|Year : 2012 | Volume
| Issue : 2 | Page : 208-211
Multidrug-resistant tuberculosis in children from 2003 to 2005: A brief report
Department of Pediatrics, B.J. Wadia Hospital for Children, Mumbai, Maharashtra, India
|Date of Submission||15-Jan-2012|
|Date of Acceptance||09-Mar-2012|
|Date of Web Publication||28-May-2012|
Department of Pediatrics, B.J. Wadia Hospital for Children, Mumbai, Maharashtra
Multidrug-resistant tuberculosis (MDR-TB) has rarely been reported from children in India. Their response to therapy is also not known. We present four HIV-negative children with MDR-TB (3 children with extra-pulmonary TB and 1 child with pulmonary TB) who presented in 2003-2005. All the four children were already on antituberculous therapy (ATT) for 3-9 months prior to being detected as MDR-TB. These patients were started on second-line ATT for 18 months. In three patients, there was complete resolution, and one patient with severe bilateral pulmonary TB had the disease localized to one lung after 18 months of therapy.
Keywords: Children, drug-resistant TB, multidrug-resistant tuberculosis, tuberculosis
|How to cite this article:|
Shah I. Multidrug-resistant tuberculosis in children from 2003 to 2005: A brief report. Indian J Med Microbiol 2012;30:208-11
|How to cite this URL:|
Shah I. Multidrug-resistant tuberculosis in children from 2003 to 2005: A brief report. Indian J Med Microbiol [serial online] 2012 [cited 2014 Dec 19];30:208-11. Available from: http://www.ijmm.org/text.asp?2012/30/2/208/96694
| ~ Introduction|| |
Tuberculosis (TB) is still a major health concern worldwide and the main cause of death by a single infectious agent, namely Mycobacterium tuberculosis (MTB). The disease spreads more easily in overcrowded settings and in the conditions of malnutrition and poverty, characteristics typical of developing countries. In 2010, it was estimated that 8.8 million incident TB cases occurred in the world. Out of the 12 million prevalent TB cases, around 650,000 were estimated to be multidrug-resistant.  According to World Health Organization [WHO], the prevalence of multidrug-resistant TB [MDR-TB] is below 4% among previously untreated patients and 69-100% in previously treated patients in six districts in India.  However, it is difficult to conclude on global or regional trends in MDR-TB incidence as a result of incomplete data on the frequency of MDR among TB cases. For some countries (e.g., Latvia, USA) and regions (e.g., Orel and Tomsk in the Russian Federation), time trends based on observations over several years indicate a decrease in MDR-TB frequency of late, while in others (e.g., Botswana and Swaziland) there appears to be an increase.  Another cause of concern is that the highest frequencies of MDR-TB ever reported occurred in recent years. In countries like Belarus and parts of the Russian Federation, more than a quarter of new TB cases now have MDR-TB. Swaziland reported the highest level of primary MDR ever reported in Africa in 2009 [7.7%].  However, over 60% of newly diagnosed MDR-TB in 2010 occurred in China, India, the Russian Federation and South Africa alone ("RICS" countries).  Data on drug-resistant TB in children is lacking. Given the fact that childhood TB represents at least 10-20% of the total cases in areas with poor epidemic control, this translates into a minimum global estimate of around 40,000 paediatric cases of MDR-TB per year.  Treatment of MDR-TB is longer, more complicated and less effective than for drug-susceptible TB. We present four HIV-negative children with MDR-TB proven on phenotypic drug-susceptibility testing after culture of MTB on broth (Bactec culture) and solid media (Lowenstein-Jensen) who presented from 2003-2005 and their response to antituberculous therapy (ATT).
A 5-year-old boy presented in April 2005 with fever, recurrent joint swellings and anorexia for 9 months. He had been investigated for the same by a private practitioner and in view of positive Mantoux test with high ESR [143 mm at end of 1 hour], he was started on three drug ATT consisting of INH, Rifampicin, Pyrazinamide [HRZ] since 3 months but there was no clinical improvement. The physician subsequently added ciprofloxacin for the past 1 month. On examination, his weight was 11 kg, had generalized lymphadenopathy and no joint swelling. Investigations are depicted in [Table 1]. ANA, ds-DNA, RA factor were negative. X-Ray Chest showed hilar lymphadenopathy with paraxial haziness on the right side. Ultrasound of abdomen showed multiple enlarged lymph nodes in mesentery, peripancreatic and para-aortic region with largest measuring 0.6 × 1.6 cm. Barium meal follow through showed jejunal mucosal spikes suggestive of TB. In view of suspected drug resistance, he was treated with HRZS (H=isoniazid; R=rifampicin; Z=pyrazinamide; S=streptomycin), Ethambutol (E) and Ciprofloxacin was continued along with steroids for intestinal involvement pending culture report from the axillary lymph node biopsy. An axillary lymph node biopsy was done; however, it showed only reactive lymphadenitis. Steroids were tapered and stopped over a period of 2 months and ATT was shifted to four drugs (HRZE) as per Consensus Statement of IAP Working Group for TB 1997 guidelines.  In July 2005, he again presented with fever for 15 days. On investigation, his X-ray chest was the same and ultrasound (USG) abdomen still showed the presence of lymph nodes. CT abdomen showed multiple large mesenteric lymph nodes. An abdominal lymph node biopsy was done that showed caseating granulomas that grew MTB and sensitivity showed resistant to HRE. The child was started on ZS, PAS and Ethionamide (Eth). Streptomycin was omitted after 3 months and remaining drugs were stopped after 18 months of therapy.
