Treatment of Latent Tuberculosis Infection Michael Kessler and James F. Smith, Jr. DOI: /neo.10-8-e396

Transcription

1 Treatment of Latent Tuberculosis Infection Michael Kessler and James F. Smith, Jr NeoReviews 2009;10;e396-e401 DOI: /neo.10-8-e396 The online version of this article, along with updated information and services, is located on the World Wide Web at: NeoReviews is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since NeoReviews is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, Copyright 2009 by the American Academy of Pediatrics. All rights reserved. Online ISSN:

2 Article infectious diseases Treatment of Latent Tuberculosis Infection Michael Kessler, MD,* James F. Smith, Jr, MD* Author Disclosure Drs Kessler and Smith have disclosed no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of a commercial product/device. Objectives After completing this article, readers should be able to: 1. List the most common cause of tuberculosis (TB). 2. Delineate the effects of TB in the perinatal period on mother, fetus, and neonate. 3. Explain the role of and risks associated with isoniazid (INH) treatment during pregnancy. 4. Describe clinical symptoms of INH-induced hepatotoxicity. Abstract Latent tuberculosis infection (LTBI) is the most common source for active tuberculosis (TB), and its treatment remains an important cornerstone of global TB eradication. Although pregnancy may represent a unique time during which LTBI may be treated successfully, pregnancy and the postpartum period have been recognized as periods during which the risk of hepatitis from isoniazid (INH), the drug of choice for LTBI, may be increased. Thus, recommendations have suggested postponing treatment of LTBI until the postpartum period. Recent programs indicate that in properly designed surveillance programs, the risk of INH-induced hepatitis is low. Similar to other ongoing clinical encounters in which targeted LTBI screening and treatment may be accomplished, such as methadone and needle exchange clinics, antenatal clinics represent an opportunity to establish trust between clinician and patient for ongoing surveillance for complications and compliance. Furthermore, the addition of a newborn into the household where LTBI has been found poses new implications for eradication of TB. Prospective data collection on outcomes for such programs will be invaluable in assessing the efficacy of these efforts. Abbreviations ATS: American Thoracic Society CDC: Centers for Disease Control and Prevention HIV: human immunodeficiency virus INH: isoniazid LTBI: infection PPD: purified protein derivative TB: tuberculosis Introduction TB is a global menace that has been present since antiquity. This bacterial infection is caused by Mycobacterium tuberculosis. Approximately one third of the world s population is infected with the bacterium. An estimated 6 million new cases and approximately 2 million deaths due to TB occurred worldwide in The highest death rates are in Africa. Approximately one third of cases are from southeast Asia. It is estimated that approximately 1 million women die annually from TB. Women have a higher progression to disease rate and are considered to have a higher case fatality rate. Approximately 10 to 15 million individuals in the United States have TB. In the early 1990s, about 30% of the cases of TB diagnosed in the United States were from foreign-born immigrants, with the percentage increasing to 50% by In New York City, the case rate for foreignborn immigrants was 26 per 100,000 compared with approximately 7 per 100,000 for United States-born individuals. In 2007, more than 13,000 cases of TB occurred in the United States, and the case rate demonstrated a 4.2% decline. Although these encouraging data confirm the lowest rate of TB since national reporting began in 1953, concern continues. The slowing decline in TB, the greater complexities of identifying and treating the condition, the increase in affected foreign-born individuals, increased rates of TB in *Department of Obstetrics and Gynecology, New York Medical College and Westchester Medical Center, Valhalla, NY. e396 NeoReviews Vol.10 No.8 August 2009

