Barriers to engagement in the care cascade for tuberculosis disease in India: A systematic review of quantitative studies.

BACKGROUND: India accounts for about one-quarter of people contracting tuberculosis (TB) disease annually and nearly one-third of TB deaths globally. Many Indians do not navigate all care cascade stages to receive TB treatment and achieve recurrence-free survival. Guided by a population/exposure/comparison/outcomes (PECO) framework, we report findings of a systematic review to identify factors contributing to unfavorable outcomes across each care cascade gap for TB disease in India. METHODS AND FINDINGS: We defined care cascade gaps as comprising people with confirmed or presumptive TB who did not: start the TB diagnostic workup (Gap 1), complete the workup (Gap 2), start treatment (Gap 3), achieve treatment success (Gap 4), or achieve TB recurrence-free survival (Gap 5). Three systematic searches of PubMed, Embase, and Web of Science from January 1, 2000 to August 14, 2023 were conducted. We identified articles evaluating factors associated with unfavorable outcomes for each gap (reported as adjusted odds, relative risk, or hazard ratios) and, among people experiencing unfavorable outcomes, reasons for these outcomes (reported as proportions), with specific quality or risk of bias criteria for each gap. Findings were organized into person-, family-, and society-, or health system-related factors, using a social-ecological framework. Factors associated with unfavorable outcomes across multiple cascade stages included: male sex, older age, poverty-related factors, lower symptom severity or duration, undernutrition, alcohol use, smoking, and distrust of (or dissatisfaction with) health services. People previously treated for TB were more likely to seek care and engage in the diagnostic workup (Gaps 1 and 2) but more likely to suffer pretreatment loss to follow-up (Gap 3) and unfavorable treatment outcomes (Gap 4), especially those who were lost to follow-up during their prior treatment. For individual care cascade gaps, multiple studies highlighted lack of TB knowledge and structural barriers (e.g., transportation challenges) as contributing to lack of care-seeking for TB symptoms (Gap 1, 14 studies); lack of access to diagnostics (e.g., X-ray), non-identification of eligible people for testing, and failure of providers to communicate concern for TB as contributing to non-completion of the diagnostic workup (Gap 2, 17 studies); stigma, poor recording of patient contact information by providers, and early death from diagnostic delays as contributing to pretreatment loss to follow-up (Gap 3, 15 studies); and lack of TB knowledge, stigma, depression, and medication adverse effects as contributing to unfavorable treatment outcomes (Gap 4, 86 studies). Medication nonadherence contributed to unfavorable treatment outcomes (Gap 4) and TB recurrence (Gap 5, 14 studies). Limitations include lack of meta-analyses due to the heterogeneity of findings and limited generalizability to some Indian regions, given the country's diverse population. CONCLUSIONS: This systematic review illuminates common patterns of risk that shape outcomes for Indians with TB, while highlighting knowledge gaps-particularly regarding TB care for children or in the private sector-to guide future research. Findings may inform targeting of support services to people with TB who have higher risk of poor outcomes and inform multicomponent interventions to close gaps in the care cascade.

ADLM Guidance Document on Laboratory Diagnosis of Respiratory Viruses.

Respiratory viral infections are among the most frequent infections experienced worldwide. The COVID-19 pandemic has highlighted the need for testing and currently several tests are available for the detection of a wide range of viruses. These tests vary widely in terms of the number of viral pathogens included, viral markers targeted, regulatory status, and turnaround time to results, as well as their analytical and clinical performance. Given these many variables, selection and interpretation of testing requires thoughtful consideration. The current guidance document is the authors' expert opinion based on the preponderance of available evidence to address key questions related to best practices for laboratory diagnosis of respiratory viral infections including who to test, when to test, and what tests to use. An algorithm is proposed to help laboratories decide on the most appropriate tests to use for the diagnosis of respiratory viral infections.

A decade of clinical microbiology: top 10 advances in 10 years: what every infection preventionist and antimicrobial steward should know.