|Table 1: Clinical and treatment profi le of children with multi-drug resistant tuberculosis|
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A 5-year-old boy presented with fever for 2 months in January 2005. MT was positive and USG abdomen showed lymphadenopathy. Investigations are depicted in [Table 1]. He was started on four drugs ATT consisting of HRZE for 2 months and then switched to continuation phase of two drugs ATT consisting of HR. In May 2005, he again started having fever. A repeat ultrasound of abdomen showed multiple lymph nodes [largest being 2 cm]. He was shifted to HRZES as per IAP guidelines. Lymph node biopsy grew MTB resistant to HRS. He was started with ATT consisting of ZE, PAS, Eth, Ofloxacin (Ofx) and Para-amino salicylic acid [PAS]. The ATT duration and course is depicted in [Table 1]. ATT was stopped after 18 months and ultrasound abdomen showed complete regression of the lymph nodes.
A 13-year-old girl on ATT for 3 months in view of gluteal abscess which on histopathology was suggestive of TB presented in March 2005 with right submandibular lymphadenopathy for 7 days. She was shifted to HRZES as per IAP guidelines. Lymph node biopsy culture grew MTB that was resistant to HRE. She was started on ZS, PAS, Eth, Ofx. ATT course and duration is depicted in [Table 1]. ATT was stopped after 18 months and the child put on 14 kg weight.
A 9-year-old boy presented with productive cough and breathlessness for 2 months in June 2003. He was diagnosed as pulmonary TB in view of left-sided consolidation and positive MT in April 2002 for which he had received ATT [2HRE/7HR] for 9 months by the referring physician. However, chest X-ray remained the same. On examination, he had decreased air entry on left side with flattening of left side of chest with bronchial breathing. He was malnourished with a weight of 19 kg. HRCT chest was done in June 2003 and is depicted in [Table 1]. Bronchoalveolar lavage [BAL] was done and pending culture reports, he was shifted to HRZES as per IAP guidelines. Culture grew MTB that was resistant to HRS. He was started on ZE, PAS, Eth, Ofx and Kanamycin. ATT course and duration is depicted in [Table 1]. At end of 18 months, he had only left upper lobe consolidation, had a weight gain of 4 kg and was not having cough. He was advised left upper lobe lobectomy which parents refused and subsequently child was lost to follow-up.
| ~ Discussion|| |
MDR-TB is defined when TB bacilli are resistant to at least INH and rifampicin.  Resistance may be primary in a patient without prior treatment or secondary where the TB bacilli were initially drug susceptible, but develop resistance during the course of ATT. In children, MDR-TB is usually primary drug resistant and infection is usually from a contact that has resistant TB.  However, in all our patients, close contacts tested negative for TB and all patients had been on ATT ranging from 3 months to 9 months prior to detection of MDR-TB suggesting that it may be secondary resistance. Such resistance can occur due to prescription of inadequate drugs, use of sub-standard drugs, addition of only one extra drug to a failing regimen, use of drugs of unproven bioavailability, poor compliance, failure to recognize resistance, diabetes, HIV, extremes of age, alcohol and drug abuse and mental illness.  In none of our patients, we could elicit any of the above-mentioned factors. Thus, the cause of resistance remained unknown except maybe failure to recognize resistance early.
Second-line ATD used in treatment of MDR-TB include aminoglycosides, thioamides, fluoroquinolones, cycloserine and PAS.  The optimal duration of MDR-TB treatment in children remains unknown; current recommendations are based on personal experience and expected efficacy of various second line drugs. WHO in 2003 stated a standardized re-treatment regimen should have treatment duration of 18 months after first negative culture.  Because children often have paucibacillary disease, shorter duration of treatment [12 months] may be sufficient.  The fluoroquinolones include ciprofloxacin, ofloxacin, levofloxacin and moxifloxacin. Although ciprofloxacin has been used in the late 1990s for treatment of TB due to in vitro sensitivity,  it has been found to be less effective than the other quinolones and therefore is not recommended for use now for treatment of drug resistant TB.  We prescribed an individualized regimen in our patients with shorter duration of therapy of PAS and injectable due to intolerance to these medications and quinolones of shorter duration of 8 months and three patients improved and one with extensive pulmonary TB had localization to left upper lobe only. Around the globe at the same time, Schaaf et al. in South Africa reported a prevalence of 6.5% of MDR TB in 2003-2005 in children <13 years of age at Tygerberg Children's Hospital.  In India, we recently presented a case series of partial XDR in children.  In a study from Saudi Arabia, Alrajhi et al.  showed that history of previous ATT was the only risk factor associated with DR-TB. Similarly, all our patients had been on ATT for variable period of time previously and that may have been a risk factor for the drug resistance in them.
