Clinical standards for drug-susceptible TB in children and adolescents.

BACKGROUND: These clinical standards aim to provide guidance for diagnosis, treatment, and management of drug-susceptible TB in children and adolescents.METHODS: Fifty-two global experts in paediatric TB participated in a Delphi consensus process. After eight rounds of revisions, 51/52 (98%) participants endorsed the final document.RESULTS: Eight standards were identified: Standard 1, Age and developmental stage are critical considerations in the assessment and management of TB; Standard 2, Children and adolescents with symptoms and signs of TB disease should undergo prompt evaluation, and diagnosis and treatment initiation should not depend on microbiological confirmation; Standard 3, Treatment initiation is particularly urgent in children and adolescents with presumptive TB meningitis and disseminated (miliary) TB; Standard 4, Children and adolescents should be treated with an appropriate weight-based regimen; Standard 5, Treating TB infection (TBI) is important to prevent disease; Standard 6, Children and adolescents should receive home-based/community-based treatment support whenever possible; Standard 7, Children, adolescents, and their families should be provided age-appropriate support to optimise engagement in care and clinical outcomes; and Standard 8, Case reporting and contact tracing should be conducted for each child and adolescent.CONCLUSION: These consensus-based clinical standards, which should be adapted to local contexts, will improve the care of children and adolescents affected by TB.

TB and TB-HIV care for adolescents and young adults.

SETTING: Nine high-burden public tuberculosis (TB) clinics in Gaborone, Botswana.OBJECTIVE: To evaluate the challenges encountered, healthcare worker (HCW) approaches, and supported interventions in TB and TB-HIV (human immunodeficiency virus) care for adolescents and young adults (AYA, aged 10-24 years).DESIGN: Semi-structured interviews with HCW in TB clinics, analyzed using thematic analysis.RESULTS: Sixteen HCWs were interviewed. AYA developmental needs included reliance on family support for care, increasing autonomy, attending school or work, building trust in HCWs, and intensive TB education and adherence support. Stigma strongly influenced care engagement, including clinic attendance and HIV testing. Health system barriers to optimal AYA TB care included limited staffing and resources to follow-up or support. HCWs utilized intensive education and counseling, and transitioned AYA to community-based directly observed therapy whenever feasible. HCWs supported implementation of youth-friendly services, such as AYA-friendly spaces or clinic days, training in AYA care, use of mobile applications, and peer support interventions, in addition to health system strengthening.CONCLUSION: HCWs utilize dedicated approaches for AYA with TB, but have limited time and resources for optimal care. They identified several strategies likely to improve care and better retain AYAs in TB treatment. Further work is needed to study interventions to improve AYA TB care and outcomes.

Diversity of Rotavirus Strains Circulating in Botswana before and after introduction of the Monovalent Rotavirus Vaccine.

BACKGROUND: Globally, rotavirus is the leading cause of acute gastroenteritis (AGE) in children aged <5 years. Botswana introduced the monovalent rotavirus vaccine (Rotarix) in July 2012. To study the impact of this vaccine on rotavirus genotypes circulating in Botswana, a comparison of the genotypes pre-vaccination (2011-2012) and post-vaccination (2013-2018) periods was conducted. SUBJECTS AND METHODS: Residual samples from 284 children <5 years of age that tested positive for rotavirus by enzyme immunoassay were genotyped. One hundred and five samples were from the pre-vaccination period and 179 were from the post-vaccination period. Genotyping was performed using two multiplexed one-step reverse transcription polymerase chain reaction (RT-PCR) assays for the amplification and genotyping of rotavirus VP7 (G) and VP4 (P) genes. RESULTS: Prior to vaccine introduction, the predominant rotavirus circulating genotypes were G9P[8] (n = 63, 60%) and G1P[8] (n = 22, 21%). During the vaccine period, G2P[4] was the predominant genotype (n = 49, 28%), followed by G9P[8] (n = 40, 22%) and G1P[8] (n = 33, 18.5%). There was a significant decline in the prevalence of G9P[8] (p = 0.001) in the post-vaccination period. There was also a notable decline in G1P[8]. A spike in G2P[4] was observed in 2013, one year post-vaccine introduction. Rotavirus strain G3P[4] (n = 8) was only detected in the post-vaccine introduction period. In 2018 there was a marked increase in genotype G3P[8] (p = 0.0003). CONCLUSIONS: The distribution of circulating rotavirus genotypes in Botswana changed after vaccine implementation. Further studies are needed to examine whether these changes are related to vaccination or simply represent natural secular variation.

