Table 3 Summary of findings from selected records

Childhood tuberculosis in Serbia. (Gledovic et al. [13]).

4 (Moderate)

1. In the period 1992–2002, 280 Serbian children were reported as having newly diagnosed tuberculosis.

2. 129 were boys and 151 were girls (gender ratio, 0.8:1).

3. The majority of children, 217 (77.5%), were in the age group 5–14 years.

4. The average annual incidence rate in the observed period was 1.79/100,000 (95% confidence interval, 0.92–3.13).

5. The rate for girls was higher than in boys.

6.The rates for both boys and girls were higher in the age group 5–14 years than for the age group 0–4 years

Missing

Missing

In Serbian children, tuberculosis was more frequent in the age 5–14 years (77.5%) than in the youngest age group. This finding is opposite to that of other countries.

1. Retrospective study in nature therefore some data could be missing or incomplete.

Multidrug-Resistant Tuberculous Meningitis in Children in Durban, South Africa. (Padayatchi et al. [17])

5.5 (High)

Missing

1. A retrospective review of medical records of children with culture-confirmed multidrug-resistant tuberculous meningitis (MDR-TBM) at King George V Hospital in Durban, South Africa.

2. Between 1992 and 2003, there were 8 children with MDR-TBM; 6 were HIV infected and 2 were HIV negative. Only one child survived.

3. All the children either had Calmette-Gue´rin bacillus (BCG) scars or a history of BCG vaccination.

Therapeutic options treated with include INH, Rif, PZA, Emb, Eth, Ofloxacin and Streptomycin

Factors that contributed to the high mortality were disseminated TB, HIV infection, delay in diagnosis and treatment, the absence of a standardized approach to the management of MDR-TBM and the poor CSF penetration of most MDR-TB drugs. MDR-TB therapy should be considered if there is a history of TB: a MDR-TB contact or a poor clinical response to TB therapy despite adequate adherence to treatment. Early diagnosis is important because TBM in children is often associated with a serious outcome.

1. The study was conducted in only one Hospital Facility.

2. The study focused on TB meningitis specifically as a form of MDR-TB.

3. Small sample size.

High prevalence of childhood multi-drug resistant tuberculosis in Johannesburg, South Africa: a cross sectional study. (Fairlie et al. [18])

6 (High)

1. 1317 children were treated for tuberculosis in 2008 between the two hospitals where the study was conducted.

2. Drug susceptibility testing was undertaken in 148 (72.5%) of the 204 children who had culture-confirmed tuberculosis.

3. The prevalence of HIV co-infection was 52.1%.

1. The prevalence of isoniazid-resistance was 14.2% (n = 21) (95%CI, 9.0-20.9%) and the prevalence of MDR-TB 8.8% (n = 13) (95%CI, 4.8-14.6%).

2. The prevalence of HIV co-infection was 53.9% in children with MDR-TB.

1. Included treatment with pyrazinamide, ethionamide, ethambutol, amikacin and ofloxacin in the intensive phase of treatment with the addition of terizidone and/or kanamycin if additional resistance patterns were present.

2. Continuation phase MDR-TB treatment consisted of ethionamide, ethambutol and ofloxacin

The study demonstrated a high prevalence of drug-resistant MTB in a cohort of children diagnosed with culture-confirmed tuberculosis in Johannesburg, South Africa; this likely represents a large burden of undiagnosed drug-resistant MTB in household and community adult contacts of these children. All child tuberculosis suspects in settings with a high prevalence of tuberculosis and HIV should have confirmation of their HIV infection status. Furthermore, we recommend that routine DST should be performed on MTB isolates obtained from children with culture-confirmed TB in these high-burdened settings.

1. May have overestimated the true MDR-TB prevalence in children in Johannesburg, as patients attending referral hospitals may be at higher risk for drug-resistant tuberculosis compared to those investigated and treated at primary care facilities. 2. Furthermore, DST was performed in only 72.5% of children with culture-confirmed tuberculosis at clinician discretion.

3. Drug susceptibility testing against pyrazinamide is not routinely performed in our setting and is only performed on clinician request. 4. As the study was retrospective and record-based, contact history data may be inaccurate. 5. Detailed data on children with drug-susceptible MTB was not available for this study, as information was collected from laboratory records.

Culture-confirmed multidrug-resistant tuberculosis in children: clinical features, treatment, and outcome. (Seddon et al. [9]).

6 (High)

Missing

1. 111 children with MDR-tuberculosis were identified, with a median age of 50 months.

2. Forty-two samples underwent DST to second-line drugs, which identified 3 MDR-tuberculosis cases resistant to amikacin, 4 resistant to ofloxacin, and 5 resistant to both ofloxacin and amikacin (XDR-tuberculosis).

3.Fifty-three (62%) of 85 children with a sputum result were smear positive; a positive sputum smear was more common in older children (median age, 85 months [IQR, 25–132 months] vs 24 months [IQR, 15–59 months].

The following drugs were used as treatment:

- High dose INH

- Rif

- PZA

- Eth

- Emb

- Streptomycin

- Amikacin

- Capreomycin

- Ofloxacin

- Terizadone or cycloserine

- Para-aminosalicylic acid

- Linezolid

In conclusion, although South African children with confirmed MDR-tuberculosis often present with severe disease and have a high frequency of HIV infection, excellent treatment outcomes can be achieved in high-burden settings with individualized clinical care under standard programmatic conditions.