3 ethnic and racial minorities, and the persistence of human immunodeficiency virus (HIV)-associated TB are examples of the challenges faced in eradication of this infection. The continued global extent of TB-related morbidity and mortality is acknowledged annually on March 24, designated World TB Day, to commemorate Robert Koch s discovery of the bacterium and to invite international focus on this global affliction. Latent Tuberculosis Infection Most cases of tuberculosis arise from activation of LTBI, not by transmission. LTBI represents a condition in which the infected individual harbors the bacteria but has no clinical manifestations of the disease. Although such individuals are not considered infectious, LTBI is the most common cause of active TB cases. Furthermore, approximately 50% of close contacts of patients who have active TB become infected. Emigrants from TB-endemic areas of the world who have LTBI represent a significant source of this bacterium, and strategies to target treatment at this reservoir of TB have been the recent focus of the Centers for Disease Control and Prevention (CDC) and the American Thoracic Society (ATS). Control and eventual eradication of TB likely is based on the success of eliminating LTBI. Writers of a report from the Institute of Medicine in 2000 estimated that targeting recent emigrants from endemic countries who have LTBI may prevent more than 1,300 cases of active TB in the United States annually. The lifetime risk of TB after acquiring LTBI is about 2% to 10%, with the highest risk in the first 2 years after infection. In HIV-infected populations, the lifetime risk is 5% to 10% and is related to the use and efficacy of highly active antiretroviral therapy. The CDC has identified five areas for focus in the challenge of eradication of TB (Table 1). Table 1. Recommendations for Eliminating Tuberculosis (TB) in the United States* 1. Interrupt person-to-person transmission. 2. Reduce TB in foreign-born residents and travelers. 3. Reduce TB in racial and ethnic minorities. 4. Reduce the global impact of multidrug-resistant TB. 5. Reduce the impact of human immunodeficiency virus-associated TB. *Summarized from the Division of Tuberculosis Elimination (DTBE) of the Centers for Disease Control and Prevention. Screening Screening for TB is recommended for all people at risk, regardless of pregnancy status. All gravidas at increased risk for TB should be screened. Screening may be performed by the traditional purified protein derivative (PPD); pregnancy does not alter the response to such testing. Although not specifically assessed during pregnancy, recent experience with interferon-gamma release in heparinized blood when exposed to TB antigens as a screening tool has been encouraging, and the CDC endorses its use in circumstances in which the PPD would be used for screening. This test has the advantage of a single visit without need for interpretation at a later time and, due to increased specificity, a higher predictive value when patients previously have received the Bacille Calmette-Guérin vaccine. Such testing aids in efficient clinic function and can be added to routine blood tests obtained at the first prenatal visit. Positive screening results should be followed up with assessments for active TB and potential risk for person-to-person transmission. In the absence of clinical or radiographic evidence of active TB during pregnancy, the gravid is considered to have LTBI. TB in the Perinatal Period: Maternal Effects TB in pregnancy once was believed to have a significant detrimental effect on outcome. With the advent of modern antitubercular chemotherapy, pregnancy outcomes are favorable. Currently, pregnancy does not appear to increase the risk of TB, although common and generally benign pregnancy complaints such as fatigue, malaise, and dyspnea may contribute to delayed diagnosis of active TB. Patients who have positive screening test results for TB should undergo chest radiography with abdominal shielding in the early second trimester or immediately if signs or symptoms of active TB are present. LTBI during pregnancy does not appear to be associated with complications of pregnancy. However, extrapulmonary TB occurs in about 16% of cases of TB in the United States and is more frequent in those infected with HIV. Extrapulmonary TB is rare in pregnancy. Unless confined to the lymph nodes, extrapulmonary TB represents a high-risk condition and is associated with adverse pregnancy outcomes, including low birthweight and lower Apgar scores at birth. TB in the Perinatal Period: Fetal and Neonatal Effects Maternal endometritis caused by TB is associated with infertility. The tubercle bacillus rarely crosses from the NeoReviews Vol.10 No.8 August 2009 e397

