|Year : 2015 | Volume
| Issue : 2 | Page : 199-202
Multidrug-resistant tuberculosis in children and response to therapy
Pediatric TB Clinic, Department of Pediatrics, B.J. Wadia Hospital for Children, Mumbai, Maharashtra, India
|Date of Web Publication||13-Mar-2015|
1/B Saguna, 271/B St Francis Road, Vile Parle (W), Mumbai - 400 056, Maharashtra
Source of Support: None, Conflict of Interest: None
There is very little information available on drug-resistant (DR) tuberculosis (TB) in children in Indian scenario and especially their response to therapy. We present a series of children who were suffering from multidrug-resistant-TB and their response to therapy.
Keywords: Children, multidrug-resistant tuberculosis, multidrug-resistant tuberculosis
|How to cite this article:|
Shah I. Multidrug-resistant tuberculosis in children and response to therapy. Med J DY Patil Univ 2015;8:199-202
| Introduction|| |
Tuberculosis (TB) remains one of the major public health problems in developing countries. India and China account for an estimated 35% of TB cases worldwide.  The current threat is the emergence of strains resistant to the two most potent anti-TB drugs viz., isoniazid (H) and rifampicin (R) (multidrug-resistant-TB [MDR-TB]). MDR-TB treatment response is poor and the mortality rate is high in adults though treatment outcome is better in children. , Reports from India on drug-resistant (DR)-TB in children are limited. , At our centre we have noticed an increasing number of children with DR-TB, both MDR and extensive DR-TB (XDR-TB; this implies MDR-TB as well as resistance to the fluoroquinolones and second-line injectable agents). From July 2007 to August 2010 we have identified 34 out of 500 (6.8%) children with DR-TB of which 3 had HIV infection and 14/34 (41.2%) had MDR-TB. Drug susceptibility testing (DST) was done in most children for 13 drugs: Isoniazid (H), rifampicin (R), pyrazinamide (Z), streptomycin (S), ethambutol (E), kanamycin (Km), amikacin (Amk), ofloxacin (Ofx), moxifloxacin (Mfx), p-aminosalicylic acid (PAS), ethionamide (Eth), clofazimine (Cfz) and capreomycin (Cm) using automated liquid broth media, by the Mycobacterial Growth Indicator Tube 960 system (Becton-Dickinson, Sparks, MD, USA). The DST was done at the Microbiology Laboratory of Hinduja Hospital which is National Accreditation Board for Testing and Calibration Laboratories certified and Revised National TB Control Programme accredited. The patients were put on treatment as per their DST reports. We present children with MDR-TB (data available until 2010) who have been on anti-TB therapy (ATT) and their response to therapy. Patients who have been lost to follow-up or those who have completed <10 months of treatment are excluded from this report.
| Case Reports|| |
A 10-year-old girl presented in November 2009 with bilateral submandibular adenopathy (4 cm × 4 cm on right side and 3 cm × 4 cm on left side) for 1-year. She had received first-line ATT in March 2009 for 6 months, however there was no response and she underwent lymphnode biopsy in October 2009. Histopathology showed epitheloid granulomas with caseous necrosis suggestive of TB. She was started on Category 2 retreatment regimen. Her culture grew Mycobacterium tuberculosis and DST showed resistance to HRZSE with susceptibility to Km, Amk, Ofx, Mfx, PAS, Eth, Cfz and Cm. She was then started on Amk, Ofx, Eth, Cs and PAS in January 2010. Amikacin was stopped in July 2010. The patient, on regular follow-up, developed elevated thyroid stimulating hormone (TSH) (6.10 μIU/ml [normal 0.270-4.2 μIU/ml]) in August 2010 for which she was started on thyroxine. Her hearing and renal profile remained normal. In November 2010, her lymph nodes had regressed in size to 2 cm on right side and 1 cm on left side. Her remaining ATT is being continued.