Initiation of anti-tuberculosis treatment in children following gastric aspirate testing, Botswana, 2008-2012.

SETTING: Diagnosing pediatric tuberculosis (TB) is difficult; to improve diagnosis, gastric aspiration (GA) was performed in 121 Botswana health facilities. OBJECTIVE: To describe treatment initiation and outcomes in children with a positive GA result and those treated empirically. METHODS: Children with smear or culture-positive GA or those clinically diagnosed were referred for anti-tuberculosis treatment. Treatment initiation and outcomes were assessed from February 2008 to December 2012 using name-based matching algorithms of the GA database; treatment initiation was captured in the electronic TB registry. Analyses included descriptive statistics and regression models. RESULTS: GA was conducted in 1268 children. Among these, 121 (9.5%) were GA-positive; and treatment was initiated in 90 (74.3%). An additional 137 (11.9%) were treated empirically. More than a third (36.4%) had known human immunodeficiency virus status (positive or negative); this was significantly associated with TB treatment initiation (adjusted odds ratio [aOR] 1.8, 95%CI 1.3-2.5); P < 0.05). Among the 90 children with a positive GA result, nearly all either completed treatment (78.9%) or were on treatment (20.0%) at the time of data collection. CONCLUSION: We could not find documentation of treatment for more than a quarter of the children with laboratory-confirmed TB, an important gap that calls for further examination. The failure to initiate prompt treatment requires investigation and urgent action.

Risk factors for gastric aspirate culture contamination in children evaluated for tuberculosis in Botswana.

SETTING: Gastric aspirate (GA) sample culture is commonly performed in children evaluated for tuberculosis (TB) who cannot expectorate sputum. Contamination limits culture yield and negatively impacts care. OBJECTIVE: To evaluate the proportion of and factors associated with GA contamination at a central TB reference laboratory in Botswana. DESIGN: This was a 5-year cross-sectional study of untreated children aged 12 years evaluated for TB with the first GA sample registered at the National Tuberculosis Reference Laboratory. We performed descriptive statistics to assess the risk of contamination with patient age, sex, transport time and distance, culture medium, and facility type. We generated multivariable logistic regression models using generalized estimating equation extension. RESULTS: We analyzed 3642 samples. The median age was 2 years (interquartile range [IQR] 1-4), median transport time was 4 days (IQR 2-7), and 64.1% of samples were from clinics or health posts. TB culture positivity was 1.6% (60/3642), and contamination was observed in 35.6% (1298/3642). Hospital collection was associated with lower contamination risk (adjusted OR [aOR] 0.53, 95%CI 0.40-0.69) and Mycobacteria Growth Indicator Tube vs. Löwenstein-Jensen medium with higher risk (aOR 1.88, 95%CI 1.51-2.34). CONCLUSION: In routine care settings, high sample contamination and low TB culture yield were observed. This raises questions about the collection technique and storage in lower-level facilities and affirms higher risk with a liquid culture medium.

Survey of health care worker knowledge about childhood tuberculosis in high-burden centers in Botswana.

BACKGROUND: Quantifying health care workers' (HCWs') knowledge about tuberculosis (TB) informs educational interventions. We assessed HCWs' knowledge about childhood TB in Botswana. METHODS: Semi-structured interviews were conducted with HCWs at 46 sites around Botswana using a piloted instrument. Transcripts were double-coded using a coding schema. Discrepancies were resolved by consensus and a systematic thematic analysis was performed. RESULTS: The sites (42 clinics and 4 hospitals) were urban (n = 9, 20%), semi-urban (n = 10, 22%) and rural (n = 27, 58%). HCWs included nurses (n = 42, 89%) and nurse assistants (n = 4, 11%). Sixteen (56%) HCWs were the TB focal persons for their site. Themes did not vary by type of site, HCW or TB focal person. Although the level of knowledge about secondary prevention using isoniazid prophylaxis therapy was fair, implementation was poor and contact tracing was not being performed. Barriers to TB diagnosis included poor knowledge about TB in the community, minimal diagnostics at site of care and not receiving test results. However, most HCWs reported that treatment initiation and the calculation of appropriate dosages were easy once the diagnosis had been made. CONCLUSIONS: In Botswana, HCWs' levels of knowledge about childhood TB varied greatly. The areas of TB diagnosis, screening and prophylaxis in children need additional attention in TB training courses; however, increased knowledge alone would not overcome all the barriers identified by the HCWs.