The past 10 years have brought paradigm-shifting changes to clinical microbiology. This paper explores the top 10 transformative innovations across the diagnostic spectrum, including not only state of the art technologies but also preanalytic and post-analytic advances. Clinical decision support tools have reshaped testing practices, curbing unnecessary tests. Innovations like broad-range polymerase chain reaction and metagenomic sequencing, whole genome sequencing, multiplex molecular panels, rapid phenotypic susceptibility testing, and matrix-assisted laser desorption ionization time-of-flight mass spectrometry have all expanded our diagnostic armamentarium. Rapid home-based testing has made diagnostic testing more accessible than ever. Enhancements to clinician-laboratory interfaces allow for automated stewardship interventions and education. Laboratory restructuring and consolidation efforts are reshaping the field of microbiology, presenting both opportunities and challenges for the future of clinical microbiology laboratories. Here, we review key innovations of the last decade.

The diagnostic and clinical utility of microbial cell-free DNA sequencing in a real-world setting.

Microbial cell free DNA sequencing is increasingly used for diagnosis of infection but few studies describe its utility in real-world settings. We performed a single-center retrospective case series of microbial cell free DNA testing using the Karius assay from 29 patient samples to define the clinical reasoning and the impact of testing. Indications fell into 3 categories, identifying a causative pathogen in patients with an infectious syndrome and negative microbiologic workup (15/29, 52%), seeking another pathogen when organisms identified by traditional diagnostics failed to explain the clinical presentation (9/29, 31%) and to "rule out" infection in patients with nonspecific symptoms and negative microbiologic workup (5/29, 17%). Clinical impact was positive in 13/29 (45%) and all were for patients with high pretest probability for infection. Impact was negative in 3/29 (10%) cases. There was no impact in 15/29 (52%) cases. Further work is needed to define the optimal timing accounting for test performance, and patient characteristics.

Evaluation of an Antifungal Stewardship Initiative Targeting Micafungin at an Academic Medical Center.

Delays in the treatment of proven invasive fungal disease have been shown to be harmful. However, empiric treatment for all patients at risk of infection has not demonstrated benefit. This study evaluates the effects of a micafungin stewardship initiative on the duration of therapy and clinical outcomes at the University of Mississippi Medical Center in Jackson, Mississippi. This single-center quasi-experiment evaluated patients who received micafungin. Adult inpatients who received at least one treatment dose of micafungin in the pre-intervention (1 October 2020 to 30 September 2021) or post-intervention (1 October 2021 to 30 April 2022) groups were included. Patients were placed on micafungin for prophylaxis and those who required definitive micafungin therapy were excluded. An algorithm was used to provide real-time recommendations in order to assess change in the treatment days of micafungin therapy. A total of 282 patients were included (141 pre-group versus 141 post-group). Over 80% of the patients included in the study were in an intensive care unit, and other baseline characteristics were similar. The median number of treatment days with micafungin was 4 [IQR 3-6] in the pre-group and 3 [IQR 2-6] in the post-group (p = 0.005). Other endpoints, such as time to discontinuation or de-escalation, hospital mortality, and hospital length of stay, were not significantly different between the groups. An antifungal stewardship initiative can be an effective way to decrease unnecessary empiric antifungal therapy for patients who are at risk of invasive fugal disease.

Approach to fever in patients with neutropenia: a review of diagnosis and management.

