World Health Organization Danger Signs Research Articles

World Health Organization Danger Signs to predict bacterial sepsis in young infants: A pragmatic cohort study.

Bacterial sepsis is generally a major concern in ill infants. To help triaging decisions by front-line health workers in these situations, the World Health Organization (WHO) has developed danger signs (DS). The objective of this study was to evaluate the extent to which nine DS predict bacterial sepsis in young infants presenting with suspected sepsis in a low-income country setting. The study pragmatically evaluated nine DS in infants younger than 3 months with suspected sepsis in a regional hospital in Lilongwe, Malawi, between June 2018 and April 2020. Main outcomes were positive blood or cerebrospinal fluid (CSF) cultures for neonatal pathogens, and mortality. Among 401 infants (gestational age [mean ± SD]: 37.1±3.3 weeks, birth weight 2865±785 grams), 41 had positive blood or CSF cultures for a neonatal pathogen. In-hospital mortality occurred in 9.7% of infants overall (N = 39/401), of which 61.5% (24/39) occurred within 48 hours of admission. Mortality was higher in infants with bacterial sepsis compared to other infants (22.0% [9/41] versus 8.3% [30/360]; p = 0.005). All DS were associated with mortality except for temperature instability and tachypnea, whereas none of the DS were significantly associated with bacterial sepsis, except for "unable to feed" (OR 2.25; 95%CI: 1.17-4.44; p = 0.017). The number of DS predicted mortality (OR: 1.75; 95%CI: 1.43-2.17; p<0.001; AUC: 0.756), but was marginally associated with positive cultures with a neonatal pathogen (OR 1.22; 95%CI: 1.00-1.49; p = 0.046; AUC: 0.743). The association between number of DS and mortality remained significant after adjusting for admission weight, the only statistically significant co-variable (OR 1.75 [95% CI: 1.39-2.23]; p<0.001). Considering all positive cultures including potential bacterial contaminants resulted a non-significant association between number of DS and sepsis (OR 1.09 [95% CI: 0.93-1.28]; p = 0.273). In conclusion, this study shows that DS were strongly associated with death, but were marginally associated with culture-positive pathogen sepsis in a regional hospital setting. These data imply that the incidence of bacterial sepsis and attributable mortality in infants in LMIC settings may be inaccurately estimated based on clinical signs alone.

The in-hospital tuberculosis diagnostic cascade and early clinical outcomes among people living with HIV before and during the COVID-19 pandemic - a prospective multisite cohort study from Ghana

ObjectivesThe COVID-19 pandemic had a disruptive impact on tuberculosis (TB) and HIV services. We assessed the in-hospital TB diagnostic care among people with HIV (PWH) overall and before and during the pandemic. MethodsIn this prospective study, adult PWH admitted at three hospitals in Ghana were recruited if they had a positive World Health Organization four-symptom screen or one or more World Health Organization danger signs or advanced HIV. We collected data on patient characteristics, TB assessment, and clinical outcomes after 8 weeks and used descriptive statistics and survival analysis. ResultsWe enrolled 248 PWH with a median clusters of differentiation 4 count of 80.5 cells/mm3 (interquartile range 24-193). Of those, 246 (99.2%) patients had a positive World Health Organization four-symptom screen. Overall, 112 (45.2%) patients obtained a sputum Xpert result, 66 (46.5%) in the prepandemic and 46 (43.4%) in the pandemic period; P-value = 0.629. The TB prevalence of 46/246 (18.7%) was similar in the prepandemic 28/140 (20.0%) and pandemic 18/106 (17.0%) population; P-value = 0.548. The 8-week all-cause mortality was 62/246 (25.2%), with no difference in cumulative survival when stratifying for the pandemic period; log-rank P-value = 0.412. ConclusionThe study highlighted a large gap in the access to TB investigation and high early mortality among hospitalized PWH, irrespective of the COVID-19 pandemic.

