Case of the Month

April 2016

Infants can get extensively drug-resistant tuberculosis (XDR-TB)

H. Simon Schaaf and Helena Rabie
Department of Paediatrics and Child Health, Tygerberg Academic Hospital and Stellenbosch University

An 11-month-old boy, weight 9.6 kg, presented to the emergency room with a short history of fever and two weeks of cough. He had no failure to thrive or weight loss. Social history revealed that the family rented a room from a woman who had tuberculosis (TB) but was not on therapy. The child was not on any antituberculosis medication or preventive therapy.

His clinical examination was unremarkable accept for a unilateral wheeze suggestive of large airway compression. The chest radiographs showed hilar lymphadenopathy, right middle lobe opacification and left main bronchus compression. The infant was not HIV exposed and his own status was negative. Mantoux tuberculin skin test was not performed because it was not available.

Figure 1. a) Anteroposterior and b) lateral chest radiographs showing hilar nodes, right middle lobe opacification and left main bronchus narrowing

Question 1: How would you further manage this child regarding the diagnosis of tuberculosis?

Answer to Q1

We need further information on the source case. If there is known contact with an infectious adult with pulmonary TB, the child will most likely be infected with the same strain as the source case. This is not only true for children but also for adults. In studies of household contacts of multidrug-resistant (MDR) cases who developed TB, 75-88% had MDR-TB as well. (1-4)

In this case, the family with whom the child’s parents stayed was a known family with several extensively drug-resistant (XDR)-TB cases over a period of 2-3 years. The current source case was discharged from hospital after therapy for XDR-TB failed. She was given the necessary advice and counselling regarding the contagious risk to other people. Despite this she took in boarders, including the patient and his family. There was no other known source case, the parents did not have TB therefore it was presumed that the child was infected with XDR-TB. It is important to remember that young age is one of the most important risk factors to develop disease after infection. In figure 1 we illustrate the age related risk to develop disease after infection and the risk of developing disseminated forms of disease.(5)

Figure 2: Age related TB disease risk after M. tuberculosis infection in HIV-uninfected children ten years and younger (5)

We need to obtain specimens from the child to try to confirm XDR-TB.
Confirming the diagnosis of TB through culture or molecular techniques is more difficult in infants and young children than in adults. Culture confirmation is only possible in 10-20% of children investigated for TB in community settings and 30-40% of children in hospital settings, the latter because the TB disease is usually more advanced once referred to hospital. The reason for the low yield is the paucibacillary nature of primary TB and the difficulty of obtaining sputum specimens from children.

The majority of children with TB are diagnosed on a history of contact, suggestive symptoms, and a CXR. This is acceptable practice for drug susceptible TB contacts. However, where there is any concern of drug resistance all efforts should be made to obtain specimens for bacteriological confirmation and drug susceptibility testing (DST) from the site(s) of disease prior to starting therapy if there is no immediate risk to the child, such as in children with tuberculous meningitis or miliary TB. Respiratory specimens should be obtained by gastric aspirate, induced sputum or, if bronchoscopy is done, by bronchoalveolar lavage. Multiple specimens are preferable. Xpert MTB/RIF could be done, but the sensitivity of Xpert is only 60-70% in smear-negative culture-positive pulmonary TB cases in children (a new, more sensitive Xpert Ultra has been developed). It also only provides rifampicin (RIF) DST and further DST cannot be performed on such a specimen. (6-9) If, however the Xpert confirms Mycobacterium tuberculosis and RIF resistance in a child with a known history of contact with a drug-resistant source case, it rapidly brings us closer to the correct diagnosis. Culture and DST is mandatory in these cases. Genotypic DST, such as the line probe assay (e.g. GenoType MTBDRplus, Hain Lifescience, Nehren, Germany) will yield results for both isoniazid (INH) and RIF resistance, as well as inform us on the mutation conferring INH resistance. The latter is important because in case of an inhA mutation conferring INH resistance, cross resistance with ethionamide is evident, but there is only low-level INH resistance, while if it is a katG mutation, high-level INH resistance is likely but ethionamide may still be an active drug. (10) With a positive culture available, further phenotypic, and possibly genotypic DST, for second-line antituberculosis drugs, especially the fluoroquinolones and second-line injectable agents can be done to confirm XDR-TB.