Febrile neutropenia (FN) is associated with mortality rates as high as 40%, highlighting the importance of appropriate clinical management in this patient population. The morbidity and mortality of FN can be attributed largely to infectious processes, with specific concern for infections caused by pathogens with antimicrobial resistance. Expeditious identification of responsible pathogens and subsequent initiation of empiric antimicrobial therapy is imperative. There are four commonly used guidelines, which have variable recommendations for empiric therapy in these populations. All agree that changes could be made once patients are stable and/or with an absolute neutrophil count (ANC) over 500 cells/mcL. Diagnostic advances have the potential to improve knowledge of pathogens responsible for FN and decrease time to results. In addition, more recent data show that rapid de-escalation or discontinuation of empiric therapy, regardless of ANC, may reduce days of therapy, adverse effects, and cost, without affecting clinical outcomes. Antimicrobial and diagnostic stewardship should be performed to identify, utilize, and respond to appropriate rapid diagnostic tests that will aid in the definitive management of this population.

Clinical Outcomes of Individuals with COVID-19 and Tuberculosis during the Pre-Vaccination Period of the Pandemic: A Systematic Review.

BACKGROUND: Tuberculosis, like COVID-19, is most often a pulmonary disease. The COVID-19 pandemic has severely disrupted tuberculosis services in myriad ways: health facility closures, lockdowns, travel bans, overwhelmed healthcare systems, restricted export of antituberculous drugs, etc. The effects of the shared risk on outcomes of the two diseases is not known, particularly for the first year of the pandemic, during the period before COVID-19 vaccines became widely available. OBJECTIVE: We embarked on a systematic review to elucidate the consequences of tuberculosis on COVID-19 outcomes and of COVID-19 on tuberculosis outcomes during the pre-vaccination period of the pandemic. METHODS: The systematic review protocol is registered in PROSPERO. We conducted an initial search of PubMed, Embase, Web of Science, WHO coronavirus database, medRxiv, bioRxiv, preprints.org, and Google Scholar using terms relating to COVID-19 and tuberculosis. We selected cohort and case-control studies for extraction and assessed quality with the Newcastle-Ottawa scale. RESULTS AND CONCLUSION: We identified 2108 unique abstracts published between December 2019 and January 2021. We extracted data from 18 studies from 8 countries. A total of 650,317 persons had a diagnosis of COVID-19, and 4179 had a diagnosis of current or prior tuberculosis. We explored links between tuberculosis and COVID-19 incidence, mortality, and other adverse outcomes. Nine studies reported on mortality and 13 on other adverse outcomes; results on the association between tuberculosis and COVID-19 mortality/adverse outcomes were heterogenous. Tuberculosis outcomes were not fully available in any studies, due to short follow-up (maximum of 3 months after COVID-19 diagnosis), so the effects of COVID-19 on tuberculosis outcomes could not be assessed. Much of the rapid influx of literature on tuberculosis and COVID-19 during this period was published on preprint servers, and therefore not peer-reviewed. It offered limited examination of the effect of tuberculosis on COVID-19 outcomes and even less on the effect of COVID-19 on tuberculosis treatment outcomes.

A novel rRNA hybridization-based approach to rapid, accurate Candida identification directly from blood culture.

Invasive fungal infections are increasingly common and carry high morbidity and mortality, yet fungal diagnostics lag behind bacterial diagnostics in rapidly identifying the causal pathogen. We previously devised a fluorescent hybridization-based assay to identify bacteria within hours directly from blood culture bottles without subculture, called phylogeny-informed rRNA-based strain identification (Phirst-ID). Here, we adapt this approach to unambiguously identify 11 common pathogenic Candida species, including C. auris, with 100% accuracy from laboratory culture (33 of 33 strains in a reference panel, plus 33 of 33 additional isolates tested in a validation panel). In a pilot study on 62 consecutive positive clinical blood cultures from two hospitals that showed yeast on Gram stain, Candida Phirst-ID matched the clinical laboratory result for 58 of 59 specimens represented in the 11-species reference panel, without misclassifying the 3 off-panel species. It also detected mixed Candida species in 2 of these 62 specimens, including the one discordant classification, that were not identified by standard clinical microbiology workflows; in each case the presence of both species was validated by both clinical and experimental data. Finally, in three specimens that grew both bacteria and yeast, we paired our prior bacterial probeset with this new Candida probeset to detect both pathogen types using Phirst-ID. This simple, robust assay can provide accurate Candida identification within hours directly from blood culture bottles, and the conceptual approach holds promise for pan-microbial identification in a single workflow. LAY SUMMARY: Candida bloodstream infections cause considerable morbidity and mortality, yet slow diagnostics delay recognition, worsening patient outcomes. We develop and validate a novel molecular approach to accurately identify Candida species directly from blood culture one day faster than standard workflows.

