Tuberculosis (TB) caused by mycobacteria of the Mycobacterium tuberculosis complex (MTBC) remains a global health problem with a high mortality rate despite effective therapeutics. In 2015, the World Health Organization (WHO) reported more than 10 million incident cases worldwide, of which nearly 1 million pediatric cases. The recent emergence of first-line drugs-resistant Mycobacterium tuberculosis strains (rifampin, also referred to as rifampicin [RMP] and isoniazid [INH]) is a growing and concerning problem. Approximately 30,000 children develop multidrug-resistant tuberculosis (MDR-TB) worldwide each year. Cases of MDR-TB in children are a sentinel event indicating the active circulation of resistant mycobacterial strain(s) within a community. MDR-TB is preceded by LTBI, and systematic treatment is recommended for children <5 years of age and on a case by case basis when older. However, there are no specific recommendations for management of resistant strains. Screening and follow-up of pediatric contact subjects are key points of TB management. In addition, very few studies have been conducted on the pharmacokinetic and pharmacodynamic properties of these drugs in the pediatric setting. We report herein the case of a 10-year-old child treated for LTBI with a regimen including a fluoroquinolone (FQ) and PZA, after contact with a smear-positive MDR TB adult, and who subsequently developed fulminant hepatitis over the course of LTBI treatment.
Upon investigation of a MDR-TB case, a 10-year-old boy living in the same household was diagnosed with LTBI.1,2 The child weighed 26 kg and was born in the Western African country Ivory Coast. He had been in close contact with his father, the smear-positive MDR TB index case. Immunologic tests were positive: tuberculin skin test (17 mm) and Interferon Gamma Release Assay (IGRA; quantiFERON-TB Gold, QUIAGEN, Hilden, Germany). The child was asymptomatic and free of chest radiography abnormality. Upon diagnosis, the child had no comorbidity, and pretreatment biologic screening including liver function was normal. After a multidisciplinary discussion between pediatric pulmonologists, infectious disease physicians and the French National Reference Center of Mycobacteria, LTBI treatment was advised. The index case drug genotypic analysis had evidenced a mutation of rpoB gene (resistance to RMP) and of katG gene (high level of resistance to INH) later confirmed by phenotypic drug susceptibility testing (DST). A 6-month period of therapy combining FQ (levofloxacin: 15 mg/kg/day) and PZA (25 mg/kg/day) was initiated with extemporaneous formulation of 400 and 650 mg capsules, respectively.
At 1-, 3- and 4-months after treatment initiation, clinical and laboratory monitoring of the patient did not detect any abnormality. The mother-supervised adherence was satisfactory. At 5.5 months (ie, 199 days of treatment), the patient developed asthenia and scleral jaundice, without other signs nor symptoms. According to the parents, he did not take any other treatment including homeopathic drugs nor herbal/dietary supplements. Laboratory data evidenced acute liver failure with cytolysis [aspartate aminotransferase (AST) = 691 IU/L (20 N) and alanine aminotransferase (ALT) 963 IU/L (27 N)] and cholestasis (total bilirubin = 291 μmol/L, conjugated bilirubin 132 μmol/L, and gamma glutamyl transferase 137 IU/L)]. The child was transferred to the pediatric emergency ward, and additional laboratory tests found severe coagulation disorders compatible with acute liver failure [prothrombin (PT) 30% and factor V = 45%].
The patient was admitted to the pediatric intensive care unit. Anti-TB treatment was promptly discontinued. The patient developed clinical encephalopathy, confirmed by electroencephalograms. The main etiologies of acute liver failure were methodically excluded one by one: autoimmune, genetic, metabolic and infectious. For the latter, viral loads were negative for Adenovirus, Parvovirus B19 and Varicella zoster virus. Qualitative tests (PCR: Polymerase Chain Reaction) were negative for Herpessimplex virus 1–2, enteroviruses and Hepatitis E virus. Serology for Cytomegalovirus, hepatitis A-B-C virus, Epstein-Barr virus, HIV and Human herpesvirus 6 were all negative or showed immunization. Histopathology analysis of liver percutaneous biopsy found nonspecific submassive necrosis of the parenchyma with inflammatory portal infiltrate and areas of plasmocytes infiltration compatible with a toxic cause (Figure 1).
The pharmacovigilance unit concluded that anti-TB treatment was responsible for the acute liver failure, and probably more related to PZA than levofloxacin with data collected at the national pharmacovigilance. After discontinuation of treatment, the patient spontaneously and gradually recovered from encephalopathy. Liver failure reversed and blood factor V returned to baseline within 10 days. Anti-TB treatment was not restarted. The child was discharged from hospital at day 12, and all laboratory parameters normalized over the course of subsequent follow-up. Two years later, the patient is asymptomatic without any apparent sequelae.
