positive cultures and cavitary disease on an initial chest x-ray, treatment should be extended to 9 months. If the second set of cultures obtained 2 months after beginning drug treatment is positive and there was cavitary disease on the initial chest x-ray, the continuation phase should be extended by 7 months (for a total of 9 months of treatment).³⁰ If a patient has either cavitary disease or persistently positive cultures (but not both), then the length of therapy is determined on an individual basis in consultation with an ID specialist.

Should a patient’s cultures show resistance to any of the first-line drugs, obtain consultation with an ID specialist. Treatment of multidrug-resistant TB (resistant to INH and RIF) and its subset, extensively drug-resistant TB (resistant to INH and RIF, plus any fluoroquinolone, plus either an aminoglycoside or capreomycin) requires prolonged courses of therapy with multiple drugs administered by DOT.^31,32

If at any point during treatment a patient shows clinical deterioration that’s believed to be due to a resurgence of his or her TB disease, obtain a new set of cultures and, in consultation with an ID specialist, add at least 2 drugs to which the patient has not been exposed. Never add only one drug to a failing regimen; active TB always requires 2 drugs to cure, and the patient may have developed resistance to all of the drugs he or she is currently receiving.

If initial cultures are negative for Mycobacterium tuberculosis but the patient responds to treatment, he or she is considered to have “culture-negative TB,” and should generally be continued on INH and RIF for 2 more months after completion of the initial treatment phase (for a total of 4 months of INH and RIF).³³

Remember to report. In the United States, active TB must be reported to your local health department, which can be invaluable in coordinating care and administering DOT.

CASE › In the hospital, Mr. J was placed in respiratory isolation, had prompt sputum cultures for TB, and was started on empiric treatment for active TB with INH, RIF, PZA, and EMB in standard doses. A search for other causes of nonresponsiveness to CAP showed no evidence of malignancy or HIV infection. He improved steadily and was discharged from the hospital after 2 weeks to complete 2 months of 4-drug therapy, with follow-up care coordinated by the local health department, including a home health nurse experienced in administering DOT. Cultures were positive for Mycobacterium tuberculosis sensitive to all drugs tested. After his initial 2 months of 4-drug therapy, he completed 4 months of additional treatment with INH and RIF, given by DOT, and recovered completely. 

CORRESPONDENCE
Jeff Hall, MD, University of South Carolina Department of Family and Preventive Medicine, 3209 Colonial Drive, Columbia, SC 29203; [email protected]

ANSWER: D

Critique

The presentation is one of intermittent solid food dysphagia in the setting of frequent heartburn in a young white male. The differential diagnosis includes reflux esophagitis and peptic stricture, as well as eosinophilic esophagitis. Sometimes, the two conditions overlap. Empiric proton pump inhibitor therapy is of value in clarifying the diagnosis of gastroesophageal reflux disease in patients with typical symptoms of heartburn and regurgitation. This is because the likelihood of gastroesophageal reflux disease is very high in patients with typical reflux symptoms. However, in this setting eosinophilic esophagitis needs to be excluded. So the optimal approach is to initiate proton pump inhibitor therapy, and then inspect and biopsy the esophagus. Treatments specific for eosinophilic esophagitis (topical fluticasone, montelukast) will only be indicated if the diagnosis of eosinophilic esophagitis is confirmed.

Prednisone is not utilized often orally for the management of eosinophilic esophagitis. Baclofen, a GABA-B receptor agonist, has been demonstrated to reduce the frequency of transient lower esophageal sphincter relaxations and improve residual symptoms in patients on PPI therapy.

ANSWER: D

Critique

The presentation is one of intermittent solid food dysphagia in the setting of frequent heartburn in a young white male. The differential diagnosis includes reflux esophagitis and peptic stricture, as well as eosinophilic esophagitis. Sometimes, the two conditions overlap. Empiric proton pump inhibitor therapy is of value in clarifying the diagnosis of gastroesophageal reflux disease in patients with typical symptoms of heartburn and regurgitation. This is because the likelihood of gastroesophageal reflux disease is very high in patients with typical reflux symptoms. However, in this setting eosinophilic esophagitis needs to be excluded. So the optimal approach is to initiate proton pump inhibitor therapy, and then inspect and biopsy the esophagus. Treatments specific for eosinophilic esophagitis (topical fluticasone, montelukast) will only be indicated if the diagnosis of eosinophilic esophagitis is confirmed.

Prednisone is not utilized often orally for the management of eosinophilic esophagitis. Baclofen, a GABA-B receptor agonist, has been demonstrated to reduce the frequency of transient lower esophageal sphincter relaxations and improve residual symptoms in patients on PPI therapy.

ANSWER: D

Critique

The presentation is one of intermittent solid food dysphagia in the setting of frequent heartburn in a young white male. The differential diagnosis includes reflux esophagitis and peptic stricture, as well as eosinophilic esophagitis. Sometimes, the two conditions overlap. Empiric proton pump inhibitor therapy is of value in clarifying the diagnosis of gastroesophageal reflux disease in patients with typical symptoms of heartburn and regurgitation. This is because the likelihood of gastroesophageal reflux disease is very high in patients with typical reflux symptoms. However, in this setting eosinophilic esophagitis needs to be excluded. So the optimal approach is to initiate proton pump inhibitor therapy, and then inspect and biopsy the esophagus. Treatments specific for eosinophilic esophagitis (topical fluticasone, montelukast) will only be indicated if the diagnosis of eosinophilic esophagitis is confirmed.

Prednisone is not utilized often orally for the management of eosinophilic esophagitis. Baclofen, a GABA-B receptor agonist, has been demonstrated to reduce the frequency of transient lower esophageal sphincter relaxations and improve residual symptoms in patients on PPI therapy.

ANSWER: D

Critique

Villous blunting is not specific to celiac disease. In this case, the patient’s history supports a diagnosis of common variable immunodeficiency (CVID), which is characterized by low levels of two Ig classes and recurrent infections. The infections most commonly involve the upper and lower respiratory tract.

Chronic diarrhea is seen in 40%-60% of patients and may lead to malabsorption. Diarrhea can be the result of infections (most commonly Salmonella, Campylobacter, Clostridium difficile, and Giardia lamblia), inflammatory disorders, or malignancy. Biopsies reveal villous blunting similar to that seen in celiac disease. Unlike celiac disease, however, the biopsies lack plasma cells. These patients also differ from those with celiac disease in that their celiac serologies are negative.

ANSWER: D

Critique

Villous blunting is not specific to celiac disease. In this case, the patient’s history supports a diagnosis of common variable immunodeficiency (CVID), which is characterized by low levels of two Ig classes and recurrent infections. The infections most commonly involve the upper and lower respiratory tract.

Chronic diarrhea is seen in 40%-60% of patients and may lead to malabsorption. Diarrhea can be the result of infections (most commonly Salmonella, Campylobacter, Clostridium difficile, and Giardia lamblia), inflammatory disorders, or malignancy. Biopsies reveal villous blunting similar to that seen in celiac disease. Unlike celiac disease, however, the biopsies lack plasma cells. These patients also differ from those with celiac disease in that their celiac serologies are negative.

ANSWER: D

Critique

Villous blunting is not specific to celiac disease. In this case, the patient’s history supports a diagnosis of common variable immunodeficiency (CVID), which is characterized by low levels of two Ig classes and recurrent infections. The infections most commonly involve the upper and lower respiratory tract.

Chronic diarrhea is seen in 40%-60% of patients and may lead to malabsorption. Diarrhea can be the result of infections (most commonly Salmonella, Campylobacter, Clostridium difficile, and Giardia lamblia), inflammatory disorders, or malignancy. Biopsies reveal villous blunting similar to that seen in celiac disease. Unlike celiac disease, however, the biopsies lack plasma cells. These patients also differ from those with celiac disease in that their celiac serologies are negative.

THE CASE

A 6-year-old girl was brought to the emergency department (ED) by her mother after the child had bumped her head while playing. While the physician examined the child’s head, the mother remarked that her daughter had recently developed bruises that appeared suddenly and only after minor, if any, known trauma. The ED physician determined that the child’s bump to the head was nothing to worry about, attributed the bruising to the child being a “healthy, active 6-year-old,” and sent her home.

Two days later the child was brought to our office because the mother was still concerned about her daughter’s easy bruising. The mother pointed out ecchymosis scattered across her daughter’s extremities and torso. The child denied any pain or other complaints, including any active or recurrent bleeding. Upon further questioning, the mother mentioned that her daughter had recovered from a cold-like illness several weeks earlier.

THE DIAGNOSIS

We ordered a complete blood count (CBC) and peripheral smear, which were normal except for the platelet count, which was 7000/mcL (normal, 150,000-450,000/mcL). Based on the child’s easy bruising and isolated thrombocytopenia, we diagnosed immune thrombocytopenia, which is also known as idiopathic thrombocytopenic purpura (ITP).

DISCUSSION

In ITP, autoantibodies are directed against platelets, leading to their sequestration and destruction in the spleen and a resultant drop in platelet count.¹ Children with ITP typically present between the ages of 2 and 10 years, with a peak incidence between 2 and 5 years.² The incidence is estimated to be as high as 8 per 100,000 children.³ However, this estimate primarily reflects symptomatic children, and the true incidence of childhood ITP may be much higher because asymptomatic children may not be brought in to see a doctor. For the majority of patients, ITP resolves within 3 months. However, for 20% to 30% of patients, thrombocytopenia will last beyond 6 months, with or without treatment.⁴ In 1% of cases, patients will have a recurrence of ITP.³

In addition to easy bruising, nearly all patients who present with possible ITP will complain of cutaneous bleeding, typically a nose bleed or bleeding in the oral cavity.² Upon questioning, 60% of patients will report a history of recent infection.⁴ Not surprisingly, bleeding severity correlates inversely with platelet count; severe bleeding is seen in patients with a platelet count <10,000/mcL.

While rare, the more worrisome complications include intracranial hemorrhage, with an incidence of 0.1% to 0.8%, and other serious hemorrhages that would require transfusion, with an estimated incidence of 2.9%.²

Vast differential seen in child bruising

When a child presents with bruising, perform a thorough history, including birth and prenatal course, as well as a physical to exclude other potential causes, such as physical abuse, use of herbal remedies or other natural supplements that may not be disclosed as medication, or even environmental exposure. When bruising is present in a child who has isolated thrombocytopenia, the diagnosis of ITP may be straightforward. However, many conditions may share thrombocytopenia in their disease process and should be considered in the differential diagnosis of a child who you suspect may have ITP.

Suspect physical abuse in a bruised child who does not have thrombocytopenia, whose mood is flat or depressed, or who has experienced recurrent injuries or bruising.

