Prevalence of non-communicable diseases among household contacts of people with tuberculosis: A systematic review and individual participant data meta-analysis.

OBJECTIVE: To investigate the prevalence of non-communicable diseases among household contacts of people with tuberculosis. METHODS: We conducted a systematic review and individual participant data meta-analysis. We searched Medline, Embase and the Global Index Medicus from inception to 16 May 2023. We included studies that assessed for at least one non-communicable disease among household contacts of people with clinical tuberculosis. We estimated the non-communicable disease prevalence through mixed effects logistic regression for studies providing individual participant data, and compared it with estimates from aggregated data meta-analyses. Furthermore, we compared age and sex-standardised non-communicable disease prevalence with national-level estimates standardised for age and sex. RESULTS: We identified 39 eligible studies, of which 14 provided individual participant data (29,194 contacts). Of the remaining 25 studies, 18 studies reported aggregated data suitable for aggregated data meta-analysis. In individual participant data analysis, the pooled prevalence of diabetes in studies that undertook biochemical testing was 8.8% (95% confidence interval [CI], 5.1%-14.9%, four studies). Age-and sex-standardised prevalence was higher in two studies (10.4% vs. 6.9% and 11.5% vs. 8.4%) than the corresponding national estimates and similar in two studies. Prevalence of diabetes mellitus based on self-report or medical records was 3.4% (95% CI 2.6%-4.6%, 14 studies). Prevalence did not significantly differ compared to estimates from aggregated data meta-analysis. There were limited data for other non-communicable diseases. CONCLUSION: The prevalence of diabetes mellitus among household contacts was high while that of known diabetes was substantially lower, suggesting the underdiagnosis. tuberculosis household contact investigation offers opportunities to deliver multifaceted interventions to identify tuberculosis infection and disease, screen for non-communicable diseases and address shared risk factors.

Seroprevalence of SARS-CoV-2 antibodies in a prospective cohort of patients admitted to an acute psychiatric ward in Norway during the initial months of the COVID-19 pandemic.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) spread around the world during the first part of 2020. The purpose of the study was to assess the prevalence of SARS-CoV-2 infection among patients acutely admitted to the Psychiatric Clinic, Haukeland University Hospital. METHODS: Serum tests to assess for antibodies to SARS-CoV-2 were administered at admission to the clinic together with a questionnaire on symptoms and demographical information. Further information was obtained from the medical records. RESULTS: The cumulative seroprevalence in the 266 participants was 0.75%, the cumulative reported cases in the Norwegian general population was 0.61% at the end of the inclusion period of the study. Twenty-five percent of participants had risk factors for a serious course of COVID-19. There was a low prevalence of cohabitation and only 20% had their main income derived from ordinary salaries (not welfare). CONCLUSION: The prevalence of SARS-CoV-2 infection in a sample of patients acutely admitted to the Psychiatric Clinic, Haukeland University Hospital, was comparable to reported cases in the general population. A possible link to governmental and municipal restrictions, general low workplace participation and cohabitation is discussed.

Seroprevalence of SARS-CoV-2 antibodies is comparable to the general population.Twenty-five percent of patients had elevated risk for a serious course of COVID-19 because of somatic conditions.Fifty-seven percent lived alone, 17% with one other person in the household.Twenty percent had regular salary as the main income source for the last three months before admission.

Diagnostic utility of oropharyngeal swabs as an alternative to lower respiratory tract samples for PCR-based syndromic testing in patients with community-acquired pneumonia.

Syndromic PCR-based analysis of lower respiratory tract (LRT) samples in patients with community-acquired pneumonia (CAP) improves the bacterial yield and time-to-results compared to culture-based methods. However, obtaining adequate sputum samples can be challenging and is frequently not prioritized in the emergency department (ED). In this study, we assess the concordance of microbiological detections between oropharyngeal- (OP) and LRT samples from patients presenting to the ED with CAP using a syndromic PCR-based respiratory panel [Biofire FilmArray Pneumonia plus (FAP plus)]. Paired OP- and high-quality LRT samples were collected from 103 patients with confirmed CAP, who had been included in a randomized controlled trial (NCT04660084) or a subsequent observational study at Haukeland University Hospital, and analyzed using the FAP plus. The LRT samples were obtained mainly by sputum induction (88%). Using the LRT samples as a reference standard, the positive percent agreement (PPA), negative percent agreement (NPA), and overall percent agreement for the most common bacterial pathogens in CAP, Streptococcus pneumoniae and Haemophilus influenzae, were 85%, 99% and 95%, and 86%, 98% and 93%, respectively. For Moraxella catarrhalis, the PPA was lower (74%), while the NPA was 100%. For bacteria that are less likely causes of uncomplicated CAP (e.g., Staphylococcus aureus and Enterobacterales) the results were more divergent. In conclusion, the FAP plus detects the most common CAP pathogens S. pneumoniae and H. influenzae from OP samples with high PPAs and excellent NPAs when compared with LRT samples. For these pathogens, the PPAs for OP samples were higher than previous reports for nasopharyngeal samples. This suggests that analysis of OP samples with syndromic PCR panels could represent an alternative approach for rapid microbiological testing in the ED, especially in patients where LRT samples are difficult to obtain. Divergent results for bacteria that are less likely to cause uncomplicated CAP do, however, emphasize the need for clinical evaluation of positive test results.

