Respiratory and diarrhoeal pathogens in Malawian children hospitalised with diarrhoea and association with short-term growth: A prospective cohort study

Background: Pneumonia and diarrhoea are the leading causes of childhood mortality and morbidity worldwide. The gut-lung axis is associated with disease, and these common infections, especially the parasite Cryptosporidium, are associated with malnutrition. We sought to evaluate the association of respiratory and gastrointestinal (GI) pathogens with short-term growth among children hospitalised with diarrhoeal disease. Methods: In this sub-study, we followed 27 children (two-24 months) who tested positive for Cryptosporidium spp. for eight weeks with two weekly sampling of the respiratory and GI tract. Respiratory and stool pathogens were detected using quantitative molecular methods. Nutritional outcomes were assessed as length-for-age (LAZ), weight-for-length (WLZ) and weight-for-age (WAZ) z-scores. Changes over the study period were compared using repeated analysis of variance and mixed effects model analysis. Results: In this period,104 sputum and stool samples were collected. All stool samples had at least one pathogen detected, with an average of 5.1 (SD 2.1) stool pathogens, compared to 84% of the sputum samples with an average 3.5 (SD 1.8). Diarrhoeagenic E. coli were the most common stool pathogens (89%), followed by Cryptosporidium (57.6%) and Adenovirus pan (41%). In sputum, Streptococcus pneumoniae was the most prevalent pathogen (84%), followed by hinovirus (56%) and Moraxella catarrhalis (50%). There was a significant change in WAZ over the follow-up period. Children who had ≥3 GI pathogens had significantly a lower LAZ mean score at enrolment (-1.8 [SD 1.4]) and across the follow-up period. No relationship between respiratory pathogens and short-term growth was observed. Out of 49 sputum samples that had ≥3 pathogens, 42 (85%) concurrent stool samples had ≥3 GI pathogens. Conclusions: Among young children hospitalised with diarrhoea, multiple GI and respiratory pathogens were prevalent over an eight-week follow-up period. The presence of more GI, but not respiratory, pathogens was significantly associated with reduced short-term growth

Respiratory cryptosporidiosis in Malawian children with diarrheal disease

BACKGROUND Respiratory cryptosporidiosis has been documented in children with diarrhea. We sought to describe the dynamics of respiratory involvement in children hospitalized with gastrointestinal (GI) diarrheal disease. METHODS We conducted a prospective, observational longitudinal study of Malawian children 2-24 months hospitalized with diarrhea. Nasopharyngeal (NP) swabs, induced sputum and stool specimens were collected. Participants that were positive by Cryptosporidium PCR in any of the three compartments were followed up with fortnightly visits up to 8 weeks post-enrollment. RESULTS Of the 162 children recruited, participants had mild-moderate malnutrition (mean HAZ -1.6 (SD 2.1)), 37 (21%) were PCR-positive for Cryptosporidium at enrollment (37 stool, 11 sputum, and 4 NP) and 27 completed the majority of follow-up visits (73%). Cryptosporidium was detected in all compartments over the 4 post-enrollment visits, most commonly in stool (100% at enrollment with mean cycle thresholds (Ct) of 28.8±4.3 to 44% at 8 weeks with Ct 29.9±4.1), followed by sputum (31% at enrollment with mean Ct 31.1±4.4 to 20% at 8 weeks with Ct 35.7±2.6), then NP (11% with mean Ct 33.5±1.0 to 8% with Ct 36.6±0.7). Participants with Cryptosporidium detection in both the respiratory and GI tract over the study period reported respiratory and GI symptoms in 81% and 62% of study visits, respectively, compared to 68% and 27%, respectively, for those with only GI detection, and had longer GI shedding (17.5±6.6 v. 15.9±2.9 days). CONCLUSION Cryptosporidium was detected in both respiratory and GI tracts throughout the 8 weeks post-enrollment. The development of therapeutics for Cryptosporidium in children should target the respiratory as well as GI tract

Performance and safety of the induced sputum procedure in young children in Malawi: a prospective study