This child presented with clinical airway obstruction which was confirmed on CXR. The extent of airway obstruction and the possible need for surgical intervention can only be truly assesed by bronchoscopy with or without computed tomography (CT) scan. In most cases, corticosteroids will first be given together with antituberculosis treatment, but with lobar or lung collapse or hyperinflation of a lung due to a ball-valve effect, surgical decompression of the nodes may be indicated.(11)
In our child the Xpert on respiratory specimens was negative, but we confirmed XDR-TB on culture from gastric aspirates, induced sputums as well as bronchoalveolar lavage. INH resistance was conferred by a katG gene mutation. Bronchoscopy confirmed airway compression, which responded to prednisone therefore surgical decompression was not indicated.

Question 2: How would you treat this child and is there any other information needed to decide on an effective treatment regimen?
Answer to Q2

The history of antituberculosis treatment of the source case (if available) is important. Not only the drug resistance pattern of the M. tuberculosis isolate of the child (if obtained) or the source case (in the absence of confirmation in the child) but also the antituberculosis treatment history of the source case (or in some cases the child) is important in deciding which drugs may still be active drugs.

In this case the source case failed >12 months XDR-TB treatment in hospital. At the time an XDR-TB regimen consisted of capreomycin, para-aminosalicylic acid (PAS), pyrazinamide, terizidone, ofloxacin (or moxifloxacin), ethionamide and high-dose INH. She previously failed MDR-TB treatment which also included ethambutol. The likelihood that few or none of these drugs are still active is therefore quite high, except maybe for PAS.

An effective treatment regimen should consist of at least three, but preferably four active drugs. For XDR-TB with an organism that already failed XDR-TB treatment, this is quite a challenge, especially in an infant and with the currently available formulations. (12-16) The World Health Organisation currently divides the antituberculosis drugs in 5 groups (which may change in the near future), and drugs from each group are added to build an effective regimen (see table) (12)

Table 1: WHO drug groups and identifying active drugs for our patient

In our patient we started empirically (based on adult XDR-TB source case’s isolate DST) at TB diagnosis with XDR-TB treatment including the following drugs: linezolid (10mg/kg/dose twice daily); clofazimine 50mg every second day (long half-life; dose 2-3mg/kg/day); PAS 200mg/kg/day; terizidone 15-20mg/kg/day; ethionamide 15-20mg/kg/day and capreomycin 20mg/kg IM daily. He also received prednisone 2mg/kg/day x 4 weeks tapered over a further 2 weeks for airway compression. He became culture-negative within a month of treatment and remained culture-negative since (18 months). Supplements included pyridoxine (vit B6).

Question 3: Which adverse effects are associated with second-line antituberculosis drugs and how should we screen for these?

Answer to Q3:

The common adverse effects of second-line antituberculosis drugs are shown in table 2:

Table 2:.

Question 4: What about the new drugs – can we use them in children?

Answer to Q4

Two new drugs are available to adults with MDR-TB – bedaquiline (BDQ) and delamanid (DLM). These drugs are not registered for use in children and paediatric dose finding and toxicity studies have started only for DLM. DLM is available for children older than 6 years and >20kg through a compassionate use programme. The drug can be accessed in selected cases through the ERS/TB consilium or MSF programmes and final approval and supply from Otsuka, the manufacturers. MCC section 21 aproval also needs to be obtained. (17)

It is expected that the WHO will soon publish new guidelines on the management of adults and children with drug-resistant TB.  

Question 5: What is the outcome of MDR and XDR-TB cases in children?

Answer to Q5

In children good theraputic outcomes are reported for both MDR and XDR-TB, the pooled estimate for treatment success was 81·67% (95% CI 72·54-90·80) in a recent systematic review.(17) Locally 90% of children with confirmed or suspected MDR-TB had a good outcome.(18) Drug-resistant TB meningitis and HIV infection was associated with increased mortality risk.(19)

Learning pionts

  • In children with suspected TB, finding a source case and considering their confirmed or suspected drug susceptibility profile is essential
  • Although confirmation of TB by culture is often not possible in children, it is essential to attempt culture and DST in all children where resistance is considered
  • Consider the DST results and the drug exposure of the source case when planning the DR-TB regimen of the child contact
  • Dosing of second-line drugs in young children is more complex due to the lack of pharmacokinetic data and absence of child-friendly formulations
  • Dose and safety of all the new TB drugs need to be studied in children of all ages; currently only delamanid can be accessed for children more than 6 years and more than 20kg body weight through compassionate care access programmes.


