Epidemiology of tuberculosis and treatment outcomes among children in Pakistan: a 5 year retrospective study

Ethics approval and consent to participate

Ethical approvals were issued by the relevant Institutional Research and Ethics Boards (IREBs) of Shah Bhitae Hospital Latifabad, Hyderabad Liaquat University Hospital Hyderabad / Jamshoro, Sindh Government Hospital Qasimabad, Hyderabad, Sayed Baqadar Shah Civil Hospital Matiari and Institute of chest diseases Kotri Sindh, Pakistan, (Vide Letter No: SBGH/L.ABAD HYD-1575; Dated: 13-04-17, LUH/Estt/-23176/14; Dated: 06-08-2016, MS-SGHQ/HYD/2187: Dated:13-04-17, CS/CH/MAT:1761; Dated:18-05-16 and ICDK/771; Dated: 12-04-17, respectively).

Study design and data collection

This was a retrospective study. Data was collected from January 2011 to December 2015 for children suffering from TB and registered under DOTS. In order to determine the proportion of childhood cases, total TB cases including the numbers of adults were collected from TB registers. The registers contain information regarding the socio-demography (age, gender, and residence), clinical manifestations and laboratory examination (sputum or gastric aspirates microbiology, HIV status, radiography and histopathology results). All that information was transferred on a data collection form specially designed for the study. Patients were grouped as ≤2 years, 3 to 5 years, 6 to 10 years and 11 to 14 years. Body weight was calculated in percentiles using the data table of weight for age charts by Centres for Disease Control and Prevention (CDC). Patients with weight <5 percentiles were recorded as underweight and those with ≥95 percentiles were considered as overweight (Centers for Disease Control and Prevention NCfHS, 2001).

Children with TB are diagnosed and treated according to NTP under the DOTS strategy (Fig. 1). Each child with clinical symptoms including a cough lasting for ≥2 weeks, fever, night sweats, dyspnoea and sputum production were examined. Assessment of nutritional status was done based on weight-for-age data from weight-for-age charts (Centers for Disease Control and Prevention, 2001). Children were diagnosed as having TB by considering suggestive clinical features, the history of contact, positive TST (≥10 mm was considered positive) (WHO, 2014), scoring charts (suggested by the Pakistan Paediatric Association) and evidence of TB in chest X-ray (CXR) for pulmonary TB (PTB). Culture and Xpert MTB/RIF assays were used as add-on tests and specifically performed to exclude resistant TB. Furthermore, common forms of EPTB were diagnosed based on a positive result of an appropriate test: peripheral lymphadenitis: lymph node biopsy or fine needle aspiration (FNAC); miliary TB: CXR; TB meningitis: lumbar puncture with cerebrospinal fluid (CSF) analysis or cerebral computed Tomography (CT); pleural effusion TB: CXR and pleural tap; abdominal TB: abdominal ultrasound and ascetic tap; and bones/joints TB: X-ray, joint tap or synovial biopsy (National TB Control Program, 2015).

The regimen was prescribed on a category basis. The four treatment categories are as follows: Category-I is new smear positive PTB (PTB+), severe forms of new extra-pulmonary TB (EPTB), new severe concomitant HIV disease and TB meningitis. Category-II is previously treated PTB+ (relapse, treatment after interruption and treatment failure). Category-III comprises new smear negative PTB (PTB-) and less severe forms of EPTB. Category-IV includes chronic and multidrug resistant TB (MDR-TB). The children diagnosed with TB always have an intensive phase of 2 to 3 months and a continuation phase of 4 to 6 months. The anti-TB drugs dosage depends on body weight and category of patient.

Treatment of children with TB aged ≤14 years as per NTP is given in Table 1. NTP follows the treatment and dosage criteria as recommended by WHO (WHO, 2010). Patients weighing <5 kg are treated with individualized dosages while those weighing more than 30 kg are treated using adult dosages.

According to the WHO (World Health Oragnization, 2014), patients who were stated “cured” and/or had “completed treatment” were termed as a “treatment success”, and all those patients who had defaulted, died, or experienced treatment failure were reported under the category of “unsuccessful treatment”. A cured patient was a bacteriologically confirmed PTB patient and became smear negative in the last month of treatment and on at least one previous occasion. Treatment completed included TB patients who completed treatment with no record to show smear negative in the last month of treatment and on at least one previous occasion.

Defaulters patients were those whose treatment was interrupted for 2 consecutive months or more for any reason and failure patients were those whose sputum smear was positive at 5 months of treatment or later.

Data analysis

Data was entered and analysed using the Statistical Package for the Social Sciences (SPSS) for Windows, version 24. Frequencies of categorical variables were generated by descriptive statistical methods. Comparisons in categorical groups were performed using the chi-square test. A logistic regression model was used to determine the predictors of unsuccessful outcome and PTB. P values <0.05 were considered statistically significant.

Proportion and trend of notification cases of childhood TB

Figure 2 shows the proportion of childhood TB cases at the study site. During 2011 to 2015, childhood TB accounted 11.3% (216719219) of all TB burden in three districts. The Proportion of childhood TB ranged from 8.5% in 2011 to 18% in 2015. In 2012, 2013 and 2014, the child cases represented 8.5%, 8.8% and 9.9% respectively, of overall TB cases at the study site. Differences in the proportion of childhood TB between the districts were observed, with the highest being in Jamshoro district and the lowest in the Matiari district.

