High Endemic Settings Research Articles

Peripheral facial palsy in children: Serum Borrelia antibodies may reduce the need for lumbar puncture.

We aimed to investigate the causes of acute peripheral facial palsy (PFP) in Danish children and to explore whether neuroborreliosis-related PFP could be diagnosed without lumbar puncture using clinical symptoms and serum Borrelia burgdorferi (Bb) antibodies. This retrospective population-based cohort study included children undergoing lumbar puncture for PFP between 2019 and 2023 in Denmark's Capital Region. Diagnostic performance measures for neuroborreliosis-related PFP were compared between serum Bb IgG alone and clinical risk scores combining Bb IgG with clinical parameters. Of the 326 patients with PFP, 137 (42%) were diagnosed with neuroborreliosis and 151 (46%) had Bell's palsy. Positive predictive value for serum Bb IgG alone was 88% (95% CI 79-93) and negative predictive value was 83% (95% CI 75-88). The positive predictive value of a risk score with seven additional parameters was 90% (95% CI 81-95) and negative predictive value 87% (95% CI 80-92). The positive predictive value of serum Bb IgG alone was high in our setting, where nearly half of children with PFP had neuroborreliosis. In high endemic settings, lumbar punctures may be reduced by (i) treating all children with PFP with doxycycline or (ii) treating Bb IgG positive children and performing lumbar puncture in seronegative children.

Clustering of Gastrointestinal Microorganisms in Human Stool Samples from Ghana.

The study was conducted to identify cluster patterns of enteric microorganisms with potential etiological relevance for infectious gastroenteritis in stool samples of individuals from Ghana, which is a known high-endemicity setting for infectious gastroenteritis. These patterns were compared to previous observations with specimens from Colombian indigenous people in order to assess potentially stable clustering for temporally and spatially distinct populations from high-endemicity regions. By doing so, the study aimed to identify stable clusters as markers of microbial interaction with potential importance for etiological relevance assignment in cases of multiple enteric pathogen detections. Stool samples from 1569 Ghanaian individuals (875 from HIV patients, 30 from HIV-negative control adult patients, and 644 from children < 2 years of age) were assessed for enteric microorganisms by applying real-time PCR. As a result, nucleic acids of bacterial microorganisms were most frequently detected, followed by protozoa, microsporidia, and helminths. Interestingly, the cluster assessment confirmed interaction patterns known from the previous analysis with Colombian indigenous people, demonstrating a high likelihood of Blastocystis hominis for clustering with other microorganisms and a prominent, potentially mediating role of Dientamoeba fragilis for microbial interactions within the clusters. In conclusion, the assessment confirmed conserved clustering of enteric microorganisms with potential etiological relevance for human infectious gastroenteritis over geographically distinct high-endemicity settings. Furthermore, the composition of abundant microorganisms is more important than regional factors for the determination of the interplay of enteric microorganisms in the human gut. Thereby, some microbial pathogens and commensals seem more susceptible to a changing microbial composition in the human gut than others.

Aetiology of pleural effusions in children living in a high TB endemic setting.

<sec id="st1"><title>BACKGROUND</title>Confirming the aetiology of pleural effusion in children may be difficult in TB-endemic settings. We investigated the role of polymerase chain reaction (PCR) and routine biochemical tests in discriminating pleural effusion caused by bacteria from other aetiologies.</sec><sec id="st2"><title>METHODS</title>This is a cross-sectional post-hoc analysis among children with pleural effusion in a tertiary hospital in South Africa, incorporating new data from PCR testing of stored pleural fluid. Aetiological classification was defined by microbiological confirmation.</sec><sec id="st3"><title>RESULTS</title>Ninety-one children were enrolled; the median age 31 months (IQR 12-102). The aetiology of pleural effusion was 40% (36/91) bacteria, 11% (10/91) TB, 3% (3/91) viruses, 11% (10/91) polymicrobial and 35% (32/91) had no pathogen identified. The most common pathogen was Staphylococcus aureus (27/91, 30%) with similar yields on culture and PCR, followed by Streptococcus pneumoniae (12/91, 13%), detected more commonly by PCR. PCR reduced the number of children with unconfirmed aetiologies from 48 to 32. Characteristics of children with no pathogen most resembled those with TB. Pleural fluid lactate dehydrogenase ≥1,716 U/L best discriminated bacterial pleural effusion from other aetiologies (sensitivity of 86%; specificity 95%).</sec><sec id="st4"><title>CONCLUSION</title>PCR improved detection of pathogens and reduced number of children with unconfirmed aetiologies in presumed exudative pleural effusion.</sec>.

