|Home | About | Journals | Submit | Contact Us | Français|
We report a case of rapidly progressive miliary tuberculosis in a 21-month old HIV-infected girl exposed to tuberculosis, despite early access to highly active antiretroviral therapy and proven adherence to isoniazid chemoprophylaxis. Post mortem revealed multidrug-resistant tuberculosis. This case report illustrates the consequences of inadequate programmatic management of children exposed to an adult case of sputum smear-positive multidrug-resistant tuberculosis. Drug susceptibility testing of the adult source case should become standard of care for all children who have been in close contact with a case of sputum smear-positive tuberculosis, and the choice of chemoprophylactic agents should be based on the sensitivities of the source case organism.
Tuberculosis (TB) is a major cause of mortality and morbidity in children under 5 years of age in the developing world1. Human immunodeficiency virus (HIV) infection increases the risk of TB disease significantly2. Drug-resistant TB is increasing, both due to poor management of TB cases and due to transmission of drug-resistant organisms. Contact tracing and chemoprophylaxis are especially important in preventing childhood TB3. We report a case of rapidly progressive miliary TB in a 21-month old HIV-infected girl despite reliable adherence to isoniazid (INH) chemoprophylaxis and early access to highly active antiretroviral therapy (HAART).
During pregnancy, the patient’s mother was identified as HIV-infected and managed in the vertical transmission prevention program. She received zidovudine (ZDV) monotherapy for six weeks prior to delivery. The baby was born at 40 weeks gestation by normal vertex delivery and received ZDV for one week after delivery along with single dose nevirapine. She received Bacille Calmette-Guérin (BCG) vaccination intradermally at birth, and developed a normal skin reaction. Nevertheless, the infant’s HIV DNA polymerase chain reaction (PCR) was positive at 8 weeks of age. She was started on co-trimoxazole and recruited into the Children with HIV Early Antiretroviral therapy (CHER) trial4. The patient’s mother gave written informed consent to participate in the trial, which was approved by the Committee for Pharmaceutical Trials of Stellenbosch University and the Medicines Control Council of South Africa. The infant commenced ZDV, lamivudine, and lopinavir/ritonavir at 9 weeks of age. Baseline HIV RNA viral load was 218 000 copies/ml, and CD4 count was 3226 × 106 cells/L (34.6%).
At the age of 3 months, her mother reported that the maternal grandmother had recently been started on TB treatment. The infant was therefore evaluated for TB. The chest radiograph (CXR) showed suspicious perihilar lymphadenopathy and perihilar infiltrate (Figure 1). The Mantoux tuberculin skin test (TST) showed induration of 2mm at 48 hours (negative), and two early morning gastric aspirates were culture-negative. No drug susceptibility test (DST) result was found for her grandmother. She was given standard three-drug TB treatment (INH, rifampicin and pyrazinamide) from 3 until 9 months of age as per the South African National TB Programme guidelines. Calculated adherence on HAART and TB therapy remained reliably above 95%. Her CD4 count remained above 1000 × 106 cells/L and above 20% throughout her course. An end-of-treatment CXR was not performed.
Her CD4 count taken during a routine visit at 16 months of age was 2235 × 106 cells/L (33.0%). At that visit, her mother revealed that the child may have been exposed to TB when she had gone to stay with her father in Hermanus outside of Cape Town. The TB workup revealed the following: Mantoux TST showed no induration; two gastric aspirates did not culture mycobacteria; CXR showed a small area of opacification in the left base, but no perihilar lymphadenopathy (Figure 2). She was diagnosed with a mild left basal pneumonia and was admitted for intravenous antibiotics. C-reactive protein levels were normal. She recovered quickly after receiving 24 hours of intravenous ampicillin and gentamicin, and was discharged to complete a five day course of oral amoxicillin at home. She was completely recovered one week later. Since there was no evidence of current TB disease, she was commenced on INH chemoprophylaxis. INH adherence was confirmed on clinic records.
