DOTS IN CHILDHOOD TUBERCULOSIS
Dr. V.V.Banu Rekha*, Dr. Soumya Swaminathan**
Tuberculosis Research Centre, Chetput, Chennai 31*, Tuberculosis Research Centre, Chetput, Chennai 31**
EPIDEMIOLOGY
Tuberculosis (TB) continues to be an important cause of morbidity and mortality in children worldwide. While the actual global disease burden of childhood TB is unclear, it is assumed that 10% of the total TB caseload is found amongst children. Global estimates of 1.5 million new cases and 130,000 deaths due to TB per year amongst children are reported 1. Recent studies have documented the increase in the occurrence of tuberculosis in children, both in developed and developing countries.(2,3) Tuberculosis is more common among the disadvantaged and vulnerable groups in each society and the impact of overcrowding, under-nutrition and poverty is particularly severe on children. The peak age of notification of tuberculosis decreases as the incidence of the disease increases in the region.(2) Tuberculosis infection can progress rapidly to disease, particularly in infancy and early childhood. Children can present with TB at any age, but the majority of cases present between 1 and 4 years. Disease usually develops within one year of infection - the younger, the earlier and the more disseminated. Pulmonary TB (PTB) is usually smear-negative. Pulmonary TB to extra-pulmonary TB (EPTB) ratio is usually around 3:1. The PTB prevalence is normally low between the ages of 5 and 12 years, and then increases in adolescence when PTB manifests like adult PTB (Post Primary Tuberculosis).(4) Proper identification and treatment of infectious adult cases will prevent childhood TB. Mortality from tuberculosis is also highest in early childhood, mainly due to disseminated forms like meningeal and military tuberculosis. The Revised National TB Control Programme (RNTCP) and Indian Academy of Pediatrics (IAP) working together have now devised guidelines for diagnosis and management of pediatric TB as well as made pediatric patient-wise boxes available in the programme.(1)
Pediatric cases in RNTCP
From a survey of RNTCP implementing districts in 2002, pediatric cases were seen to make up 3% of the total load of new cases registered under RNTCP. Lymph node (LN) TB cases predominated (>75%) amongst the pediatric EPTB cases registered under RNTCP. Many EPTB cases (>40% of LN cases) were diagnosed on clinical grounds with no confirmatory tests performed. An almost equivalent number of pediatric TB cases were being diagnosed in the same health facilities, but were not being registered under RNTCP.(1) Of those pediatric cases treated under RNTCP, cure and completion rates were both above 90%. Comparative figures for those cases not treated under RNTCP were 80% and 70%, with default rates between 27-33%. (Central TB Division. Unpublished data) Hence for RNTCP, there are the issues of under diagnosis and under registration of pediatric TB cases in the programme. To seek consensus on improved case detection and improved treatment outcomes for all diagnosed pediatric TB cases, a workshop on the "Formulation of guidelines for diagnosis and treatment of pediatric TB cases under RNTCP" was held in 2003. (1,5)
Diagnosis of Childhood TB
Suspect cases of PTB should include children presenting with: fever and/or cough for more than 3 weeks, with or without weight loss or no weight gain; and history of contact with a case of active TB disease within the last 2 years.

Diagnosis is based on a combination of clinical features, sputum examination wherever possible, Chest X-ray (PA view), Mantoux test (1 TU PPD RT23 with Tween 80, positive if induration> 10 mm after 48-72 hours) and history of contact.

The use of currently available scoring systems is not recommended for diagnosis of pediatric TB patients.

Children showing neurological symptoms like irritability, refusal to feed, headache, vomiting or altered sensorium may be suspected to have TB meningitis and investigated. Similarly other organ related symptoms should prompt the investigations for TB elsewhere.

Diagnostic algorithm for Pediatric TB in RNTCP is given in Figure 1.

Scientific basis of DOTS strategy
Based on the recommendations of the review of the previous National TB programme, the RNTCP, incorporating the internationally recommended DOTS strategy, was developed. In 1993, RNTCP was started in pilot areas covering a population of 18 million. Since 1998, the RNTCP has been rapidly expanding and in April 2006 covered the entire nation (http://www.tbcindia.org/impRNTCP.asp).