4 placenta. Fetal and neonatal cases of TB, therefore, are rare and usually occur only when the placenta is infected by recent acquisition of TB by the mother, either during or shortly before pregnancy. Reported cases of congenital TB are complicated by the presence of extrapulmonary TB in the mother and lack of treatment during the pregnancy. Most cases of newborn and childhood TB arise from transmission from household contacts. Congenital TB is suggested by four criteria. First, the presence of TB lesions in the newborn must be identified within the first postnatal week. Second, a primary hepatic complex in the newborn should be present. Because one route of congenital TB infection is by hematogenous transplacental spread, the fetus is infected via the umbilical vein, with the fetal liver and its lymphatics being the first organ encountered. Third, maternal genital tract or placental TB should be present. Fourth, exclusion of postnatal infection by investigation of household or health-care contacts further suggests congenital acquisition. Because most cases of newborn and infant TB arise from transmission, care should be taken to screen the mother carefully at the time of delivery for active (and, therefore, infectious) TB. Isoniazid INH inhibits the oxygen-dependent steps in the synthesis of the mycolic acid portion of the mycobacterial cell wall. INH was introduced in the early 1950s, and after subsequent clinical trials over the next decade, the ATS recommended INH for treatment of LTBI. By 1968, after its introduction as an agent for LTBI, a 68% reduction in TB activation was noted, attesting to the drug s effectiveness. With compliance, a 93% to 98% cure rate was noted. Furthermore, the protective effect in reducing reactivation appeared to last for 20 years and possibly longer. INH is considered safe for use in pregnancy. It does cross the placenta, but its use has not been shown to cause birth defects or adverse outcome in offspring related to direct embryotoxicity. INH also crosses into the human milk, but breastfeeding is not contraindicated. The use of INH has been associated with peripheral neuropathy, and when used, the addition of pyridoxine is recommended to decrease such risk. Isoniazid-induced Hepatitis The most significant complication of INH therapy is associated hepatotoxicity. Initially INH was believed to be a safe medication, but the first reports of INHinduced hepatitis surfaced in During the outbreak of TB in Washington, DC, in 1970, approximately 2,000 people who had LTBI were treated with INH. About 1% developed hepatitis, and two patients died from this complication (0.1%). The risk of hepatitis appeared to be associated with age. As a result, the recommendation to avoid treatment of LTBI in patients older than age 35 years was made. Overall, the use of INH for LTBI decreased in subsequent years. In 1983, the ATS recommended clinical and laboratory surveillance in patients treated with INH. Hepatic damage caused by INH can be categorized into two patterns. Mild hepatotoxicity occurs in 10% to 20% of patients and is characterized by mild elevations of aminotransferases early in the course of the treatment. Patients are asymptomatic, and the elevation in aminotransferase concentrations usually is less than five times the upper limit of normal for the reference laboratory being used. Drug therapy is continued with careful clinical and serologic monitoring, and the outcome is excellent. INH hepatitis represents much more serious liver damage that occurs in fewer than 1% of patients receiving the medication. INH hepatitis is characterized by signs and symptoms of hepatitis, including malaise, fatigue, anorexia, nausea and vomiting, and abdominal pain. Jaundice can occur later, but may be the first feature in up to 10% of patients. Treatment is largely supportive, with discontinuation of INH and other medications known to be associated with INH toxicity. The prognosis appears worse when hepatitis develops after more than 2 months of INH treatment. Liver transplant has been used in severe and refractory cases. The case fatality rate of INH hepatitis may be as high as 10%. The identification of risk factors for INH hepatitis has represented a significant step in selectively treating those patients most likely to benefit while minimizing the risk of hepatitis. One of the primary risk factors for INH hepatitis is age, with the incidence rising as age increases. For those younger than 35 years of age, the risk is about 0.3%, and for those older than 65 years of age, the risk is 4% to 5%. Other risk factors include concomitant use of alcohol or medications known to affect the liver, concurrent liver disease, and female sex, particularly if nonwhite. Significantly, INH hepatitis also has been associated with pregnancy status. Retrospective reports in 1989 and 1992 suggested that pregnancy and the peripartum period were potential risk factors for INH-induced liver damage. Since that time, caution has been advocated for INH use for LTBI during pregnancy, and both the American College of Obstetricians and Gynecologists and the CDC suggest delaying treatment until the postpartum period. Exceptions include the presence of e398 NeoReviews Vol.10 No.8 August 2009