Registrar wellness in Botswana: Measuring burnout and identifying ways to improve wellness

Background. Burnout during registrar training is high, especially in resource-limited settings where stressors are intensified. Burnout leads to decreased quality of life for doctors, poor job and patient satisfaction, and difficulty retaining doctors.Objectives. Primary: to measure burnout among registrars working at Princess Marina Hospital in Gaborone, Botswana. Secondary: to determine factors contributing to burnout and identify potential wellness interventions.Methods. The validated Maslach Burnout Inventory was used to measure the degree of emotional exhaustion, depersonalisation and personal accomplishment. Work-related difficulties and potential wellness interventions were explored through multiple-choice and open-ended questions.Results. Of 40 eligible registrars, 20 (50%) completed the survey. High levels of burnout were reported for emotional exhaustion in 65% (13/20), depersonalisation in 45% (9/20), and personal accomplishment in 35% (7/20) of registrars. A high degree of burnout was reported by 75% (15/20) of registrars in one or more domains. In the previous 7 days, registrars worked an average of 77 hours, took 1.5 overnight calls, slept 5.7 hours per night, and 53% (10/19) had ≥1 of their patients die. Five (25%) registrars considered leaving Botswana to work in another country, which correlated with those with the highest degree of burnout. The most common frustrations included insufficient salary and limited medical resources. Suggested interventions included improved mentorship and wellness lectures.Conclusions. There is a high degree of burnout, especially emotional exhaustion, among registrars. Encouragingly, most registrars have a desire to work in Botswana after training. Future research on improving registrar wellness in low-resource settings is urgently needed

'That's when I struggle' Exploring challenges faced by care givers of children with tuberculosis in Botswana.

SETTING: Government-funded public health clinics in and around Gaborone, Botswana. OBJECTIVE: To explore the challenges faced by care givers of children on treatment for tuberculosis (TB) to inform a more child-friendly approach to Botswana's National TB Programme (NTP) strategy. DESIGN: Qualitative study using 28 in-depth interviews with care givers of children receiving anti-tuberculosis treatment. RESULTS: Care givers identified five main challenges: long delays in their child's diagnosis, difficulty attending clinic for daily treatment, difficulty administering TB medications, stock-outs of TB medications leading to treatment interruptions, and inadequate TB education. Care givers prioritized these same five areas to improve the overall management of their child's TB. CONCLUSION: Our findings suggest that despite accessing care through an NTP that adheres to World Health Organization guidelines, care givers for children on treatment in Botswana continue to encounter significant challenges. While each of these represents a potential threat to successful treatment, they can be addressed with relatively small systematic and programmatic adjustments. These results will inform the next version of the Botswana NTP guidelines towards a more child- and care giver-centered approach.

Loss to follow-up among adolescents with tuberculosis in Gaborone, Botswana.

SETTING: Nine high-burden public tuberculosis (TB) clinics in Gaborone, Botswana. OBJECTIVE: To describe clinical characteristics and outcomes among adolescents with TB and compare loss to follow-up (LTFU) rates with that among youth and adult cases. DESIGN: Retrospective cohort study of TB cases registered from 2012 to 2014. Clinical characteristics and treatment outcomes were compared among adolescents (age 10-19 years), youth (20-24 years) and a systematic sample of adults (⩾25 years). RESULTS: We analyzed 120 adolescent, 210 youth, and 548 adult cases. Adolescents had twice the risk of LTFU over adults (RR 2.0, 95%CI 1.1-3.7, P = 0.03), and higher LTFU than youth; this was not significant (RR 1.4, 95%CI 0.7-2.9, P = 0.32). Of those with human immunodeficiency virus (HIV) infection, 8/35 (22.9%) adolescents were LTFU, compared with 3/51 (5.9%) youth, and 25/407 (6.1%) adults (P = 0.001). In a multivariable model, adolescence (OR 3.0, 95%CI 1.3-6.5, P < 0.01), HIV positivity (OR 2.2, 95%CI 1.1-4.5, P = 0.02), and extra-pulmonary TB (OR 2.2, 95%CI 1.2-4.0, P = 0.01) were each associated with LTFU. CONCLUSION: Adolescents treated for TB had greater LTFU than youth and adults, particularly in the setting of TB-HIV coinfection. Further work should clarify the generalizability of these findings and investigate poor outcomes among adolescents with TB.

The effect of exposure to wood smoke on outcomes of childhood pneumonia in Botswana.