An 8-year-old boy presented in April 2010 with bilateral cervical adenopathy (4 cm × 4 cm) for 4 years for which he has been on ATT consisting of HR for 4 years but there was no response. An excision biopsy was done that showed caseating granulomas and acid fast bacilli (AFB) on smear microscopy. He was started on Category 2 retreatment ATT. After 6 weeks, culture grew M. tuberculosis resistant to HRS and sensitive to Z, E, Amk, Km, Ofx, Mfx, Cfz, Eth, PAS and Cm. He was started on Amk, E, Z and Ofx from July 2010. In August 2010, on follow-up, his serum creatinine was 1.2 mg/dl and a murmur was heard in the right infrascapular region. Amikacin was withheld and Cs and Cfz were added. Echocardiography showed moderate mitral regurgitation with mild aortic regurgitation and left ventricular hypertrophy. Abdominal aorta was nonpulsatile with a gradient of 60 mm in descending aorta with collateral circulation and thickened intima suggestive of aorto-arteritis. All pulses were palpable and blood pressure (BP) in all 4 limbs was normal though BP in lower limbs was less than that in upper limbs. He was started on steroids (0.5 mg/kg/day) and restarted on Amk as creatinine normalized. Computed tomography (CT) angiography showed diffuse narrowing of axillary and distal subclavian arteries with collateral filling of the right brachial artery, diffuse noncalcified wall plaque involving descending thoracic aorta and suprarenal abdominal aorta with a patent lumen of 3 mm in the lower thoracic aorta. There was osteal tight stenosis of celiac artery suggestive of multivessel aorto-arteritis. His erythrocyte sedimentation rate (ESR) was still 45 mm after 1 h in December 2010 and the lesion appeared inoperable as per the interventional radiologist. Amk was stopped in February 2011 and ESR was 18 mm after 1 h. He is continued on remaining ATT, weight has increased to 21 kg and there are no hearing, ophthalmological, liver or renal dysfunction.
A 12-year-old girl was referred in July 2009 for management of MDR-TB. In 2005, she had received first-line ATT for 6 months. On referral she had swelling in right axilla (10 cm × 8 cm) for 3 months. Abscess was aspirated and pus was drained that showed AFB on smear microscopy. She was started on 4 drug ATT consisting of HRZE. After 6 weeks, her pus culture grew M. tuberculosis resistant to HRE. She was started on Amk, Ofx, PAS, Eth and Z. By August 2009 the abscess had decreased in size to 3 cm × 3 cm, but she had lost weight. In November 2009, she underwent excision of the entire node. In December 2009, on hearing evaluation, she had sensory loss at higher frequency and thus Amk was made alternate day therapy. She is on regular follow-up and Amk has been omitted in February 2010.
A 9-year-old girl presented in March 2009 with supraclavicular and axillary abscesses. She had been treated for abdominal TB in January 2007 for 9 months with first-line ATT. In April 2008, she developed left shoulder septic arthritis and was on first-line ATT from May 2008 until she presented in March 2009. Ultrasound of the abdomen showed a mesenteric abscess. All abscesses were drained and she was started on Category 2 ATT. Her pus culture grew M. tuberculosis at end of 6 weeks resistant to HR. She was started on Amk, Mfx, Z, E, Eth in May 2009, She had no adverse effects on follow-up. Her nodes regressed in the next 3 months and ultrasound of the abdomen was normal on follow-up. Amk was stopped after 6 months in December 2009. In July 2010, she had jaundice and Z and Eth were stopped. Her hepatitis A IgM was positive at that time. In August 2010, Z and Eth were restarted. She completed 18 months of ATT in November 2010 and ATT was stopped. On follow-up after 6 months, she remains asymptomatic.