Chikungunya seroprevalence, force of infection, and prevalence of chronic disability after infection in endemic and epidemic settings: a systematic review, meta-analysis, and modelling study

Chikungunya is an arboviral disease transmitted by Aedes aegypti and Aedes albopictus mosquitoes with a growing global burden linked to climate change and globalisation. We aimed to estimate chikungunya seroprevalence, force of infection (FOI), and prevalence of related chronic disability and hospital admissions in endemic and epidemic settings. In this systematic review, meta-analysis, and modelling study, we searched PubMed, Ovid, and Web of Science for articles published from database inception until Sept 26, 2022, for prospective and retrospective cross-sectional studies that addressed serological chikungunya virus infection in any geographical region, age group, and population subgroup and for longitudinal prospective and retrospective cohort studies with data on chronic chikungunya or hospital admissions in people with chikungunya. We did a systematic review of studies on chikungunya seroprevalence and fitted catalytic models to each survey to estimate location-specific FOI (ie, the rate at which susceptible individuals acquire chikungunya infection). We performed a meta-analysis to estimate the proportion of symptomatic patients with laboratory-confirmed chikungunya who had chronic chikungunya or were admitted to hospital following infection. We used a random-effects model to assess the relationship between chronic sequelae and follow-up length using linear regression. The systematic review protocol is registered online on PROSPERO, CRD42022363102. We identified 60 studies with data on seroprevalence and chronic chikungunya symptoms done across 76 locations in 38 countries, and classified 17 (22%) of 76 locations as endemic settings and 59 (78%) as epidemic settings. The global long-term median annual FOI was 0·007 (95% uncertainty interval [UI] 0·003-0·010) and varied from 0·0001 (0·00004-0·0002) to 0·113 (0·07-0·20). The highest estimated median seroprevalence at age 10 years was in south Asia (8·0% [95% UI 6·5-9·6]), followed by Latin America and the Caribbean (7·8% [4·9-14·6]), whereas median seroprevalence was lowest in the Middle East (1·0% [0·5-1·9]). We estimated that 51% (95% CI 45-58) of people with laboratory-confirmed symptomatic chikungunya had chronic disability after infection and 4% (3-5) were admitted to hospital following infection. We inferred subnational heterogeneity in long-term average annual FOI and transmission dynamics and identified both endemic and epidemic settings across different countries. Brazil, Ethiopia, Malaysia, and India included both endemic and epidemic settings. Long-term average annual FOI was higher in epidemic settings than endemic settings. However, long-term cumulative incidence of chikungunya can be similar between large outbreaks in epidemic settings with a high FOI and endemic settings with a relatively low FOI. International Vaccine Institute.

Mediastinal teratoma in children: A case series of misdiagnoses in a high-endemic tuberculosis setting

Introduction and importanceMediastinal teratoma is a rare extragonadal teratoma that frequently manifests with non-specific symptoms and is commonly misdiagnosed, particularly in Indonesia, where tuberculosis (TB) is endemic. Case presentationHerein, we present two cases of children aged 19 months and 17 years old who were referred with chronic nonspecific symptoms of cough, tachypnea, chest pain, and hemoptysis. Both children were initially diagnosed with TB and both completed anti-tuberculosis treatment. After visiting several healthcare facilities, a mediastinal mass was finally diagnosed and they all underwent thoracotomy without any further complication. The histopathology findings revealed mature teratoma. All patients had satisfactory outcomes at follow-up visits. Clinical discussionsPatients presented with non-specific symptoms are often clinically diagnosed with TB. However, primary healthcare doctors should consider other differential diagnoses when a child has non-specific respiratory symptoms, especially when chest X-ray findings are nonspecific and TB workup is negative. ConclusionsThe diagnosis of mediastinal masses is still challenging in Indonesia, as the diagnosis requires a vast array of work-up examinations, therefore, early recognition and referral are crucial for management.

Clinico-Epidemiological Trends of Leprosy at a Tertiary Care Centre of South Rajasthan: A 10-Year Retrospective Study.