Leukemia, particularly acute lymphoblastic leukemia (ALL), the predominant leukemia found in children, should be ruled out, as well. Symptoms that may distinguish a child with ALL from one with ITP include fever, weight loss, and joint pain, as well as signs such as lymphadenopathy, hepatosplenomegaly, anemia, and leukocytosis. A peripheral smear may be ordered to help confirm or exclude a diagnosis of ALL should any of the above be present in a child with thrombocytopenia.⁵ It may show lymphoblasts and/or atypical cells in a patient with ALL.⁵

Infections should also be included in a differential when a patient is suspected of having ITP, particularly if he or she has systemic symptoms. Viral infections that may cause thrombocytopenia include mononucleosis, dengue virus, human herpesvirus-6, and human immunodeficiency virus.^6,7

The incidence of ITP may be higher during the winter months, when infections are more common. ITP often follows an infection, and the incidence of ITP may be higher during winter months, when infections are more common. However, infection may not always be the cause of ITP. Sepsis may also lead to thrombocytopenia, but a child with sepsis would present very differently from a child who has only ITP. A septic child would present acutely ill with signs and symptoms of severe systemic illness, such as high fever, altered mental status, tachycardia, pallor, diaphoresis, and hypotension.

Drug-induced thrombocytopenia (DIT) should be considered in any child who is taking or recently took a medication that may cause thrombocytopenia. Medications that can cause thrombocytopenia include heparin, quinine, vancomycin, trimethoprim-sulfamethoxazole, rifampin, carbamazepine, phenytoin, piperacillin, linezolid, and valproic acid.⁸ The measles, mumps, and rubella vaccine also can cause thrombocytopenia.⁸ A careful medication history may determine if the child is at risk for DIT.

To narrow the differential, obtain a CBC and peripheral smear when evaluating a patient you suspect may have ITP⁵ (strength of recommendation [SOR]: A). A CBC will determine the patient’s platelet count and a peripheral smear should be obtained to exclude other possible diagnoses.⁵

If there are any questions regarding the results of a peripheral smear, it may be necessary to perform a bone marrow aspiration. This, however, is not usually necessary in an otherwise typical case of ITP.⁹ Bone marrow aspiration may, however, be necessary to reevaluate the initial diagnosis for a child who does not respond to treatment for ITP.

Corticosteroids, IVIg are usually effective

To start ITP treatment, limit the patient’s risk of further injury or bleeding by stopping NSAIDs and ending participation in contact sports. The first step in treating a patient with ITP is to limit the risk of further injury or bleeding, by stopping nonsteroidal anti-inflammatory drugs or ending participation in contact sports^2,9 (SOR: C). The next step is to determine if pharmacologic therapy is warranted.

Medication, if necessary, is the mainstay of treatment for patients with ITP, particularly those experiencing significant bleeding.² Corticosteroids, intravenous (IV) immunoglobulin (IVIg), and IV Rh_o(D) immune globulin (also known as anti-D) are the medications typically used to treat a child with ITP, depending on availability of the drugs, bleeding or bleeding risk, as well as convenience of dosing. For example, corticosteroids can be used orally or IV, whereas IVIg and IV Rh_o(D) may not be readily available in some treatment settings.

Corticosteroids have been shown to more rapidly increase platelet count compared to placebo and appear to have a dose-related effect.^10,11 Oral prednisone can be dosed at 1 to 2 mg/kg/d for 14 days and then tapered over the course of one week^10,11 or one may prescribe 4 mg/kg/d for 4 days.^10,11 IV methylprednisolone typically is given at 30 mg/kg/d for 3 to 4 days.⁹

IVIg may have greater efficacy than corticosteroids in treating ITP, but it may also cause adverse effects, including nausea, headache, and fever. IVIg can be administered as a single 800 to 1000 mg/kg dose, or as a daily 400 mg/kg dose for 5 days; higher doses should be reserved for patients with severe bleeding.¹²

If ITP persists despite the use of corticosteroids or IVIg, IV Rh_o(D) Ig may be used in patients with Rh_o(D)-positive blood at a single dose of 25 to 50 mcg/kg, with additional doses administered on separate days as required to elevate platelet count. However, only Rh_o(D)-positive patients are eligible for anti-D treatment.

The response rates/times and adverse effects of common treatments for ITP are summarized in the TABLE.⁹ A small randomized study found that oral methylprednisolone 30 mg/kg/d for 3 days followed by 20 mg/kg/d for an additional 4 days was comparable to IVIg 0.4 g/kg/d for 5 days.¹¹ A different study that compared oral methylprednisolone (30 mg/kg/d or 50 mg/kg/d for 7 days) and IVIg (0.5 g/kg/d for 5 days) found no difference in outcomes among the 3 treatments.¹³ One advantage, though, of IVIg is that it can be administered as a single IV dose, rather than multiple doses over several weeks, as is the case with oral prednisone.^9,11-13

Follow platelet counts closely. Patients with ITP should have their platelet counts monitored at least once weekly and as often as twice weekly. The frequency of monitoring may be tapered depending on an individual patient’s response to treatment and the severity of the thrombocytopenia.¹⁴

We referred our patient to a nearby children’s hospital, where a repeat CBC showed her platelets had decreased to 3000/mcL. She received a 6-hour infusion of IVIg and was discharged with instructions to have her CBC closely monitored. Her platelets remained stable until 4 weeks later, when they decreased from 102,000/mcL to 71,000/mcL. She received a second infusion of IVIg as an outpatient.

Soon after, she went to our ED with a headache, nausea, and fever of 102°F. A computed tomography scan of her head was normal; a repeat CBC showed no elevation in white blood cells but her hemoglobin had decreased from 11.9 g/dL to 9.7 g/dL. (Her platelets were 254,000/mcL.) The patient’s complaints were likely adverse effects of the IVIg. The CBC abnormalities, fever, headache, and malaise resolved shortly thereafter and the patient remains asymptomatic with no recurrence of ITP.

THE TAKEAWAY

Patients with ITP should have their platelet count monitored at least once a week until platelets have increased to 150,000/mcL or higher. Suspect ITP in a child who bruises easily and who also has thrombocytopenia. Order a CBC and peripheral blood smear to rule out other potential illnesses. Pharmacotherapy, if needed, typically consists of an oral or IV corticosteroid or IVIg; IV Rh_o(D) Ig may be used in patients who are Rh_o(D)-positive who don’t respond to other treatments. Patients with ITP should have their platelet count monitored at least once weekly until platelets have increased to 150,000/mcL or higher. Frequency of monitoring may be reduced as the clinical picture improves and the patient remains stable. More frequent monitoring may be necessary based on severity, complications, and response to treatment.

Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

THE CASE

A 6-year-old girl was brought to the emergency department (ED) by her mother after the child had bumped her head while playing. While the physician examined the child’s head, the mother remarked that her daughter had recently developed bruises that appeared suddenly and only after minor, if any, known trauma. The ED physician determined that the child’s bump to the head was nothing to worry about, attributed the bruising to the child being a “healthy, active 6-year-old,” and sent her home.

Two days later the child was brought to our office because the mother was still concerned about her daughter’s easy bruising. The mother pointed out ecchymosis scattered across her daughter’s extremities and torso. The child denied any pain or other complaints, including any active or recurrent bleeding. Upon further questioning, the mother mentioned that her daughter had recovered from a cold-like illness several weeks earlier.

THE DIAGNOSIS

We ordered a complete blood count (CBC) and peripheral smear, which were normal except for the platelet count, which was 7000/mcL (normal, 150,000-450,000/mcL). Based on the child’s easy bruising and isolated thrombocytopenia, we diagnosed immune thrombocytopenia, which is also known as idiopathic thrombocytopenic purpura (ITP).

DISCUSSION

In ITP, autoantibodies are directed against platelets, leading to their sequestration and destruction in the spleen and a resultant drop in platelet count.¹ Children with ITP typically present between the ages of 2 and 10 years, with a peak incidence between 2 and 5 years.² The incidence is estimated to be as high as 8 per 100,000 children.³ However, this estimate primarily reflects symptomatic children, and the true incidence of childhood ITP may be much higher because asymptomatic children may not be brought in to see a doctor. For the majority of patients, ITP resolves within 3 months. However, for 20% to 30% of patients, thrombocytopenia will last beyond 6 months, with or without treatment.⁴ In 1% of cases, patients will have a recurrence of ITP.³

In addition to easy bruising, nearly all patients who present with possible ITP will complain of cutaneous bleeding, typically a nose bleed or bleeding in the oral cavity.² Upon questioning, 60% of patients will report a history of recent infection.⁴ Not surprisingly, bleeding severity correlates inversely with platelet count; severe bleeding is seen in patients with a platelet count <10,000/mcL.

While rare, the more worrisome complications include intracranial hemorrhage, with an incidence of 0.1% to 0.8%, and other serious hemorrhages that would require transfusion, with an estimated incidence of 2.9%.²

Vast differential seen in child bruising

When a child presents with bruising, perform a thorough history, including birth and prenatal course, as well as a physical to exclude other potential causes, such as physical abuse, use of herbal remedies or other natural supplements that may not be disclosed as medication, or even environmental exposure. When bruising is present in a child who has isolated thrombocytopenia, the diagnosis of ITP may be straightforward. However, many conditions may share thrombocytopenia in their disease process and should be considered in the differential diagnosis of a child who you suspect may have ITP.

Suspect physical abuse in a bruised child who does not have thrombocytopenia, whose mood is flat or depressed, or who has experienced recurrent injuries or bruising.

Leukemia, particularly acute lymphoblastic leukemia (ALL), the predominant leukemia found in children, should be ruled out, as well. Symptoms that may distinguish a child with ALL from one with ITP include fever, weight loss, and joint pain, as well as signs such as lymphadenopathy, hepatosplenomegaly, anemia, and leukocytosis. A peripheral smear may be ordered to help confirm or exclude a diagnosis of ALL should any of the above be present in a child with thrombocytopenia.⁵ It may show lymphoblasts and/or atypical cells in a patient with ALL.⁵

Infections should also be included in a differential when a patient is suspected of having ITP, particularly if he or she has systemic symptoms. Viral infections that may cause thrombocytopenia include mononucleosis, dengue virus, human herpesvirus-6, and human immunodeficiency virus.^6,7

The incidence of ITP may be higher during the winter months, when infections are more common. ITP often follows an infection, and the incidence of ITP may be higher during winter months, when infections are more common. However, infection may not always be the cause of ITP. Sepsis may also lead to thrombocytopenia, but a child with sepsis would present very differently from a child who has only ITP. A septic child would present acutely ill with signs and symptoms of severe systemic illness, such as high fever, altered mental status, tachycardia, pallor, diaphoresis, and hypotension.

Drug-induced thrombocytopenia (DIT) should be considered in any child who is taking or recently took a medication that may cause thrombocytopenia. Medications that can cause thrombocytopenia include heparin, quinine, vancomycin, trimethoprim-sulfamethoxazole, rifampin, carbamazepine, phenytoin, piperacillin, linezolid, and valproic acid.⁸ The measles, mumps, and rubella vaccine also can cause thrombocytopenia.⁸ A careful medication history may determine if the child is at risk for DIT.

To narrow the differential, obtain a CBC and peripheral smear when evaluating a patient you suspect may have ITP⁵ (strength of recommendation [SOR]: A). A CBC will determine the patient’s platelet count and a peripheral smear should be obtained to exclude other possible diagnoses.⁵

If there are any questions regarding the results of a peripheral smear, it may be necessary to perform a bone marrow aspiration. This, however, is not usually necessary in an otherwise typical case of ITP.⁹ Bone marrow aspiration may, however, be necessary to reevaluate the initial diagnosis for a child who does not respond to treatment for ITP.