5 Table 2. Indications of Isoniazid Hepatotoxicity During Pregnancy 1. Clinical manifestations of liver disease such as jaundice, malaise, nausea, vomiting, and abdominal pain. 2. Increase in aspartate aminotransferase or alanine aminotransferase to five times the upper limit in the absence of symptoms. 3. Increase in aspartate aminotransferase or alanine aminotransferase to three times the upper limit in the presence of symptoms. 4. Any increase of bilirubin above the normal limit. HIV, a recent contact, or recent PPD conversion. Approximately 2% to 5% of such patients develop active TB within 2 years, so when such circumstances are identified, INH treatment is started without delay during the pregnancy. Treating LTBI During Pregnancy Effective measures to eliminate TB require the identification and treatment of LTBI. Treatment of LTBI requires 6 to 9 months of antitubercular medication. Strategies that delay treatment until the postpartum period are associated with low compliance and a lost opportunity for efforts to eliminate TB. In fact, completion of a regimen of at least 6 months of INH occurs in fewer than 10% of pregnant patients. The cost-effectiveness of screening and treating LTBI during pregnancy with INH has been addressed in a decision analysis in 2000, and treatment compares favorably to no treatment or postpartum treatment. Fewer TB cases are assumed to occur with antepartum treatment of LTBI compared with no treatment or postpartum treatment. Although the incidence of hepatitis-related deaths is slightly higher, life expectancy is improved with antepartum treatment because of reduced TB-related deaths. Such decision analyses offer insight into anticipated benefits and risks of treatment of LTBI in the absence of prospectively collected data. A more favorable balance would be anticipated if the risks of INH hepatitis could be predicted and reduced. Recently, the risk of INH-induced hepatotoxicity has been shown to be reduced greatly by structured surveillance programs. Such surveillance has been associated with a sixfold decrease in the risk of hepatitis in the nonpregnant population; overt hepatotoxicity occurs in 0.1%, with virtually all patients recovering following discontinuation of INH. Limiting screening to only those individuals considered at risk for active TB or progression to active TB serves two purposes: 1) Focusing of resources on patients most likely to benefit from screening and treatment, and 2) Selective treatment of patients, thereby reducing the exposure of low-risk patients to INH-associated complications. Furthermore, avoiding INH use in patients with risk factors, such as increased age, concomitant use of hepatotoxic medications (including acetaminophen) or ethanol, and malnutrition is appropriate. Approximately 10% to 20% of patients treated with INH develop low-grade elevations of transaminases within days to weeks of beginning therapy. With continued use in the asymptomatic patient, the elevations usually resolve, representing adaptation of the liver to INH exposure. Clinical symptoms of INH-induced hepatotoxicity include nausea, vomiting, malaise, and abdominal pain, occasionally with fever (Table 2). In this circumstance, prompt discontinuation of INH usually results in normalization of transaminases and resolution of symptoms, if present. Pregnancy is a state well known to be associated with fatigue, nausea, and vomiting, and a high index Table 3. Proposed Latent Tuberculosis (TB) Infection Treatment Protocol During Pregnancy 1. Screen for evidence of active TB and treat accordingly if found. 2. Screen for increase risk of hepatotoxicity by history and laboratory assessments. 3. Educate patients about: goals, advantages, disadvantages, options, and risks for screening and treating latent TB infection during pregnancy; signs and symptoms of hepatotoxicity; and importance of compliance for success. 4. Establish date for completion of medications (9 months). 5. Administer isoniazid (INH) 300 mg daily for 9 months, beginning in the second trimester. 6. Administer pyridoxine 50 mg daily with INH use. 7. Dispense only 1 month of medications at a time. 8. Obtain monthly clinical and serologic assessments for evidence of hepatotoxicity before refilling medications. 9. Coordinate with local health agencies for family screening and treatment. 10. Encourage breastfeeding while treatment continues in the postpartum period. NeoReviews Vol.10 No.8 August 2009 e399