#70: Comparing Prospectively Identified Etiologic Agents of Neonatal Sepsis in Southwest Ethiopia with WHO Empiric Antibiotic Guidelines

Abstract Background Neonatal sepsis accounts for one third of global neonatal mortality. To improve access to treatment for neonatal sepsis, in 2015 the World Health Organization (WHO) released guidance for outpatient treatment (when referral is not possible or refused) of Possible Serious Bacterial Infection (PSBI).1 However, studies from low and middle-income countries suggest that bacteria causing neonatal infection differ from high-income countries, with higher rates of Staphylococcus aureus, Escherichia coli, and Klebsiella species and high rates of antimicrobial resistance. For this reason, local surveillance is vital to develop local antibiograms and tailor appropriate prescribing. Methods This is an analysis of the first 6 months of a prospective study of young infants admitted to Jimma University Hospital with PSBI. Young infants admitted to Jimma University Hospital with PSBI (defined by WHO danger signs: poor feeding, seizures, fever, lethargy, hypothermia, tachypnea, and increased work of breathing) are being recruited over a 12-month period. Blood cultures are obtained on admission, incubated in the BACTEC system and positive cultures evaluated for antibiotic susceptibility by Kirby-Bauer Disc diffusion. Primary outcomes are culture positivity, organism identification, and rates of antimicrobial resistance. Secondary outcomes include mortality rates and duration of hospital stay. The data included in this analysis were collected from March 21, 2019, through September 20, 2019. Data collection is ongoing. Results In total, 196 infants have been enrolled with a culture positivity rate of 58%. At this time, most frequently identified organisms are Klebsiella spp. (43.4%) and Staphylococcus aureus (12.2%). Gram-negative rods represent 67.8% of the isolates and gram-positive cocci 32.2%. Less than half the isolates (44.4%) were susceptible to either first-line antibiotic (ampicillin and gentamicin). Only 17.4% of the gram-positive cocci were sensitive to oxacillin. In-hospital mortality rates for those with positive cultures approached 15% (compared with 5% for culture negative). The average hospital stay for infants with positive cultures was 13.9 days compared with 10.1 for those with negative cultures. Conclusion Klebsiella spp. are responsible for a plurality of neonatal sepsis admissions at Jimma University Hospital. The organisms responsible for neonatal sepsis in southwest Ethiopia are highly resistant to the WHO recommended first-line antibiotics. It is possible that adoption of the WHO guidelines may be inappropriate in this population, which could be better served by tailoring empiric antibiotics to the identified organisms. Reference 1. World Health Organization. Guideline: Managing possible serious bacterial infection in young infants when a referral is not feasible. (2015) Geneva, CH.

Predictive value of pulse oximetry for mortality in infants and children presenting to primary care with clinical pneumonia in rural Malawi: A data linkage study.

The mortality impact of pulse oximetry use during infant and childhood pneumonia management at the primary healthcare level in low-income countries is unknown. We sought to determine mortality outcomes of infants and children diagnosed and referred using clinical guidelines with or without pulse oximetry in Malawi. We conducted a data linkage study of prospective health facility and community case and mortality data. We matched prospectively collected community health worker (CHW) and health centre (HC) outpatient data to prospectively collected hospital and community-based mortality surveillance outcome data, including episodes followed up to and deaths within 30 days of pneumonia diagnosis amongst children 0-59 months old. All data were collected in Lilongwe and Mchinji districts, Malawi, from January 2012 to June 2014. We determined differences in mortality rates using <90% and <93% oxygen saturation (SpO2) thresholds and World Health Organization (WHO) and Malawi clinical guidelines for referral. We used unadjusted and adjusted (for age, sex, respiratory rate, and, in analyses of HC data only, Weight for Age Z-score [WAZ]) regression to account for interaction between SpO2 threshold (pulse oximetry) and clinical guidelines, clustering by child, and CHW or HC catchment area. We matched CHW and HC outpatient data to hospital inpatient records to explore roles of pulse oximetry and clinical guidelines on hospital attendance after referral. From 7,358 CHW and 6,546 HC pneumonia episodes, we linked 417 CHW and 695 HC pneumonia episodes to 30-day mortality outcomes: 16 (3.8%) CHW and 13 (1.9%) HC patients died. SpO2 thresholds of <90% and <93% identified 1 (6%) of the 16 CHW deaths that were unidentified by integrated community case management (iCCM) WHO referral protocol and 3 (23%) and 4 (31%) of the 13 HC deaths, respectively, that were unidentified by the integrated management of childhood illness (IMCI) WHO protocol. Malawi IMCI referral protocol, which differs from WHO protocol at the HC level and includes chest indrawing, identified all but one of these deaths. SpO2 < 90% predicted death independently of WHO danger signs compared with SpO2 ≥ 90%: HC Risk Ratio (RR), 9.37 (95% CI: 2.17-40.4, p = 0.003); CHW RR, 6.85 (1.15-40.9, p = 0.035). SpO2 < 93% was also predictive versus SpO2 ≥ 93% at HC level: RR, 6.68 (1.52-29.4, p = 0.012). Hospital referrals and outpatient episodes with referral decision indications were associated with mortality. A substantial proportion of those referred were not found admitted in the inpatients within 7 days of referral advice. All 12 deaths in 73 hospitalised children occurred within 24 hours of arrival in the hospital, which highlights delay in appropriate care seeking. The main limitation of our study was our ability to only match 6% of CHW episodes and 11% of HC episodes to mortality outcome data. Pulse oximetry identified fatal pneumonia episodes at HCs in Malawi that would otherwise have been missed by WHO referral guidelines alone. Our findings suggest that pulse oximetry could be beneficial in supplementing clinical signs to identify children with pneumonia at high risk of mortality in the outpatient setting in health centres for referral to a hospital for appropriate management.