The five main components of DOTS strategy are:(4)

  1. Political and administrative commitment - Essential for ensuring adequate funds and provision of key staff for the smooth operation of the programme.
  2. Diagnosis by sputum smear microscopy - Sputum smear microscopy is a simple, less expensive, definitive tool for TB diagnosis. It identifies the infective cases in the community. X-ray is used only as a complementary tool.
  3. Regular and uninterrupted supply of ATT - Ensured by individual patient-wise boxes, which contain quality drugs for the entire treatment duration. This enhances patient adherence and prevents emergence of drug resistance. Categorization of patients for treatment is based on the severity of illness, bacillary load, site of the disease and previous ATT received.
  4. Direct observation of treatment (DOT) - Scientific proof of the safety and favourable response of domiciliary treatment established by the Madras trial was an important landmark and the basis of out patient treatment in TB. Under optimal conditions treatment without observation achieves a success rate of 50-60%, whereas direct observation results in 85-95% success rate.6 In this way DOT ensures that patient adhere to treatment till completion. RNTCP uses intermittent short course chemotherapy (SCC) regimens, which can be easily supervised.
  5. Systematic monitoring, reporting and cohort analysis for effectiveness of the control programme.
Principles of SCC
The biological characteristics of the tubercle bacilli (lag phase, size and type of bacterial population, easy development of resistance when exposed to a single drug and the presence of natural drug resistant mutants) determine the principles of SCC,(7) (a) A combination of at least 3-4 drugs should be used in the initial intensive phase, which ensures rapid killing of all population of bacilli. The first line Anti-TB drugs are Isoniazid (H), Rifampicin ®, Pyrazinamide (Z), Ethambutol (E), (b) Drugs can be given either daily or intermittently, (c) Minimum duration of treatment is 6 months when Rifampicin is used throughout and Pyrazinamide is used in the initial intensive phase and (d) Drugs should be preferably given together and administered as a single dose.

Table 1 shows the results of SCC studies in children. In these trials the overall success rate was greater than 95% for complete cure and 99% for significant clinical improvement. The incidence of clinically significant adverse reactions was less than 2%. Though radiographic abnormalities persist at the end of treatment in a significant proportion of the children they continue to improve even after completion of therapy. (11)

Advantages of SCC are (7): (a) Faster and more powerful sterilizing and bactericidal action, (b) Patients are exposed to potentially toxic drugs for shorter periods, (c) Regimens are less expensive and cost-effective, (d) Facilitates DOT, (e) More time and resources can be allotted to ensuring adherence.

Table 1. Results of six-month treatment regimen for Tuberculosis

Author,
Country, Publication

Diagnostic criteria

No. of
Children

Regimen

Results

Dossary Al, et al,
USA, (Pediatr
Infect Dis J
2002;21:91-97.)

Clinical and
Radiological

175

2 wk daily
HRZ, followed by 6 weeks
HRZ 2 / 4HR 2

81% treatment
completion,
1 relapse

Naude et al,
S.Africa. (Pediatr
Infect Dis
J 2000;19:405-10.)

Clinical and
Radiological

89
117

2HRZ 2 / 4HR 2 6RHZ

Rx outcome and adherence same, 1 relapse

Ramachandran
et al. India J Tub
1998;45:83-87).

Clinical and
Bacteriological
Clinical, Radiological and bacteriological

68
69

2HRZ 3 / 4HR 2

2% died,
0 failures,
3 relapses

Kumar et al, India, (Pediatr Infect Dis J 1990;9:802-806)

Clinical and
Bacteriological

37
39

2HRZ / 4HR 2
9HR

2 non-TB
deaths,
0 relapse

Biddulp, New <
Guinea, (Pediatr
Infect Dis
J 1990;9:794-801.)

Clinical and
bacteriological

639

2SHRZ / 4HR 2
2HRZ 2 /4HR 2

2% died,
1% relapse



Table 2. RNTCP treatment categories and regimens for children
Category of treatment

Type of patients

Intensive phase Continuation phase

CAT I

  • New sputum smear positive PTB
  • Seriously ill sputum smear negative PTB-All forms of PTB other than primary complex
  • Seriously ill extrapulmonary TB- TB meningitis, disseminated TB, TB pericarditis, TB peritonitis & intestinal TB, bilateral/extensive pleurisy, spinal TB, CUT TB, bone & joint TB.
2 HRZE
thrice
weekly
4 HR
thrice
weekly

CAT II

  • Sputum smear positive relapse,
  • Sputum smear positive treatment failure, Sputum smear positive default

2 SHRZE + 1 HRZE thrice weekly

5 HRE
thrice
weekly

CAT III

  • Sputum smear Negative PTB including primary complex
  • Not seriously ill extrapulmonary TB - TB lymphadenitis & unilateral pleural effusion
2 HRZ
thrice
weekly
4 HR
thrice
weekly