Leprosy is a major public health problem in India, which affects many people every year and has significantly high new case detection rates in certain districts and blocks. According to the National Leprosy Elimination Program (NLEP) report of March 2019, there were a total of 1.14 lakhs new cases of leprosy in India with an Annual New Case Detection Rate (ANCDR) of 8.1 per 100,000 population. The present study aimed at determining the epidemiological and clinical profile of leprosy patients from a tertiary level teaching hospital in South Rajasthan. A retrospective, record-based study was carried out on patients registered in the leprosy clinic of a tertiary level teaching hospital of South Rajasthan during a period of ten years (2010-2019). Data regarding the demographic profile, clinical features, treatment given, and complications were analysed. A total of 1372 patients registered in the leprosy clinic during a period of 10 years were evaluated. There were 1007 (73.4%) males and 365 (26.6%) females with a male-female ratio of 2.76:1. The majority of patients 671 (48.9%) belonged to the middle age group (21-40 years). Multibacillary leprosy was the most common clinical type seen in 1109 patients (80.8%). Borderline leprosy was the most common morphological type, determined in 625 (45.6%) patients, of which BL (21.0%) was the most common group. 16.7% patients presented with leprosy reaction at the time of initial diagnosis. Type 1 reaction was seen in 91(6.6%) and type 2 reaction in 138 (10.1%) patients. Grade I disability was observed in 347 (25.3%) patients whereas grade II disability was seen in 456 (33.2%) patients. 54 patients (3.9%) had a definite history of contact in the family. 28 patients defaulted during the study period. Yearly trend of epidemiological and operational parameters was observed, and the parameters were compared with the national data. Persistent high proportion of multibacillary cases and grade 2 disability indicates that leprosy continues to be a significant health care problem despite statistical elimination. There is a clear need to strengthen early detection, treatment and regular follow-up of these cases in both high and low endemic settings.

The Variation of Malaria Prevention Measures Knowledge and their Associated Factors in Rural East Nusa Tenggara Province, Indonesia

BACKGROUND: Malaria is one of the major public health problems in African and Southeast Asian countries including Indonesia. However, knowledge of malaria prevention measures (MPM) is not well studied, particularly in Indonesia. AIM: This study aimed to investigate the level of MPM knowledge and associated factors among rural adults in high, moderate, and low endemic settings of East Nusa Tenggara Province (ENTP), Indonesia. MATERIALS AND METHODS: A community-based cross-sectional study was conducted among a randomly selected 1495 households at rural ENTP. Multistage sampling technique was employed to recruit participants. Univariate and multivariable logistic regression model was used to assess factors affecting knowledge of MPM. RESULTS: The MPM knowledge in long-lasting insecticide-treated net was the highest in high endemic settings (76.8%), while MPM knowledge on keeping the surrounding house clean was the highest in low-endemic settings (71.9%). The level of MPM knowledge in low, moderate, and high endemic settings differs significantly with the highest in low settings (57%, 95% CI: 50.5–63.5) and the lowest in high settings (19.3%, 95% CI: 11.1–27.5). In all settings, good level of MPM knowledge was significantly higher for adults with high socioeconomic status (SES) (adjusted odds ratio [AOR] = 2.52, 95% CI: 1.20–5.30; AOR = 20.5, 95% CI: 4.64–90.8, AOR = 3.31, 95% CI: 1.34–8.15, respectively) compared to those having low SES. In high and moderate settings, the likelihood of good MPM knowledge was considerately higher for adults with at least secondary (AOR = 2.35, 95% CI = 1.29–4.36, AOR = 2.66, 95% CI = 1.32–5.39, respectively) than those with primary or no education level. CONCLUSION: The good level of MPM knowledge was very low in three different malaria endemic settings. Higher level of education and high SES were significantly associated with the good level. Therefore, health education promotion on MPM knowledge is critical to support malaria elimination program in the province.

Very low prevalence of Mansonella perstans-specific cell-free DNA in serum samples of Ghanaian HIV patients.

Mansonellosis is a widely neglected helminth disease which is predominantly observed in tropical regions. This study was conducted to assess potential associations of the prevalence of circulating Mansonella perstans-specific cell-free DNA in human serum and HIV infection in Ghanaian individuals. For this purpose, serum samples obtained from Ghanaian HIV-patients (n = 989) and non-HIV-infected Ghanaian control individuals (n = 91) were subjected to real-time PCR targeting the ITS-(internal transcribed spacer-)2 sequence of M. perstans and Mansonella sp. Deux. Mansonella-specific cell-free DNA was detected in serum samples of only 2 HIV-positive and 0 HIV-negative individuals, making any reliable conclusions on potential associations between HIV and mansonellosis in tropical Ghana unfeasible. Future epidemiological studies on hypothetical associations between mansonellosis and HIV infections should focus more specifically on high-endemicity settings for both Mansonella spp.-infections and HIV-infections, include higher case numbers and be based on real-time PCR from whole blood rather than from serum, in which only circulating parasite DNA but no more cell-bound parasite DNA can be detected. However, the study did not show associations of HIV infections in Ghanaian individuals with Mansonella worm loads high enough to detect cell-free Mansonella DNA in serum by PCR.

Diagnostic probability classification in suspected borreliosis by a novel Borrelia C6-peptide IgG1- subclass antibody test.