  1. Shah NS, Yuen CM, Heo M, et al. Yield of contact investigations in households of patients with drug-resistant tuberculosis: systematic review and meta-analysis. Clin Infect Dis 2014; 58:381–391.
  2. Schaaf HS, Van Rie A, Gie RP, Beyers N, Victor JC, Van Helden PD, Donald PR. Transmission of multidrug resistant tuberculosis. Pediatr Infect Dis J 2000;19:695-699.
  3. Parr JB, Mitnick CD, Atwood SS, Chalco K, Bayona J, Becerra MC. Concordance of resistance profiles in households of patients with multidrug-resistant tuberculosis. Clin Infect Dis 2014;58:392–395.
  4. Seddon JA, Warren RM, Enarson DA, Beyers N, Schaaf HS. Drug-resistant tuberculosis transmission and resistance amplification within families. Emerg Infect Dis 2012;18:1342-1345.
  5. Marais BJ, Gie RP, Schaaf HS, Hesseling AC, Obihara CC, Starke JJ, Enarson DA, Donald PR, Beyers N. The natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis 2004;8:392-402.
  6. Moore HA, Apolles P, de Villiers PJ, Zar HJ. Sputum induction for microbiological diagnosis of childhood pulmonary tuberculosis in a community setting. Int J Tuberc Lung Dis 2011;15:1185-1190.
  7. Nicol MP, Workman L, Isaacs W, Munro J, Black F, Eley B, Boehme CC, Zemanay W, Zar HJ. Accuracy of the Xpert MTB/RIF test for the diagnosis of pulmonary tuberculosis in children admitted to hospital in Cape Town, South Africa: a descriptive study. Lancet Infect Dis 2011;11:819-824.
  8. Zar HJ, Workman L, Isaacs W, Dheda K, Zemanay W, Nicol MP. Rapid diagnosis of pulmonary tuberculosis in African children in a primary care setting by use of Xpert MTB/RIF on respiratory specimens: a prospective study. Lancet Glob Health 2013;1(2):e97-104.
  9. Connell TG, Zar HJ, Nicol MP .Advances in the diagnosis of pulmonary tuberculosis in HIV-infected and HIV-uninfected children. J Infect Dis 2011;204 Suppl 4:S1151-8
  10. Schaaf HS, Victor TC, Venter A, Brittle W, Jordaan AM, Hesseling AC, Marais BJ, van Helden PD, Donald PR. Ethionamide cross- and co-resistance in children with isoniazid-resistant tuberculosis. Int J Tuberc Lung Dis 2009;13:1355-1359.
  11. Goussard P, Gie RP, Janson JT, et al. Decompression of enlarged mediastinal lymph nodes due to mycobacterium tuberculosis causing severe airway obstruction in children. Ann Thorac Surg 2015;99:1157-1163.
  12. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis: emergency update 2008. WHO, Geneva, Switzerland.WHO/HTM/TB/2008.402; 2008.
  13. Schaaf HS, Garcia-Prats AJ, Hesseling AC, Seddon JA. Managing multidrug-resistant tuberculosis in children: review of recent developments. Curr Opin Infect Dis 2014;27:211-219.
  14. Seddon JA, Hesseling AC, Schaaf HS. Retooling existing tuberculosis drugs for children. Clin Infect Dis 2013;56:167-168.
  15. Seddon JA, Furin JJ, Gale M, Del Castillo Barrientos H, Hurtado RM, Amanullah F, Ford N, Starke JR, Schaaf HS; Sentinel Project on Pediatric Drug-Resistant Tuberculosis. Caring for children with drug-resistant tuberculosis: practice-based recommendations. Am J Respir Crit Care Med 2012;186:953-964.
  16. Seddon JA, Thee S, Jacobs K, Ebrahim A, Hesseling AC, Schaaf HS. Hearing loss in children treated for multidrug-resistant tuberculosis. J Infect. 2013;66:320-329.
  17. Ettehad D, Schaaf HS, Seddon JA, Cooke GS, Ford N. Treatment outcomes for children with multidrug-resistant tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis 2012;12:449-456.
  18. Seddon JA, Hesseling AC, Godfrey-Faussett P, Schaaf HS. High treatment success in children treated for multidrug-resistant tuberculosis: an observational cohort study. Thorax 2014;69:458-464.
  19. Seddon JA, Visser DH, Bartens M, Jordaan AM, Victor TC, van Furth AM, Schoeman JF, Schaaf HS. Impact of drug resistance on clinical outcome in children with tuberculous meningitis. Pediatr Infect Dis J 2012;31:711-716.


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