Treatment of childhood TB in RNTCP
  • DOTS is the recommended strategy for treatment of TB and all pediatric TB patients should be registered under RNTCP. The recommended treatment regimens are given in Table 2.
  • Intermittent short course chemotherapy given under direct observation, as advocated in the RNTCP, should be used.
  • In patients with TB meningitis on Category I treatment, the four drugs used during the intensive phase should be HRZ along with Streptomycin (S) as Ethambutol does not penetrate the CSF well.
  • Continuation phase of treatment in TB meningitis and spinal TB with neurological complications should be given for 6-7 months, extending the total duration of treatment to 8-9 months.
  • Steroids should be used initially in hospitalized cases of TB meningitis and TB pericarditis at a dose of 1-2 mg/kg and reduced gradually over 6-8 weeks.
  • In all instances before starting a child on Category II treatment, (s) he should be examined by a pediatrician or TB expert wherever available.
  • As recommended by WHO and in view of the growing evidence that the use of Ethambutol in young children is safe, it can be used in all as per RNTCP guidelines.
Patient-wise boxes
To assist in calculating required dosages and administration of anti-TB for children, the medication has been made available in the form of combipacks in patient wise-boxes (PWB). This will allow optimal dosage for the patients without resorting to breaking of the tablets.
  • Treatment will be based on the child's body weight and there will be two generic pediatric PWB's - Product code 13, Product code 14.
  • New formulation to be used in the programme consists of.
    • Rifampicin - 75/150 mg.
    • Isoniazid - 75/150 mg.
    • Ethambutol - 200/400 mg.
    • Pyrazinamide - 250/500 mg.
  • For the purpose of treatment, the pediatric population is divided into four weight bands and the corresponding PWB's are as follows:


Weight in Kg

Patient-wise box (PWB)

6-10

1 box of Product Code 13

11-17

1 box of Product Code 14

18-25

1 box of Product Code 13 +
1 box of Product Code 14

26-30

2 boxes of Product Code 14



  • Prolongation pouches are also available for extension of therapy.
Monitoring and Evaluation of Treatment
  • Pediatric-focused monitoring should be an integral part of the programme.
  • Wherever possible, follow-up sputum examination is to be performed with the same frequency as in adults.
  • Clinical or symptomatic improvement is to be assessed at the end of the intensive phase and at the end of treatment. Improvement should be judged by absence of fever or cough, a decrease in the size of lymph node(s) and weight gain.
  • Radiological improvement is to be assessed by chest X-ray examination in all smear-negative pulmonary TB cases at the end of treatment.
  • Adverse drug reactions though uncommon should be monitored.
Short Course Chemotherapy for extrapulmonary TB
  • In the developing world TB meningitis is still a disease of childhood with the highest incidence in the first three years of life.
  • Lymph node (LN) TB cases predominated (> 75%) amongst the pediatric EPTB cases registered under RNTCP.
  • When EPTB is suspected as a possible diagnosis, every attempt should be made to obtain samples of tissue/relevant body fluids for histopathological, cytopathological and microbiological diagnosis.
  • In the RNTCP, the DOTS strategy advocates the use of short course chemotherapy for patients with all forms of EPTB.(4)
  • In TB meningitis the treatment outcome is related to the stage of the disease at the time of treatment initiation and only a minority of the patients with severe disease recovers completely. Predictors of poor outcome are younger age and advanced stage. Neurological sequelae are directly related to the stage of the disease and the duration of symptoms prior to admission. (8)
  • Lymph nodes can enlarge, persist and become super infected with bacteria during the course of TB treatment, which are called paradoxical reactions. Generally no modifications or prolongation of ATT is indicated.
Feasibility of DOTS in children and longterm impact of SCC
A study was conducted in India in a tertiary care hospital to evaluate the feasibility of classification and treatment of various types of tuberculosis in children in line with the existing World Health Organization's proposed DOTS strategy for adults. The overall cure rate with primary treatment regimen was 98%, side effect in the form of hepatitis was observed in 2.6% of patients. Almost 15% of children referred with a diagnosis of tuberculosis, actually did not appear to have the disease, which emphasized the need for caution in diagnosis of tuberculosis in children. The study concluded that it is feasible to categorize tuberculosis in children based on WHO guidelines for adult tuberculosis, category based treatment of different types of tuberculosis gives good success rate and children with different types of tuberculosis can be included in DOTS programme.(9) A randomized controlled trial in India compared the treatment outcome of tuberculosis in children by DOTS given by an official DOTS provider or committed workers from NGO and concluded that both were equally effective and stressed the importance of NGO involvement in RNTCP. (10)