The changing spectrum of microbial aetiology of respiratory tract infections in hospitalized patients before and during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic was met with strict containment measures. We hypothesized that societal infection control measures would impact the number of hospital admissions for respiratory tract infections, as well as, the spectrum of pathogens detected in patients with suspected community acquired pneumonia (CAP). METHODS: This study is based on aggregated surveillance data from electronic health records of patients admitted to the hospitals in Bergen Hospital Trust from January 2017 through June 2021, as well as, two prospective studies of patients with suspected CAP conducted prior to and during the COVID-19 pandemic (pre-COVID cohort versus COVID cohort, respectively). In the prospective cohorts, microbiological detections were ascertained by comprehensive PCR-testing in lower respiratory tract specimens. Mann-Whitney's U test was used to analyse continuous variables. Fisher's exact test was used for analysing categorical data. The number of admissions before and during the outbreak of SARS-CoV-2 was compared using two-sample t-tests on logarithmic transformed values. RESULTS: Admissions for respiratory tract infections declined after the outbreak of SARS-CoV-2 (p < 0.001). The pre-COVID and the COVID cohorts comprised 96 and 80 patients, respectively. The proportion of viruses detected in the COVID cohort was significantly lower compared with the pre-COVID cohort [21% vs 36%, difference of 14%, 95% CI 4% to 26%; p = 0.012], and the proportion of bacterial- and viral co-detections was less than half in the COVID cohort compared with the pre-COVID cohort (19% vs 45%, difference of 26%, 95% CI 13% to 41%; p < 0.001). The proportion of bacteria detected was similar (p = 0.162), however, a difference in the bacterial spectrum was observed in the two cohorts. Haemophilus influenzae was the most frequent bacterial detection in both cohorts, followed by Streptococcus pneumoniae in the pre-COVID and Staphylococcus aureus in the COVID cohort. CONCLUSION: During the first year of the COVID-19 pandemic, the number of admissions with pneumonia and the microbiological detections in patients with suspected CAP, differed from the preceding year. This suggests that infection control measures related to COVID-19 restrictions have an overall and specific impact on respiratory tract infections, beyond reducing the spread of SARS-CoV-2.

Identification of subclinical tuberculosis in household contacts using exposure scores and contact investigations.

BACKGROUND: The goal of tuberculosis elimination put forward in the End TB Strategy prioritizes diagnosis and treatment of incipient and subclinical TB, recently defined by key stakeholders as "asymptomatic, early pre-clinical disease during which pathology evolves". Regarded as indicative of a high risk of TB progression, considerable efforts have been made to identify these cases through exploration of biomarkers. The present study aimed to evaluate simple scoring systems for TB exposure as screening tools for subclinical TB, the only identifiable of the incipient and subclinical disease states, in a contact investigation (CI) setting of low HIV-prevalence. METHODS: Nested within a large prospective study in household contacts (HHCs) of smear positive pulmonary TB cases in South-India conducted 2010-2012, we assessed 1) the association between the Tuberculosis Contact Score (TCS) and the Infectivity Score, with established tools for Mycobacterium tuberculosis (Mtb) infection, corrected for established TB risk factors, and 2) the capability of the TB exposure scores to identify subclinical TB defined by Mtb-culture positivity in sputum or gastric aspirate (subjects < 5 years) specimen. RESULTS: Of 525 HHCs, 29 were Mtb-culture positive and 96.6% of these asymptomatic. The TCS and the Infectivity Score associated with positive Tuberculin Skin Test and QuantiFeron TB-Gold In-tube assay (QFT) results in multivariate analyses (TCS: ORTST 1.16, 95% CI: 1.01, 1.33; ORQFT 1.33 95% CI: 1.16, 1.51. Infectivity Score: ORTST 1.39, 95% CI: 1.10, 1.76; ORQFT 1.41 95% CI: 1.16, 1.71). The Infectivity Score showed a moderate capability to identify subclinical TB (AUC of 0.61, 95% CI: 0.52, 0.70). CONCLUSIONS: Although our results did not identify an easily applicable screening tool for subclinical TB, the present study indicates that focusing on TB-related symptoms in CI settings may be of limited value for early identification of HHCs with high risk for TB progression.