Digital auscultation in PERCH: Associations with chest radiography and pneumonia mortality in children

BackgroundWhether digitally recorded lung sounds are associated with radiographic pneumonia or clinical outcomes among children in low‐income and middle‐income countries is unknown. We sought to address these knowledge gaps.MethodsWe enrolled 1 to 59monthold children hospitalized with pneumonia at eight African and Asian Pneumonia Etiology Research for Child Health sites in six countries, recorded digital stethoscope lung sounds, obtained chest radiographs, and collected clinical outcomes. Recordings were processed and classified into binary categories positive or negative for adventitial lung sounds. Listening and reading panels classified recordings and radiographs. Recording classification associations with chest radiographs with World Health Organization (WHO)‐defined primary endpoint pneumonia (radiographic pneumonia) or mortality were evaluated. We also examined case fatality among risk strata.ResultsAmong children without WHO danger signs, wheezing (without crackles) had a lower adjusted odds ratio (aOR) for radiographic pneumonia (0.35, 95% confidence interval (CI): 0.15, 0.82), compared to children with normal recordings. Neither crackle only (no wheeze) (aOR: 2.13, 95% CI: 0.91, 4.96) or any wheeze (with or without crackle) (aOR: 0.63, 95% CI: 0.34, 1.15) were associated with radiographic pneumonia. Among children with WHO danger signs no lung recording classification was independently associated with radiographic pneumonia, although trends toward greater odds of radiographic pneumonia were observed among children classified with crackle only (no wheeze) or any wheeze (with or without crackle). Among children without WHO danger signs, those with recorded wheezing had a lower case fatality than those without wheezing (3.8% vs. 9.1%, p = .03).ConclusionsAmong lower risk children without WHO danger signs digitally recorded wheezing is associated with a lower odds for radiographic pneumonia and with lower mortality. Although further research is needed, these data indicate that with further development digital auscultation may eventually contribute to child pneumonia care.

The Predictive Performance of a Pneumonia Severity Score in Human Immunodeficiency Virus-negative Children Presenting to Hospital in 7 Low- and Middle-income Countries.

BackgroundIn 2015, pneumonia remained the leading cause of mortality in children aged 1−59 months.MethodsData from 1802 human immunodeficiency virus (HIV)−negative children aged 1–59 months enrolled in the Pneumonia Etiology Research for Child Health (PERCH) study with severe or very severe pneumonia during 2011−2014 were used to build a parsimonious multivariable model predicting mortality using backwards stepwise logistic regression. The PERCH severity score, derived from model coefficients, was validated on a second, temporally discrete dataset of a further 1819 cases and compared to other available scores using the C statistic.ResultsPredictors of mortality, across 7 low- and middle-income countries, were age <1 year, female sex, ≥3 days of illness prior to presentation to hospital, low weight for height, unresponsiveness, deep breathing, hypoxemia, grunting, and the absence of cough. The model discriminated well between those who died and those who survived (C statistic = 0.84), but the predictive capacity of the PERCH 5-stratum score derived from the coefficients was moderate (C statistic = 0.76). The performance of the Respiratory Index of Severity in Children score was similar (C statistic = 0.76). The number of World Health Organization (WHO) danger signs demonstrated the highest discrimination (C statistic = 0.82; 1.5% died if no danger signs, 10% if 1 danger sign, and 33% if ≥2 danger signs).ConclusionsThe PERCH severity score could be used to interpret geographic variations in pneumonia mortality and etiology. The number of WHO danger signs on presentation to hospital could be the most useful of the currently available tools to aid clinical management of pneumonia.