A 5 year follow-up of children with respiratory TB enrolled in a randomized clinical trial of two different ATT regimens of 9 months daily (9HR) versus 6 months of intermittent therapy (2HRZ3 / 4HR2) found similar cure rates and concluded that SCC in children is safe, effective and well tolerated leading to excellent long term results with a small proportion of children left with radiological sequelae. Thrice weekly regimen which had no relapses and lower rates of radiological sequelae will be operationally more feasible to implement in a programme setting.(11)
Childhood HIV/TB co-infection
HIV infection is probably one of the most important factors for the resurgence of TB in adults as well as in children. The impact of the HIV epidemic on pediatric TB has been documented in several studies. A prospective cohort study of children with TB reported that HIV-positive children were younger, more underweight and had a 6-fold higher mortality as well as a decreased cure rate than HIV-negative children.12 The study concluded that HIV-positive children are at risk of diagnostic error as well as delayed diagnosis of TB and weight for age may be used to identify children at high risk of a fatal outcome. A retrospective study from South Africa showed that TB-HIV co-infection in children is common, the presentation of tuberculosis may be acute and supportive tests are individually useful in confirming the diagnosis in a third of cases.(13) The changing pattern of presentation of childhood tuberculosis and the high prevalence of TB in HIV endemic areas have made it imperative to maintain a high index of suspicion with culture evaluation being an important part of clinical practice.

The prevalence of TB among HIV-infected children in various Indian studies ranges from 16-68%.(14,15) TB hastens the progression of HIV disease by increasing viral replication and reducing CD4 counts further.(16) However more studies are required to assess the role of newer diagnostic tests, TB preventive therapy and co-administration of anti-retroviral therapy in the management of TB among HIV-infected children. In a small study from Mumbai, 18% of children with disseminated tuberculosis (n=50) were HIV seropositive.(17) Children with TB should be tested for HIV infection if they have other suggestive clinical features like diarrhea, oral thrush, recurrent infections, failure to thrive, developmental delay or a history of HIV in the parents.
DOTS in childhood HIV/TB
The management of childhood HIV/TB is similar to that followed in HIV negative TB in children according to the guidelines of RNTCP. Category 1 regimen is to be used under the DOTS strategy. All HIV co-infected TB patients should received a rifampicin-containing regimen. To address the problem of drug interaction between Rifampicin and some of the anti-retroviral drugs (ARV) drugs such as Nevirapine, ARV treatment can be initiated after DOTS treatment is completed. For patients having more advanced stages of immunosuppression, concomitant anti-retroviral and ATT may be required. In such cases ARV needs to be suitably modified by replacing Nevirapine with Efavirenz (in children> 3 years and> 10 kg). Similarly if the child on ART develops active TB and ART should be suitably modified for compatibility with the RNTCP regimen.(18)

Drug-resistant TB in children

Pattern of drug resistance among children with TB tends to mirror that found among adults in the same population. Multidrug resistant TB (MDR-TB) is defined as resistance to both isoniazid and rifampicin with or without other drugs.

Drug resistant TB in India is mainly due to poor treatment adherence by the patient and poor management by the physicians. Initial drug resistance in adults to Isoniazid is reported to be in the range of 10-15%, for rifampicin 2-3% and MDR-TB 1-3%. These rates are much higher in patients who have taken prior, irregular treatment. A multicentric study to evaluate a diagnostic algorithm for TB in children in Chennai revealed an isoniazid resistance rate of 13% and MDR-TB of 3.5% (TRC, unpublished observation). As it is difficult to isolate M. tuberculosis from children with TB, the clue to drug resistance usually comes from the adult contact. Drug resistant TB should be suspected in the following circumstances:
  1. The child is in contact with a known case of drug-resistant TB.
  2. The child's adult contact has been on chronic irregular treatment and continues to be sputum positive.
  3. The adult contact died after taking irregular treatment; and
  4. The child shows initial improvement to ATT and deteriorates (clinically and radiologically).

The only definitive way of diagnosing drug resistance is by isolating M. tuberculosis from the sputum/tissue and assessing its susceptibility pattern, which takes up to 8 weeks.
Treatment for Drug-resistant TB in children
Child contacts of adults with drug resistant TB should be treated according to the drug susceptibility patterns of the M. tuberculosis strain of the source cases unless their own strain's susceptibility testing indicates otherwise. Contact tracing is of fundamental importance in identifying children at risk.

