Abstract Multidrug-resistant tuberculosis (MDR-TB) is a well-identified raising public health concern worldwide. However, the data available on MDR-TB in children and particularly in the neonate age group are limited. Congenital tuberculosis (TB) is rare, and its diagnosis is challenging because of non-specific manifestations. The choice of anti-tubercular drugs is difficult because of the lack of international consensus as a consequence of the scarcity of evidence-based data on this age group. We hereby present a case from Bhutan of a 23-day-old male neonate with congenital MDR-TB. His mother was diagnosed with disseminated TB, and treatment was commenced 11 days post-partum. Congenital transmission of TB was suspected, as direct postnatal transmission was unlikely and thorough screening of contacts for TB was negative. In this case, the mother’s MDR-TB status was revealed only after her newborn’s MDR-TB diagnosis. multidrug-resistant tuberculosis, congenital infection, Bhutan INTRODUCTION Tuberculosis (TB) is caused by Mycobacterium tuberculosis, causing significant morbimortality. Around 1 million of children become ill with TB annually and in 2015, 210 000 children died of TB worldwide . In Bhutan, TB remains a major health problem, with increasing rate of multidrug-resistant tuberculosis (MDR-TB) among new cases . Total 14% of the TB cases registered in 2010 were children <15 years . According to the national Drug Resistance Survey report, the proportion of new MDR-TB cases was 5% and 10% in 2013 and 2014, respectively. It is possible that more drug-resistant cases will be diagnosed after the introduction of line probe assay (LPA) and GeneXpert (real-time polymerase chain reaction) in 2016 . Congenital TB infection by vertical transmission is rare with <400 cases reported worldwide until 2005  but carries a poor prognosis, especially when MDR-TB is involved . Diagnosis in neonates is challenging because of non-specific manifestations and clinical overlap with common neonatal diseases. Hence, diagnostic delays have been associated with high neonatal mortality up to 60% . MDR-TB treatment guidance for children is based on adult data, as specific guidance to children and neonates is limited . We hereby present the first case in Bhutan as per our knowledge of congenitally acquired MDR-TB and explore the challenges in its diagnosis and management. CASE A 23-day-old male neonate was admitted to Jigme Dorji Wangchuk National Referral Hospital on 15th February 2017, with episodes of apnoea and cyanosis in the previous 12 h. He was born late preterm (36 + 5) with low birth weight (1990 gm). Before pregnancy in late 2015, his 28-year-old mother was ill with respiratory symptoms for 1 month, not responding to antibiotics. She was investigated for pulmonary TB. Acid-fast bacilli (AFB) were not detected on microscopic examination of three sputum smears; however, her chest radiograph and computerised tomography (CT)-chest scan showed enlarged nodes with rim enhancement and central necrosis in the right paratracheal, perivascular, subcarinal and left hilar regions. She was diagnosed as tuberculous mediastinal lymphadenitis, and completed 6 months of first-line anti-tubercular therapy (ATT) under direct observation (DOT). At the end of treatment, it was declared that she was successfully treated with negative chest radiograph and sputum microscopy. Three months later, the mother was found to be pregnant. At 35 + 6 weeks, she was admitted with fever, night sweats, cough, vomits, loose stools and abdominal pain for 3 months. Blood and urine investigations were unremarkable. HIV serology was negative. Abdominal ultrasound revealed bilateral hydroureteronephrosis, multiple enlarged peripancreatic lymph nodes and ascites. Emergent caesarean delivery was performed on 23rd January 2017 because of foetal distress. The histopathology of fallopian tube revealed chronic inflammation, and microscopy for AFB was negative. Placenta was not sent for histopathology. The ascitic fluid analysis showed numerous lymphocytes. Abdominal CT disclosed multiple lymph nodes with central necrosis. We could not trace any chest radiograph nor sputum microscopy reports. Abdominal TB was inferred, and she was started on first-line ATT for the second time. At birth, baby was asymptomatic, and investigations for active TB, including blood analyses, gastric aspirates for AFB and GeneXpert, chest radiograph and abdominal ultrasound were normal. He was started on isoniazid prophylaxis with pyridoxine and immunized with Bacillus Calmette–Guérin vaccine. On follow-up at 14 days of life (DOL), there were no issues except for poor weight gain, which was attributed to breastfeeding difficulties because of maternal illness. At 23 DOL, baby presented with respiratory distress and apnoea. He was pale, lethargic and hypoxic. Investigations showed