Corticosteroids, IVIg are usually effective

To start ITP treatment, limit the patient’s risk of further injury or bleeding by stopping NSAIDs and ending participation in contact sports. The first step in treating a patient with ITP is to limit the risk of further injury or bleeding, by stopping nonsteroidal anti-inflammatory drugs or ending participation in contact sports^2,9 (SOR: C). The next step is to determine if pharmacologic therapy is warranted.

Medication, if necessary, is the mainstay of treatment for patients with ITP, particularly those experiencing significant bleeding.² Corticosteroids, intravenous (IV) immunoglobulin (IVIg), and IV Rh_o(D) immune globulin (also known as anti-D) are the medications typically used to treat a child with ITP, depending on availability of the drugs, bleeding or bleeding risk, as well as convenience of dosing. For example, corticosteroids can be used orally or IV, whereas IVIg and IV Rh_o(D) may not be readily available in some treatment settings.

Corticosteroids have been shown to more rapidly increase platelet count compared to placebo and appear to have a dose-related effect.^10,11 Oral prednisone can be dosed at 1 to 2 mg/kg/d for 14 days and then tapered over the course of one week^10,11 or one may prescribe 4 mg/kg/d for 4 days.^10,11 IV methylprednisolone typically is given at 30 mg/kg/d for 3 to 4 days.⁹

IVIg may have greater efficacy than corticosteroids in treating ITP, but it may also cause adverse effects, including nausea, headache, and fever. IVIg can be administered as a single 800 to 1000 mg/kg dose, or as a daily 400 mg/kg dose for 5 days; higher doses should be reserved for patients with severe bleeding.¹²

If ITP persists despite the use of corticosteroids or IVIg, IV Rh_o(D) Ig may be used in patients with Rh_o(D)-positive blood at a single dose of 25 to 50 mcg/kg, with additional doses administered on separate days as required to elevate platelet count. However, only Rh_o(D)-positive patients are eligible for anti-D treatment.

The response rates/times and adverse effects of common treatments for ITP are summarized in the TABLE.⁹ A small randomized study found that oral methylprednisolone 30 mg/kg/d for 3 days followed by 20 mg/kg/d for an additional 4 days was comparable to IVIg 0.4 g/kg/d for 5 days.¹¹ A different study that compared oral methylprednisolone (30 mg/kg/d or 50 mg/kg/d for 7 days) and IVIg (0.5 g/kg/d for 5 days) found no difference in outcomes among the 3 treatments.¹³ One advantage, though, of IVIg is that it can be administered as a single IV dose, rather than multiple doses over several weeks, as is the case with oral prednisone.^9,11-13

Follow platelet counts closely. Patients with ITP should have their platelet counts monitored at least once weekly and as often as twice weekly. The frequency of monitoring may be tapered depending on an individual patient’s response to treatment and the severity of the thrombocytopenia.¹⁴

We referred our patient to a nearby children’s hospital, where a repeat CBC showed her platelets had decreased to 3000/mcL. She received a 6-hour infusion of IVIg and was discharged with instructions to have her CBC closely monitored. Her platelets remained stable until 4 weeks later, when they decreased from 102,000/mcL to 71,000/mcL. She received a second infusion of IVIg as an outpatient.

Soon after, she went to our ED with a headache, nausea, and fever of 102°F. A computed tomography scan of her head was normal; a repeat CBC showed no elevation in white blood cells but her hemoglobin had decreased from 11.9 g/dL to 9.7 g/dL. (Her platelets were 254,000/mcL.) The patient’s complaints were likely adverse effects of the IVIg. The CBC abnormalities, fever, headache, and malaise resolved shortly thereafter and the patient remains asymptomatic with no recurrence of ITP.

THE TAKEAWAY

Patients with ITP should have their platelet count monitored at least once a week until platelets have increased to 150,000/mcL or higher. Suspect ITP in a child who bruises easily and who also has thrombocytopenia. Order a CBC and peripheral blood smear to rule out other potential illnesses. Pharmacotherapy, if needed, typically consists of an oral or IV corticosteroid or IVIg; IV Rh_o(D) Ig may be used in patients who are Rh_o(D)-positive who don’t respond to other treatments. Patients with ITP should have their platelet count monitored at least once weekly until platelets have increased to 150,000/mcL or higher. Frequency of monitoring may be reduced as the clinical picture improves and the patient remains stable. More frequent monitoring may be necessary based on severity, complications, and response to treatment.

Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

THE CASE

A 6-year-old girl was brought to the emergency department (ED) by her mother after the child had bumped her head while playing. While the physician examined the child’s head, the mother remarked that her daughter had recently developed bruises that appeared suddenly and only after minor, if any, known trauma. The ED physician determined that the child’s bump to the head was nothing to worry about, attributed the bruising to the child being a “healthy, active 6-year-old,” and sent her home.

Two days later the child was brought to our office because the mother was still concerned about her daughter’s easy bruising. The mother pointed out ecchymosis scattered across her daughter’s extremities and torso. The child denied any pain or other complaints, including any active or recurrent bleeding. Upon further questioning, the mother mentioned that her daughter had recovered from a cold-like illness several weeks earlier.

THE DIAGNOSIS

We ordered a complete blood count (CBC) and peripheral smear, which were normal except for the platelet count, which was 7000/mcL (normal, 150,000-450,000/mcL). Based on the child’s easy bruising and isolated thrombocytopenia, we diagnosed immune thrombocytopenia, which is also known as idiopathic thrombocytopenic purpura (ITP).

DISCUSSION

In ITP, autoantibodies are directed against platelets, leading to their sequestration and destruction in the spleen and a resultant drop in platelet count.¹ Children with ITP typically present between the ages of 2 and 10 years, with a peak incidence between 2 and 5 years.² The incidence is estimated to be as high as 8 per 100,000 children.³ However, this estimate primarily reflects symptomatic children, and the true incidence of childhood ITP may be much higher because asymptomatic children may not be brought in to see a doctor. For the majority of patients, ITP resolves within 3 months. However, for 20% to 30% of patients, thrombocytopenia will last beyond 6 months, with or without treatment.⁴ In 1% of cases, patients will have a recurrence of ITP.³

In addition to easy bruising, nearly all patients who present with possible ITP will complain of cutaneous bleeding, typically a nose bleed or bleeding in the oral cavity.² Upon questioning, 60% of patients will report a history of recent infection.⁴ Not surprisingly, bleeding severity correlates inversely with platelet count; severe bleeding is seen in patients with a platelet count <10,000/mcL.

While rare, the more worrisome complications include intracranial hemorrhage, with an incidence of 0.1% to 0.8%, and other serious hemorrhages that would require transfusion, with an estimated incidence of 2.9%.²

Vast differential seen in child bruising

When a child presents with bruising, perform a thorough history, including birth and prenatal course, as well as a physical to exclude other potential causes, such as physical abuse, use of herbal remedies or other natural supplements that may not be disclosed as medication, or even environmental exposure. When bruising is present in a child who has isolated thrombocytopenia, the diagnosis of ITP may be straightforward. However, many conditions may share thrombocytopenia in their disease process and should be considered in the differential diagnosis of a child who you suspect may have ITP.

Suspect physical abuse in a bruised child who does not have thrombocytopenia, whose mood is flat or depressed, or who has experienced recurrent injuries or bruising.

Leukemia, particularly acute lymphoblastic leukemia (ALL), the predominant leukemia found in children, should be ruled out, as well. Symptoms that may distinguish a child with ALL from one with ITP include fever, weight loss, and joint pain, as well as signs such as lymphadenopathy, hepatosplenomegaly, anemia, and leukocytosis. A peripheral smear may be ordered to help confirm or exclude a diagnosis of ALL should any of the above be present in a child with thrombocytopenia.⁵ It may show lymphoblasts and/or atypical cells in a patient with ALL.⁵

Infections should also be included in a differential when a patient is suspected of having ITP, particularly if he or she has systemic symptoms. Viral infections that may cause thrombocytopenia include mononucleosis, dengue virus, human herpesvirus-6, and human immunodeficiency virus.^6,7

The incidence of ITP may be higher during the winter months, when infections are more common. ITP often follows an infection, and the incidence of ITP may be higher during winter months, when infections are more common. However, infection may not always be the cause of ITP. Sepsis may also lead to thrombocytopenia, but a child with sepsis would present very differently from a child who has only ITP. A septic child would present acutely ill with signs and symptoms of severe systemic illness, such as high fever, altered mental status, tachycardia, pallor, diaphoresis, and hypotension.

Drug-induced thrombocytopenia (DIT) should be considered in any child who is taking or recently took a medication that may cause thrombocytopenia. Medications that can cause thrombocytopenia include heparin, quinine, vancomycin, trimethoprim-sulfamethoxazole, rifampin, carbamazepine, phenytoin, piperacillin, linezolid, and valproic acid.⁸ The measles, mumps, and rubella vaccine also can cause thrombocytopenia.⁸ A careful medication history may determine if the child is at risk for DIT.

To narrow the differential, obtain a CBC and peripheral smear when evaluating a patient you suspect may have ITP⁵ (strength of recommendation [SOR]: A). A CBC will determine the patient’s platelet count and a peripheral smear should be obtained to exclude other possible diagnoses.⁵

If there are any questions regarding the results of a peripheral smear, it may be necessary to perform a bone marrow aspiration. This, however, is not usually necessary in an otherwise typical case of ITP.⁹ Bone marrow aspiration may, however, be necessary to reevaluate the initial diagnosis for a child who does not respond to treatment for ITP.

Corticosteroids, IVIg are usually effective

To start ITP treatment, limit the patient’s risk of further injury or bleeding by stopping NSAIDs and ending participation in contact sports. The first step in treating a patient with ITP is to limit the risk of further injury or bleeding, by stopping nonsteroidal anti-inflammatory drugs or ending participation in contact sports^2,9 (SOR: C). The next step is to determine if pharmacologic therapy is warranted.

Medication, if necessary, is the mainstay of treatment for patients with ITP, particularly those experiencing significant bleeding.² Corticosteroids, intravenous (IV) immunoglobulin (IVIg), and IV Rh_o(D) immune globulin (also known as anti-D) are the medications typically used to treat a child with ITP, depending on availability of the drugs, bleeding or bleeding risk, as well as convenience of dosing. For example, corticosteroids can be used orally or IV, whereas IVIg and IV Rh_o(D) may not be readily available in some treatment settings.