A 7-year-old girl presented in March 2009 with fever and cough for 2 months. She had been started on 3-drug ATT consisting of HRZ in January 2009 in view of nonresolving pneumonia and positive Mantoux test but had no response. She had lost 2 kg weight in past 2 months. There was no contact with an adult suffering from TB. On examination, she had decreased air entry in left infra-mammary region with bronchial breathing. Chest X-ray showed left lower lobe consolidation. Her sputum smear showed AFB and HIV ELISA was negative. She was started on Category 2 ATT. In April 2009, her sputum culture grew M. tuberculosis resistant to HRES. She was started on Z, Amk, Ofx, PAS and Eth. In August 2009, she developed hypothyroidism and thyroxine was supplemented. In November 2009, her chest X-ray was normal and Amk was omitted after 6 months of therapy. In November 2010, chest X-ray showed healed TB and she had completed 18 months of ATT. Thus, all medications were omitted. Her thyroid function tests were normal in December 2010. She remains asymptomatic after 6 months of stopping ATT.
A 2-year 2-month-old girl was referred in July 2009 for management of her TB. In September 2008, she had fever for 15 days and a positive Mantoux test for which she received first-line ATT for 6 months till March 2009. However, she developed multiple enlarged lymph nodes. An axillary lymph node biopsy was done in June 2009, from which M. tuberculosis was cultured resistant to HRZS, Eth and susceptible to E, Km, PAS, fluoroquinolones, Amk, Cfz and Cm. She was started on Amk, Ofx, PAS and E in August 2009. Amk was stopped in March 2010 after 6 months of therapy and rest of the drugs were stopped in February 2011 after 18 months of total ATT. Her lymph nodes had completely regressed. She had no adverse reactions to the ATT.
A 12-year-old girl was referred in April 2009 for further management. She was treated for pulmonary TB at 8 years of age with first-line ATT for 1-year. She had axillary lymph nodes in July 2007. Fine needle aspiration showed TB and she was given first-line ATT for 1½ years. In October 2008, she was detected to have large abdominal lymph nodes (3-8 cm), omental mass and mediastinal nodes (3 cm × 2 cm) on CT chest and abdomen for which she underwent biopsy of axillary lymph node that grew M. tuberculosis resistant to HRSE. She was subsequently on Eth, Amk, Ofx, clarithromycin from October 2008. In April 2009, she had right sided axillary node (2 cm × 2 cm), right lower zone cavity with fibrosis on chest X-ray, multiple calcified lymphadenopathy measuring 3.4 × 2.4 cm × 2.8 cm on ultrasound abdomen. She was continued on same medicines and PAS was added. In September 2009, she had hypothyroidism and was started on thyroxine. Her Amk was omitted in October 2009. She was detected to have moderate hearing loss at higher frequencies in November 2009. In March 2011, her ultrasound abdomen was normal, chest X-ray showed fibrosis and treatment was stopped.
A 12-year-old girl presented in February 2009 with cough and loss of appetite for 1-month. She had been treated for TB with first-line ATT in October 2007 for 9 months and September 2008 for 6 months. Her sister had died of pulmonary TB 5 months ago. Chest X-ray showed right upper zone fibrocavitatory TB and cavity in left upper zone. Sputum for AFB was positive on smear microscopy. She was suspected to have DR-TB as the patient had been treated for TB twice in the past and thus second-line ATT (Amk, Mfx, PAS and Eth) were added to HRZE pending the DST report. In April 2009, her TB culture grew M. tuberculosis resistant to HRZ. She was then continued on Amk, PAS, E, Eth and Mfx. In May 2009, she had hypothyroidism and required thyroxine. In August 2009, Amk was stopped. She had no hearing loss and renal functions were normal. In August 2010, she had completed 18 months of ATT, chest X-ray showed residual fibrosis in right upper zone and all medications were stopped. In October 2010 her thyroid function tests were normal.
| Discussion|| |
Development of DR-TB adversely impacts the management of the disease. MDR-TB occurring primarily as a consequence of poor treatment services in adults and older children (in younger children, MDR-TB usually is transmitted from adults) and could lead to emergence of XDR-TB if MDR-TB is not managed properly. An increasing prevalence of DR-TB in several parts of the world including India has been one of the major reasons for declaring TB control as a global emergency by the World Health Organization (WHO). 