6 of suspicion must be in place for assessing liver function immediately if a pregnant patient being treated with INH reports any of these symptoms. Data-driven guidelines can be established with current scientific knowledge and prudence and diligence in patient selection and surveillance (Table 3). The paucity of literature on the establishment and efficacy of an antenatal program for the treatment of LTBI makes this a fertile and important area for research. Patients can be seen at well-defined intervals for pregnancy care at antenatal clinics, which allows for serial clinical and laboratory assessments for pregnancy-related care and the establishment of a unique patient-clinician relationship. Clinics also usually are well-networked with community health resources, allowing referral for health assessments, family and contact screening, and state reporting. The collection and review of data during pregnancy aid in quality assessments of health programs. Prospective data collection would offer the best insight into treatment successes and challenges and the true risks of INH treatment in pregnant women. Summary Treatment of LTBI during pregnancy is reasonable and may offer a significant benefit to the patient, her offspring and family, and her community. The treatment of LTBI during pregnancy presents an opportunity to reduce the health threat of this global infectious condition and has specific maternal, fetal, and neonatal implications. American Board of Pediatrics Neonatal-Perinatal Medicine Content Specification Know the epidemiology, pathogenesis, and prevention of perinatal infections with Mycobacterium tuberculosis. Suggested Reading American Academy of Pediatrics/American College of Obstetrics and Gynecology. Perinatal infections. In: Guidelines for Perinatal Care. 6th ed. Elk Grove Village, Ill: American Academy of Pediatrics; 2007: American Thoracic Society, CDC, Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med. 2003;167: Bergeron KG, Bonebrake RG, Allen C, Gray CJ. Latent tuberculosis in pregnancy: screening and treatment. Curr Womens Health Report. 2003;3: Boggess KA, Myers ER, Hamilton CD. Antepartum or postpartum isoniazid treatment of infection. Obstet Gynecol. 2000;96: Cantwell MF, Shehab AM, Costello AM. Brief report: congenital tuberculosis. N Engl J Med. 1994;330:1051 Centers for Disease Control and Prevention. Guidelines for the QuantiFERON-TB gold test for the detection of Mycobacterium tuberculosis infection, United States. MMWR Morbid Mortal Wkly Rep. 2005;54(RR15):49 55 Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of infection. MMWR Morbid Mortal Wkly Rep. 2000;49(RR06):1 54 Efferen LS. Tuberculosis and pregnancy. Curr Opin Pulm Med. 2007;13: Franks AL, Binkin NJ, Snider DE, et. al. Isoniazid hepatitis among pregnant and postpartum Hispanic patients. Public Health Rep. 1989;104: Hamadeh MA, Glassroth J. Tuberculosis in pregnancy. Chest. 1992;101:1114 Jana N, Vasishta K, Saha SC, Ghosh K. Obstetrical outcomes among women with extrapulmonary tuberculosis. N Engl J Med. 1999;341: Kwara A, Herold JS, Machan JT, Carter EJ. Factors associated with failure to complete isoniazid treatment for infection in Rhode Island. Chest. 2008;133: Nolan CM, Goldberg SV, Buskin SE. Hepatitis associated with isoniazid preventive therapy: a 7-year survey from a public health TB clinic. JAMA. 1999;281: Polson JE. Hepatotoxicity due to antibiotics. Clin Liver Dis. 2007; 11: Sackoff JE, Pfeiffer MR, Driver CR, et al. Tuberculosis prevention for non-us-born pregnant women. Am J Obstet Gynecol. 2006; 194: Snider DE Jr, Caras GJ. Isoniazid-associated hepatitis deaths: a review of available information. Am Rev Respir Dis. 1992;145: Steele MA, Burke RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin: a meta-analysis. Chest. 1991;99: Whitty JE, Dombrowski MP. Respiratory diseases in pregnancy. In: Gabbe SG, Niebyl JR, Simpson JL, eds. Obstetrics: Normal and Problem Pregnancies. 5th ed. Philadelphia, Pa: Churchill Livingstone; 2007: e400 NeoReviews Vol.10 No.8 August 2009

7 NeoReviews Quiz 5. TB is a global menace; approximately one third of the world s population is infected. Several strategies are promulgated by the Centers for Disease Control and Prevention for curtailment and eventual eradication of the disease. Of the following, the strategy most likely to yield the goal of global eradication of TB is to: A. Interrupt person-to-person transmission. B. Reduce TB in racial and ethnic minorities. C. Reduce the impact of HIV-associated TB. D. Reduce the impact of multidrug-resistant TB. E. Target treatment to TB-endemic areas of the world. 6. A 34-year-old primiparous woman, a recent emigrant from Africa, who is in her 20th week of pregnancy, has a positive screening test result for TB. She appears to be in good health and without clinical manifestations of the infection. She inquires about the potential effects of TB on her pregnancy. Of the following, the most accurate statement regarding TB and its perinatal effects is that: A. Extrapulmonary TB is common during pregnancy. B. Most newborn TB arises from transmission from household contacts. C. Pregnancy increases the risk of TB. D. TB increases the risk of complications of pregnancy. E. Tubercle bacillus readily crosses the placenta. 7. One of the criteria for the diagnosis of congenital TB is the detection of TB lesions in the newborn within the first week after birth. Of the following, the first organ affected in congenital TB is the neonatal: A. Brain. B. Heart. C. Kidney. D. Liver. E. Lung. NeoReviews Vol.10 No.8 August 2009 e401

8 Treatment of Latent Tuberculosis Infection Michael Kessler and James F. Smith, Jr NeoReviews 2009;10;e396-e401 DOI: /neo.10-8-e396 Updated Information & Services Permissions & Licensing Reprints including high-resolution figures, can be found at: s;10/8/e396 Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: Information about ordering reprints can be found online: