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.

Fungal diversity in the gut microbiome of young South African children.

BACKGROUND: The fungal microbiome, or mycobiome, is a poorly described component of the gut ecosystem and little is known about its structure and development in children. In South Africa, there have been no culture-independent evaluations of the child gut mycobiota. This study aimed to characterise the gut mycobiota and explore the relationships between fungi and bacteria in the gut microbiome of children from Cape Town communities. METHODS: Stool samples were collected from children enrolled in the TB-CHAMP clinical trial. Internal transcribed spacer 1 (ITS1) gene sequencing was performed on a total of 115 stool samples using the Illumina MiSeq platform. Differences in fungal diversity and composition in relation to demographic, clinical, and environmental factors were investigated, and correlations between fungi and previously described bacterial populations in the same samples were described. RESULTS: Taxa from the genera Candida and Saccharomyces were detected in all participants. Differential abundance analysis showed that Candida spp. were significantly more abundant in children younger than 2 years compared to older children. The gut mycobiota was less diverse than the bacterial microbiota of the same participants, consistent with the findings of other human microbiome studies. The variation in richness and evenness of fungi was substantial, even between individuals of the same age. There was significant association between vitamin A supplementation and higher fungal alpha diversity (p = 0.047), and girls were shown to have lower fungal alpha diversity (p = 0.003). Co-occurrence between several bacterial taxa and Candida albicans was observed. CONCLUSIONS: The dominant fungal taxa in our study population were similar to those reported in other paediatric studies; however, it remains difficult to identify the true core gut mycobiota due to the challenges set by the low abundance of gut fungi and the lack of true gut colonising species. The connection between the microbiota, vitamin A supplementation, and growth and immunity warrants exploration, especially in populations at risk for micronutrient deficiencies. While we were able to provide insight into the gut mycobiota of young South African children, further functional studies are necessary to explain the role of the mycobiota and the correlations between bacteria and fungi in human health.

High burden of viral respiratory co-infections in a cohort of children with suspected pulmonary tuberculosis.

BACKGROUND: The presentation of pulmonary tuberculosis (PTB) in young children is often clinically indistinguishable from other common respiratory illnesses, which are frequently infections of viral aetiology. As little is known about the role of viruses in children with PTB, we investigated the prevalence of respiratory viruses in children with suspected PTB at presentation and follow-up. METHODS: In an observational cohort study, children < 13 years were routinely investigated for suspected PTB in Cape Town, South Africa between December 2015 and September 2017 and followed up for 24 weeks. Nasopharyngeal aspirates (NPAs) were tested for respiratory viruses using multiplex PCR at enrolment, week 4 and 8. RESULTS: Seventy-three children were enrolled [median age 22.0 months; (interquartile range 10.0-48.0); 56.2% male and 17.8% HIV-infected. Anti-tuberculosis treatment was initiated in 54.8%; of these 50.0% had bacteriologically confirmed TB. At enrolment, ≥1 virus were detected in 95.9% (70/73) children; most commonly human rhinovirus (HRV) (74.0%). HRV was more frequently detected in TB cases (85%) compared to ill controls (60.6%) (p = 0.02). Multiple viruses were detected in 71.2% of all children; 80% of TB cases and 60.6% of ill controls (p = 0.07). At follow-up, ≥1 respiratory virus was detected in 92.2% (47/51) at week 4, and 94.2% (49/52) at week 8. CONCLUSIONS: We found a high prevalence of viral respiratory co-infections in children investigated for PTB, irrespective of final PTB diagnosis, which remained high during follow up. Future work should include investigating the whole respiratory ecosystem in combination with pathogen- specific immune responses.

Droplets, dust and guinea pigs: an historical review of tuberculosis transmission research, 1878-1940.

The transmission of tuberculosis (TB) occurs mainly via inhalation of airborne droplet nuclei; however, the precise details of this process remain uncertain. We reviewed the literature from 1870 to 1940, when Mycobacterium tuberculosis was discovered and the concept of transmission emerged as a hallmark of the infectious disease. By 1940, laboratory experiments, animal studies and clinical observation had demonstrated that cough was central to TB transmission, and that guinea pigs close to patients with cough could be infected, mainly by patients coughing small droplets likely containing only 1-2 bacilli. A minority of pulmonary TB patients, usually during the early stages of the disease, with thin watery sputum, more successfully coughed small infectious droplets than patients with heavily smear-positive tenacious sputum who were often too ill and too weak to cough vigorously. There was ongoing debate regarding the possible importance of desiccated sputum particles found in surface dust. Investigation of TB transmission has a history of more than 130 years.

Use of simulated sputum specimens to estimate the specificity of laboratory-diagnosed tuberculosis.