Background Collecting sputum specimens is a challenge in infants and young children. We assessed the performance and safety of induced sputum (IS) collection in this population, embedded in a prospective study evaluating respiratory cryptosporidiosis in Malawian children with diarrheal disease. Methods We assessed the sputum quality and correlation with detection of Cryptosporidium spp. and evaluated safety and adverse events in 162 children. Results Among 159 stool specimens tested, 34 (21%, 95% CI 15.0 to 28%) were positive for Cryptosporidium spp. There were 160 IS and 161 nasopharyngeal (NP) specimens collected. IS and NP specimen collection was performed for each patient. The majority of IS specimens (122/147; 83%) were clear in appearance and 132/147 (90%) were of good quality. Among the respiratory specimens tested, 10 (6.3%, 95% CI 2.5 to 10%) IS and 4 (3%, 95% CI 0 to 5%) NP were positive for Cryptosporidium spp. When stool cryptosporidium PCR was the gold standard, IS PCR sensitivity was higher (29%, 95% CI 22 to 37%) compared with NP PCR (12%, 95% CI 7 to 17%) for detection of Cryptosporidium spp. One (0.4%) adverse event occurred, consisting of a drop in oxygen saturations at the 30-min postprocedure evaluation. Consciousness level, median respiratory rate and oxygen saturations were unchanged, before or after IS. Conclusions IS provides good quality specimens, is more sensitive than NP specimens for diagnosis of respiratory cryptosporidiosis, and collection can be performed safely in children hospitalized with diarrheal disease

The Sensitivity and Specificity of Loop-Mediated Isothermal Amplification (LAMP) Assay for Tuberculosis Diagnosis in Adults with Chronic Cough in Malawi.

BACKGROUND: Current tuberculosis diagnostics lack sensitivity, and are expensive. Highly accurate, rapid and cheaper diagnostic tests are required for point of care use in low resource settings with high HIV prevalence. OBJECTIVE: To investigate the sensitivity and specificity, and cost of loop-mediated isothermal amplification (LAMP) assay for tuberculosis diagnosis in adults with chronic cough compared to Xpert® MTB/RIF, fluorescence smear microscopy. METHODS: Between October 2013 and March 2014, consecutive adults at a primary care clinic were screened for cough, offered HIV testing and assessed for tuberculosis using LAMP, Xpert® MTB/RIF and fluorescence smear microscopy. Sensitivity and specificity (with culture as reference standard), and costs were estimated. RESULTS: Of 273 adults recruited, 44.3% (121/273) were HIV-positive and 19.4% (53/273) had bacteriogically confirmed tuberculosis. The sensitivity of LAMP compared to culture was 65.0% (95% CI: 48.3% to 79.4%) with 100% (95% CI: 98.0% to 100%) specificity. The sensitivity of Xpert® MTB/RIF (77.5%, 95% CI: 61.5% to 89.2%) was similar to that of LAMP, p = 0.132. The sensitivity of concentrated fluorescence smear microscopy with routine double reading (87.5%, 95% CI: 73.2% to 95.8%) was higher than that of LAMP, p = 0.020. All three tests had high specificity. The lowest cost per test of LAMP was at batch size of 14 samples (US$9.98); this was lower than Xpert® MTB/RIF (US$ 13.38) but higher than fluorescence smear microscopy (US$ 0.65). CONCLUSION: The sensitivity of LAMP was similar to Xpert® MTB/RIF but lower than fluorescence smear microscopy; all three tests had high specificity. These findings support the Malawi policy that recommends a combination of fluorescence smear microscopy and Xpert® MTB/RIF prioritised for people living with HIV, already found to be smear-negative, or being considered for retreatment of tuberculosis

Respiratory and diarrhoea pathogens in Malawian children presenting woth diarrhoea and association with short term growth dataset

  This is a dataset of participants enrolled and followed in the CryptoResp sub-study looking at the association between    respiratory and diarrhoea pathogens and growth in children 2-24 months.</p

Neurodevelopmental, cognitive, behavioural and mental health impairments following childhood malnutrition: a systematic review.

BackgroundSevere childhood malnutrition impairs growth and development short-term, but current understanding of long-term outcomes is limited. We aimed to identify studies assessing neurodevelopmental, cognitive, behavioural and mental health outcomes following childhood malnutrition.MethodsWe systematically searched MEDLINE, EMBASE, Global Health and PsycINFO for studies assessing these outcomes in those exposed to childhood malnutrition in low-income and middle-income settings. We included studies assessing undernutrition measured by low mid-upper arm circumference, weight-for-height, weight-for-age or nutritional oedema. We used guidelines for synthesis of results without meta-analysis to analyse three outcome areas: neurodevelopment, cognition/academic achievement, behaviour/mental health.ResultsWe identified 30 studies, including some long-term cohorts reporting outcomes through to adulthood. There is strong evidence that malnutrition in childhood negatively impacts neurodevelopment based on high-quality studies using validated neurodevelopmental assessment tools. There is also strong evidence that malnutrition impairs academic achievement with agreement across seven studies investigating this outcome. Eight of 11 studies showed an association between childhood malnutrition and impaired cognition. This moderate evidence is limited by some studies failing to measure important confounders such as socioeconomic status. Five of 7 studies found a difference in behavioural assessment scores in those exposed to childhood malnutrition compared with controls but this moderate evidence is similarly limited by unmeasured confounders. Mental health impacts were difficult to ascertain due to few studies with mixed results.ConclusionsChildhood malnutrition is associated with impaired neurodevelopment, academic achievement, cognition and behavioural problems but evidence regarding possible mental health impacts is inconclusive. Future research should explore the interplay of childhood and later-life adversities on these outcomes. While evidence on improving nutritional and clinical therapies to reduce long-term risks is also needed, preventing and eliminating child malnutrition is likely to be the best way of preventing long-term neurocognitive harms.Prospero registration numberCRD42021260498

