PEDIATRICS Vol. 121 No. 6 June 2008, pp. e1732-e1733 (doi:10.1542/peds.2007-2773)
EXPERIENCE & REASON |
Unintended Consequences: Mandatory Tuberculin Skin Testing and Severe Isoniazid Hepatotoxicity
a Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia
b Department of Pediatrics, Baylor College of Medicine, Houston, Texas
ABSTRACT
After mandatory school-enrollment tuberculin skin testing, a 4-year-old girl who was at low risk for Mycobacterium tuberculosis infection had severe isoniazid hepatotoxicity that was managed with a liver transplant. Although severe isoniazid hepatotoxicity is very uncommon in children, this case emphasizes the need to limit skin testing to persons who have a risk factor for infection and to educate parents on how to monitor for adverse effects during treatment.
Key Words: latent tuberculosis infection • prevention • tuberculin skin test • isoniazid • hepatotoxicity • liver transplantation
Abbreviations: TST, tuberculin skin test • LTBI, latent tuberculosis infection • AAP, American Academy of Pediatrics • CDC, Centers for Disease Control and Prevention
Tuberculin skin testing is the principal method for detecting latent tuberculosis infection (LTBI). The American Academy of Pediatrics (AAP) and the Centers for Disease Control and Prevention (CDC) discourage universal or administrative skin testing for school entry.1,2 Both organizations recommend screening for the risk of Mycobacterium tuberculosis infection by using a questionnaire and testing only those children who are at risk.
Isoniazid is the standard for treating LTBI and preventing tuberculosis disease. The generally low likelihood of hepatotoxicity, a recognized hazard of isoniazid, increases with age, and isoniazid is regarded to be safe for children. However, severe hepatotoxicity (including fatalities) has been reported for patients in all age groups.3,4
CASE REPORT
The patient was a healthy US-born black girl aged 4 years 8 months who was HIV-negative at the time of her hospital admission. She had never traveled outside the United States and had no known exposure to anyone who had tuberculosis disease. Her school district required a tuberculin skin test (TST) for registration in school. The skin test was administered at a primary care clinic, with a result of 12 mm of induration, and her chest radiograph was interpreted as normal. Her mother received a drug-information sheet and a prescription for isoniazid 150 mg per day (9 mg/kg per day). To determine if any adult had tuberculosis disease, the health department performed an investigation at the home; all 4 persons were healthy, each with a skin-test result of 0 mm induration. All the adults were free of tuberculosis symptoms at the day care center that the patient attended.
At the clinic follow-up appointment after 3 weeks of treatment, the mother reported that the patient was taking isoniazid without problems. After 11 weeks of treatment, the mother brought the patient back because of a week of episodic vomiting, irregular appetite, pale stools, and progressive abdominal pain along with 4 days of yellowing of the eyes. The mother attributed the initial symptoms to "stomach flu." The patient had a temperature of 99.1°F, scleral icterus, abdominal tenderness, and a tender, enlarged liver palpable 3 cm below the right costal margin. The patient was not taking any medications, other than isoniazid, that may have contributed to her hepatitis.
The patient had blood test results indicative of severe liver injury (aspartate transaminase: 4795 U/L; alanine transaminase: 3580 U/L; total bilirubin: 9.0 mg/dL), and she was referred for hospital admission. Test results were negative for hepatitis A, B, and C viruses, cytomegalovirus, Epstein-Barr virus, herpes simplex viruses 1 and 2, parvovirus B19, and toxoplasmosis. Other negative or normal test results included serum 
-1 antitrypsin, antinuclear antibody, anti–smooth muscle antibody, and ceruloplasmin. The patient's liver function deteriorated, and she was moved to a transplantation center, where she received a cadaveric liver.
DISCUSSION
This patient received a TST because of an administrative requirement for school entry. The small likelihood of infection would have argued against skin testing for medical reasons. Health departments and school districts should collaborate to review and revise their policies so that skin testing, if required at all, is relevant to individual tuberculosis risk factors and public health indications. The AAP, American Thoracic Society, and CDC have long recommended against universal skin testing for school entry. One study showed that targeting at-risk school children for tuberculosis testing is more cost-effective than universal testing.5 More recently, a cost-effectiveness analysis of children entering kindergarten demonstrated the benefit of testing only children at risk for LTBI.6
When the pretest probability of M tuberculosis infection is as low as it is for most US children, the predictive value of a positive TST result may be as low as 10%.7 The other 90% represent falsely positive results (eg, infection from mycobacterium other than tuberculosis), subjecting families to unwarranted burdens and unnecessarily introducing the hazard of serious adverse treatment effects. The recommendation to use a risk-stratified interpretation of skin-test results (to increase the specificity of the test) was not applied for this patient.1,2 For an individual with no tuberculosis risk factors, a threshold of 15 mm could be considered to be a positive TST result.8
The AAP, American Thoracic Society, and CDC recommend against routinely measuring serum transaminase concentrations at the start of isoniazid treatment or subsequently, but these organizations also advise scheduling monthly clinic visits for treatment supervision and limiting isoniazid prescriptions to the number of doses needed between clinic visits.1,8 Isoniazid was being given to this child for 1 week beyond the onset of hepatitis symptoms, which is a probable exacerbating factor that has been noted in other reports of severe liver injury.4 Health care providers who prescribe treatment for LTBI should clinically monitor patients on a monthly basis to ensure early detection and evaluation of possible adverse drug effects. More importantly, at each visit parent education should be reinforced, including giving the parent or guardian a written summary of possible adverse effects and what to do in the event that a possible adverse event occurs.9 Because severe hepatotoxicity and death have been associated with continued treatment after the onset of clinical signs of hepatitis, parent education should emphasize stopping therapy if any possible adverse effects are noted.10,11
CONCLUSIONS
General pediatricians and specialists who care for children with possible LTBI should perform a tuberculosis risk assessment to determine if a child should have a TST administered. Lacking a risk or clinical presentation of disease consistent with tuberculosis, TST should not be administered. However, once TST is performed, the correct interpretation based on standard criteria should be used. Standards of treatment include monthly clinical monitoring and parent education regarding the need to stop treatment at the onset of signs and symptoms of possible hepatotoxicity, which are important interventions for avoiding serious adverse drug effects.
FOOTNOTES
Accepted Nov 26, 2007.
Address correspondence to Mark N. Lobato, MD, Connecticut Department of Public Health, 410 Capitol Ave, MS 11-TUB, PO Box 340308, Hartford, CT 06134. E-mail: mark.lobato{at}ct.gov
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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