Corticosteroids have been shown to more rapidly increase platelet count compared to placebo and appear to have a dose-related effect.^10,11 Oral prednisone can be dosed at 1 to 2 mg/kg/d for 14 days and then tapered over the course of one week^10,11 or one may prescribe 4 mg/kg/d for 4 days.^10,11 IV methylprednisolone typically is given at 30 mg/kg/d for 3 to 4 days.⁹

IVIg may have greater efficacy than corticosteroids in treating ITP, but it may also cause adverse effects, including nausea, headache, and fever. IVIg can be administered as a single 800 to 1000 mg/kg dose, or as a daily 400 mg/kg dose for 5 days; higher doses should be reserved for patients with severe bleeding.¹²

If ITP persists despite the use of corticosteroids or IVIg, IV Rh_o(D) Ig may be used in patients with Rh_o(D)-positive blood at a single dose of 25 to 50 mcg/kg, with additional doses administered on separate days as required to elevate platelet count. However, only Rh_o(D)-positive patients are eligible for anti-D treatment.

The response rates/times and adverse effects of common treatments for ITP are summarized in the TABLE.⁹ A small randomized study found that oral methylprednisolone 30 mg/kg/d for 3 days followed by 20 mg/kg/d for an additional 4 days was comparable to IVIg 0.4 g/kg/d for 5 days.¹¹ A different study that compared oral methylprednisolone (30 mg/kg/d or 50 mg/kg/d for 7 days) and IVIg (0.5 g/kg/d for 5 days) found no difference in outcomes among the 3 treatments.¹³ One advantage, though, of IVIg is that it can be administered as a single IV dose, rather than multiple doses over several weeks, as is the case with oral prednisone.^9,11-13

Follow platelet counts closely. Patients with ITP should have their platelet counts monitored at least once weekly and as often as twice weekly. The frequency of monitoring may be tapered depending on an individual patient’s response to treatment and the severity of the thrombocytopenia.¹⁴

We referred our patient to a nearby children’s hospital, where a repeat CBC showed her platelets had decreased to 3000/mcL. She received a 6-hour infusion of IVIg and was discharged with instructions to have her CBC closely monitored. Her platelets remained stable until 4 weeks later, when they decreased from 102,000/mcL to 71,000/mcL. She received a second infusion of IVIg as an outpatient.

Soon after, she went to our ED with a headache, nausea, and fever of 102°F. A computed tomography scan of her head was normal; a repeat CBC showed no elevation in white blood cells but her hemoglobin had decreased from 11.9 g/dL to 9.7 g/dL. (Her platelets were 254,000/mcL.) The patient’s complaints were likely adverse effects of the IVIg. The CBC abnormalities, fever, headache, and malaise resolved shortly thereafter and the patient remains asymptomatic with no recurrence of ITP.

THE TAKEAWAY

Patients with ITP should have their platelet count monitored at least once a week until platelets have increased to 150,000/mcL or higher. Suspect ITP in a child who bruises easily and who also has thrombocytopenia. Order a CBC and peripheral blood smear to rule out other potential illnesses. Pharmacotherapy, if needed, typically consists of an oral or IV corticosteroid or IVIg; IV Rh_o(D) Ig may be used in patients who are Rh_o(D)-positive who don’t respond to other treatments. Patients with ITP should have their platelet count monitored at least once weekly until platelets have increased to 150,000/mcL or higher. Frequency of monitoring may be reduced as the clinical picture improves and the patient remains stable. More frequent monitoring may be necessary based on severity, complications, and response to treatment.

Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

THE CASE

A 26-year-old Hispanic woman presented to the emergency department (ED) with myalgia and weakness. The work-up revealed profound hyperthyroidism, with a thyroid-stimulating hormone (TSH) <0.01 mIU/mL (normal, 0.4-4.2 mIU/L), potassium 2.4 mEq/L (normal, 3.7-5.2 mEq/L), hypophosphatemia, and low urinary potassium. There were no prior symptoms and family history was negative for endocrinopathies. She was admitted and started on methimazole 10 mg twice a day for thyroid suppression and given propranolol 10 mg twice a day for anticipated hyperadrenergic adverse effects. The remainder of her hospital stay was uneventful and she was discharged 6 days after admission. Soon after, an outpatient thyroid scan ordered by her primary care physician confirmed that the patient had Graves’ disease.

Eight months later, the patient returned to the ED with myalgia and rapidly progressing paralysis from the neck down; she was immediately intubated. Her potassium level was 1.2 mEq/L. An electrocardiogram (EKG) revealed conduction abnormalities consistent with hypokalemia.

THE DIAGNOSIS

Based on our patient’s paralysis, hyperthyroidism, and hypokalemia, we diagnosed thyrotoxic hypokalemic periodic paralysis (THPP), a rare endocrinopathy that causes electrolyte disturbances that can result in paralysis and lethal tachyarrhythmias.^1-6

Patients with THPP typically have a history of myalgia, cramping, and stiffness followed by weakness or paralysis that tends to develop rapidly, most commonly in the late evening or early morning^1-4,6,7 (TABLE^1-9). Proximal muscles are predominantly affected symmetrically and the attacks usually resolve in a period of hours to several days. Ocular, bulbar, and respiratory muscles are usually spared, but these can be affected by the hypokalemia.¹

DISCUSSION

Traditionally THPP has been seen primarily in Asia, with an incidence as high as 2%.^1-6 The incidence in the United States is lower (0.1%-0.2%) and THPP occurs primarily in Asian, African, Hispanic, and Native American populations.^1,4,6

Although thyrotoxicosis is more common in women, THPP has a predilection for men (20:1).^1,3-6 THPP occurs in patients with hyperthyroidism, most commonly from Graves’ disease,^1,6 who are exposed to certain precipitating factors, such as exercise, carbohydrate loading, high-salt diet, excessive alcohol consumption, trauma, cold exposure, infection, menstruation, or emotional stress.^1,6 THPP can also occur in people taking medications such as corticosteroids, β₂-adrenergic bronchodilators, epinephrine, acetazolamide, insulin, nonsteroidal anti-inflammatory drugs, thyroxine, amiodarone, and tiratricol.^1,5,6 THPP is more common in the summer.¹

A genetic basis for THPP. A Kir2.6 mutation results in a thyroid hormone-sensitive channelopathy involving the sodium-potassium-adenosine triphosphate (Na⁺,K⁺-ATPase) pump, which appears to be responsible for THPP.^1-6,8,9 This mutation should not be confused with the pathogenesis of familial periodic paralysis (FPP)—a hereditary disorder resulting in abnormalities in calcium, sodium, and potassium channels on skeletal muscle cells that leads to multiple electrolyte derangements and paralysis identical to that observed in THPP.¹

Hypokalemia may be exacerbated by catecholamine-induced potassium shifts.^1,4,6 This is from the increased β₂-adrenergic stimulation from the concurrent hyperadrenergic state caused by the underlying hyperthyroidism.^1,4,6 Hyperinsulinemia from sympathetic stimulation of the insulin-releasing pancreatic beta cells also exacerbates hypokalemia.^1,4,6

Focus treatment on correcting electrolytes

Acute management of THPP centers on electrolyte correction; definitive treatments include antithyroid medication, radioactive iodine ablation, and/or thyroidectomy. Initial evaluation of a patient suspected of having THPP should include a complete blood count, TSH and serum and urine electrolyte tests, and an EKG. Further work-up may require ultrasound and scan of the thyroid upon confirmation of thyrotoxicosis and hypokalemia. Physical examination may reveal thyromegaly. Exophthalmos and other hyperthyroidism symptoms often are absent.¹

Diagnosis confirmed? Treat the hypokalemia first. Acute management of THPP centers on electrolyte correction. Total body stores of potassium in patients with THPP  are usually normal, so the physician must use care to avoid excessive potassium administration.^1-5 Rebound hyperkalemia can occur in patients who receive >90 mEq/L of potassium chloride within 24 hours.¹

Definitive therapy may include antithyroid medication, radioactive iodine ablation (RIA), and/or thyroidectomy.^1-5 All have the common goal of controlling the hyperthyroidism and preventing recurrent paralysis, which occurs in 62.2% of patients within the first 3 months following diagnosis.³ If antithyroid medications fail, then RIA is the next choice.¹ Beta-blockers work by decreasing the Na⁺,K⁺-ATPase activity from the underlying hyperadrenergic state.¹ Administration of acetazolamide—which is the primary treatment modality for FPP and idiopathic periodic paralysis—can precipitate THPP attacks and is contraindicated.^1,5

Consider thyroidectomy for patients for whom medical management is unsuccessful or who develop compression symptoms. If medical management is unsuccessful or the patient develops compression symptoms, then thyroidectomy should be considered.³ If the patient chooses thyroidectomy, medical optimization with antithyroid medications is indicated to mitigate the risks of anesthesia. When the thyroidectomy is performed by an experienced thyroid surgeon, the long-term results are excellent.

Our patient. Once our patient’s hypokalemia was corrected, she was successfully extubated. Despite appropriate medical therapy, her hyperthyroidism was poorly controlled. The endocrinologist believed that RIA was suboptimal for 3 reasons: 1) it might result in incomplete ablation, 2) it required a long treatment period to be effective, and 3) its prolonged course of treatment extended the time interval that the patient would be at risk for recurrent paralysis.

A surgeon was consulted for definitive treatment with thyroidectomy. Our patient’s medications were changed to propylthiouracil 150 mg every 8 hours and propranolol 10 mg twice a day until a euthyroid state was achieved and she could tolerate a general anesthetic without precipitating a thyroid storm. Two months later, she underwent total thyroidectomy without complication. Her postoperative course was normal.

THE TAKEAWAY

Thyrotoxic hypokalemic periodic paralysis is rare. Patients typically present with myalgia, cramping, and stiffness that progress to paralysis. Prompt electrolyte repletion is paramount for successful outcomes.^1-5 Control of hyperthyroidism is the long-term goal.^1-5 Definitive therapy can be achieved medically or surgically. Total thyroidectomy is a reasonable treatment option for medically refractory hyperthyroidism or when RIA is contraindicated. Long-term prognosis is excellent.

THE CASE

A 26-year-old Hispanic woman presented to the emergency department (ED) with myalgia and weakness. The work-up revealed profound hyperthyroidism, with a thyroid-stimulating hormone (TSH) <0.01 mIU/mL (normal, 0.4-4.2 mIU/L), potassium 2.4 mEq/L (normal, 3.7-5.2 mEq/L), hypophosphatemia, and low urinary potassium. There were no prior symptoms and family history was negative for endocrinopathies. She was admitted and started on methimazole 10 mg twice a day for thyroid suppression and given propranolol 10 mg twice a day for anticipated hyperadrenergic adverse effects. The remainder of her hospital stay was uneventful and she was discharged 6 days after admission. Soon after, an outpatient thyroid scan ordered by her primary care physician confirmed that the patient had Graves’ disease.

Eight months later, the patient returned to the ED with myalgia and rapidly progressing paralysis from the neck down; she was immediately intubated. Her potassium level was 1.2 mEq/L. An electrocardiogram (EKG) revealed conduction abnormalities consistent with hypokalemia.

THE DIAGNOSIS

Based on our patient’s paralysis, hyperthyroidism, and hypokalemia, we diagnosed thyrotoxic hypokalemic periodic paralysis (THPP), a rare endocrinopathy that causes electrolyte disturbances that can result in paralysis and lethal tachyarrhythmias.^1-6

Patients with THPP typically have a history of myalgia, cramping, and stiffness followed by weakness or paralysis that tends to develop rapidly, most commonly in the late evening or early morning^1-4,6,7 (TABLE^1-9). Proximal muscles are predominantly affected symmetrically and the attacks usually resolve in a period of hours to several days. Ocular, bulbar, and respiratory muscles are usually spared, but these can be affected by the hypokalemia.¹

DISCUSSION

Traditionally THPP has been seen primarily in Asia, with an incidence as high as 2%.^1-6 The incidence in the United States is lower (0.1%-0.2%) and THPP occurs primarily in Asian, African, Hispanic, and Native American populations.^1,4,6

Although thyrotoxicosis is more common in women, THPP has a predilection for men (20:1).^1,3-6 THPP occurs in patients with hyperthyroidism, most commonly from Graves’ disease,^1,6 who are exposed to certain precipitating factors, such as exercise, carbohydrate loading, high-salt diet, excessive alcohol consumption, trauma, cold exposure, infection, menstruation, or emotional stress.^1,6 THPP can also occur in people taking medications such as corticosteroids, β₂-adrenergic bronchodilators, epinephrine, acetazolamide, insulin, nonsteroidal anti-inflammatory drugs, thyroxine, amiodarone, and tiratricol.^1,5,6 THPP is more common in the summer.¹

A genetic basis for THPP. A Kir2.6 mutation results in a thyroid hormone-sensitive channelopathy involving the sodium-potassium-adenosine triphosphate (Na⁺,K⁺-ATPase) pump, which appears to be responsible for THPP.^1-6,8,9 This mutation should not be confused with the pathogenesis of familial periodic paralysis (FPP)—a hereditary disorder resulting in abnormalities in calcium, sodium, and potassium channels on skeletal muscle cells that leads to multiple electrolyte derangements and paralysis identical to that observed in THPP.¹

Hypokalemia may be exacerbated by catecholamine-induced potassium shifts.^1,4,6 This is from the increased β₂-adrenergic stimulation from the concurrent hyperadrenergic state caused by the underlying hyperthyroidism.^1,4,6 Hyperinsulinemia from sympathetic stimulation of the insulin-releasing pancreatic beta cells also exacerbates hypokalemia.^1,4,6

Focus treatment on correcting electrolytes

Acute management of THPP centers on electrolyte correction; definitive treatments include antithyroid medication, radioactive iodine ablation, and/or thyroidectomy. Initial evaluation of a patient suspected of having THPP should include a complete blood count, TSH and serum and urine electrolyte tests, and an EKG. Further work-up may require ultrasound and scan of the thyroid upon confirmation of thyrotoxicosis and hypokalemia. Physical examination may reveal thyromegaly. Exophthalmos and other hyperthyroidism symptoms often are absent.¹

Diagnosis confirmed? Treat the hypokalemia first. Acute management of THPP centers on electrolyte correction. Total body stores of potassium in patients with THPP  are usually normal, so the physician must use care to avoid excessive potassium administration.^1-5 Rebound hyperkalemia can occur in patients who receive >90 mEq/L of potassium chloride within 24 hours.¹

Definitive therapy may include antithyroid medication, radioactive iodine ablation (RIA), and/or thyroidectomy.^1-5 All have the common goal of controlling the hyperthyroidism and preventing recurrent paralysis, which occurs in 62.2% of patients within the first 3 months following diagnosis.³ If antithyroid medications fail, then RIA is the next choice.¹ Beta-blockers work by decreasing the Na⁺,K⁺-ATPase activity from the underlying hyperadrenergic state.¹ Administration of acetazolamide—which is the primary treatment modality for FPP and idiopathic periodic paralysis—can precipitate THPP attacks and is contraindicated.^1,5

Consider thyroidectomy for patients for whom medical management is unsuccessful or who develop compression symptoms. If medical management is unsuccessful or the patient develops compression symptoms, then thyroidectomy should be considered.³ If the patient chooses thyroidectomy, medical optimization with antithyroid medications is indicated to mitigate the risks of anesthesia. When the thyroidectomy is performed by an experienced thyroid surgeon, the long-term results are excellent.

Our patient. Once our patient’s hypokalemia was corrected, she was successfully extubated. Despite appropriate medical therapy, her hyperthyroidism was poorly controlled. The endocrinologist believed that RIA was suboptimal for 3 reasons: 1) it might result in incomplete ablation, 2) it required a long treatment period to be effective, and 3) its prolonged course of treatment extended the time interval that the patient would be at risk for recurrent paralysis.

A surgeon was consulted for definitive treatment with thyroidectomy. Our patient’s medications were changed to propylthiouracil 150 mg every 8 hours and propranolol 10 mg twice a day until a euthyroid state was achieved and she could tolerate a general anesthetic without precipitating a thyroid storm. Two months later, she underwent total thyroidectomy without complication. Her postoperative course was normal.

THE TAKEAWAY

Thyrotoxic hypokalemic periodic paralysis is rare. Patients typically present with myalgia, cramping, and stiffness that progress to paralysis. Prompt electrolyte repletion is paramount for successful outcomes.^1-5 Control of hyperthyroidism is the long-term goal.^1-5 Definitive therapy can be achieved medically or surgically. Total thyroidectomy is a reasonable treatment option for medically refractory hyperthyroidism or when RIA is contraindicated. Long-term prognosis is excellent.

THE CASE

A 26-year-old Hispanic woman presented to the emergency department (ED) with myalgia and weakness. The work-up revealed profound hyperthyroidism, with a thyroid-stimulating hormone (TSH) <0.01 mIU/mL (normal, 0.4-4.2 mIU/L), potassium 2.4 mEq/L (normal, 3.7-5.2 mEq/L), hypophosphatemia, and low urinary potassium. There were no prior symptoms and family history was negative for endocrinopathies. She was admitted and started on methimazole 10 mg twice a day for thyroid suppression and given propranolol 10 mg twice a day for anticipated hyperadrenergic adverse effects. The remainder of her hospital stay was uneventful and she was discharged 6 days after admission. Soon after, an outpatient thyroid scan ordered by her primary care physician confirmed that the patient had Graves’ disease.

Eight months later, the patient returned to the ED with myalgia and rapidly progressing paralysis from the neck down; she was immediately intubated. Her potassium level was 1.2 mEq/L. An electrocardiogram (EKG) revealed conduction abnormalities consistent with hypokalemia.

THE DIAGNOSIS

Based on our patient’s paralysis, hyperthyroidism, and hypokalemia, we diagnosed thyrotoxic hypokalemic periodic paralysis (THPP), a rare endocrinopathy that causes electrolyte disturbances that can result in paralysis and lethal tachyarrhythmias.^1-6

Patients with THPP typically have a history of myalgia, cramping, and stiffness followed by weakness or paralysis that tends to develop rapidly, most commonly in the late evening or early morning^1-4,6,7 (TABLE^1-9). Proximal muscles are predominantly affected symmetrically and the attacks usually resolve in a period of hours to several days. Ocular, bulbar, and respiratory muscles are usually spared, but these can be affected by the hypokalemia.¹

DISCUSSION

Traditionally THPP has been seen primarily in Asia, with an incidence as high as 2%.^1-6 The incidence in the United States is lower (0.1%-0.2%) and THPP occurs primarily in Asian, African, Hispanic, and Native American populations.^1,4,6

Although thyrotoxicosis is more common in women, THPP has a predilection for men (20:1).^1,3-6 THPP occurs in patients with hyperthyroidism, most commonly from Graves’ disease,^1,6 who are exposed to certain precipitating factors, such as exercise, carbohydrate loading, high-salt diet, excessive alcohol consumption, trauma, cold exposure, infection, menstruation, or emotional stress.^1,6 THPP can also occur in people taking medications such as corticosteroids, β₂-adrenergic bronchodilators, epinephrine, acetazolamide, insulin, nonsteroidal anti-inflammatory drugs, thyroxine, amiodarone, and tiratricol.^1,5,6 THPP is more common in the summer.¹

A genetic basis for THPP. A Kir2.6 mutation results in a thyroid hormone-sensitive channelopathy involving the sodium-potassium-adenosine triphosphate (Na⁺,K⁺-ATPase) pump, which appears to be responsible for THPP.^1-6,8,9 This mutation should not be confused with the pathogenesis of familial periodic paralysis (FPP)—a hereditary disorder resulting in abnormalities in calcium, sodium, and potassium channels on skeletal muscle cells that leads to multiple electrolyte derangements and paralysis identical to that observed in THPP.¹

Hypokalemia may be exacerbated by catecholamine-induced potassium shifts.^1,4,6 This is from the increased β₂-adrenergic stimulation from the concurrent hyperadrenergic state caused by the underlying hyperthyroidism.^1,4,6 Hyperinsulinemia from sympathetic stimulation of the insulin-releasing pancreatic beta cells also exacerbates hypokalemia.^1,4,6

Focus treatment on correcting electrolytes

Acute management of THPP centers on electrolyte correction; definitive treatments include antithyroid medication, radioactive iodine ablation, and/or thyroidectomy. Initial evaluation of a patient suspected of having THPP should include a complete blood count, TSH and serum and urine electrolyte tests, and an EKG. Further work-up may require ultrasound and scan of the thyroid upon confirmation of thyrotoxicosis and hypokalemia. Physical examination may reveal thyromegaly. Exophthalmos and other hyperthyroidism symptoms often are absent.¹

Diagnosis confirmed? Treat the hypokalemia first. Acute management of THPP centers on electrolyte correction. Total body stores of potassium in patients with THPP  are usually normal, so the physician must use care to avoid excessive potassium administration.^1-5 Rebound hyperkalemia can occur in patients who receive >90 mEq/L of potassium chloride within 24 hours.¹

Definitive therapy may include antithyroid medication, radioactive iodine ablation (RIA), and/or thyroidectomy.^1-5 All have the common goal of controlling the hyperthyroidism and preventing recurrent paralysis, which occurs in 62.2% of patients within the first 3 months following diagnosis.³ If antithyroid medications fail, then RIA is the next choice.¹ Beta-blockers work by decreasing the Na⁺,K⁺-ATPase activity from the underlying hyperadrenergic state.¹ Administration of acetazolamide—which is the primary treatment modality for FPP and idiopathic periodic paralysis—can precipitate THPP attacks and is contraindicated.^1,5

Consider thyroidectomy for patients for whom medical management is unsuccessful or who develop compression symptoms. If medical management is unsuccessful or the patient develops compression symptoms, then thyroidectomy should be considered.³ If the patient chooses thyroidectomy, medical optimization with antithyroid medications is indicated to mitigate the risks of anesthesia. When the thyroidectomy is performed by an experienced thyroid surgeon, the long-term results are excellent.

Our patient. Once our patient’s hypokalemia was corrected, she was successfully extubated. Despite appropriate medical therapy, her hyperthyroidism was poorly controlled. The endocrinologist believed that RIA was suboptimal for 3 reasons: 1) it might result in incomplete ablation, 2) it required a long treatment period to be effective, and 3) its prolonged course of treatment extended the time interval that the patient would be at risk for recurrent paralysis.