Optimizing the detection of recent tuberculosis infection in children in a high tuberculosis-HIV burden setting.

RATIONALE: Children who are young, malnourished, and infected with HIV have significant risk of tuberculosis (TB) morbidity and mortality following TB infection. Treatment of TB infection is hindered by poor detection and limited pediatric data. OBJECTIVES: Identify improved testing to detect pediatric TB infection. METHODS: This was a prospective community-based study assessing use of the tuberculin skin test and IFN-γ release assays among children (n = 1,343; 6 mo to <15 yr) in TB-HIV high-burden settings; associations with child characteristics were measured. MEASUREMENTS AND MAIN RESULTS: Contact tracing detects TB in 8% of child contacts within 3 months of exposure. Among children with no documented contact, tuberculin skin test and QuantiFERON-TB Gold In-Tube positivity was greater than T-SPOT.TB. Nearly 8% of children had IFN-γ release assay positive and skin test negative discordance. In a model accounting for confounders, all tests correlate with TB contact, but IFN-γ release assays correlate better than the tuberculin skin test (P = 0.0011). Indeterminate IFN-γ release assay results were not associated with age. Indeterminate QuantiFERON-TB Gold In-Tube results were more frequent in children infected with HIV (4.7%) than uninfected with HIV (1.9%), whereas T-SPOT.TB indeterminates were rare (0.2%) and not affected by HIV status. Conversion and reversion were not associated with HIV status. Among children infected with HIV, tests correlated less with contact as malnutrition worsened. CONCLUSIONS: Where resources allow, use of IFN-γ release assays should be considered in children who are young, recently exposed, and infected with HIV because they may offer advantages compared with the tuberculin skin test for identifying TB infection, and improve targeted, cost-effective delivery of preventive therapy. Affordable tests of infection could dramatically impact global TB control.

Incidence of tuberculosis among school-going adolescents in South India.

BACKGROUND: Tuberculosis (TB) incidence data in vaccine target populations, particularly adolescents, are important for designing and powering vaccine clinical trials. Little is known about the incidence of tuberculosis among adolescents in India. The objective of current study is to estimate the incidence of pulmonary tuberculosis (PTB) disease among adolescents attending school in South India using two different surveillance methods (active and passive) and to compare the incidence between the two groups. METHODS: The study was a prospective cohort study with a 2-year follow-up period. The study was conducted in Palamaner, Chittoor District of Andhra Pradesh, South India from February 2007 to July 2010. A random sampling procedure was used to select a subset of schools to enable approximately 8000 subjects to be available for randomization in the study. A stratified randomization procedure was used to assign the selected schools to either active or passive surveillance. Participants who met the criteria for being exposed to TB were referred to the diagnostic ward for pulmonary tuberculosis confirmation. A total number of 3441 males and 3202 females between the ages 11 and less than 18 years were enrolled into the study. RESULTS: Of the 3102 participants in the active surveillance group, four subjects were diagnosed with definite tuberculosis, four subjects with probable tuberculosis, and 71 subjects had non-tuberculous Mycobacteria (NTM) isolated from their sputum. Of the 3541 participants in the passive surveillance group, four subjects were diagnosed with definite tuberculosis, two subjects with probable tuberculosis, and 48 subjects had non-tuberculosis Mycobacteria isolated from their sputum. The incidence of definite + probable TB was 147.60 / 100,000 person years in the active surveillance group and 87 / 100,000 person years in the passive surveillance group. CONCLUSION: The incidence of pulmonary tuberculosis among adolescents in our study is lower than similar studies conducted in South Africa and Eastern Uganda - countries with a higher incidence of tuberculosis and human immunodeficiency virus (HIV) than India. The study data will inform sample design for vaccine efficacy trials among adolescents in India.

Xpert MTB/RIF assay can be used on archived gastric aspirate and induced sputum samples for sensitive diagnosis of paediatric tuberculosis.