The tick-borne multisystemic infection caused by Borrelia burgdorferi sensu lato, Lyme borreliosis, or Lyme disease, occurring in temperate regions of the northern hemisphere, continues to spread geographically with the expanding tick population. Despite the rising perceived risk of infection in the population, the clinical diagnosis of Borrelia infection is not always obvious and the most important laboratory test, antibody detection, has limited accuracy in diagnosing active disease. According to international guidelines, the primary serology test, which has a high sensitivity-low specificity, should, be verified using a high specificity confirmation test to improve the specificity. However, this enhancement in specificity comes at the cost of lower sensitivity. This two-step procedure is often omitted in everyday clinical practice. An optimal primary test would be one where no secondary tests for confirmation would be necessary. In the present study, the performance of a novel assay for quantitating IgG1-subclass antibodies to Borrelia C6-peptide was compared to a commercial reference assay of total IgG and IgM antibodies to Borrelia C6-peptide in the setting of a high endemic area for borreliosis. A derivation study on a retrospective clinical material was performed to compare the performance parameters and assess the discriminatory properties of the assays, followed by a prospective validation study. The IgG1-antibody assay achieved comparable summary performance parameters to those of the reference assay. The sensitivity was almost 100% while the specificity was about 50%. In a high-endemic setting, characterized by high background seropositivity of about 50% and disease prevalence of approximately 10%, antibody tests are unable to rule-in active Borrelia infection. The rule-out assessment of the methods revealed that of 1000 patients, 7 - 54 with negative results based on the reference method could have an active Borrelia infection. Such uncertainty was not found for the index test and may help improve the risk classification of patients.

Correlates of physical activity among people living with and without HIV in rural Uganda.

Antiretroviral therapy (ART) has led to diminishing AIDS-related mortality but a concomitant increase in non-communicable diseases (NCDs) for people with HIV (PWH). Whereas physical activity (PA) has been shown to help prevent NCDs and NCD outcomes in other settings, there are few data on PA and its correlates among PWH in high-endemic settings. We aimed to compare PA by HIV serostatus in rural Uganda. We analysed data from the UGANDAC study, an observational cohort including PWH in ambulatory HIV care in Mbarara, Uganda, and age- and gender-matched people without HIV (PWOH). Our primary outcome of interest was PA, which we assessed using the International Physical Activity Questionnaire and considered as a continuous measure of metabolic equivalents in minutes/week (MET-min/week). Our primary exposure of interest was HIV serostatus. We fit univariable and multivariable linear regression models to estimate the relationship between HIV and PA levels, with and without addition of sociodemographic and clinical correlates of PA (MET-min/week). In secondary analyses, we explored relationships restricted to rural residents, and interactions between gender and serostatus. We enrolled 309 participants, evenly divided by serostatus and gender. The mean age of PWH was 52 [standard deviation (SD) 7.2] and 52.6 (SD 7.3) for PWOH. In general, participants engaged in high levels of PA regardless of serostatus, with 81.2% (251/309) meeting criteria for high PA. However, PWOH reported higher mean levels of PA met-minutes/week than PWH (9,128 vs 7,152, p ≤ 0.001), and a greater proportion of PWOH (88.3%; 136/154) met the criteria for high PA compared to PWH (74.2%; 115/155). In adjusted models, lower levels of PA persisted among PWH (β = -1,734, 95% CI: -2,645, -824, p ≤ 0.001). Results were similar in a sensitivity analysis limited to people living in rural areas. In a rural Ugandan cohort, PWOH had higher levels of PA than PWH. Interventions that encourage PA among PWH may have a role in improving NCD risk profiles among PWH in the region.

Risk factors for colonization with multidrug-resistant Gram-negative bacteria and Clostridioides difficile in Long Term Care Facilities (LTCFs) residents: the evidence from 27 facilities in a high endemic setting.