Etiology of Pulmonary Infections in Human Immunodeficiency Virus-infected Inpatients Using Sputum Multiplex Real-time Polymerase Chain Reaction.

BackgroundThere are limited data on the etiology of respiratory infections in human immunodeficiency virus (HIV)–infected patients in resource-limited settings.MethodsWe performed quantitative multiplex real-time polymerase chain reaction (PCR) for Pneumocystis jirovecii and common bacterial and viral respiratory pathogens on sputum samples (spontaneous or induced) from a prospective cohort study of HIV-infected inpatients with World Health Organization danger signs and cough. Mycobacterial culture was done on 2 sputum samples, blood cultures, and relevant extrapulmonary samples.ResultsWe enrolled 284 participants from 2 secondary-level hospitals in Cape Town, South Africa: median CD4 count was 97 cells/μL, 64% were women, and 38% were on antiretroviral therapy. One hundred forty-eight had culture-positive tuberculosis, 100 had community-acquired pneumonia (CAP), 26 had P. jirovecii pneumonia (PJP), and 64 had other diagnoses. Probable bacterial infection (>105 copies/mL) was detected in 133 participants; the prevalence was highest in those with CAP (52%). Haemophilus influenzae and Streptococcus pneumoniae were the commonest bacterial pathogens detected; atypical bacteria were uncommon. Viruses were detected in 203 participants; the prevalence was highest in those with PJP (85%). Human metapneumovirus was the commonest virus detected. Multiple coinfections were commonly detected.ConclusionsSputum multiplex PCR could become a useful diagnostic tool for bacterial respiratory infections in HIV-infected inpatients, but its value is limited as quantitative cutoffs have only been established for a few bacterial pathogens and validation has not been done in this patient population. We found a high prevalence of respiratory viruses, but it is unclear whether these viruses were causing infection as there are no accepted quantitative PCR cutoffs for diagnosing respiratory viral infections.

Abdominal Ultrasound for the Diagnosis of Tuberculosis Among Human Immunodeficiency Virus-Positive Inpatients With World Health Organization Danger Signs.

BackgroundStudies of the value of abdominal ultrasound for diagnosing human immunodeficiency virus (HIV)-associated tuberculosis have major limitations.MethodsWe conducted a prospective study of HIV-positive inpatients with cough and World Health Organization danger signs. The reference standard was positive Mycobacterium tuberculosis culture from any site. Participants had at least 2 sputa and 1 blood specimen sent for mycobacterial cultures. Standardized data capture sheets were used for ultrasound reports. A blinded radiologist interpreted chest radiographs, categorized as “likely”, “possible”, and “unlikely” for HIV-associated tuberculosis.ResultsWe enrolled 377 participants: 249 women, median age 35 years, 201 with tuberculosis, and median CD4 count 75 cells/µL. The following abdominal ultrasound findings independently predicted tuberculosis: lymph node long-axis ≥10 mm (adjusted odds ratio [aOR], 4.76; 95% confidence interval [CI], 2.41–9.38), splenic hypoechoic lesions (aOR, 3.45; 95% CI, 1.91–6.24), and abdominal/pleural/pericardial effusions (aOR, 1.95; 95% CI, 1.16–3.29). Presence of ≥1 of these 3 features had a sensitivity of 76.4% (95% CI, 69.8–82.3), a specificity of 68.6% (95% CI, 61.1–75.4), and a c-statistic of 0.784 (95% CI, 0.739–0.830). The sensitivity and specificity of chest radiograph assessed as likely tuberculosis was 55.2% (95% CI, 47.2–62.9) and 83.9% (95% CI, 77.0–89.4), respectively.ConclusionsThree features of tuberculosis on abdominal ultrasound independently predicted tuberculosis with moderate diagnostic performance in seriously ill HIV-positive inpatients. Abdominal ultrasound was more sensitive but less specific than chest radiograph for diagnosing tuberculosis in this patient population.