IgM Positivity for Both EBV and CMV: A Clinical Conundrum.

A review of 28 patients who tested positive for both Epstein-Barr virus and cytomegalovirus immunoglobulin M at an academic medical center revealed that dual positivity is more common than previously reported. These cases require careful review of the history and sometimes supplemental testing. This report highlights features of patients with dual positivity and provides recommendations on interpretation of the results.

Diagnostic Performance Assessment of Saliva RT-PCR and Nasopharyngeal Antigen for the Detection of SARS-CoV-2 in Peru.

Widely available and reliable testing for SARS-CoV-2 is essential for the public health response to the COVID-19 pandemic. We estimated the diagnostic performance of reverse transcription PCR (RT-PCR) performed on saliva and the SD Biosensor STANDARD Q antigen test performed on nasopharyngeal swab compared to the reference standard, nasopharyngeal swab (NP) RT-PCR. We enrolled participants living and/or seeking care in health facilities in North Lima, Peru from November 2020 to January 2021. Consenting participants underwent same-day RT-PCR on both saliva and nasopharyngeal swab specimens, antigen testing on a nasopharyngeal swab specimen, pulse oximetry, and standardized symptom assessment. We calculated sensitivity, specificity, and predictive values for the nasopharyngeal antigen and saliva RT-PCR compared to nasopharyngeal RT-PCR. Of 896 participants analyzed, 567 (63.3%) had acute signs/symptoms of COVID-19. The overall sensitivity and specificity of saliva RT-PCR were 85.8% and 98.1%, respectively. Among participants with and without acute signs/symptoms of COVID-19, saliva sensitivity was 87.3% and 37.5%, respectively. Saliva sensitivity was 97.4% and 56.0% among participants with cycle threshold (CT) values of ≤30 and >30 on nasopharyngeal RT-PCR, respectively. The overall sensitivity and specificity of nasopharyngeal antigen were 73.2% and 99.4%, respectively. The sensitivity of the nasopharyngeal antigen test was 75.1% and 12.5% among participants with and without acute signs/symptoms of COVID-19, and 91.2% and 26.7% among participants with CT values of ≤30 and >30 on nasopharyngeal RT-PCR, respectively. Saliva RT-PCR achieved the WHO-recommended threshold of >80% for sensitivity for the detection of SARS-CoV-2, while the SD Biosensor nasopharyngeal antigen test did not. IMPORTANCE In this diagnostic validation study of 896 participants in Peru, saliva reverse transcription PCR (RT-PCR) had >80% sensitivity for the detection of SARS-CoV-2 among all-comers and symptomatic individuals, while the SD Biosensor STANDARD Q antigen test performed on nasopharyngeal swab had <80% sensitivity, except for participants whose same-day nasopharyngeal RT-PCR results showed cycle threshold values of <30, consistent with a high viral load in the nasopharynx. The specificity was high for both tests. Our results demonstrate that saliva sampling could serve as an alternative noninvasive technique for RT-PCR diagnosis of SARS-CoV-2. The role of nasopharyngeal antigen testing is more limited; when community transmission is low, it may be used for mass screenings among asymptomatic individuals with high testing frequency. Among symptomatic individuals, the nasopharyngeal antigen test may be relied upon for 4 to 8 days after symptom onset, or in those likely to have high viral load, whereupon it showed >80% sensitivity.

Bacteriophage treatment of disseminated cutaneous Mycobacterium chelonae infection.