BACKGROUND: Tuberculosis (TB) in children is neglected, mainly due to lack of sensitive diagnostic tools. Recently Xpert MTB/RIF assay has revolutionized the diagnostic field, but its usefulness in pediatric TB has not been reported from India and no report is available on its use on long term archived samples. METHODS: We recruited 130 pediatric patients with probable intrathoracic tuberculosis and their gastric aspirate (GA) and induced sputum (IS) samples on 2 consecutive days were collected between January 2009 and December 2012. All samples (n = 520) were subjected to smear examination, BACTEC-MGIT culture and in-house multiplex PCR. An aliquot of each sample was stored at -80 °C and tested in Xpert MTB/RIF assay in 2013. RESULTS: Sample wise and patient wise detection rate of smear microscopy was 4.4 % and 10 %, while for BACTEC-MGIT culture this rate was 24.4 % and 46.9 %, respectively. Of the 130 day 1 GA samples, 31.5 % and 27.7 % day 2 GA samples were culture positive. Only 17.7 % GA samples were positive on both days. Of the 130 IS samples collected on day 1 and day 2, 15.4 % and 23.1 % samples were culture positive. A combination of GA and IS yielded best results. Combining both GA and IS, the overall sensitivity of Xpert MTB/RIF on smear and culture positive samples was 95.6 %. In smear negative and culture positive samples its sensitivity was 62.5 %. The duration of sample storage impacted the Xpert MTB/RIF test performance (p = 0.0001). In smear positive samples stored for 650-849 days, its sensitivity was 85.7 % and 77.1 % for IS and GA samples which dropped to 33.3 % and 50 %, respectively, if stored for more than 1050 days. DISCUSSION: Confirmatory diagnosis of tuberculosis particularly in children is a medical challenge. No laboratory or radiological test can reach to a satisfactory level of diagnostic sensitivity. However, in this study we found that combination of multiple samples and multiple diagnostic tests can give much better yield, though not optimum. In present study, combination of 2 gastric aspirates (GA) and 2 induced sputum (IS) samples collected on two consecutive days, and tested on three diagnostic methods yielded a significantly high detection rate. Despite long term storage, the overall sensitivity of Xpert MTB/RIF on smear and -culture positive samples remained very high. But after storing these samples under subfreezing conditions the sensitivity of Xpert MTB/RIF decreased significantly. This is expected because even if the sample is smear and culture positive, the count of surviving mycobacteria goes down, after several years this count can reach to a undetectable level. CONCLUSION: This report shows that smear and culture positive samples stored at subfreezing conditions for several years can be used in the Xpert MTB/RIF assay, while maintaining appreciable diagnostic test sensitivity and specificity.

The tuberculin skin test in school going adolescents in South India: associations of socio-demographic and clinical characteristics with TST positivity and non-response.

BACKGROUND: India has generally used 1 TU purified protein derivative (PPD) as opposed to 2 TU PPD globally, limiting comparisons. It is important to assess latent TB infection in adolescents given that they may be a target group for new post-exposure TB vaccines. The aim of this study is to describe the pattern and associations of tuberculin skin test (TST) responses (0.1 ml 2 TU) in adolescents in South India. METHODS: 6643 school-going adolescents (11 to <18 years) underwent TST. Trained tuberculin reader made the reading visit between 48 and 96 hours after the skin test RESULTS: Of 6608 available TST results, 9% had 0 mm, and 12% ≥10 mm responses. The proportion of TST positive (≥10 mm) was higher among older children, boys, those with a history of TB contact and reported BCG immunization Those with no TST response (0 mm) included younger participants (<14 years), those whose mothers were illiterate and those with a recent history of weight loss. Those of a higher socio-economic status (houses with brick walls, LPG gas as cooking fuel) and those with a visible BCG scar were less likely to be non-responders. CONCLUSION: Proportion of non-responders was lower than elsewhere in the world. Proportion of TST positivity was higher in those already exposed to TB and in children who had been BCG immunized, with a zero response more likely in younger adolescents and those with recent weight loss.

Increased level of acute phase reactants in patients infected with modern Mycobacterium tuberculosis genotypes in Mwanza, Tanzania.

BACKGROUND: There is increasing evidence to suggest that different Mycobacterium tuberculosis lineages cause variations in the clinical presentation of tuberculosis (TB). Certain M. tuberculosis genotypes/lineages have been shown to be more likely to cause active TB in human populations from a distinct genetic ancestry. This study describes the genetic biodiversity of M. tuberculosis genotypes in Mwanza city, Tanzania and the clinical presentation of the disease caused by isolates of different lineages. METHODS: Two-hundred-fifty-two isolates from pulmonary TB patients in Mwanza, Tanzania were characterized by spoligotyping, and 45 isolates were further characterized by mycobacterium interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR). The patients' level of the acute phase reactants AGP, CRP and neutrophil counts, in addition to BMI, were measured and compared to the M. tuberculosis lineage of the infectious agent for each patient. RESULTS: The most frequent genotype was ST59 (48 out of 248 [19.4%]), belonging to the Euro-American lineage LAM11_ZWE, followed by ST21 (CAS_KILI lineage [44 out of 248 [17.7%]). A low degree of diversity (15.7% [39 different ST's out of 248 isolates]) of genotypes, in addition to a high level of mixed M. tuberculosis sub-populations among isolates with an unreported spoligotype pattern (10 out of 20 isolates [50.0%]) and isolates belonging to the ST53 lineage (13 out of 25 [52%]) was observed. Isolates of the 'modern' (TbD1-) Euro-American lineage induced higher levels of α1-acid glycoprotein (ß = 0.4, P = 0.02; 95% CI [0.06-0.66]) and neutrophil counts (ß = 0.9, P = 0.02; 95% CI [0.12-1.64]) and had lower BMI score (ß = -1.0, P = 0.04; 95% CI[-1.89 - (-0.03)]). LAM11_ZWE ('modern') isolates induced higher levels of CRP (ß = 24.4, P = 0.05; 95% CI[0.24-48.63]) and neutrophil counts (ß = 0.9, P = 0.03; 95% CI[0.09-1.70]). CONCLUSION: The low diversity of genotypes may be explained by an evolutionary advantage of the most common lineages over other lineages combined with optimal conditions for transmission, such as overcrowding and inadequate ventilation. The induction of higher levels of acute phase reactants in patients infected by 'modern' lineage isolates compared to 'ancient' lineages may suggest increased virulence among 'modern' lineage isolates.