Incremental yield and cost of urine Determine TB-LAM and sputum induction in seriously ill adults with HIV

BackgroundTuberculosis is a major cause of mortality among HIV-infected inpatients, and the World Health Organization (WHO) recommends an algorithm to improve diagnosis. The urine lateral flow lipoarabinomannan (LAM) and sputum Xpert MTB/RIF tests are promising tools, but the optimal diagnostic algorithm is unclear. MethodsThis prospective cohort study enrolled HIV-positive inpatients with cough and WHO danger signs. The Xpert MTB/RIF test and mycobacterial culture were performed on sputum using sputum induction when necessary, and the LAM test was performed on stored urine. Tuberculosis was diagnosed by culture from any site. The diagnostic accuracy and costs of testing were determined for single and combined tests. ResultsTuberculosis was confirmed in 169 of 332 patients (50.9%). The yield of LAM, Xpert MTB/RIF on spontaneous sputum (Xpert Spot), and Xpert MTB/RIF on spontaneous or induced sputum (Xpert SI) was 35.5%, 23.1%, and 90.5%, respectively. When LAM was placed before Xpert Spot and Xpert SI in an algorithm, the yield was 50.9% and 92.3%, respectively. Adding culture to Xpert MTB/RIF only increased the yield by 1.2% and 2.7%, respectively. Use of the LAM test reduced costs. ConclusionsSputum induction is important to increase the yield of Xpert MTB/RIF for seriously ill patients with HIV and cough. LAM testing has little effect on yield when sputum induction is available, but reduces costs and may have other benefits.

Development of a clinical prediction rule to diagnose Pneumocystis jirovecii pneumonia in the World Health Organization’s algorithm for seriously ill HIV-infected patients

BackgroundThe World Health Organization (WHO) algorithm for the diagnosis of tuberculosis in seriously ill HIV-infected patients recommends that treatment for Pneumocystis jirovecii pneumonia (PJP) should be considered without giving clear guidance on selecting patients for empiric PJP therapy. PJP is a common cause of hospitalisation in HIV-infected patients in resource-poor settings where diagnostic facilities are limited.MethodsWe developed clinical prediction rules for PJP in a prospective cohort of HIV-infected inpatients with WHO danger signs and cough of any duration. The reference standard for PJP was > 1000 copies/mL of P. jirovecii DNA on real-time sputum polymerase chain reaction (PCR). Four potentially predictive variables were selected for regression models: dyspnoea, chest X-ray, haemoglobin and oxygen saturation. Respiratory rate was explored as a replacement for oxygen saturation as pulse oximetry is not always available in resource-poor settings.ResultsWe enrolled 500 participants. After imputation for missing values, there were 56 PJP outcome events. Dyspnoea was not independently associated with PJP. Oxygen saturation and respiratory rate were inversely correlated. Two clinical prediction rules were developed: chest X-ray possible/likely PJP, haemoglobin ≥ 9 g/dL and either oxygen saturation < 94% or respiratory rate. The area under the receiver operating characteristic curve of the clinical prediction rule models was 0.761 (95% CI 0.683–0.840) for the respiratory rate model and 0.797 (95% CI 0.725–0.868) for the oxygen saturation model. Both models had zero probability for PJP for scores of zero, and positive likelihood ratios exceeded 10 for high scores.ConclusionWe developed simple clinical prediction rules for PJP, which, if externally validated, could assist decision-making in the WHO seriously ill algorithm.

Determinants of care seeking for children with pneumonia and diarrhea in Guatemala: implications for intervention strategies.

We identified barriers to care seeking for pneumonia and diarrhea among rural Guatemalan children. A population-based survey was conducted twice from 2008 to 2009 among 1605 households with children younger than 5 years. A 14-day calendar recorded episodes of carer-reported pneumonia (n = 364) and diarrhea (n = 481), and formal (health services, public, private) and informal (neighbors, traditional, local shops, pharmacies) care seeking. Formal care was sought for nearly half of severe pneumonias but only for 27% within 2 days of onset, with 31% and 18%, respectively, for severe diarrhea. In multivariable analysis, factors independently associated with formal care seeking were knowing the Community Emergency Plan, mother's perception of illness severity, recognition of World Health Organization danger signs, distance from the health center, and having someone to care for family in an emergency. Proximal factors associated with recognizing need for care were important in determining formal care, and were strongly linked to social determinants. In addition to specific action by the health system with an enhanced community health worker role, a systems approach can help ensure barriers are addressed among poorer and more remote homes.