A total of 2,167 patients meeting the inclusion criteria were enrolled in the study. In Hyderabad, childhood TB cases are registered at Sindh Government Hospital Qasimabad, Hyderabad (SGH-QH), Shah Bhitai Government Hospital, Latifabad, Hyderabad (SBGH-LH) and Liaquat University of Medical and Health Sciences Civil Hospital, Hyderabad (LUMHS-CHH) where treatment is provided under the DOTS program. Among these three hospitals, the maximum numbers of patients were registered in LUMHS-CHH (487) as compared to SBGH-LH (136) and SGH-QH (52). Overall, the highest numbers of children with TB (1,172) were registered in the Institute of Chest Diseases Kotri, Sindh (ICDK) during the present study which was almost four times the number of cases (320) registered at Syed Baqadar Shah Taluka Hospital, Matiari (SBS-THM). The increased trend was observed from 2011 to 2015 in SBGH-LH and ICDK. Conversely, in SGH-QH and LUMHS-CHH, the highest numbers of cases were reported at the start of the study and then a steady decline was observed. For SBS-THM, the increasing trend was seen from 2011 to 2014, and that dropped off in 2015.

Trend of type of TB from 2011–2015

Initially, the proportion of PTB- was 15.2% that declined to 14.7% in 2012. A slight increase was noticed in the rate of PTB- (15.4%) during 2013 that dropped to 14% in 2014 but then went up to 15.6% at the end of the period. Conversely, the proportion of PTB+ was low (12.4%) during 2011 but then rose steadily to 13.4% and 14.2% in 2012 and 2013, respectively. The rate of PTB + subsequently descended from 12.7% in 2014 to 8.7% in 2015. In terms of EPTB, the rate gradually climbed between 2011 and 2014 (21.2–29.2%) (Fig. 3) and subsequently dropped to 18.7% at the end of study period.

Demographic and clinical characteristics of patients

Of the total 2,167 patients, 1,199 (55.3%) were females and 968 (44.7%) were males with a mean age of 7.4 ± 4.4 years. The majority of the children were aged between 11 to 14 years (33%) followed by 28% in the age group of 6 to 10 years. Children aged 3 to 5 years were the smallest group comprising 17% of the total (Table 2). Baseline weight was documented for all patients and 75.2% of them were found to be underweight. Over three-quarter, 1,666 (76.9%) of children were diagnosed with PTB. Of the total PTB cases, 331 (15.3%) had PTB- and 221 (10.2%) presented with PTB +. The remaining 1,114 (51.4%) of PTB cases were those who had no sputum examination (PTBNS). The majority (91%) of PTB+ were ≥9 years with the remaining 9% aged 7 to 8 years. In 501 cases of EPTB, peripheral lymphadenitis was the most frequent (62.4%) followed by 17.3% with abdominal TB (Table 2).

Concerning therapeutic categorization, 2,083 (96.1%) were new cases (patients had either received no ATT or received for <1 month in the past) and 84 (3.9%) were cases of re-treatment (those received ATT >1 month in the past). Of re-treatment cases, 9 (10.7%) were registered as relapse cases, 28 (33.3%) were default, 14 (16.7%) were failure and 33 (39.3%) cases were recorded as others. Similarly, 41 (48.8%) presented with PTB+ and 20 (23.8%) had PTB- while 23 (27.4%) were cases of EPTB.

Risk factors of PTB

In univariate analysis, variables which had statistically significant positive association with PTB were being male (OR: 1.329, p = 0.006), age group ≤2 years (OR: 2.230, p < 0.001) and patients documented as underweight (OR: 1.285, p = 0.029) with higher odd ratios comparatively to their counterparts. There was no significant difference observed between rural and urban residents.

After adjusting for risk factors of PTB in univariate logistic regression, variables which were significantly associated with PTB in multivariate analysis were male (OR: 1.262, p = 0.029), children aged ≤2 years (OR: 1.953, p < 0.001) and those reported as underweight (OR: 1.342, p = 0.008) (Table 3).

Treatment outcomes

Among the 2,167 registered children, 56 (2.6%) had no documented treatment outcomes. Of 97.4% patients with documented treatment outcomes, 92.4% successfully completed treatment. There was no significant difference in the treatment success among male and female patients (p > 0.05). Children aged 11 to 14 years had the lowest treatment success (90.2%). The death rate was higher among ≤2 years (2.4%) followed by age group 3 to 5 years with a death rate of 1% (Table 4). The highest rate of default (5.6%) and failure (2.3%) was presented among those aged 11 to 14 years. Female patients had a non-significantly increased rate of default compared to male patients.

Patients from urban areas had the highest proportion of treatment success (94.7%) whereas the rate of failure, default, and death was high among rural and re-treated patients. Correspondingly, among all sputum smear grading, +2 and +3 had lower treatment success rate. Those suffering from EPTB were seen with more successful treatment outcomes relative to those with PTB.

Factors associated with unsuccessful treatment outcomes

Table 5 presents the risk factors for unsuccessful treatment outcomes in logistic regression analysis. In univariate analysis, age group 11 to 14 years (OR: 1.571, p < 0.001), rural residents (OR: 2.101, p < 0.001), PTB+ (OR: 3.986, p < 0.001), underweight patients (OR: 1.581, p = 0.033) and retreated patients (OR: 7.962, p < 0.001), were observed as potential predictors of unsuccessful treatment outcomes with higher odd ratios value.

In multivariate analysis, rural residents (OR: 2.146, p < 0.001), PTB+ (OR: 3.409, p < 0.001) and re-treated patients (OR: 5.919, p < 0.001), were positively associated with unsuccessful treatment outcomes with higher odd ratios.

Limitations of study

The study has some limitations. Firstly, since the study was retrospective it was not possible to collect socioeconomic data and adverse effects observed during the treatment. Factors like family income and parents’ education, that could affect the treatment outcomes were not recorded and thus not examined. Secondly, features such as household size, household contacts and nutritional status, which might serve as risk factors for childhood TB, were also not documented.