Residency in LTCFs increases the likelihood of colonization with multidrug resistant Gram-negative bacteria (MDR-GNB). We assessed the prevalence and risk factors for enteric colonization by III-generation cephalosporins-resistant and carbapenem-resistant (CR) GNB in a large group of LTCFs in a high endemic setting. We also assessed the prevalence and risk factors for C. difficile colonization. A point prevalence survey with rectal screening (RS) was conducted in 27 LTCFs in north Italy. Epidemiological and clinical variables on the survey day, history of hospitalization and surgery within one year, and antibiotics within three months, were collected. The presence of III-generation cephalosporin resistant and CR GNB was assessed using a selective culture on chromogenic medium and PCR for carbapenemase detection. The presence of C. difficile was assessed using ELISA for GDH and RT-PCR to identify toxigenic strains. Multi-variable analyses were performed using two-level logistic regression models. In the study period 1947 RSs were performed. The prevalence of colonization by at least one GNB resistant to III-generation cephalosporin was 51% (E. coli 65%, K. pneumoniae 14% of isolates). The prevalence of colonization by CR GNB was 6%. 6% of all isolates (1150 strains) resulted in a carbapenem-resistant K. pneumoniae, and 3% in a carbapenem-resistant E. coli. KPC was the most frequent carbapenemase (73%) identified by PCR, followed by VIM (23%). The prevalence of colonization by C. difficile was 11.7%. The presence of a medical device (OR 2.67) and previous antibiotic use (OR 1.48) were significantly associated with III-generation cephalosporin resistant GNB colonization. The presence of a medical device (OR 2.67) and previous hospitalization (OR 1.80) were significantly associated with CR GNB. The presence of a medical device (OR 2.30) was significantly associated with C. difficile colonization. Main previously used antibiotic classes were fluoroquinolones (32% of previously treated subjects), III-generation cephalosporins (21%), and penicillins (19%). Antimicrobial stewardship in LTCFs is a critical issue, being previous antibiotic treatment a risk factor for colonization by MDR-GNB. The prevalence of colonization by III-generation cephalosporin and CR GNB among LTCF residents also underlines the importance to adhere to hand hygiene indications, infection prevention and control measures, and environmental hygiene protocols, more achievable than rigorous contact precautions in this type of social setting.

294. Risk factors of COVID-19 associated pulmonary aspergillosis in a high endemic setting and development of a bedside clinical risk prediction score.

Abstract Background India has a high burden of invasive fungal infections. Although invasive aspergillosis was also reported during the COVID-19 pandemic, the real world data on the risk factors and outcome of CAPA are limited. Our aim is to determine risk factors and clinical outcomes of CAPA and develop a prediction model for patient stratification. Methods A retrospective, case-control study was conducted at a 1300-bedded South Indian tertiary care academic centre from June 1st, 2020 to May 31st, 2021. CAPA cases were defined by 2020 ECMM/ISHAM consensus criteria as possible, probable, and proven infection. Age and admission period matched control group with COVID-19 but without aspergillosis was selected in a 1:1 ratio. A risk scoring stratification for CAPA was developed based on the significant CAPA risk factors using logistic regression model. Figure 1:Receiving operating characteristic curve of CAPA incidence score for predicting CAPA in the study cohort Results 95 CAPA cases, of which 75(79%) were probable and 20(21%) possible, were diagnosed during the study period. 84(88.4%) patients had moderate to severe COVID-19, and 75(78.9%) were treated with steroids, most commonly dexamethasone (Table 1). The time from COVID-19 diagnosis to CAPA was 13 days (IQR 12). 40(42.1%) of patients were on mechanical ventilation at CAPA diagnosis. Outcome measures (MV, NIV and hospital/ICU stay) were significantly higher in CAPA patients compared to controls(Table 2). Neutropenia, use of steroids, broad spectrum antibiotic use, fluconazole prophylaxis and absence of co-infecting pathogen were found to be significant factors associated with CAPA(p&amp;lt; 0.05) (Table 3). An optimal risk score of ≥10.00 predicted CAPA with a sensitivity of 84.2% and a specificity of 59% with an area under the curve of 0.77 (PPV=67.23%, NPV=78.87%)(Fig 1). 75(78.9%) patients had positive serum aspergillus galactomannan with an average value of 1.89±1.65. 28-day (41.1% vs 33.7%, p=0.13) and 6-week all cause-mortality (48.4% vs 37.9%, p=0.07) were higher, but not statistically significant, for CAPA. Table 1:Baseline characteristics and risk factorsTable 2:Primary and secondary outcomesTable 3:CAPA incidence scoring table Significant univariate variables were included in the multivariate logistic regression model and predicted probabilities based on the beta co-efficients of the significant variables in the model were transformed to generate CAPA incidence score for patients. Conclusion Risk factors of CAPA in Indian were similar to those reported previously in other countries. CAPA can be seen in severe COVID-19 patients who are not mechanically ventilated. A CAPA risk scoring system, that needs external validation, is a simple and feasible tool that could be useful in stratification of patients suspected of CAPA. Disclosures All Authors: No reported disclosures.