SETTING: Tertiary hospital in Gaborone, Botswana. OBJECTIVE: To examine whether exposure to wood smoke worsens outcomes of childhood pneumonia. DESIGN: Prospective cohort study of children aged 1-23 months meeting clinical criteria for pneumonia. Household use of wood as a cooking fuel was assessed during a face-to-face questionnaire with care givers. We estimated crude and adjusted risk ratios (RRs) and 95% confidence intervals (CIs) for treatment failure at 48 h by household use of wood as a cooking fuel. We assessed for effect modification by age (1-5 vs. 6-23 months) and malnutrition (none vs. moderate vs. severe). RESULTS: The median age of the 284 enrolled children was 5.9 months; 17% had moderate or severe malnutrition. Ninety-nine (35%) children failed treatment at 48 h and 17 (6%) died. In multivariable analyses, household use of wood as a cooking fuel increased the risk of treatment failure at 48 h (RR 1.44, 95%CI 1.09-1.92, P = 0.01). This association differed by child nutritional status (P = 0.02), with a detrimental effect observed only among children with no or moderate malnutrition. CONCLUSIONS: Exposure to wood smoke worsens outcomes for childhood pneumonia. Efforts to prevent exposure to smoke from unprocessed fuels may improve pneumonia outcomes among children.

Diagnosis of paediatric tuberculosis using sputum induction in Botswana: programme description and findings.

SETTING: Four public hospitals in Botswana, a high tuberculosis (TB) burden setting. OBJECTIVES: To assess the feasibility and utility of sputum induction in the diagnosis of paediatric TB. DESIGN: From 2008 to 2010, children aged ≤18 years referred for suspected pulmonary TB underwent sputum induction. Confirmed TB was defined as the presence of at least one of the signs and symptoms suggestive of TB and positive Mycobacterium tuberculosis culture. Information on TB-associated symptoms (cough, fatigue, night sweats, low appetite, chest pain, weight loss, haemoptysis and contact with a TB case) was collected for three risk groups: human immunodeficiency virus (HIV) positive children, HIV-negative children aged <3 years and HIV-negative children aged ≥3 years. RESULTS: The median age of the 1394 subjects who underwent sputum induction was 3.8 years (IQR 1.3-8.4); 373 (27%) were HIV-positive, 419 (30%) were HIV-negative and 602 (43%) had unknown HIV status. TB was confirmed in 84 (6.0%); cases were more likely to have weight loss, chest pain or TB household contacts. There were no serious complications attributable to sputum induction during and after the procedure; only 0.8% (9/1174) of patients reported minor complications. CONCLUSIONS: In Botswana, paediatric sputum induction was feasible, safe and assisted bacteriological confirmation in a subgroup of children treated for TB.

Cohort study of diabetes in HIV-infected adult patients: evaluating the effect of diabetes mellitus on immune reconstitution.

We conducted a retrospective cohort study assessing the association between diabetes mellitus (DM) and immune recovery in HIV-infected adults. Immune reconstitution after initiating antiretroviral therapy was more rapid in DM patients (120.4 cells/year) compared to non-DM patients (94.2 cells/year, p<0.023). Metformin use was associated with improved CD4 recovery (p=0.034).

Outcomes in HIV-infected adults with tuberculosis at clinics with and without co-located HIV clinics in Botswana.

SETTING: Gaborone, Botswana. OBJECTIVE: To determine if starting anti-tuberculosis treatment at clinics in Gaborone without co-located human immunodeficiency virus (HIV) clinics would delay time to highly active antiretroviral therapy (HAART) initiation and be associated with lower survival compared to starting anti-tuberculosis treatment at clinics with on-site HIV clinics. DESIGN: Retrospective cohort study. Subjects were HAART-naïve, aged ≥ 21 years with pulmonary tuberculosis (TB), HIV and CD4 counts ≤ 250 cells/mm(3) initiating anti-tuberculosis treatment between 2005 and 2010. Survival at completion of anti-tuberculosis treatment or at 6 months post-treatment initiation and time to HAART after anti-tuberculosis treatment initiation were compared by clinic type. RESULTS: Respectively 259 and 80 patients from clinics without and with on-site HIV facilities qualified for the study. Age, sex, CD4, baseline sputum smears and loss to follow-up rate were similar by clinic type. Mortality did not differ between clinics without or with on-site HIV clinics (20/250, 8.0% vs. 8/79, 10.1%, relative risk 0.79, 95%CI 0.36-1.72), nor did median time to HAART initiation (respectively 63 and 66 days, P = 0.53). CONCLUSION: In urban areas where TB and HIV programs are separate, geographic co-location alone without further integration may not reduce mortality or time to HAART initiation among co-infected patients.

Yield of contact tracing from pediatric tuberculosis index cases in Gaborone, Botswana.