Vitamin D levels in Indian children with intrathoracic tuberculosis.

BACKGROUND & OBJECTIVES: Deficiency of vitamin D, an immunomodulator agent, is associated with increased susceptibility to tuberculosis in adults, but only limited studies are available in the paediatric age group, especially regarding association of vitamin D with type and outcome of tuberculosis. We conducted this study to determine the baseline 25-hydroxy vitamin D levels in children suffering from intrathoracic tuberculosis and its association with type and outcome of tuberculosis. METHODS: Children with intrathoracic tuberculosis, diagnosed on the basis of clinico-radiological criteria, were enrolled as part of a randomized controlled trial on micronutrient supplementation in paediatric tuberculosis patients. Levels of 25-hydroxy vitamin D were measured in serum samples collected prior to starting antitubercular therapy by chemiluminescent immunoassay technology. RESULTS: Two hundred sixty six children (mean age of 106.9 ± 43.7 months; 57.1% girls) were enrolled. Chest X-ray was suggestive of primary pulmonary complex, progressive disease and pleural effusion in 81 (30.5%), 149 (56%) and 36 (13.5%) subjects, respectively. Median serum 25-hydroxy vitamin D level was 8 ng/ml (IQR 5, 12). One hundred and eighty six (69.9%) children were vitamin D deficient (serum 25-hydroxy vitamin D <12 ng/ml), 55 (20.7%) were insufficient (12 to <20 ng/ml) and 25 (9.4%) were vitamin D sufficient (≥ 20 ng/ml). Levels of 25-hydroxy vitamin D were similar in all three types of intrathoracic tuberculosis, and in microbiologically confirmed and probable cases. Levels of 25-hydroxy vitamin D did not significantly affect outcome of the disease. Children who were deficient or insufficient were less likely to convert (become smear/culture negative) at two months as compared to those who were 25-hydroxy vitamin D sufficient ( p <0.05). INTERPRETATION & CONCLUSIONS: Majority of Indian children with newly diagnosed intrathoracic tuberculosis were deficient in vitamin D. Type of disease or outcome was not affected by 25-hydroxy vitamin D levels in these children. However, children who did not demonstrate sputum conversion after intensive phase of antitubercular therapy had lower baseline 25-hydroxy vitamin D levels as compared to those who did.

A retrospective study of non-ventilator hospital-acquired pneumonia in a Norwegian hospital: a serious medical condition in need of better and timelier microbiological diagnostics.

BACKGROUND: Hospital-acquired pneumonia (HAP) is the most common hospital-acquired infection (HAI). HAP is associated with a high burden of morbidity and mortality, but the diagnosis is difficult to establish and the incidence uncertain. METHODS: Patients aged ≥ 18 years hospitalised with radiologically verified non-ventilator hospital acquired pneumonia (NV-HAP) during 2018 were retrospectively identified at Drammen Hospital, a Norwegian general hospital. Infectious Diseases Society of America and the American Thoracic Society's definition of HAP was used. RESULTS: In total 119 cases of NV-HAP were identified among 27,701 admissions. The incidence was 4.3 per 1000 admissions and 1.2 per 1000 patient-days. The median age was 74 years, 63% were male and median Charlson comorbidity index was 5. Coronary heart disease (42%) was the most common comorbidity. Median length of stay was 17.2 days. A blood culture was obtained in 53.8% of patients, while samples from lower airways were seldom obtained (10.9%). In-hospital mortality was 21%, accumulated 30-day mortality was 27.7% and accumulated 1-year mortality was 39.5%. Thirty-day readmission rate among survivors was 39.4%. CONCLUSION: NV-HAP was present in approximately 1 in 250 hospitalisations, most had multiple comorbidities, and 1 in 5 died in hospital. Although thorough microbiological sampling is recommended when NV-HAP is suspected, our data indicate that airway sampling is infrequent in clinical practice. Our findings underscore the need to develop microbiological diagnostic strategies to achieve targeted antimicrobial treatment that may improve patient outcomes and reduce broad-spectrum antibiotic usage.