The potential for the double risk of rabies and antimicrobial resistance in a high rabies endemic setting: detection of antibiotic resistance in bacterial isolates from infected dog bite wounds in Uganda

BackgroundPost-exposure treatment for dog bites in humans aims at alleviating the risk of rabies and promoting wound healing. Wound healing may be complicated by bacteria. This study identified the different bacteria and their antibiotic susceptibilities in infected dog bite wounds (DBWs) in Uganda.MethodsA cross-sectional study was conducted among 376 dog bite patients. Wound swabs from patients with infected DBWs were collected and inoculated into recommended media. They were cultured for both aerobic and anaerobic bacteria. All isolated bacteria were identified based on colony characteristics, gram stain, and standard biochemical tests. Molecular identification was performed for strains that were resistant to three or more antibiotics. Antibiotic susceptibility testing was conducted using the disc diffusion method following the modified Kirby-Bauer method. The data were analysed using Stata version 15 software.ResultsApproximately half of the patients (52.9%, 199/376) presented with infected wounds. Majority of the swabs (84.4%, 168/199) were culture positive, and yielded a total of 768 isolates where about half (52.9%, 406/768) were gram positive bacteria, and about two-thirds (64.6%, 496/768) were recovered from category II wounds. Among the gram positive bacteria, 339 (83.5%) were aerobes where Staphylococcus aureus (103, 30.4%), Coagulase-negative staphylococci (68, 20.1%), and Corynebacterium spp (33, 9.7%) had the highest prevalence. For the 362 Gram negative isolates, 217 (59.9%) were aerobes and the commonest isolates were P. maltocida (64, 29.5%), Capnocytophaga canimorsus (36, 16.6%) and P. canis (26, 12.0%). Gram-positive isolates were resistant to metronidazole (93.6%), oxacillin (68.5%), ceftriaxone (14.6%) and amoxicillin/clavulanic acid (14.0%). Gram negative isolates were resistant to metronidazole (100%), ampicillin (30.7%), oxacillin (29.3%), and doxycycline (22.9%). Multidrug resistance was in 105 (29.0%) and 121/406 (29.8%) of the gram-negative and gram-positive isolates, respectively. All gram-positive isolates were susceptible to vancomycin and ciprofloxacin.ConclusionsInfection rates of DBWs in Uganda are high and the dominant bacterial isolates are Staphylococcus aureus, Pasteurella spps, and Capnocytophaga canimorsus. Multidrug resistance to commonly used antibiotics is high. The recommendation in the Uganda Clinical Guidelines to use metronidazole in the management of DBWs should be reviewed. DBWs should be enlisted for routine antimicrobial resistance surveillance and rational use of antimicrobial agents should be promoted.

Impacts of tuberculosis services strengthening and the COVID-19 pandemic on case detection and treatment outcomes in Mimika District, Papua, Indonesia: 2014-2021.

Indonesia is a high-burden tuberculosis (TB) country with a wide case detection gap, exacerbated by the COVID-19 pandemic. We aimed to review the epidemiology of TB in a high-endemic setting of Indonesia before and during the implementation of health system strengthening activities for TB, including during the first two years of the COVID-19 pandemic. We analysed TB program data from Mimika District, Papua, Indonesia from 2014 to 2021. Health system strengthening activities to improve the programmatic management of TB were implemented from 2017 onwards. Activities included decentralization of TB services, training and mentoring of healthcare workers, improved screening for co-morbidities, and introduction and optimisation of Xpert testing in 2018. A total of 11,803 TB cases were notified to the Mimika District Health Office over eight years (2014-21). Between 2015 and 2019, there was a 67% increase in annual case notifications, an 89% increase in bacteriologically confirmed cases and the proportion of TB cases detected in primary care increased from 26% to 46%. In 2020, coinciding with the COVID-19 pandemic, investigation of people with presumptive TB fell by 38%, but the proportion of those tested with Xpert increased. TB case notifications decreased by 19% from 1,796 in 2019 to 1,461 in 2020, but then increased by 17% to 1,716 in 2021. Routine screening for co-morbidities (HIV, diabetes) among TB patients improved over time and was not affected by the pandemic. Treatment success overall was 71% and remained relatively unchanged. Loss to follow-up and death were 18% and 3.7% respectively. Improvements in TB case finding were observed over a period in which a range of health system strengthening activities were implemented. While COVID-19 had a negative impact on the TB program in Mimika District, there are encouraging signs of recovery. Further work is needed to improve TB treatment outcomes.

Tobacco smoking impact on tuberculosis treatment outcome: an observational study from West Africa

ObjectiveBoth tuberculosis (TB) and tobacco smoking are preventable health hazards. Few studies have examined the relationship between TB and tobacco smoking in an African setting, where the two health burdens collide heavily. This study aimed to describe the severity of TB disease and treatment outcomes among smokers with TB compared with nonsmokers with TB in Guinea-Bissau. MethodsWe conducted a prospective follow-up study between 2003-2017 in Guinea-Bissau, enrolling adult patients with TB classified as nonsmokers or smokers. Disease severity was assessed using the Bandim TBscore. Multivariate logistic and Cox proportional hazard regressions were used to analyse treatment outcomes. ResultsOf 1780 included patients, 385 were smokers who had smoked for a median 10 years (interquartile range [IQR] 5-20). No difference in disease severity at the time of diagnosis was observed. Smokers were not significantly more prone to a nonsuccessful treatment outcome, although a trend was seen (adjusted odds ratio [OR] 1.24, 95% confidence interval [CI] 0.91-1.70), and smokers tended to be more often lost to follow-up, but this also was not a significant finding (adjusted hazard ratio [HR] 2.09, 95% CI 0.89-4.94). ConclusionIn a TB high-endemic setting with few tobacco smokers, smoking was not associated with disease severity or worse outcome, possibly because of socioeconomic confounders.