haemoglobin of 11.2 g%, total leucocyte counts of 27, 150 cells/cumm (82% neutrophils), erythrocyte sedimentation rate of 26/mmhr, C-reactive protein of 3.9 mg/dl and HIV serology negative. Chest radiograph revealed bronchopneumonic changes. Abdominal ultrasonography and cerebrospinal fluid (CSF) analysis were normal. No growth was detected in CSF and blood cultures after 5 days of incubation. Gastric aspirates for AFB under microscopy were positive for all three samples, and GeneXpert detected positive for M. tuberculosis with rifampicin resistance. The three gastric samples underwent LPA, which revealed both rifampicin and isoniazid resistance. Isoniazid resistance was because of Kat G gene mutation. A diagnosis of congenital MDR-TB was inferred, and the infant was started on second-line ATT with oral pyrazinamide (35 mg/kg/day), levofloxacin (15 mg/kg/day), ethionamide (15 mg/kg/day), cycloserine (15 mg/kg/day) and linezolid (20 mg/kg/day) and injection amikacin (15 mg/kg/day), with pyridoxine supplementation. The gastric aspirate cultures on automate liquid MGIT 960 medium were negative at 6 weeks of incubation. Meanwhile, the mother’s condition deteriorated despite treatment. Diagnosis was updated to disseminated TB after finding pleural effusion. She was unable to expectorate for sputum microscopy. Her condition improved considerably after changing to MDR-TB therapy once her child’s diagnosis. All close contacts were negative for active TB after extensive investigations. The child is currently doing well under DOT, with adequate weight gain. We monitored for drug toxicity, including monthly haemogram, renal, liver and thyroid function, as well as hearing and vision assessment. So far, tolerance is good, and no drug toxicity has been detected. Amikacin was stopped after 7 months, and the total duration of ATT is planned for 15 months. DISCUSSION Infants acquire TB congenitally from infected mother or postnatally from any person affected with TB. Differentiating congenitally from postnatally acquired TB can be challenging. Diagnostic criteria for congenital TB by Cantwell  require proven TB lesions in the neonate plus one or more of the following: lesions occurring in the first week of life, a primary hepatic complex, maternal genital or placental TB and exclusion of postnatal transmission by extensive investigations of the contacts. In this case, M.tuberculosis was isolated from the infant at 23 DOL. His mother’s infection was disseminated, with involvement of the fallopian tubes, abdominal lymph nodes, ascites and pleural effusion. Previous serial sputum microscopy was negative, and post-delivery mother was unable to expectorate, so airborne transmission from mother to baby was unlikely. Additionally, thorough contact screening was negative, making the likelihood of vertical transmission even more likely. Therefore, our case meets the Cantwell’s criteria, as it is a proven case of TB in a neonate born from a mother with disseminated TB with abdominal and pelvic involvement, with exclusion of postnatal transmission. During pregnancy, the mother can have diagnostic delays because of non-specificity of the symptoms, which in this case was further complicated by findings of hydroureteronephrosis . Diagnosis of the newborn often prompts a search for illness in the mother rather than the reverse. In this case, TB was initially found in mother, but detection of MDR-TB in her child allowed diagnosis of MDR-TB in the mother. The median age of presentation of congenital TB is 24 days with non-specific clinical manifestations that masquerade usual complications related to prematurity, sepsis or acute or chronic intrauterine infections . In this case, the neonate became symptomatic at 23 DOL, and he was reinvestigated thoroughly with both conventional and new diagnostic methods. WHO recommends GeneXpert for rapid diagnosis in the communities with high burden of TB . In our case, GeneXpert played a significant role in diagnosing MDR-TB. We would like to remark the limitations of culture in making a confirmed diagnosis of TB, as cultures from both the neonate and mother were negative despite seeing AFB under microscopy in neonate samples. LPA report was crucial to determine MDR-TB status. We acknowledge that LPA can give false-positive results. However, in our case, we believe it is a true-positive result, as the mother’s clinical condition improved after changing her treatment from first line to MDR-TB therapy. There are no standard guidelines for congenital MDR-TB treatment regimen, making the choice of anti-tubercular regimen difficult for clinicians when such cases present. WHO recommends to treat neonates as children, mainly based on adult data, while others recommend consultation with experts [7, 11, 12]. Limited evidence on pharmacokinetic and efficacy data of the second-line agents in this age