Protein and transcriptional biomarker profiling may inform treatment strategies in lower respiratory tract infections by indicating bacterial-viral differentiation.

Lower respiratory tract infections (LRTIs) remain a significant global cause of infectious disease-related mortality. Accurate discrimination between acute bacterial and viral LRTIs is crucial for optimal patient care, prevention of unnecessary antibiotic prescriptions, and resource allocation. Plasma samples from LRTI patients with bacterial (n = 36), viral (n = 27; excluding SARS-CoV-2), SARS-CoV-2 (n = 22), and mixed bacterial-viral (n = 38) etiology were analyzed for protein profiling. Whole-blood RNA samples from a subset of patients (bacterial, n = 8; viral, n = 8; and SARS-CoV-2, n = 8) were analyzed for transcriptional profiling. Lasso regression modeling identified a seven-protein signature (CRP, IL4, IL9, IP10, MIP1α, MIP1ß, and TNFα) that discriminated between patients with bacterial (n = 36) vs viral (n = 27) infections with an area under the curve (AUC) of 0.98. When comparing patients with bacterial and mixed bacterial-viral infections (antibiotics clinically justified; n = 74) vs patients with viral and SARS-CoV-2 infections (antibiotics clinically not justified; n = 49), a 10-protein signature (CRP, bFGF, eotaxin, IFNγ, IL1ß, IL7, IP10, MIP1α, MIP1ß, and TNFα) with an AUC of 0.94 was identified. The transcriptional profiling analysis identified 232 differentially expressed genes distinguishing bacterial (n = 8) from viral and SARS-CoV-2 (n = 16) etiology. Protein-protein interaction enrichment analysis identified 20 genes that could be useful in the differentiation between bacterial and viral infections. Finally, we examined the performance of selected published gene signatures for bacterial-viral differentiation in our gene set, yielding promising results. Further validation of both protein and gene signatures in diverse clinical settings is warranted to establish their potential to guide the treatment of acute LRTIs. IMPORTANCE: Accurate differentiation between bacterial and viral lower respiratory tract infections (LRTIs) is vital for effective patient care and resource allocation. This study investigated specific protein signatures and gene expression patterns in plasma and blood samples from LRTI patients that distinguished bacterial and viral infections. The identified signatures can inform the design of point-of-care tests that can aid healthcare providers in making informed decisions about antibiotic prescriptions in order to reduce unnecessary use, thereby contributing to reduced side effects and antibiotic resistance. Furthermore, the potential for faster and more accurate diagnoses for improved patient management in acute LRTIs is compelling.

Comprehensive contact tracing during an outbreak of alpha-variant SARS-CoV-2 in a rural community reveals less viral genomic diversity and higher household secondary attack rates than expected.

Sequencing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes throughout the COVID-19 pandemic has generated a wealth of data on viral evolution across populations, but only a few studies have so far explored SARS-CoV-2 evolution across large connected transmission networks. Here, we couple data from SARS-CoV-2 sequencing with contact tracing data from an outbreak with a single origin in a rural Norwegian community where samples from all exposed persons were collected prospectively. A total of 134 nasopharyngeal samples were positive by PCR. Among the 121 retrievable genomes, 81 were identical to the genome of the introductor, thus demonstrating that genomics beyond clustering genotypically similar viral genomes to confirm relatedness offers limited additional value to manual contact tracing. In the cases where mutations were discovered, five small genetic clusters were identified. We observed a household secondary attack rate of 77%, with 92% of household members infected among households with secondary transmission, suggesting that SARS-CoV-2 introduction into large families is likely to affect all household members. IMPORTANCE: In outbreak investigations, obtaining a full overview of infected individuals within a population is seldom achieved. We here present an example where a single introduction of B1.1.7 SARS-CoV-2 within a rural community allowed for tracing of the virus from an introductor via dissemination through larger gatherings into households. The outbreak occurred before widespread vaccination, allowing for a "natural" outbreak development with community lockdown. We show through sequencing that the virus can infect up to five consecutive persons without gaining mutations, thereby showing that contact tracing seems more important than sequencing for local outbreak investigations in settings with few alternative introductory transmission pathways. We also show how larger households where a child introduced transmission appeared more likely to promote further spread of the virus compared to households with an adult as the primary introductor.

Perspectives on development and advancement of new tuberculosis vaccines.