A surgeon was consulted for definitive treatment with thyroidectomy. Our patient’s medications were changed to propylthiouracil 150 mg every 8 hours and propranolol 10 mg twice a day until a euthyroid state was achieved and she could tolerate a general anesthetic without precipitating a thyroid storm. Two months later, she underwent total thyroidectomy without complication. Her postoperative course was normal.

THE TAKEAWAY

Thyrotoxic hypokalemic periodic paralysis is rare. Patients typically present with myalgia, cramping, and stiffness that progress to paralysis. Prompt electrolyte repletion is paramount for successful outcomes.^1-5 Control of hyperthyroidism is the long-term goal.^1-5 Definitive therapy can be achieved medically or surgically. Total thyroidectomy is a reasonable treatment option for medically refractory hyperthyroidism or when RIA is contraindicated. Long-term prognosis is excellent.

To the Editor: We read with interest the article by Ching Sun et al¹ on the relationship between diabetes therapy and cancer risk. We noted that there was no reference in the text to the long-acting insulins detemir and degludec, and we would like to add some relevant information.

With regard to detemir, a meta-analysis published in 2009 showed that patients treated with this insulin had a lower or similar rate of occurrence of a cancer compared with patients treated with neutral protamine Hagedorn insulin or insulin glargine.² In addition, in a cohort study, no difference in cancer risk between insulin detemir users and nonusers was reported.³

Insulin detemir has a lower binding affinity for human insulin receptor isoform A  (IR-A) relative to human insulin, and a much lower affinity for isoform B  (IR-B). The binding affinity ratio of insulinlike growth factor-1 (IGF-1) receptor to insulin receptor for detemir is less than or equal to 1 relative to human insulin and displays a dissociation pattern from the insulin receptor that is similar to or faster than that of human insulin. Consequently, the relative mitogenic potency of detemir in cell types predominantly expressing either the IGF-1 receptor or the insulin receptor is low and corresponds to its IGF-1 receptor and insulin receptor affinities.⁴

Regarding insulin degludec, its affinity for both IR-A and IR-B, as well as for the IGF-1 receptor, has been found to be lower than human insulin. Its mitogenic response, in the absence of albumin, was reported to range from 4% to 14% relative to human insulin.⁵ Furthermore, in cellular assays, in which no albumin was added, the in vitro metabolic potency was determined to be in the range of 8% to 20%, resulting in a mitogenic-to-metabolic potency ratio of 1 or lower.⁵

It appears that insulins detemir and degludec have low mitogenic potential. However, additional studies are needed, especially with degludec, to further determine long-term safety.

To the Editor: We read with interest the article by Ching Sun et al¹ on the relationship between diabetes therapy and cancer risk. We noted that there was no reference in the text to the long-acting insulins detemir and degludec, and we would like to add some relevant information.

With regard to detemir, a meta-analysis published in 2009 showed that patients treated with this insulin had a lower or similar rate of occurrence of a cancer compared with patients treated with neutral protamine Hagedorn insulin or insulin glargine.² In addition, in a cohort study, no difference in cancer risk between insulin detemir users and nonusers was reported.³

Insulin detemir has a lower binding affinity for human insulin receptor isoform A  (IR-A) relative to human insulin, and a much lower affinity for isoform B  (IR-B). The binding affinity ratio of insulinlike growth factor-1 (IGF-1) receptor to insulin receptor for detemir is less than or equal to 1 relative to human insulin and displays a dissociation pattern from the insulin receptor that is similar to or faster than that of human insulin. Consequently, the relative mitogenic potency of detemir in cell types predominantly expressing either the IGF-1 receptor or the insulin receptor is low and corresponds to its IGF-1 receptor and insulin receptor affinities.⁴

Regarding insulin degludec, its affinity for both IR-A and IR-B, as well as for the IGF-1 receptor, has been found to be lower than human insulin. Its mitogenic response, in the absence of albumin, was reported to range from 4% to 14% relative to human insulin.⁵ Furthermore, in cellular assays, in which no albumin was added, the in vitro metabolic potency was determined to be in the range of 8% to 20%, resulting in a mitogenic-to-metabolic potency ratio of 1 or lower.⁵

It appears that insulins detemir and degludec have low mitogenic potential. However, additional studies are needed, especially with degludec, to further determine long-term safety.

To the Editor: We read with interest the article by Ching Sun et al¹ on the relationship between diabetes therapy and cancer risk. We noted that there was no reference in the text to the long-acting insulins detemir and degludec, and we would like to add some relevant information.

With regard to detemir, a meta-analysis published in 2009 showed that patients treated with this insulin had a lower or similar rate of occurrence of a cancer compared with patients treated with neutral protamine Hagedorn insulin or insulin glargine.² In addition, in a cohort study, no difference in cancer risk between insulin detemir users and nonusers was reported.³

Insulin detemir has a lower binding affinity for human insulin receptor isoform A  (IR-A) relative to human insulin, and a much lower affinity for isoform B  (IR-B). The binding affinity ratio of insulinlike growth factor-1 (IGF-1) receptor to insulin receptor for detemir is less than or equal to 1 relative to human insulin and displays a dissociation pattern from the insulin receptor that is similar to or faster than that of human insulin. Consequently, the relative mitogenic potency of detemir in cell types predominantly expressing either the IGF-1 receptor or the insulin receptor is low and corresponds to its IGF-1 receptor and insulin receptor affinities.⁴

Regarding insulin degludec, its affinity for both IR-A and IR-B, as well as for the IGF-1 receptor, has been found to be lower than human insulin. Its mitogenic response, in the absence of albumin, was reported to range from 4% to 14% relative to human insulin.⁵ Furthermore, in cellular assays, in which no albumin was added, the in vitro metabolic potency was determined to be in the range of 8% to 20%, resulting in a mitogenic-to-metabolic potency ratio of 1 or lower.⁵

It appears that insulins detemir and degludec have low mitogenic potential. However, additional studies are needed, especially with degludec, to further determine long-term safety.

In Reply: Dr. Fountas et al highlight further data on insulin therapy and cancer risk, specifically in regard to insulin detemir and insulin degludec. Detemir first gained US Food and Drug Administration (FDA) approval in 2005 as a basal insulin, dosed once or twice daily.¹ Compared with regular human insulin, detemir has demonstrated proliferative and antiapoptotic activities in vitro in various cancer cell lines—eg, HCT-116 (colorectal cancer), PC-3 (prostate cancer), and MCF-7 (breast adenocarcinoma).² But clinically, detemir has not demonstrated increased cancer risk compared with other basal insulins in randomized controlled trials or cohort studies.^3–5

Degludec (U-200 insulin) is equal to twice the concentration of the usual U-100 insulin therapies presently available. In February 2013, the drug application for insulin degludec failed to obtain FDA approval, and the FDA requested additional data on cardiovascular safety. Thus, degludec is not currently available in the United States.⁶

Besides ameliorating nocturnal hypoglycemia,⁷ U-200 insulin may mitigate potential mitogenic effects.⁸ However, there are still very few data on degludec compared with the amount of data on insulin glargine. Insulin analogues with a decreased dissociation rate from the insulin receptor are associated with higher mitogenic potency than metabolic potency compared with human insulin.^9,10 Degludec, like detemir, has an elevated dissociation rate from the insulin receptor, a low affinity for IGF-1 receptors, and a low mitogenic activity in vitro.⁸

At this juncture, neither detemir nor degludec has been associated with higher cancer risk, but these therapies are relatively new. And as Dr. Fountas et al indicated, their safety, particularly in regard to cancer risk in diabetes patients, should continue to be assessed.

In Reply: Dr. Fountas et al highlight further data on insulin therapy and cancer risk, specifically in regard to insulin detemir and insulin degludec. Detemir first gained US Food and Drug Administration (FDA) approval in 2005 as a basal insulin, dosed once or twice daily.¹ Compared with regular human insulin, detemir has demonstrated proliferative and antiapoptotic activities in vitro in various cancer cell lines—eg, HCT-116 (colorectal cancer), PC-3 (prostate cancer), and MCF-7 (breast adenocarcinoma).² But clinically, detemir has not demonstrated increased cancer risk compared with other basal insulins in randomized controlled trials or cohort studies.^3–5

Degludec (U-200 insulin) is equal to twice the concentration of the usual U-100 insulin therapies presently available. In February 2013, the drug application for insulin degludec failed to obtain FDA approval, and the FDA requested additional data on cardiovascular safety. Thus, degludec is not currently available in the United States.⁶

Besides ameliorating nocturnal hypoglycemia,⁷ U-200 insulin may mitigate potential mitogenic effects.⁸ However, there are still very few data on degludec compared with the amount of data on insulin glargine. Insulin analogues with a decreased dissociation rate from the insulin receptor are associated with higher mitogenic potency than metabolic potency compared with human insulin.^9,10 Degludec, like detemir, has an elevated dissociation rate from the insulin receptor, a low affinity for IGF-1 receptors, and a low mitogenic activity in vitro.⁸

At this juncture, neither detemir nor degludec has been associated with higher cancer risk, but these therapies are relatively new. And as Dr. Fountas et al indicated, their safety, particularly in regard to cancer risk in diabetes patients, should continue to be assessed.

In Reply: Dr. Fountas et al highlight further data on insulin therapy and cancer risk, specifically in regard to insulin detemir and insulin degludec. Detemir first gained US Food and Drug Administration (FDA) approval in 2005 as a basal insulin, dosed once or twice daily.¹ Compared with regular human insulin, detemir has demonstrated proliferative and antiapoptotic activities in vitro in various cancer cell lines—eg, HCT-116 (colorectal cancer), PC-3 (prostate cancer), and MCF-7 (breast adenocarcinoma).² But clinically, detemir has not demonstrated increased cancer risk compared with other basal insulins in randomized controlled trials or cohort studies.^3–5

Degludec (U-200 insulin) is equal to twice the concentration of the usual U-100 insulin therapies presently available. In February 2013, the drug application for insulin degludec failed to obtain FDA approval, and the FDA requested additional data on cardiovascular safety. Thus, degludec is not currently available in the United States.⁶

Besides ameliorating nocturnal hypoglycemia,⁷ U-200 insulin may mitigate potential mitogenic effects.⁸ However, there are still very few data on degludec compared with the amount of data on insulin glargine. Insulin analogues with a decreased dissociation rate from the insulin receptor are associated with higher mitogenic potency than metabolic potency compared with human insulin.^9,10 Degludec, like detemir, has an elevated dissociation rate from the insulin receptor, a low affinity for IGF-1 receptors, and a low mitogenic activity in vitro.⁸

At this juncture, neither detemir nor degludec has been associated with higher cancer risk, but these therapies are relatively new. And as Dr. Fountas et al indicated, their safety, particularly in regard to cancer risk in diabetes patients, should continue to be assessed.

The plasma cell disorders are a spectrum of conditions that include asymptomatic precursor conditions—monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM)—as well as symptomatic multiple myeloma (MM) and solitary plasmacytoma. Other plasma cell disorders include immunoglobulin light chain amyloidosis and POEMS syndrome, which are characterized by a unique set of end-organ manifestations. There are other related plasma cell and B-cell proliferations, such as light chain deposition disease and cryoglobulinemia, that are beyond the scope of this review but are relevant to the hematologist/oncologist and have been reviewed in detail elsewhere.