Although for several years, DR strains of M. tuberculosis were considered to be less infectious than the drug-susceptible ones, recent studies have demonstrated that the DR strains are equally infectious and can cause severe disease in an individual exposed to the same. ,
Drug-resistance in TB is broadly classified as primary or acquired. Primary resistance occurs in persons who are initially exposed to and infected with resistant organisms as seen in young children. Secondary resistance, or acquired resistance develops during TB therapy because of inadequate regimen, patient not taking prescribed regimen appropriately, drug malabsorption, or drug-drug interactions leading to low serum levels.  In all our patients, drug-resistance was detected at the start of therapy and not in between therapy suggesting primary resistance.
As per WHO, children should be suspected to have DR-TB if they are in contact with a known case of DR-TB or not responding to the standard ATT regimen or have recurrence of TB after treatment to which they were adherent.  Out of eight patients in our series, 7 had been treated with ATT in the past and only 2 had been in contact with a known adult TB source case. Thus it is may suggest that previous exposure to ATT may have been a predisposing factor towards the development of drug-resistance. As children with TB usually represent cases that have recently acquired infection with M. tuberculosis, they serve as an indicator of the drug-susceptibility patterns and circulating strains of M. tuberculosis in a community.  In our patients we have found that along with resistance to HR, most of the strains had additional resistance to S and E. Thus it should be imperative to do the DST for all possible first-line anti-TB drugs so that appropriate treatment regimen can be devised.
World Health Organization has provided guidance for the programmatic management of DR-TB.  WHO guidelines recommend treatment until 18 months after the first negative culture (24 months in XDR-TB). Depending on the severity of disease and adverse effects experienced, parenteral agents should be administered for at least 6 months. , Because children often have paucibacillary disease shorter duration of treatment (12 months) may be sufficient for early, nonextensive disease. 
Adverse effects of therapy can be in form of hepatotoxicity with isoniazid, Z and the thioamides, gastric disturbances with thioamides and PAS, hypothyroidism with thioamides and PAS combination, optic neuritis with ethambutol and ototoxicity and nephrotoxicity with injectable agents. Joint or musculoskeletal adverse effects from the fluoroquinolones in children seem mild and are rare. Psychosis is rarely seen in children, but could be caused by isoniazid or cycloserine.  In our series, two patients had hearing loss at high frequency, four patients had elevated TSH and one had jaundice due to hepatitis A infection. None had optic neuritis or joint problem. Thus regular monitoring for adverse effects and timely intervention is needed. However none of them required complete omission of a drug although temporary stoppage was required till the hepatitis resolved.
Outcome of children with MDR-TB is variable. A study by Fairlie et al. in in Johannesburg, South Africa found that 30.8% children with MDR-TB died during their treatment. However 75% of these children were HIV-infected.  The current series of our patients who have been on treatment for 10 months and more have responded to treatment and only one has gone on to develop an incurable illness of multi-vessel aorto-arteritis. This child had been on ATT for 4 years for cervical adenopathy and thus it is likely that the disease has progressed to involve the various blood vessels. Five out of the 8 children have completed 18 months of therapy and their treatment has been stopped. None of these children have relapse of the disease on follow-up. Thus, with appropriate screening for drug-resistance, adequate treatment, and adherence can lead to a favourable outcome. However in our case series there is a selection bias (exclusion of children lost to follow-up or not having received treatment for 10 months) which may play a role in the relatively good outcome of our patients. Also most patients had extrathoracical lymph node disease which does have a good outcome.
| Conclusion|| |
Multidrug-resistant tuberculosis should be suspected in children with relapse of TB and previous anti-TB treatment exposure. Preferably DST should be done for all first-line and second-line anti-TB drugs to determine additional drug-resistance. Therapy would be needed for an extensive period and monitoring for adverse effects should be done on regular basis while on therapy.
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