Investigating resistance in clinical Mycobacterium tuberculosis complex isolates with genomic and phenotypic antimicrobial susceptibility testing: a multicentre observational study

SummaryBackgroundWhole-genome sequencing (WGS) of Mycobacterium tuberculosis complex has become an important tool in diagnosis and management of drug-resistant tuberculosis. However, data correlating resistance genotype with quantitative phenotypic antimicrobial susceptibility testing (AST) are scarce.MethodsIn a prospective multicentre observational study, 900 clinical M tuberculosis complex isolates were collected from adults with drug-resistant tuberculosis in five high-endemic tuberculosis settings around the world (Georgia, Moldova, Peru, South Africa, and Viet Nam) between Dec 5, 2014, and Dec 12, 2017. Minimum inhibitory concentrations (MICs) and resulting binary phenotypic AST results for up to nine antituberculosis drugs were determined and correlated with resistance-conferring mutations identified by WGS.FindingsConsidering WHO-endorsed critical concentrations as reference, WGS had high accuracy for prediction of resistance to isoniazid (sensitivity 98·8% [95% CI 98·5–99·0]; specificity 96·6% [95% CI 95·2–97·9]), levofloxacin (sensitivity 94·8% [93·3–97·6]; specificity 97·1% [96·7–97·6]), kanamycin (sensitivity 96·1% [95·4–96·8]; specificity 95·0% [94·4–95·7]), amikacin (sensitivity 97·2% [96·4–98·1]; specificity 98·6% [98·3–98·9]), and capreomycin (sensitivity 93·1% [90·0–96·3]; specificity 98·3% [98·0–98·7]). For rifampicin, pyrazinamide, and ethambutol, the specificity of resistance prediction was suboptimal (64·0% [61·0–67·1], 83·8% [81·0–86·5], and 40·1% [37·4–42·9], respectively). Specificity for rifampicin increased to 83·9% when borderline mutations with MICs overlapping with the critical concentration were excluded. Consequently, we highlighted mutations in M tuberculosis complex isolates that are often falsely identified as susceptible by phenotypic AST, and we identified potential novel resistance-conferring mutations.InterpretationThe combined analysis of mutations and quantitative phenotypes shows the potential of WGS to produce a refined interpretation of resistance, which is needed for individualised therapy, and eventually could allow differential drug dosing. However, variability of MIC data for some M tuberculosis complex isolates carrying identical mutations also reveals limitations of our understanding of the genotype and phenotype relationships (eg, including epistasis and strain genetic background).FundingBill & Melinda Gates Foundation, German Centre for Infection Research, German Research Foundation, Excellence Cluster Precision Medicine of Inflammation (EXC 2167), and Leibniz ScienceCampus EvoLUNG.

Expression of mycobacterium tuberculosis induced SOCS3 and STAT3 and the implications on innate immunity in TB patients vs healthy contacts in high TB/HIV endemic setting: A cross-sectional analytical study.

BackgroundMycobacterium tuberculosis (TB) remains a disease of global health concern and a leading cause of mortality arising from an infectious agent. Protective immunity to TB remains unclear. Suppressor of cytokine signaling-3 (SOCS3) and signal transduction and activator of transcription-3 (STAT3) genes have shown potential to influence innate immunity. We, therefore, explored the expression of SOCS3 and STAT3 and their implications on the innate immunity in TB patients and their healthy close contacts.MethodsWe recruited 72 TB patients and 62 healthy contacts from a high TB and HIV endemic setting (Lusaka, Zambia). We used RT-PCRT and flow cytometry to quantify the expression of SOCS, STAT3 and cytokines respectively. Data was analysed Stata version 14.0 and figures were developed in GraphPad prism version 9.1.0 (221). Assessment for associations for categorical and continuous variables was analysed using the Chi-square test and Mann-Whitney test respectively. Spearman’s rank correlation was used to evaluate the relationship between SOCS3 and IL-6. A p-value < 0.05 was considered statistically significant.ResultsHealthy contacts markedly expressed SOCS3 in both unstimulated and stimulated whole blood in comparison to TB patients (p <0.0001). STAT3 was elevated in TB patients in TB patients in stimulated blood only. IL-6 (P = < 0.0001) and IL-10 (P = <0.0001), were significantly expressed in Healthy contacts in comparison to TB patients. TNF-α (p = 0.044) were markedly elevated in TB patients in comparison to healthy contacts. IL-6 and SOCS3 correlated significantly in healthy contacts only (r = 0.429, p = 0.02).ConclusionsBoth SOCS3 and STAT3 are genes of importance in mounting protective innate immunity against TB. We propose that SOCS3 stimulation and inhibition of STAT3 as possible approaches in gene therapy and vaccine development for TB.