To read the full article in PDF:

Click here

The plasma cell disorders are a spectrum of conditions that include asymptomatic precursor conditions—monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM)—as well as symptomatic multiple myeloma (MM) and solitary plasmacytoma. Other plasma cell disorders include immunoglobulin light chain amyloidosis and POEMS syndrome, which are characterized by a unique set of end-organ manifestations. There are other related plasma cell and B-cell proliferations, such as light chain deposition disease and cryoglobulinemia, that are beyond the scope of this review but are relevant to the hematologist/oncologist and have been reviewed in detail elsewhere.

To read the full article in PDF:

Click here

The plasma cell disorders are a spectrum of conditions that include asymptomatic precursor conditions—monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM)—as well as symptomatic multiple myeloma (MM) and solitary plasmacytoma. Other plasma cell disorders include immunoglobulin light chain amyloidosis and POEMS syndrome, which are characterized by a unique set of end-organ manifestations. There are other related plasma cell and B-cell proliferations, such as light chain deposition disease and cryoglobulinemia, that are beyond the scope of this review but are relevant to the hematologist/oncologist and have been reviewed in detail elsewhere.

To read the full article in PDF:

Click here

Monoclonal antibodies

Credit: Linda Bartlett

SAN FRANCISCO—Combination therapy involving a novel monoclonal antibody (mAb) produces encouraging activity in relapsed or refractory multiple myeloma (MM), according to researchers.

The team conducted a phase 1b trial testing the IgG1 mAb SAR650984 in combination with lenalidomide and dexamethasone (SAR-len-dex).

The treatment produced an overall response rate (ORR) of 58% and a higher ORR among patients who received the highest dose of SAR.

Furthermore, the combination had a “very manageable safety profile,” according to study investigator Thomas Martin, MD, of the University of California at San Francisco.

“The safety findings are really consistent with those of the individual drugs,” he said.

Dr Martin presented these findings at the 2014 ASH Annual Meeting as abstract 83.* The trial was  sponsored by Sanofi (the company developing SAR), but investigators also received research funding from Karyopharm, Bristol Myers Squibb, Millennium, and Celgene.

Dr Martin explained that SAR is a humanized IgG1 mAb that binds selectively to a unique epitope on the human CD38 receptor, and it has 4 potential mechanisms of action: antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, direct apoptosis without crosslinking, and inhibition of CD38 enzyme activity.

He said there is “ample evidence” to suggest that SAR-len-dex would be active in MM. First, both lenalidomide and SAR have demonstrated single-agent activity in MM. Second, lenalidomide can increase IL-2 production, which leads to enhanced antibody-dependent cellular cytotoxicity. And finally, SAR and lenalidomide showed additive effects in a mouse model of MM.

With that in mind, Dr Martin and his colleagues decided to test SAR-len-dex in patients with relapsed or refractory MM.

The team enrolled 31 patients and administered SAR at 3 different dose levels. Patients received 3 mg/kg (n=4), 5 mg/kg (n=3), or 10 mg/kg (n=24) every 2 weeks. They received lenalidomide at 25 mg on days 1-21 per 28-day cycle and dexamethasone at 40 mg once a week on days 1, 8, 15, and 22.

The patients’ median age was 59 (range, 45-74), the median time since diagnosis was 4 years (range, 1-12), the median number of prior treatment regimens was 7 (range, 2-14), and the median number of prior lines of therapy was 4 (range, 1-11).

“The median time from the last lenalidomide-containing regimen was 9 months,” Dr Martin noted. “Ninety-four percent of the patients had prior lenalidomide, and 74% of these patients were lenalidomide refractory.”

Of the 29% of patients who had received prior pomalidomide, all were refractory to it. The same was true of the 48% of patients who received carfilzomib. And of the 94% of patients who received prior bortezomib, 52% were refractory to it.

Adverse events

The maximum-tolerated dose of SAR was not reached. Treatment-emergent adverse events occurring in 30% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, diarrhea, fatigue, insomnia, muscle spasms, nausea, pneumonia, pyrexia, and upper respiratory tract infections.

Grade 3/4 events occurring in 5% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, fatigue, insomnia, and pneumonia.

“All of these events are commonly associated with the backbone treatment of lenalidomide and dexamethasone, and no unexpected or untoward adverse events were seen,” Dr Martin noted.

The most common SAR-associated adverse events were infusion reactions. About 35% of patients experienced an infusion reaction in cycle 1, and 10% did so in cycle 2.

Most reactions were grade 1 and 2 and did not lead to treatment discontinuation. Two patients did discontinue treatment due to grade 3 infusion reactions, but both events were ultimately resolved.

Response and survival

The ORR was 58% (n=18), and the clinical benefit rate was 65% (n=20). Two patients had a stringent complete response, 7 had a very good partial response, 9 had a partial response, 2 had a minimal response, 6 had stable disease, 4 progressed, and 1 was not evaluable.

Responses were seen at all dose levels, but the best responses occurred in patients who received the highest dose of SAR. Among patients who received the highest dose, the ORR was 68%, and the clinical benefit rate was 65%.

The ORR was 50% in patients who were refractory to prior treatment with an immunomodulatory drug, 40% in patients who were refractory to carfilzomib, and 33% in patients who were refractory to pomalidomide.

At 9 months of follow-up, the median progression-free survival was 6.2 months. The median progression-free survival was not reached for patients who had received 1 to 2 prior lines of therapy, and it was 5.8 months for patients who had received 3 or more prior lines of therapy.

“SAR in combination with lenalidomide/dexamethasone showed encouraging activity in this heavily pretreated population,” Dr Martin said in closing, adding that the combination compares favorably to other treatments tested in patients who received the same number of prior lines of therapy.

*Information in the abstract differs from that presented at the meeting.

Monoclonal antibodies

Credit: Linda Bartlett

SAN FRANCISCO—Combination therapy involving a novel monoclonal antibody (mAb) produces encouraging activity in relapsed or refractory multiple myeloma (MM), according to researchers.

The team conducted a phase 1b trial testing the IgG1 mAb SAR650984 in combination with lenalidomide and dexamethasone (SAR-len-dex).

The treatment produced an overall response rate (ORR) of 58% and a higher ORR among patients who received the highest dose of SAR.

Furthermore, the combination had a “very manageable safety profile,” according to study investigator Thomas Martin, MD, of the University of California at San Francisco.

“The safety findings are really consistent with those of the individual drugs,” he said.

Dr Martin presented these findings at the 2014 ASH Annual Meeting as abstract 83.* The trial was  sponsored by Sanofi (the company developing SAR), but investigators also received research funding from Karyopharm, Bristol Myers Squibb, Millennium, and Celgene.

Dr Martin explained that SAR is a humanized IgG1 mAb that binds selectively to a unique epitope on the human CD38 receptor, and it has 4 potential mechanisms of action: antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, direct apoptosis without crosslinking, and inhibition of CD38 enzyme activity.

He said there is “ample evidence” to suggest that SAR-len-dex would be active in MM. First, both lenalidomide and SAR have demonstrated single-agent activity in MM. Second, lenalidomide can increase IL-2 production, which leads to enhanced antibody-dependent cellular cytotoxicity. And finally, SAR and lenalidomide showed additive effects in a mouse model of MM.

With that in mind, Dr Martin and his colleagues decided to test SAR-len-dex in patients with relapsed or refractory MM.

The team enrolled 31 patients and administered SAR at 3 different dose levels. Patients received 3 mg/kg (n=4), 5 mg/kg (n=3), or 10 mg/kg (n=24) every 2 weeks. They received lenalidomide at 25 mg on days 1-21 per 28-day cycle and dexamethasone at 40 mg once a week on days 1, 8, 15, and 22.

The patients’ median age was 59 (range, 45-74), the median time since diagnosis was 4 years (range, 1-12), the median number of prior treatment regimens was 7 (range, 2-14), and the median number of prior lines of therapy was 4 (range, 1-11).

“The median time from the last lenalidomide-containing regimen was 9 months,” Dr Martin noted. “Ninety-four percent of the patients had prior lenalidomide, and 74% of these patients were lenalidomide refractory.”

Of the 29% of patients who had received prior pomalidomide, all were refractory to it. The same was true of the 48% of patients who received carfilzomib. And of the 94% of patients who received prior bortezomib, 52% were refractory to it.

Adverse events

The maximum-tolerated dose of SAR was not reached. Treatment-emergent adverse events occurring in 30% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, diarrhea, fatigue, insomnia, muscle spasms, nausea, pneumonia, pyrexia, and upper respiratory tract infections.

Grade 3/4 events occurring in 5% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, fatigue, insomnia, and pneumonia.

“All of these events are commonly associated with the backbone treatment of lenalidomide and dexamethasone, and no unexpected or untoward adverse events were seen,” Dr Martin noted.

The most common SAR-associated adverse events were infusion reactions. About 35% of patients experienced an infusion reaction in cycle 1, and 10% did so in cycle 2.

Most reactions were grade 1 and 2 and did not lead to treatment discontinuation. Two patients did discontinue treatment due to grade 3 infusion reactions, but both events were ultimately resolved.

Response and survival

The ORR was 58% (n=18), and the clinical benefit rate was 65% (n=20). Two patients had a stringent complete response, 7 had a very good partial response, 9 had a partial response, 2 had a minimal response, 6 had stable disease, 4 progressed, and 1 was not evaluable.

Responses were seen at all dose levels, but the best responses occurred in patients who received the highest dose of SAR. Among patients who received the highest dose, the ORR was 68%, and the clinical benefit rate was 65%.

The ORR was 50% in patients who were refractory to prior treatment with an immunomodulatory drug, 40% in patients who were refractory to carfilzomib, and 33% in patients who were refractory to pomalidomide.

At 9 months of follow-up, the median progression-free survival was 6.2 months. The median progression-free survival was not reached for patients who had received 1 to 2 prior lines of therapy, and it was 5.8 months for patients who had received 3 or more prior lines of therapy.

“SAR in combination with lenalidomide/dexamethasone showed encouraging activity in this heavily pretreated population,” Dr Martin said in closing, adding that the combination compares favorably to other treatments tested in patients who received the same number of prior lines of therapy.

*Information in the abstract differs from that presented at the meeting.

Monoclonal antibodies

Credit: Linda Bartlett

SAN FRANCISCO—Combination therapy involving a novel monoclonal antibody (mAb) produces encouraging activity in relapsed or refractory multiple myeloma (MM), according to researchers.

The team conducted a phase 1b trial testing the IgG1 mAb SAR650984 in combination with lenalidomide and dexamethasone (SAR-len-dex).

The treatment produced an overall response rate (ORR) of 58% and a higher ORR among patients who received the highest dose of SAR.

Furthermore, the combination had a “very manageable safety profile,” according to study investigator Thomas Martin, MD, of the University of California at San Francisco.

“The safety findings are really consistent with those of the individual drugs,” he said.