At the age of 21 months, the child died unexpectedly. No obvious cause of death was noted by the medical personnel on the scene.
A forensic post-mortem performed two weeks after death revealed TB bronchopneumonia with miliary spread, particularly to the spleen. Unfortunately, since all post-mortem specimens were placed in formalin and subsequently paraffin-embedded, mycobacterial culture could not be performed. Bacterial DNA was extracted from the paraffin-embedded tissue using the NucliSENS DNA purification kit (bioMérieux, France). Subsequent analysis using the GenoType® MTBDRplus assay (Hain Lifescience, Germany) confirmed Mycobacterium tuberculosis complex and revealed a mutation in codon 315 of the katG gene, conferring resistance to high-dose INH. The results for the rpoB loci were too feint to analyse by the GenoType® MTBDRplus assay, therefore, the Rifampicin Resistance Determining Region (RRDR) of the rpoB gene was re-evaluated by sequencing analysis as previously described5. This sequencing primer is specific to M. tuberculosis complex5. Alignment of the DNA sequence to the H37Rv fully susceptible laboratory strain showed a G to C transversion in codon 531, conferring resistance to rifampicin6. Additional sequencing was performed on the embB gene and a G to A transition was identified in codon 315, indicating ethambutol resistance. Molecular genotyping therefore confirmed multidrug-resistant TB (MDR-TB) and resistance to ethambutol. Testing for resistance to aminoglycosides and flouroquinolones was not performed. Both the Hain MTBDRplus assay and the specificity of the RRDR primer confirmed that the isolate being tested was M. tuberculosis complex and not a non-tuberculous mycobacterium (NTM). These assays are not able to differentiate M. tuberculosis from M. bovis.
Screening of household contacts at the mother’s residence revealed a 12 year old female cousin with night-sweats, marked weight-loss and significantly productive cough for the previous six months. Her sputum was smear-positive for acid-fast bacilli. Culture revealed a fully susceptible M. tuberculosis strain on sputum culture and on fine needle aspirate biopsy of a lymph node. She was admitted to an in-patient TB hospital in Cape Town. All other household contacts tested negative for pulmonary TB. Household contacts at the father’s residence in Hermanus could not be traced for testing.
The father of the index case was first diagnosed with pulmonary TB at a local clinic in Cape Town when the index case was 9 months old. Microscopy of his sputum showed 3+ acid-fast bacilli (AFB) and cultured M.tuberculosis, however drug susceptibility testing was not performed. He was started on standard 4-drug TB therapy but defaulted.
One month after the index case had died, the father presented to a primary care clinic in Hermanus outside of Cape Town. At that assessment, his sputum showed 3+ AFB and cultured M.tuberculosis. However DST was again not requested even though the South African National TB Programme guidelines require DST in cases of retreatment due to previous non-compliance. Clinic staff empirically started him on regimen 2 (INH, rifampicin, pyrazinamide, ethambutol and streptomycin) because of his previous non-compliance. Clinic records confirmed daily attendance and adherence to TB therapy.
A chest radiograph (CXR) was performed six months after starting regimen 2 because he was still severely symptomatic (productive cough, weight loss and night sweats). His CXR showed multiple cavities in his right upper lobe with bronchiectatic changes, and a right pleural effusion. This occurred despite documented directly observed compliance on regimen 2 for six full months. For the first time, his sputum was sent for TB culture and DST. Unfortunately, multiple sputum specimens did not culture M.tuberculosis, and therefore routine DST could not be done. Since he continued to deteriorate, and since his child had been proven to have had MDR-TB, he was empirically started on an MDR regimen (kanamycin, pyrazinamide, ofloxacin, ethambutol, ethionamide). Unfortunately he experienced significant side-effects and his MDR-TB regimen had to be interrupted. Team discussion regarding the possibility of a right pneumonectomy concluded that he was not a suitable candidate. He remains chronically breathless.