Tuberculosis (TB) remains a leading cause of death worldwide and is estimated to have caused 1.3 million deaths worldwide in 2022. Approximately one quarter of the world's population are infected with Mycobacterium tuberculosis, of whom up to 10% will progress to developing active TB disease. Achieving the World Health Organization End TB Strategy targets of a 95% reduction in TB mortality and a 90% reduction in TB incidence worldwide by 2035 remains a daunting task. The continuing spread of multidrug-resistant TB adds another obstacle to achieving global TB control. Larger funding pledges coupled with technological advances have recently enabled the enhancement of TB vaccine development efforts. These are yielding a pipeline of over 17 products currently in different stages of clinical trials. Emerging promising phase I and II trial results and advancement to phase III trials have necessitated "vaccine preparedness" in parallel so that a smooth transition from any positive clinical trial result to phase IV evaluation and implementation into policy and practice can follow. Promotion of a human rights-based approach, which recognizes and upholds the fundamental rights of all affected by the disease, is essential to ensure universal access to quality TB vaccines, regardless of their background or personal circumstances.

Diagnostic Stewardship in Community-Acquired Pneumonia With Syndromic Molecular Testing: A Randomized Clinical Trial.

Importance: Lower respiratory tract (LRT) infections, including community-acquired pneumonia (CAP), are a leading cause of hospital admissions and mortality. Molecular tests have the potential to optimize treatment decisions and management of CAP, but limited evidence exists to support their routine use. Objective: To determine whether the judicious use of a syndromic polymerase chain reaction (PCR)-based panel for rapid testing of CAP in the emergency department (ED) leads to faster, more accurate microbiological test result-based treatment. Design, Setting, and Participants: This parallel-arm, single-blinded, single-center, randomized clinical superiority trial was conducted between September 25, 2020, and June 21, 2022, in the ED of Haukeland University Hospital, a large tertiary care hospital in Bergen, Norway. Adult patients who presented to the ED with suspected CAP were recruited. Participants were randomized 1:1 to either the intervention arm or standard-of-care arm. The primary outcomes were analyzed according to the intention-to-treat principle. Intervention: Patients randomized to the intervention arm received rapid syndromic PCR testing (BioFire FilmArray Pneumonia plus Panel; bioMérieux) of LRT samples and standard of care. Patients randomized to the standard-of-care arm received standard microbiological diagnostics alone. Main Outcomes and Measures: The 2 primary outcomes were the provision of pathogen-directed treatment based on a microbiological test result and the time to provision of pathogen-directed treatment (within 48 hours after randomization). Results: There were 374 patients (221 males [59.1%]; median (IQR) age, 72 [60-79] years) included in the trial, with 187 in each treatment arm. Analysis of primary outcomes showed that 66 patients (35.3%) in the intervention arm and 25 (13.4%) in the standard-of-care arm received pathogen-directed treatment, corresponding to a reduction in absolute risk of 21.9 (95% CI, 13.5-30.3) percentage points and an odds ratio for the intervention arm of 3.53 (95% CI, 2.13-6.02; P < .001). The median (IQR) time to provision of pathogen-directed treatment within 48 hours was 34.5 (31.6-37.3) hours in the intervention arm and 43.8 (42.0-45.6) hours in the standard-of-care arm (mean difference, -9.4 hours; 95% CI, -12.7 to -6.0 hours; P < .001). The corresponding hazard ratio for intervention compared with standard of care was 3.08 (95% CI, 1.95-4.89). Findings remained significant after adjustment for season. Conclusions and Relevance: Results of this randomized clinical trial indicated that routine deployment of PCR testing for LRT pathogens led to faster and more targeted microbial treatment for patients with suspected CAP. Rapid molecular testing could complement or replace selected standard, time-consuming, laboratory-based diagnostics. Trial Registration: ClinicalTrials.gov Identifier: NCT04660084.

Microbial aetiology of community-acquired pneumonia in hospitalised adults: A prospective study utilising comprehensive molecular testing.