Dr Martin presented these findings at the 2014 ASH Annual Meeting as abstract 83.* The trial was  sponsored by Sanofi (the company developing SAR), but investigators also received research funding from Karyopharm, Bristol Myers Squibb, Millennium, and Celgene.

Dr Martin explained that SAR is a humanized IgG1 mAb that binds selectively to a unique epitope on the human CD38 receptor, and it has 4 potential mechanisms of action: antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, direct apoptosis without crosslinking, and inhibition of CD38 enzyme activity.

He said there is “ample evidence” to suggest that SAR-len-dex would be active in MM. First, both lenalidomide and SAR have demonstrated single-agent activity in MM. Second, lenalidomide can increase IL-2 production, which leads to enhanced antibody-dependent cellular cytotoxicity. And finally, SAR and lenalidomide showed additive effects in a mouse model of MM.

With that in mind, Dr Martin and his colleagues decided to test SAR-len-dex in patients with relapsed or refractory MM.

The team enrolled 31 patients and administered SAR at 3 different dose levels. Patients received 3 mg/kg (n=4), 5 mg/kg (n=3), or 10 mg/kg (n=24) every 2 weeks. They received lenalidomide at 25 mg on days 1-21 per 28-day cycle and dexamethasone at 40 mg once a week on days 1, 8, 15, and 22.

The patients’ median age was 59 (range, 45-74), the median time since diagnosis was 4 years (range, 1-12), the median number of prior treatment regimens was 7 (range, 2-14), and the median number of prior lines of therapy was 4 (range, 1-11).

“The median time from the last lenalidomide-containing regimen was 9 months,” Dr Martin noted. “Ninety-four percent of the patients had prior lenalidomide, and 74% of these patients were lenalidomide refractory.”

Of the 29% of patients who had received prior pomalidomide, all were refractory to it. The same was true of the 48% of patients who received carfilzomib. And of the 94% of patients who received prior bortezomib, 52% were refractory to it.

Adverse events

The maximum-tolerated dose of SAR was not reached. Treatment-emergent adverse events occurring in 30% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, diarrhea, fatigue, insomnia, muscle spasms, nausea, pneumonia, pyrexia, and upper respiratory tract infections.

Grade 3/4 events occurring in 5% of patients or more included anemia, neutropenia, thrombocytopenia, febrile neutropenia, fatigue, insomnia, and pneumonia.

“All of these events are commonly associated with the backbone treatment of lenalidomide and dexamethasone, and no unexpected or untoward adverse events were seen,” Dr Martin noted.

The most common SAR-associated adverse events were infusion reactions. About 35% of patients experienced an infusion reaction in cycle 1, and 10% did so in cycle 2.

Most reactions were grade 1 and 2 and did not lead to treatment discontinuation. Two patients did discontinue treatment due to grade 3 infusion reactions, but both events were ultimately resolved.

Response and survival

The ORR was 58% (n=18), and the clinical benefit rate was 65% (n=20). Two patients had a stringent complete response, 7 had a very good partial response, 9 had a partial response, 2 had a minimal response, 6 had stable disease, 4 progressed, and 1 was not evaluable.

Responses were seen at all dose levels, but the best responses occurred in patients who received the highest dose of SAR. Among patients who received the highest dose, the ORR was 68%, and the clinical benefit rate was 65%.

The ORR was 50% in patients who were refractory to prior treatment with an immunomodulatory drug, 40% in patients who were refractory to carfilzomib, and 33% in patients who were refractory to pomalidomide.

At 9 months of follow-up, the median progression-free survival was 6.2 months. The median progression-free survival was not reached for patients who had received 1 to 2 prior lines of therapy, and it was 5.8 months for patients who had received 3 or more prior lines of therapy.

“SAR in combination with lenalidomide/dexamethasone showed encouraging activity in this heavily pretreated population,” Dr Martin said in closing, adding that the combination compares favorably to other treatments tested in patients who received the same number of prior lines of therapy.

*Information in the abstract differs from that presented at the meeting.

Vials of drug

Credit: Bill Branson

The US Food and Drug Administration (FDA) has approved a supplemental biologics license application for obinutuzumab (Gazyva) in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).

The approval adds to the drug’s label data from stage 2 of the CLL11 study, which showed that obinutuzumab plus chlorambucil offers significant clinical improvements when compared head-to-head with rituximab plus chlorambucil.

This includes progression-free survival (PFS), complete response (CR), and minimal residual disease (MRD) data from stage 2 of the study. In addition, overall survival data was added from stage 1, in which researchers compared obinutuzumab plus chlorambucil to chlorambucil alone.

The label now reflects that obinutuzumab plus chlorambucil improved PFS compared to rituximab plus chlorambucil. The median PFS was 26.7 months and 14.9 months, respectively (hazard ratio=0.42, P<0.0001).

Additionally, obinutuzumab plus chlorambucil nearly tripled the CR rate when compared to rituximab plus chlorambucil. The CR rates were 26.1% and 8.8%, respectively.

Of the patients who achieved a CR with or without complete recovery from abnormal blood cell counts, 19% (18/94) of patients in the obinutuzumab arm and 6% (2/34) in the rituximab arm were MRD negative in the bone marrow.

Forty-one percent (39/94) of patients in the obinutuzumab arm and 12% (4/34) in the rituximab arm were MRD-negative in the peripheral blood.

At nearly 2 years, the rate of death was 9% (22/238) for patients who received obinutuzumab plus chlorambucil and 20% (24/118) for those who received chlorambucil alone (hazard ratio=0.41). The median overall survival has not yet been reached.

About obinutuzumab

Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20 on B cells. The drug attacks targeted cells both directly and together with the body’s immune system.

The prescribing information for obinutuzumab includes warnings that the drug can cause serious or life-threatening side effects. These include hepatitis B reactivation, progressive multifocal leukoencephalopathy, infusion reactions, tumor lysis syndrome, infections, and neutropenia.

The most common side effects of the drug are infusion reactions, neutropenia, thrombocytopenia, anemia, fever, cough, nausea, and diarrhea.

Obinutuzumab was FDA-approved for use in combination with chlorambucil to treat previously untreated CLL in November 2013. The drug (which is known as Gazyvaro in Europe) was approved by the European Commission for the same indication in July 2014.

Obinutuzumab was discovered by Roche Glycart AG, an independent research unit of Roche. In the US, the drug is part of a collaboration between Genentech and Biogen Idec.

Vials of drug

Credit: Bill Branson

The US Food and Drug Administration (FDA) has approved a supplemental biologics license application for obinutuzumab (Gazyva) in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).

The approval adds to the drug’s label data from stage 2 of the CLL11 study, which showed that obinutuzumab plus chlorambucil offers significant clinical improvements when compared head-to-head with rituximab plus chlorambucil.

This includes progression-free survival (PFS), complete response (CR), and minimal residual disease (MRD) data from stage 2 of the study. In addition, overall survival data was added from stage 1, in which researchers compared obinutuzumab plus chlorambucil to chlorambucil alone.

The label now reflects that obinutuzumab plus chlorambucil improved PFS compared to rituximab plus chlorambucil. The median PFS was 26.7 months and 14.9 months, respectively (hazard ratio=0.42, P<0.0001).

Additionally, obinutuzumab plus chlorambucil nearly tripled the CR rate when compared to rituximab plus chlorambucil. The CR rates were 26.1% and 8.8%, respectively.

Of the patients who achieved a CR with or without complete recovery from abnormal blood cell counts, 19% (18/94) of patients in the obinutuzumab arm and 6% (2/34) in the rituximab arm were MRD negative in the bone marrow.

Forty-one percent (39/94) of patients in the obinutuzumab arm and 12% (4/34) in the rituximab arm were MRD-negative in the peripheral blood.

At nearly 2 years, the rate of death was 9% (22/238) for patients who received obinutuzumab plus chlorambucil and 20% (24/118) for those who received chlorambucil alone (hazard ratio=0.41). The median overall survival has not yet been reached.

About obinutuzumab

Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20 on B cells. The drug attacks targeted cells both directly and together with the body’s immune system.

The prescribing information for obinutuzumab includes warnings that the drug can cause serious or life-threatening side effects. These include hepatitis B reactivation, progressive multifocal leukoencephalopathy, infusion reactions, tumor lysis syndrome, infections, and neutropenia.

The most common side effects of the drug are infusion reactions, neutropenia, thrombocytopenia, anemia, fever, cough, nausea, and diarrhea.

Obinutuzumab was FDA-approved for use in combination with chlorambucil to treat previously untreated CLL in November 2013. The drug (which is known as Gazyvaro in Europe) was approved by the European Commission for the same indication in July 2014.

Obinutuzumab was discovered by Roche Glycart AG, an independent research unit of Roche. In the US, the drug is part of a collaboration between Genentech and Biogen Idec.

Vials of drug

Credit: Bill Branson

The US Food and Drug Administration (FDA) has approved a supplemental biologics license application for obinutuzumab (Gazyva) in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).

The approval adds to the drug’s label data from stage 2 of the CLL11 study, which showed that obinutuzumab plus chlorambucil offers significant clinical improvements when compared head-to-head with rituximab plus chlorambucil.

This includes progression-free survival (PFS), complete response (CR), and minimal residual disease (MRD) data from stage 2 of the study. In addition, overall survival data was added from stage 1, in which researchers compared obinutuzumab plus chlorambucil to chlorambucil alone.

The label now reflects that obinutuzumab plus chlorambucil improved PFS compared to rituximab plus chlorambucil. The median PFS was 26.7 months and 14.9 months, respectively (hazard ratio=0.42, P<0.0001).

Additionally, obinutuzumab plus chlorambucil nearly tripled the CR rate when compared to rituximab plus chlorambucil. The CR rates were 26.1% and 8.8%, respectively.

Of the patients who achieved a CR with or without complete recovery from abnormal blood cell counts, 19% (18/94) of patients in the obinutuzumab arm and 6% (2/34) in the rituximab arm were MRD negative in the bone marrow.

Forty-one percent (39/94) of patients in the obinutuzumab arm and 12% (4/34) in the rituximab arm were MRD-negative in the peripheral blood.

At nearly 2 years, the rate of death was 9% (22/238) for patients who received obinutuzumab plus chlorambucil and 20% (24/118) for those who received chlorambucil alone (hazard ratio=0.41). The median overall survival has not yet been reached.

About obinutuzumab

Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20 on B cells. The drug attacks targeted cells both directly and together with the body’s immune system.

The prescribing information for obinutuzumab includes warnings that the drug can cause serious or life-threatening side effects. These include hepatitis B reactivation, progressive multifocal leukoencephalopathy, infusion reactions, tumor lysis syndrome, infections, and neutropenia.

The most common side effects of the drug are infusion reactions, neutropenia, thrombocytopenia, anemia, fever, cough, nausea, and diarrhea.

Obinutuzumab was FDA-approved for use in combination with chlorambucil to treat previously untreated CLL in November 2013. The drug (which is known as Gazyvaro in Europe) was approved by the European Commission for the same indication in July 2014.

Obinutuzumab was discovered by Roche Glycart AG, an independent research unit of Roche. In the US, the drug is part of a collaboration between Genentech and Biogen Idec.