Costs and cost-effectiveness of treatment setting for children with wasting, oedema and growth failure/faltering: a systematic review

This systematic review aimed to address the existing evidence gaps, and guide policy decisions on the settings within which to treat infants <12 months of age with growth faltering/failure, and infants and children aged <60 months with moderate wasting or severe wasting and/or bilateral pitting oedema. Thirteen electronic databases were searched for studies published before 10 December 2021. The searches yielded 16,709 records from which 31 studies were eligible and included in the review. Three studies were judged as low quality, whilst 14 were moderate and the remaining 14 were high quality. We identified very few cost and cost-effectiveness analyses for most of the models of care with the certainty of evidence being judged at very low or low. However, there were 17 cost and 6 cost-effectiveness analyses for the initiation of treatment in outpatient settings for severe wasting and/or bilateral pitting oedema in infants and children <60 months of age. From this evidence, the costs appear lowest for initiating treatment in community settings, followed by initiating treatment in community and transferring to outpatient settings, initiating treatment in outpatients then transferring to community settings, initiating treatment in outpatient settings, and lastly initiating treatment in inpatient settings. In addition, the evidence suggested that initiation of treatment in outpatient settings is highly cost-effective when compared to doing nothing or no programme implementation scenarios, using country-specific WHO GDP per capita thresholds. The incremental cost-effectiveness ratios ranged from $20 to$145 per DALY averted from a provider perspective, and $68 to$161 per DALY averted from a societal perspective. However, the certainty of the evidence was judged as moderate because of comparisons to do nothing/ no programme scenarios which potentially limits the applicability of the evidence in real-world settings. There is therefore a need for evidence that compare the different available alternatives

LAMP minimal dataset

Current tuberculosis diagnostics lack sensitivity, and are expensive. Highly accurate, rapid and cheaper diagnostic tests are required for point of care use in low resource settings with high HIV prevalence. To investigate the sensitivity and specificity, and cost of loop-mediated isothermal amplification (LAMP) assay for tuberculosis diagnosis in adults with chronic cough compared to Xpert® MTB/RIF, fluorescence smear microscopy. Between October 2013 and March 2014, consecutive adults at a primary care clinic were screened for cough, offered HIV testing and assessed for tuberculosis using LAMP, Xpert® MTB/RIF and fluorescence smear microscopy. Sensitivity and specificity (with culture as reference standard), and costs were estimated. Of 273 adults recruited, 44.3% (121/273) were HIV-positive and 19.4% (53/273) had bacteriogically confirmed tuberculosis. The sensitivity of LAMP compared to culture was 65.0% (95% CI: 48.3% to 79.4%) with 100% (95% CI: 98.0% to 100%) specificity. The sensitivity of Xpert® MTB/RIF (77.5%, 95% CI: 61.5% to 89.2%) was similar to that of LAMP, p = 0.132. The sensitivity of concentrated fluorescence smear microscopy with routine double reading (87.5%, 95% CI: 73.2% to 95.8%) was higher than that of LAMP, p = 0.020. All three tests had high specificity. The lowest cost per test of LAMP was at batch size of 14 samples (US$9.98); this was lower than Xpert® MTB/RIF (US$ 13.38) but higher than fluorescence smear microscopy (US$ 0.65). The sensitivity of LAMP was similar to Xpert® MTB/RIF but lower than fluorescence smear microscopy; all three tests had high specificity. These findings support the Malawi policy that recommends a combination of fluorescence smear microscopy and Xpert® MTB/RIF prioritised for people living with HIV, already found to be smear-negative, or being considered for retreatment of tuberculosis

Sensitivity and specificity of LAMP (compared to MGIT) by HIV status and smear status (n = 233).

<p>Sensitivity and specificity of LAMP (compared to MGIT) by HIV status and smear status (n = 233).</p