OBJECTIVES: This study aimed to describe the microbial aetiology of community-acquired pneumonia (CAP) in adults admitted to a tertiary care hospital and assess the impact of syndromic polymerase chain reaction (PCR) panels on pathogen detection. METHODS: Conducted at Haukeland University Hospital, Norway, from September 2020 to April 2023, this prospective study enrolled adults with suspected CAP. We analysed lower respiratory tract samples using both standard-of-care tests and the BIOFIRE® FILMARRAY® Pneumonia Plus Panel (FAP plus). The added value of FAP Plus in enhancing the detection of clinically relevant pathogens, alongside standard-of-care diagnostics, was assessed. RESULTS: Of the 3238 patients screened, 640 met the inclusion criteria, with 384 confirmed to have CAP at discharge. In these patients, pathogens with proven or probable clinical significance were identified in 312 (81.3%) patients. Haemophilus influenzae was the most prevalent pathogen, found in 118 patients (30.7%), followed by SARS-CoV-2 in 74 (19.3%), and Streptococcus pneumoniae in 64 (16.7%). Respiratory viruses were detected in 186 (48.4%) patients. The use of FAP plus improved the pathogen detection rate from 62.8% with standard-of-care methods to 81.3%. CONCLUSIONS: Pathogens were identified in 81% of CAP patients, with Haemophilus influenzae and respiratory viruses being the most frequently detected pathogens. The addition of the FAP plus panel, markedly improved pathogen detection rates compared to standard-of-care diagnostics alone.

BCG protects against tuberculosis irrespective of HIV status: a matched case-control study in Mwanza, Tanzania.

While BCG vaccine protects against severe tuberculosis (TB) in children, its effect against adult TB is questionable. Furthermore, it is not known if HIV co-infection modifies the effect of BCG. Among 352 pairs of Tanzanian TB cases and matched controls, the BCG scar was associated with a reduced risk of TB (OR 0.3, 95% CI 0.2 to 0.7, p=0.005), irrespective of HIV status (interaction, p=0.623). BCG vaccination considerably reduced the risk of TB, both among individuals with and without HIV infection.

Does neutralization of gastric aspirates from children with suspected intrathoracic tuberculosis affect mycobacterial yields on MGIT culture?

The microbiological confirmation of pulmonary tuberculosis in children relies on cultures of gastric aspirate (GA) specimens. Conventionally, GAs are neutralized to improve culture yields of mycobacteria. However, there are limited data to support this practice. To study the utility of neutralization of GAs with sodium bicarbonate in children with intrathoracic tuberculosis, a total of 116 children of either sex, aged 6 months to 14 years (median age, 120 months; interquartile range [IQR], 7 to 192 months), underwent gastric aspiration on 2 consecutive days. Gastric aspirates were divided into two aliquots, and only one aliquot was neutralized with 1% sodium bicarbonate. Both aliquots were processed for smear and culture examinations. Out of the 232 gastric aspirates, 12 (5.17%) were acid-fast bacilli (AFB) smear positive. There were no differences in smear positivity rates from samples with or without neutralization. The yield of Mycobacterium tuberculosis on a Bactec MGIT 960 culture system was significantly lower in the neutralized samples (16.3% [38/232]) than in the nonneutralized samples (21.5% [50/232]) (P = 0.023). There was no significant difference between the neutralized and the nonneutralized samples in time to detection using the MGIT 960 system (average, 24.6 days; IQR, 12 to 37 days) (P = 0.9). The contamination rates were significantly higher in the neutralized samples than in the nonneutralized samples (17.2% [40/232] versus 3.9% [9/232]) (P = 0.001). The agreement for positive mycobacterial culture between the two approaches was 66.5% (P = 0.001). Hence, we recommend that gastric aspirate samples not be neutralized with sodium bicarbonate prior to culture for M. tuberculosis.

Diabetes is a strong predictor of mortality during tuberculosis treatment: a prospective cohort study among tuberculosis patients from Mwanza, Tanzania.

OBJECTIVE: Strong evidence suggests diabetes may be associated with tuberculosis (TB) and could influence TB treatment outcomes. We assessed the role of diabetes on sputum culture conversion and mortality among patients undergoing TB treatment. METHODS: A total of 1250 Tanzanian TB patients were followed prospectively during TB treatment with sputum culture after 2 and 5 months. Survival status was assessed at least 1 year after initiation of treatment. At baseline, all participants underwent testing for diabetes and HIV, and the serum concentration of the acute phase reactant alpha-1 glycoprotein (AGP) was determined. RESULTS: There were no differences between participants with and without diabetes regarding the proportion of positive cultures at 2 (3.8% vs. 5.8%) and 5 (1.3% vs. 0.9%) months (P > 0.46). However, among patients with a positive TB culture, relatively more patients with diabetes died before the 5-month follow-up. Within the initial 100 days of TB treatment, diabetes was associated with a fivefold increased risk of mortality (RR 5.09, 95% CI 2.36; 11.02, P < 0.001) among HIV uninfected, and a twofold increase among HIV co-infected patient (RR 2.33 95% CI 1.20; 4.53, P = 0.012), while diabetes was not associated with long-term mortality. Further adjustment with AGP did not change the estimates. CONCLUSION: Diabetes considerably increases risk of early mortality during TB treatment. The effect may not be explained by increased severity of TB, but could be due to impaired TB treatment response. Research is needed to clarify the mechanism and to assess whether glycaemic control improves survival.