However, now with increasing resistance to ethambutol, pyrazinamide and ofloxacin resistance being reported in 2007  as compared to 2001 and with subsequent emergence of XDR [extensively drug resistant] TB, WHO issued an emergency update on treatment guidelines in 2008 for MDR and XDR-TB.  Now with total drug resistant (TDR) TB reported in India,  the situation is now grim and physicians need to keep a high index of suspicion of DR-TB in children and ensure adequate and proper therapy.
| ~ Conclusion|| |
MDR-TB in children requires early suspicion, prompt diagnosis and aggressive treatment with combination second-line ATD which may be life-saving. A child should be considered at risk for MDR-TB if there is clinical and/or radiological progression of TB in spite of chemotherapy and history of previous treatment for tuberculosis.
| ~ References|| |
|1.||World Health Organization (WHO) Global Tuberculosis Control Report 2011. Available from: http://www.who.int/tb/publications/global_report/2011/gtbr11_full.pdf. [Last accessed on 2012 Mar 8 th ]. |
|2.||TB India 2003, Revised National Tuberculosis Control Program (RNTCP) Status Report. p. 46. |
|3.||STOP TB. Available from: http://www.stoptb.org/wg/mdrtb/assets/documents/MDR_tuberculosis_2011update.pptx. [Last accessed on 2012 Mar 8 th ]. |
|4.||Seddon JA, Hesseling AC, Marais BJ, McIlleron H, Peloquin CA, Donald PR, et al. Paediatric use of second-line anti-tuberculosis agents: A review. Tuberculosis 2012;92:9-17. |
|5.||Consensus statement of the IAP working group: Treatment of childhood tuberculosis. Indian Pediatr 1997;34:1093-6. |
|6.||Crofton J. Multidrug resistance: Danger for the Third World. In: Porter JD, McAdam KD, editors. Tuberculosis Back to the Future. Chichester: John Wiley and Son Ltd.; 1994. p. 231-3. |
|7.||Starke JR. Current chemotherapy for tuberculosis in children. Pediatr Clin North Am 1992;6:215-39. |
|8.||Sharma S. Drug resistant tuberculosis in India. In: MDR Infection in Children - Tuberculosis. Ganguly N, Kundu R, Ghosh TK, editors. New Delhi: CBS Publishers; 2007. p. 42-60. |
|9.||World Health Organization (WHO). Treatment of Tuberculosis: Guidelines For National Programmes. Available from: http://whqlibdoc.who.int/hq/2003/who_cds_tb_2003.313_eng.pdf. [Last accessed on 2005 July 1]. |
|10.||Schaaf HS. Drug-resistant tuberculosis in children. S Afr Med J 2007;97:995-7. |
|11.||Bergstermann H, Rüchardt A. Ciprofloxacin once daily versus twice daily for the treatment of pulmonary tuberculosis. Infection 1997;25:227-32. |
|12.||Caminero JA, Sotgiu G, Zumla A, Migliori GB. Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Lancet Infect Dis 2010;10:621-9. |
|13.||Shah I, Rahangdale A. Partial extensively drug resistance (XDR) tuberculosis in children. Indian Pediatr 2011;48:977-8. |
|14.||Alrajhi AA, Abdulwahab S, Almodovar E, Al-Abdely HM. Risk factors for drug-resistant Mycobacterium tuberculosis in Saudi Arabia. Saudi Med J 2002;23:305-10. |
|15.||Pillay M, Sturm AW. Evolution of the extensively drug-resistant F15/LAM4/KZN strain of Mycobacterium tuberculosis in KwaZulu-Natal, South Africa. Clin Infect Dis 2007;45:1409-14. |
|16.||World Health Organization (WHO). Guidelines for the programmatic management of drug-resistant tuberculosis. Emergency Update 2008. Available from: http://whqlibdoc.who.int/publications/2008/9789241547581_eng.pdf. [Last accessed on 2009 Jan 1]. |
|17.||Udwadia ZF, Amale RA, Ajbani KK, Rodrigues C. Totally Drug-Resistant Tuberculosis in India. Clin Infect Dis 2012;54:579-81. |