SETTING: Cross-contamination is not uncommon in mycobacteriology laboratories of high-income countries, as documented by bacterial genotyping. The extent of this problem in low-income countries is largely unknown, where this method is impractical. OBJECTIVE: To estimate the rate of cross-contamination in a high-volume tuberculosis (TB) laboratory in South Africa. DESIGN: Simulated sputum specimens labelled with false names were sent from a TB clinic, interspersed with patient samples, and processed for culture and microscopy. Results were interpreted in the context of the observed proportion of samples with positive microscopy and culture results. RESULTS: With microscopy, 6/190 (3.2%) simulated specimens were positive (estimated specificity = 96.8%). Considering the 881 positive microscopy results in 6093 clinical samples, we extrapolate that 19.3% (95%CI 7.0-42.8) of positive smears were false-positives. On culture, 2/190 (1.1%) of the simulated specimens were positive for Mycobacterium tuberculosis (estimated specificity = 98.9%). Considering the 1862 positive cultures from 6093 clinical samples, we estimate that 2.4% (95%CI 0.3-8.8) of positive cultures were false-positives. CONCLUSION: Simulated specimens offer a simple means of estimating the proportion of false-positive results, providing information on all sources of potential error from the clinic, through the laboratory and to reporting of results.

Acute lower respiratory infections among children hospitalized in Bangui, Central African Republic: toward a new case-management algorithm.

To measure the performance of the current WHO algorithm in identifying children at higher risk of death, children aged 2-59 months who presented with cough and/or difficult breathing and were admitted into the paediatric hospital of Bangui (Central African Republic) during a 1-year period (1996/97) were investigated. Among children with subcostal indrawing, mortality and severity of oxygen desaturation were identical whether or not they also had tachypnoea. Among children with a 'severe pneumonia', those who also fulfilled the 'very severe disease' definition had a higher risk of death (31/132, 23.5%) than those who did not (12/106, 11.3%, P = 0.02). However, this 'very severe disease' definition did not predict death when used in children who did not have severe pneumonia. To identify variables that would better predict death, combinations of symptoms and signs were examined among the subgroup of children with indrawing. Nine combinations had both a sensitivity and specificity over 60%. 'Grunting and/or nasal flaring' had a sensitivity of 72% and a specificity of 66% in predicting death, and might be easier to use by primary health care personnel than other combinations. A new algorithm is proposed for the management of children aged 2-59 months presenting with cough and/or difficult breathing. The definition of pneumonia would be unchanged (tachypnoea). Severe pneumonia would remain defined on indrawing regardless of respiratory rate, except that indrawing should be lower chest wall and/or intercostal. In health facilities where intravenous antibiotics, chloramphenicol and/or oxygen are available, entry into a 'very severe pneumonia' category would be based on 'grunting and/or nasal flaring' among children with indrawing. In our study population, the mortality rates in the categories based on these definitions were 0.8% (1/127) in children with no pneumonia, 0.9% (1/116) in children with pneumonia, 7.7% (12/156) in children with severe pneumonia and 31.1% (33/106) in children with very severe pneumonia.

Risk factors for mortality among children hospitalized because of acute respiratory infections in Bangui, Central African Republic.

BACKGROUND: Acute respiratory infections are the most common cause of death in children in developing countries. Little information is available on risk factors for mortality among African children presenting with symptoms compatible with acute respiratory infections. OBJECTIVE: To identify risk factors for death among children hospitalized for respiratory complaints who satisfy the WHO clinical definition for pneumonia or severe pneumonia. METHODS: Children <5 years of age who presented with cough and/or difficult breathing and were hospitalized in Bangui during a 1-year period were investigated for risk factors for mortality. The study population consisted of 395 children who satisfied the WHO clinical definition for pneumonia/severe pneumonia. The associations between death and demographic, nutritional, socioeconomic, laboratory and clinical variables were examined. RESULTS: Of the 49 (12.4%) children who died, all but one had had indrawing of the chest which, in univariate analysis, was the risk factor most strongly associated with death [odds ratio, 22.99; 95% confidence interval (CI), 3.81 to 935.2]. In a multivariate model the independent risk factors for death were indrawing of the chest [adjusted odds ratio (AOR) 8.35, CI 1.04 to 66.82], hepatomegaly (AOR 6.72, CI 2.35 to 19.21), age between 2 and 11 months (AOR 6.37, CI 2.18 to 18.59), grunting (AOR 4.53, CI 1.96 to 10.45), a moderate/severe alteration of general status (AOR 3.23, CI 1.17 to 8.94) and acute malnutrition (AOR 2.74, CI 0.96 to 7.78). CONCLUSIONS: These findings could be used in flow charts for the management of children with respiratory complaints to identify children at increased risk of death who need to receive aggressive therapy.