SETTING: Contact tracing using pediatric index cases has not been adequately investigated in high tuberculosis (TB) and human immunodeficiency virus (HIV) prevalence settings. OBJECTIVE: To determine the yield of contact tracing in household contacts of pediatric TB index cases in Botswana. DESIGN: Index cases included all pediatric (age ≤ 13 years) TB admissions from January 2009 to December 2011 to Botswana's largest referral hospital. A contact tracing team identified cases, conducted home visits, symptom-screened contacts and referred those with ≥ 1 TB symptoms. The primary outcome was newly diagnosed TB in a contact. RESULTS: From 163 pediatric index cases, 548 contacts were screened (median 3 contacts/case, interquartile range [IQR] 2-4). Of these, 49 (9%) were referred for positive symptoms on screening and 27/49 (55%) were evaluated for active TB. Twelve new TB cases were diagnosed (12/548, 2.2%); the median age was 31 years (IQR 23-38); 11 (92%) were smear-positive. Ten (83%) had known HIV status: 7 (70%) were HIV-positive. To find one new TB case, the number needed to contact trace (index cases/new cases) was 13.6, and the number needed to screen (contacts/new cases) was 46. CONCLUSION: This yield of contact tracing using pediatric index cases is similar to the traditional adult index case approach. Improving the proportion of symptomatic contacts evaluated may increase yield.

Impact of the human immunodeficiency virus on early multidrug-resistant tuberculosis treatment outcomes in Botswana.

SETTING: The impact of the human immunodeficiency virus (HIV) on multidrug-resistant tuberculosis (MDR-TB) treatment outcomes in sub-Saharan Africa, where extensive rollout of highly active antiretroviral therapy (HAART) has occurred, remains unclear. OBJECTIVE: To compare the time to initial culture conversion among patients with and those without HIV infection in a setting of individualized MDR-TB care in Botswana. DESIGN: Prospective cohort study of MDR-TB patients receiving ambulatory, integrated TB-HIV care at two public clinics in Botswana. The time to culture conversion was compared by HIV status using Cox proportional hazard ratios (HRs). RESULTS: A total of 40 HIV-infected and 30 non-HIV-infected patients with MDR-TB and follow-up cultures were identified. The median time to initial culture conversion was 78 days (interquartile range [IQR] 42-186) for HIV-infected and 95 days (IQR 70-133) for non-HIV-infected individuals (log rank P > 0.5; unadjusted HR 0.9, 95%CI 0.5-1.5). Adjusting for age, sex, treatment history and number of active anti-tuberculosis drugs did not change this result (adjusted HR 0.8, 95%CI 0.4-1.4). CONCLUSION: We found no difference in the proportion of or time to initial sputum culture conversion between an HIV-infected and a non-infected cohort of MDR-TB patients in Botswana, suggesting that outcomes may be comparable in similar settings with access to individualized anti-tuberculosis treatment and HAART.

Diabetes mellitus in HIV-infected patients receiving antiretroviral therapy.

BACKGROUND: There is little in the literature on HIV and diabetes mellitus (DM) in sub-Saharan Africa. OBJECTIVE: To assess the characteristics of HIV and DM in patients receiving antiretroviral therapy (ART) in Botswana. METHODS: A retrospective case-control study was conducted at 4 sites. Each HIV-infected patient with DM (n=48) was matched with 2 HIV-infected controls (n=108) by age (±2 years) and sex. Primary analysis was conditional logistic regression to estimate univariate odds and 95% confidence intervals (CIs) for each characteristic. RESULTS: There was no significant association between co-morbid diseases, tuberculosis, hypertension or cancer and risk of diabetes. DM patients were more likely to have higher pre-ART weight (odds ratio (OR) 1.09; 95% CI 1.04 - 1.14). HIV-infected adults >70 kg were significantly more likely to have DM (OR 12.30; 95% CI 1.40 - 107.98). Participants receiving efavirenz (OR 4.58; 95% CI 1.44 - 14.57) or protease inhibitor therapy (OR 20.7; 95% CI 1.79 - 240.02) were more likely to have DM. Neither mean pre-ART CD4 cell count (OR 1.0; 95% CI 0.99 - 1.01) nor pre-ART viral load >100 000 copies/ml (OR 0.71; 95% CI 0.21 - 2.43) were associated with a significant risk of diabetes. CONCLUSIONS: These findings suggest a complex interrelation among traditional host factors and treatment-related metabolic changes in the pathogenesis of DM inpatients receiving ART. Notably, pre-ART weight, particularly if >70 kg, is associated with the diagnosis of diabetes in HIV-infected patients in Botswana.