Asymptomatic School-Aged Children Are Important Drivers of Malaria Transmission in a High Endemicity Setting in Uganda.

Achieving malaria elimination requires a better understanding of the transmissibility of human infections in different transmission settings. This study aimed to characterize the human infectious reservoir in a high endemicity setting in eastern Uganda, using gametocyte quantification and mosquito feeding assays. In asymptomatic infections, gametocyte densities were positively associated with the proportion of infected mosquitoes (β = 1.60; 95% CI, 1.32–1.92; P < .0001). Combining transmissibility and abundance in the population, symptomatic and asymptomatic infections were estimated to contribute to 5.3% and 94.7% of the infectious reservoir, respectively. School-aged children (5–15 years old) contributed to 50.4% of transmission events and were important drivers of malaria transmission.

Multicentric Evaluation of SeeGene Allplex Real-Time PCR Assays Targeting 28 Bacterial, Microsporidal and Parasitic Nucleic Acid Sequences in Human Stool Samples.

Prior to the implementation of new diagnostic techniques, a thorough evaluation is mandatory in order to ensure diagnostic reliability. If positive samples are scarcely available, however, such evaluations can be difficult to perform. Here, we evaluated four SeeGene Allplex real-time PCR assays amplifying a total of 28 bacteria, microsporidal and parasitic nucleic acid sequence targets in human stool samples in a multicentric approach. In the assessments with strongly positive samples, sensitivity values ranging between 13% and 100% were recorded for bacteria, between 0% and 100% for protozoa and between 7% and 100% for helminths and microsporidia; for the weakly positive samples, the recorded sensitivity values for bacteria ranged from 0% to 100%; for protozoa, from 0% to 40%; and for helminths and microsporidia, from 0% to 53%. For bacteria, the recorded specificity was in the range between 87% and 100%, while a specificity of 100% was recorded for all assessed PCRs targeting parasites and microsporidia. The intra- and inter-assay variations were generally low. Specifically for some helminth species, the sensitivity could be drastically increased by applying manual nucleic acid extraction instead of the manufacturer-recommended automatic procedure, while such effects were less obvious for the bacteria and protozoa. In summary, the testing with the chosen positive control samples showed varying degrees of discordance between the evaluated Allplex assays and the applied in-house reference assays associated with higher cycle threshold values in the Allplex assays, suggesting that samples with very low pathogen densities might be missed. As the targeted species can occur as harmless colonizers in the gut of individuals in high-endemicity settings as well, future studies should aim at assessing the clinical relevance of the latter hint.

Diagnostic method-based underestimation of leptospirosis in clinical and research settings; an experience from a large prospective study in a high endemic setting.

BackgroundLeptospirosis has globally significant human mortality and morbidity, yet estimating the clinical and public health burden of leptospirosis is challenging because timely diagnosis remains limited. The goal of the present study was to evaluate leptospirosis undercounting by current standard methods in both clinical and epidemiological study settings.Methodology/Principal findingsA prospective hospital-based study was conducted in multiple hospitals in Sri Lanka from 2016 to 2019. Culture, whole blood, and urine samples were collected from clinically suspected leptospirosis cases and patients with undifferentiated fever. Analysis of biological samples from 1,734 subjects confirmed 591 (34.1%) cases as leptospirosis and 297 (17.1%) were classified as “probable” leptospirosis cases. Whole blood quantitative PCR (qPCR) did identify the most cases (322/540(60%)) but missed 40%. Cases missed by each method include; urine qPCR, 70% (153/220); acute sample microscopic agglutination test (MAT), 80% (409/510); paired serum sample MAT, 58% (98/170); and surveillance clinical case definition, 53% (265/496). qPCR of negative culture samples after six months of observation was of diagnostic value retrospectively with but missed 58% of positives (109/353).ConclusionLeptospirosis disease burden estimates should consider the limitations of standard diagnostic tests. qPCR of multiple sample types should be used as a leading standard test for diagnosing acute leptospirosis.