This case highlights the toxicity of second-line anti-TB treatment in children. Fulminant hepatitis occurred after 6 months of well-tolerated treatment (without cytolysis until four months after initiation); this suggests that prolonged treatment may have played a role in the occurrence of severe hepatotoxicity. The first reports of PZA toxicity in adults were published in the 1950–1960s.3 The mechanism of hepatotoxicity remains unclear (dose-dependent or idiosyncratic).4 However, only one pediatric case report has described hepatotoxicity of PZA and in the absence of FQ: in 1987, a case of fulminant hepatitis in a 10-year-old girl with cervical lymph node TB treated by RMP, ethambutol (EMB) and PZA was reported; she initially received RMP associated with EMB and INH but she developed liver disorders 2 weeks after initiation leading to switch INH to PZA. Six weeks later, she died of fulminant hepatitis that was finally attributed to PZA.5
In cases reported in adults, PZA was often associated with FQ as was the case herein. In the study reported by Horn et al6, 16 adults were treated with ofloxacin and PZA for LTBI after MDR-TB contact in a medical institution: 14 discontinued prophylaxis after adverse effects, of whom four had hepatitis. Papastavros et al7 evaluated adverse events of the association FQ-PZA in 17 adults with LTBI: 5 patients had liver enzymes abnormalities and the combination PZA-FQ was considered to be probably responsible for this adverse event. Regarding pediatric cases in the study reported by Adler-Shohet et al8, 26 children started treatment with PZA and levofloxacin for MDR-LTBI: 8 patients had elevated liver enzymes, including 5 patients for whom PZA was discontinued and levofloxacin alone was continued; all children had complete resolution of adverse effects; 11 patients did not complete treatment, but none of the children developed TB disease during the 2 years follow up. Taken together, these studies highlight the hepatotoxic potential of a combination such as PZA-FQ in MDR-LTBI treatment. This must be carefully considered before deciding to introduce second-line anti-TB drugs in children.
In France, it is recommended to treat LTBI cases in children <15 years of age and to treat all children <2 years of age in contact with TB disease. However, there are no clear recommendations for children in contact with MDR-TB.9,10 The proposed treatment regimens are (1) close monitoring for 2 years with initiation of curative treatment if progression towards TB disease and (2) preventive treatment with second-line anti-TB drugs adapted to the index case strain.11 Each therapeutic strategy has its advantages and disadvantages. In particular, prolonged monitoring over a long period may be difficult to accept for some populations, resulting in loss to follow-up. Conversely, some families may require treatment because of the important risk of progression to active disease. In children <5 years of age, an interventionist strategy is more often proposed because of the higher risk to develop TB disease, but this case is an example of the severity of the adverse effects of anti-TB treatment. Once treatment is initiated, physicians must be vigilant about follow-up both during and after treatment completion. This late severe adverse effect raises the issue of cumulative toxicity of these drugs when administered over a long period of time.
In conclusion, in the absence of recommendations, physicians must be aware of the risk/benefit ratio of anti-TB second-line treatment in order to propose the best strategy for pediatric LTBI. If treatment is advised, close and prolonged monitoring should be performed due to the risk of adverse effects at any moment during the course of treatment, especially elevation of hepatic enzymes. The case presented herein highlights the hepatotoxicity of PZA-FQ combination. More studies are needed to evaluate the safety of these treatments and to standardize prescribing practices and monitoring recommendations.
1. Jenkins HE, Tolman AW, Yuen CM, et al. Incidence of multidrug-resistant tuberculosis
disease in children
: systematic review and global estimates. Lancet. 2014;383:1572–1579.
3. Girling DJ. The hepatic toxicity of antituberculosis regimens containing isoniazid, rifampicin and pyrazinamide. Tubercle. 1978;59:13–32.
4. Chang KC, Leung CC, Yew WW, et al. Hepatotoxicity of pyrazinamide: cohort and case-control analyses. Am J Respir Crit Care Med. 2008;177:1391–1396.
5. van Aalderen WM, Knoester H, Knol K. Fulminant hepatitis
during treatment with rifampicin, pyrazinamid and ethambutol. Eur J Pediatr. 1987;146:290–291.
6. Horn DL, Hewlett D Jr, Alfalla C, et al. Limited tolerance of ofloxacin and pyrazinamide prophylaxis against tuberculosis
. N Engl J Med. 1994;330:1241.
7. Papastavros T, Dolovich LR, Holbrook A, et al. Adverse events associated with pyrazinamide and levofloxacin in the treatment of latent multidrug-resistant tuberculosis
. CMAJ. 2002;167:131–136.
8. Adler-Shohet FC, Low J, Carson M, et al. Management of latent tuberculosis
infection in child contacts of multidrug-resistant tuberculosis
. Pediatr Infect Dis J. 2014;33:664–666.
9. Seddon JA, Godfrey-Faussett P, Hesseling AC, et al. Management of children
exposed to multidrug-resistant Mycobacterium tuberculosis
. Lancet Infect Dis. 2012;12:469–479.
10. Seddon JA, Hesseling AC, Finlayson H, et al. Preventive therapy for child contacts of multidrug-resistant tuberculosis
: a prospective cohort study. Clin Infect Dis. 2013;57:1676–1684.
11. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis
: emergency update 2008. 2008. Available at: http://www.who.int/iris/handle/10665/43965
. Accessed June 25, 2019.