group are most likely contributing factors to this lack of consensus. The optimal duration of treatment for MDR-TB in children and congenital cases is also unknown [7, 11, 12]. We consulted with international experts, with their recommendations consistent with the data recently published by the Sentinel Project on Paediatric Drug-Resistant TB . Duration of treatment may be based on the severity of the disease, and most guidelines accept a minimum of 16 months. However, as for TB meningitis and some other forms of extra-pulmonary TB , there is limited evidence on optimal duration of treatment. As the child improved with ATT and CNS was not involved, we decided to follow the expert recommendation of 15 months treatment. Close clinical and laboratory monitoring are recommended for toxicity and safety of the drugs [11, 14]. While laboratory and hearing evaluation are relatively easy to monitor, the detection of peripheral neuritis in infants is challenging. CONCLUSION Congenital TB in neonates is an infrequent condition, and congenital MDR-TB is even more rarely reported till date. Testing for MDR-TB in low- and middle-income countries is not widely performed; therefore, MDR-TB is likely to be significantly under-reported. Non-specific presentations in the neonate born to a mother with TB should be suspected of congenital TB. Choice of anti-tubercular regimen for a neonate with congenital MDR-TB is difficult, available evidence-based data and international experts should be consulted. ACKNOWLEDGMENTS The authors are grateful to the Department of Paediatric and Laboratory Medicine at Jigme Dorji Wangchuk National Referral Hospital, and to the Royal Centre of Disease Control in Serbithang, Thimphu, Bhutan. The authors would like to thank Professor Schaaf and Dr. Adrie Bekker, international experts on MDR-TB in children, South Africa, whom we consulted for the management of the neonate. REFERENCES 1 WHO . Global tuberculosis report 2017. http://apps.who.int/iris/bitstream/10665/259366/1/9789241565516-eng.pdf? ua=1 (22 January 2018, date last accessed). 2 National TB Control Programme. Bhutan National Guidelines for Management of Tuberculosis . 6th edn. Thimphu, Bhutan : Ministry of Health , 2016 . 3 Dendup T , Dorji T , Edgnton ME , et al. Childhood tuberculosis in Bhutan: profile and treatment outcomes . Public Health Action 2013 ; 3 : 11 – 14 . Google Scholar CrossRef Search ADS PubMed 4 Hasang G , Qureshi W , Kadri SM. Congenital tuberculosis . JK Sci 2006 ; 8 : 193 – 4 . 5 Espiritu N , Aguirre L , Jave O , et al. Case report: congenital transmission of multidrug-resistant tuberculosis . Am J Trop Med Hyg 2014 ; 91 : 92 – 5 . Google Scholar CrossRef Search ADS PubMed 6 Hema M , Saurabhi D , Faridi MM. Management of newborn infant born to mother suffering from tuberculosis: current recommendations and gaps in knowledge . Indian J Med Res 2014 ; 140 : 32 – 9 . Google Scholar PubMed 7 WHO . Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children. 2nd edn. 2014 . http://apps.who.int/medicinedocs/documents/s21535en/s21535en.pdf (22 January 2018, date last accessed). 8 Cantwell MF , Shebab ZM , Costello AM , et al. Brief report: congenital tuberculosis . N Engl J Med 1994 ; 330 : 1015 – 54 . Google Scholar CrossRef Search ADS PubMed 9 Llewelyn M , Cropley I , Wilkinson RJ , et al. Tuberculosis diagnosed during pregnancy: a prospective study from London . Thorax 2000 ; 55 : 129 – 32 . Google Scholar CrossRef Search ADS PubMed 10 Bate TWP , Sinclair RE , Robinson MJ. Neonatal tuberculosis . Arch Dis Child 1986 ; 61 : 512 – 14 . Google Scholar CrossRef Search ADS PubMed 11 WHO . WHO Treatment Guidelines for Drug-resistant Tuberculosis: The End TB Strategy . Geneva, Switzerland : WHO . 2016 . PubMed PubMed 12 The Sentinel Project on Pediatric Drug Resistant Tuberculosis . Management of Multi-Resistant tuberculosis in Children: A Field Guide. 3rd edn. 2016 . http://sentinel-project.org/2016/12/13/management-of-multidrug-resistant-tuberculosis-in-children-a-field-guide-third-edition/ (16 February 2018, date last accessed). 13 Jullien S , Ryan H , Modi M , Bhatia R. Six months therapy for tuberculous meningitis . Cochrane Database Syst Rev 2016 ; 9 : CD012091 . doi: 10.1002/14651858.CD012091.pub2. Google Scholar PubMed 14 Loeffler MA. Pediatrics Drug-Resistant Tuberculosis, A Survival guide for Clinicians. 3rd edn. 2016 . http://www.currytbcenter.ucsf.edu/products/cover-pages/drug-resistant-tuberculosis-survival-guide-clinicians-3rd-edition (16 February 2018, date last accessed). © The Author(s) . Published by Oxford University Press. All rights reserved. For permissions, please email: firstname.lastname@example.org This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)
Journal of Tropical Pediatrics – Oxford University Press
Published: Apr 20, 2018
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