Therapy for drug resistant TB is successful when at least 2 bactericidal drugs to which the infecting strain of M. tuberculosis is susceptible are given. Exact treatment regimens can be individually tailored to the specific pattern of drug resistance. If not at least 3 drugs to which the patient is not exposed earlier should be given. Resistance to INH or Streptomycin alone can be managed with standard 4-drug regimen with good results. However when resistance to both INH and rifampicin is present (MDR-TB) the management is more complicated and requires second line drugs (e.g., Ethionamide, aminoglycoside). A standard regimen used is 6S3/Oflox acid, Ethambutol, Ethionamide, Pyrazinamide. The duration of therapy is usually 18-24 months with an injectable drug for the 1st 6 months. Occasionally surgical resection of the diseased lung or lobe is required.
DOTS - Plus
DOTS-Plus, conceived by WHO and several of its partners is a strategy currently under development for the management of MDR-TB. As the treatment for MDR-TB is very complex, treatment will follow the internationally recommended DOTS-Plus guidelines and will be done in designated RNTCP-DOTS-Plus sites. The RNTCP is establishing a network of State level quality assured culture and drug susceptibility testing laboratories. There will be systems in place to deliver ambulatory DOT after an initial short period of an-patient care. The DOTS-Plus sites will be initiated in a phased manner for providing care to MDR-TB patient.(6)
References :
  1. Chauhan LS, Arora VK. Management of pediatric tuberculosis under the revised national tuberculosis control program (RNTCP). Indian Pediatr 2004;41:901-906.
  2. Adhilakshmi AR and Swaminathan S. Epidemiology of TB in children. In: 'Common MDR infections in Children-Typhoid, Tuberculosis, Malaria' eds by Nupur Ganguly, Ritabrata Kundu, Tapan Kr Ghosh. CBS publishers, pp 51-56.
  3. Swaminathan S and M. Global aspects of TB in children. Pediatr Respir Reviews 2001;2:91-96.
  4. WHO. Treatment of tuberculosis. Guidelines for National Programmes. Geneva: WHO;2003 (WHO/CDS/TB 2003;313).
  5. Formulation of guideline for diagnosis and treatment of pediatric TB cases under RNTCP. Consensus statement. A Joint Statement of the Central TB Division, Directorate General of Health Services, Ministry of Health and Family Welfare and Experts from Indian Academy of Pediatrics. Indian J Tuberc 2004;51:102-105.
  6. TB India 2006.RNTCP status report. Central TB division (www.tbcindia.org)
  7. Swaminathan S. Treatment of tuberculosis. Indian J Pediatr. 2000;67(2) Suppl):S14-20.
  8. Humpries MJ, Tech R, Lure J, Gabriel M. Factors of prognostic significance in Chinese children with tuberculous meningitis. Tubercle 1990;71:161-168.
  9. Kabra SK, Lodha R, Seth V. Category based treatment of tuberculosis in children. Indian Pediatr 2004;41:927-937.
  10. Meenu Singh, Lata Kumar. A Randomized Controlled Trial of Directly Observed Treatment Short course (DOTS) for Childhood Tuberculosis by Using an Official DOTS Provider and Non Governmental Organizations. Chest 2004;126(4):910S.
  11. Swaminathan S, Raghavan A, Duraipandian, et al. Short course chemotherapy for pediatric respiratory tuberculosis: 5 year report. Int J Tuberc Lung Dis 2005;9(6):693-696.
  12. Palme IB, Gudetta B, Bruchfeld J, Muhe L, Giesecke J. Impact of human immunodeficiency virus-1 infection on clinical presentation, treatment outcome and survival in a cohort of Ethiopian children with tuberculosis. Pediatr Infect Dis J 2002;21:1053-1061.
  13. Jeena PM, Pillay P, Pillay T, Coovadia HM. Impact of HIV-1 co-infection on presentation and hospital-related mortality in children with culture proven pulmonary tuberculosis in Durban, South Africa. Int J Tuberc Lung Dis 2002;6:672-8.
  14. Merchant RH, Oswal JS, Bhagwat RV, Karkare J. Clinical profile of HIV infection. Indian Pediatr 2001;38:239-246.
  15. Lodha R, Singhal T, Jain Y, Kabra SK, Seth P, Seth V. Pediatric HIV infection in a tertiary care center in north India: early impressions. Indian Pediatr 2000;37:982-986.
  16. Swaminathan S. Tuberculosis in HIV-infected children. Paediatr Respir Rev. 2004 Sep;5(3):225-230.
  17. Merchant RH, Shroff RC. HIV seroprevalence in disseminated tuberculosis and chronic diarrhea. Indian Pediatr 1998;35:883-887.
  18. World Health Organization. TB/HIV: A clinical manual. WHO/HTM/TB/2004.329. Geneva: World Health Organisation;2004.
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