Despite knowing of an adult TB source case and having a high index of suspicion, TB remains a difficult diagnosis in HIV-infected children. In particular, children presenting with miliary TB have relatively few signs, such as weight loss, tachypnoea and hepatosplenomegaly, which could easily be attributed to other causes. HIV-infected children have a significantly higher risk of recurrent TB7. HAART reduces the risk for TB, but the risk remains higher than in HIV-uninfected children8. Even after immune reconstitution, the specific immune response to TB remains impaired. It has been shown that in the context of HIV, recovery of M. tuberculosis-specific Th-1 cells occurs far more slowly than the recovery of other specific Th-1 responses9.
Since no HIV viral loads were performed on this child after the initiation of HAART, it is possible that viral suppression may have been suboptimal despite a reasonable CD4 count and good calculated adherence. She may therefore have been more susceptible to TB infection and disease after exposure.
The child’s drug resistance may have developed in several possible ways:
Primary infection with MDR-TB is likely to significantly reduce the effectiveness of INH chemoprophylaxis. Failure of INH chemoprophylaxis represents a major threat to the effectiveness of national TB control programs. Children under 5 years of age or HIV-infected children of any age who are exposed to sputum-positive TB should receive a six month course of INH, or alternative regimen, in order to prevent disease after TB infection3. However, since children are not perceived as a public health threat, overburdened clinics often neglect to trace and provide chemoprophylaxis to the pediatric contacts of adult cases. In a retrospective study of 596 children with culture-confirmed tuberculosis in Cape Town, of the 182 children under 5 years of age with a known adult TB source case 117 (64%) had received no chemoprophylaxis2. Unfortunately, in this case the child died from overwhelming TB disease despite being started on INH chemoprophylaxis by the consulting clinician.
Chemoprophylaxis against MDR-TB is difficult. The World Health Organization recommends that prophylaxis against MDR-TB should be the same as for that of drug-susceptible TB10. However, Sneag et al showed that INH chemoprophylaxis is inadequate to prevent MDR-TB in children exposed to MDR-TB contacts11. In a review of paediatric MDR cases, Schaaf et al showed that when the DST results of the adult source case’s organism were not known, there was a delay of 8 months in starting an effective drug regimen, resulting in significant morbidity and mortality12.
Studies are needed to determine the optimal chemoprophylaxis regimens for exposure to drug-resistant M. tuberculosis. This is especially true in children, for whom TB drug options are limited. The choice between chemoprophylaxis and full treatment is often difficult, since the diagnosis of TB disease in children is challenging, particularly in resource limited settings. Once the choice between chemoprophylaxis and treatment has been made, the choice of anti-tuberculosis drugs relies heavily on the drug susceptibility result of the adult source case’s organism. There is evidence to suggest that, in the context of MDR-TB, chemoprophylaxis with at least two drugs to which the adult source case’s organism is susceptible is more effective than standard INH chemoprophylaxis13. DST needs to be done on all patients with culture-positive isolates.
This child’s death was related to an inadequate programmatic response to a known case of PTB. Diligent contact tracing and DST must become routine in all centers if the spread of drug-resistant TB is to be controlled. We recommend that DST be done in all patients with a positive smear or culture for M.tuberculosis. Confirmation of the DST result of the adult source case should become the standard of care for all children who have been in close contact with a case of sputum smear-positive TB.
Financial support: National Institute of Allergy and Infectious Diseases (NIAID) of the US National Institutes for Health (NIH), through the Comprehensive International Program of Research on AIDS (CIPRA) network, grant number U19 AI53217. In addition, financial support was received from the Departments of Health of the Western Cape and of Gauteng, South Africa, as well as GlaxoSmithKline plc. The content of this publication does not necessarily reflect the views or policies of NIAID, nor does mention of trade names, commercial projects, or organizations imply endorsement by the US Government. The study was also conducted as an Investigational New Drug (IND) Number: IND 71,494 under the supervision of the Food and Drug Administration. HS Schaaf received funding from a Fogarty Center grant (grant number U2RTW007370/3).
The authors have no commercial or other association that might pose a conflict of interest.