Mycobacterium chelonae is a rare cause of chronic disseminated cutaneous infections in immunocompromised patients. Multidrug-resistant M. chelonae infections present a challenge for treatment, and prolonged antimicrobial courses lead to significant toxicities and further antimicrobial resistance. We report a case of refractory cutaneous disseminated M. chelonae infection in a patient with seronegative arthritis on immunotherapy with tofacitinib that was treated with combination antimicrobial, surgical, and single bacteriophage therapy with excellent clinical response. The patient developed neutralizing antibodies against the bacteriophage but continues to have stable improvement of disease with negative biopsies and no evidence of bacterial resistance to the phage.

High Prevalence of Rectal Chlamydia trachomatis Infection With the Same Genotype as Urogenital Infection in Female Outpatients in Sexually Transmitted Disease Clinics in China.

BACKGROUND: Little is known about rectal Chlamydia trachomatis (CT) infection in outpatients attending sexually transmitted disease (STD) clinics in China. In this study, we aimed to explore the clinical and epidemiologic features of rectal CT infection in this population. METHODS: A cross-sectional study was conducted among patients attending STD clinics in Tianjin and Guangxi provinces of China from June 2018 to August 2020. Bivariate and multivariate logistic regression analysis were developed to explore the association of different risk factors for urogenital and rectal CT infection. RESULTS: The prevalence of urogenital and rectal CT was 11.2% (154/1374) and 4.9% (68/1377), respectively. The rectal CT prevalence among female and male patients was 7.8% (60/767) and 1.3% (8/610), respectively. The most common genotype in urogenital CT-positive samples was genotype E (29.9%), while the most common genotype among rectal CT-positive samples was genotype J (23.4%). More than 85% (52/60) of women infected with rectal CT were co-infected with urogenital CT. About 90.0% (36/40) of women shared similar genotypes between rectal and urogenital samples. Females and patients infected with urogenital CT were deemed to be at an increased risk for rectal CT infection. A high proportion of rectal CT infection had concurrent urogenital CT infection, especially in women, and most of the co-infections were shared among the same genotypes. CONCLUSIONS: It would be prudent to encourage awareness and introduce detection tests and treatment strategies for rectal CT infection particularly in female patients visiting STD clinics in China.

Rectal Mycoplasma genitalium in Patients Attending Sexually Transmitted Disease Clinics in China: An Infection That Cannot Be Ignored.

BACKGROUND: Previous studies have investigated rectal Mycoplasma genitalium (MG) in men who have sex with men (MSM), while little is known about the prevalence of rectal MG infection in individuals attending sexually transmitted disease (STD) clinics in China. We aimed to estimate the prevalence of rectal MG infection in this population and identified the potential risk factors for rectal MG infection. METHODS: A cross-sectional study was conducted among individuals attending STD clinics located in China from June 2018 to August 2020. Univariate and multivariate logistic regression analyses were conducted to explore the association of different risk factors for rectal MG infection. RESULTS: A total of 1,382 patients were included in the final analyses. A total of 30 of 1377 rectal swabs (2.2%) and 77 of 1374 urogenital samples (5.6%) were positive for MG. In Guangxi, 18 of 47 patients (38.3%) infected with urogenital MG and 5 of 19 patients (26.3%) infected with rectal MG received the recommended treatment. Factors found to be significantly associated with rectal MG infection included: male (adjusted odds ratio (AOR) 0.232, [95% CI: 0.072-0.745]) compared to female, homosexual or bisexual (AOR 40.427, [95% CI: 3.880-421.196]) compared to heterosexual, and those infected with urogenital MG (AOR 7.215, [95% CI: 2.898-17.965]) compared to those who did not get infected with urogenital MG. CONCLUSION: Rectal MG infection should be thought of not only in MSM population but also in STD clinic patients, especially females who have urogenital MG infection. Appropriate strategy for rectal MG screening and treatment needs to be developed for these patients in China.