1. Reliance on routine data.

2. No systematic data regarding adverse effects, and the tolerability of multiple medications, frequently unpalatable, was not systematically assessed.

3. Although all samples were confirmed to be MDR-tuberculosis, DST for second-line drugs was not routinely completed during the study period.

4. Finally, although treatment outcomes were good, no comment on morbidity as a result of MDR-tuberculosis disease and treatment.

The epidemiology of childhood tuberculosis in the Netherlands: still room for prevention. (Erkens et al. [19])

6 (High)

1. The absolute number of children with TB decreased from 106 in 1993 to 50 in 2012

2. Overall childhood TB incidence has declined over the last two decades from 3.6 in 1993 to 1.9 per 100,000 children in 2012.

Missing

Missing

Children with TB in the Netherlands are generally detected at an early stage and treatment completion rates are high. However, more TB cases among children can be prevented through enhancing TB case finding and screening and preventive treatment of latent TB infection among migrant children, and improving the coverage of BCG vaccination among eligible risk groups.

1. A limitation of the study is that the data are retrieved from the routine TB surveillance registry and are not collected systematically with a strict research design. 2.The Dutch surveillance system is generally regarded as sound and representative of TB incidence.

2.In passively detected TB cases BCG status is not relevant for the clinical management and therefore more likely to be missing. Thus BCG vaccination coverage among the child TB cases may be underestimated.

Presentation and outcome of tuberculous meningitis among children: experiences from a tertiary children's hospital. (Nabukeera-Barungi et al. [20])

3.5 (Moderate)

1. Of 22,943 children admitted to RCWMCH during the study period, we identified 40 children newly diagnosed with TBM; an incidence rate of 1.7 per 1000 admissions.

2. Of the 40 children diagnosed with TBM, 6 (15%) had definitive TBM, 17 (42.5%) had probable TBM and 17 (42.5%) had possible TBM.

Missing

Missing

We found that TBM mainly presented with acute non specific symptoms but the rigorous diagnostics helped make a quick diagnosis and start early treatment. Outcome of treatment at discharge was good with less than 10% mortality and half with neurological sequelae at discharge from hospital. Poor outcome was associated with TBM stage III disease.

1. Retrospective design in which data recording was not standardized and as such some information was missing.

2. Another limitation was with our entry point which was the hospital records department.

3. Some TBM diagnoses may have been missed out just as we found that some codes were in error.

The growing burden of childhood tuberculosis in Southern Tunisia: temporal trends across two decades: 1995-2016. (Ben Ayed et al. [21])

6 (High)

1. Overall, 204 cases of TB were noted in children. 2. The average incidence rate of overall TB was 4.09/100000 population/year.

3. There was a significant rise in extrapulmonary tuberculosis (EPTB) incidence (APC=2.76%; 95% confidence interval (95% CI)=[0.40-5.00]), while pulmonary tuberculosis PTB incidence rate showed a non-significant decrease over time.

4. The under-fives had a significant growing trend (APC of 3.95%; 95% CI=[0.80-7.30]).

5. A significant upward trend of TB incidence in rural districts (APC=4.91%; 95% CI=[1.90-8.10]).

Missing

Missing

The study provided an insight into the burden of childhood TB in South of Tunisia. A significant rise in TB incidence rate was observed among high risk groups. Therefore, implementing preventive and control strategies must be urgently prioritized, with an emphasis on contact screening, maintaining a high BCG vaccination coverage and awareness-raising activities in the community in order to reduce TB transmission in this highly vulnerable population.

1. Firstly, because of the retrospective data collection, the patients were not followed-up during the study period and the treatment outcome as well as the response to therapy could not be assessed.

2. Secondly, analyzing data from a delimited area may not reflect the real burden of childhood TB in the whole country.

3. Another limitation of this study is possible missing or incomplete data, as well as potential biases and errors during date entry.

Epidemiological, clinical characteristics and drug resistance situation of culture-confirmed children TBM in southwest of China: a 6-year retrospective study. (Wang et al. [22])

4.5 (High)

1. Among 319 patients clinically diagnosed with TBM, 42 (13.2%) were Mycobacterial culture positive.

2. Their median age was nine years, and the distribution was equal among female and male patients.

Missing

Missing

TBM among children in Southwest China was mainly concentrated in the minority areas of western Sichuan and more than 95% of patients did not receive BCG vaccination at birth. The most common symptoms were fever, headache, and neck stiffness and all patients had positive chest X-ray findings. In addition, high rates of drug resistance were found.

1. Major limitation was that the study was retrospective in nature.

Prevalence of multidrug-resistant tuberculosis in suspected childhood tuberculosis in Shandong, China: a laboratory-based study. (Zhou et al. [23])

5.5 (High)

Missing

1. In Shandong, the prevalence of MDR-TB in childhood TB was low, at 5.6%. 2.Between 2008-2013 and 2014-2018 among children with TB, the prevalence of MDR-TB remained unchanged, the proportion with pulmonary TB decreased from 78.3% to 64.9%

Missing

The prevalence of MDR-TB among childhood TB in Shandong, China was low and has remained stable over the past years. However, non-tuberculous mycobacterial diseases may be a new challenge in the management of suspected childhood TB.

Some limitations exist. In our study, 12 MDR-TB patients were included, and the average annual number of patients with MDR-TB was fewer than two. If comparing results in each year from 2008 to 2018, statistical significance may never be achieved. For this reason, we divided the study into two periods: 2008 to 2013 and 2014 to 2018.