Phenotyping in acute respiratory distress syndrome: state of the art and clinical implications.

PURPOSE OF REVIEW: Decades of research in acute respiratory distress syndrome (ARDS) have led to few interventions that impact clinical outcomes. The pandemic of patients with ARDS due to the novel SARS-CoV-2 infection has stressed the need for more effective therapies in ARDS. Phenotyping may enable successful trials and precision therapeutics in this patient population. RECENT FINDINGS: Clinical phenotypes that group patients by shared cause, time-course or radiographic presentation are of prognostic value, but their use is limited by misclassification. Physiological phenotypes, including the P/F ratio, ventilatory ratio and dead space fraction, predict poor outcomes but can rapidly change, making them unstable over time. Biologic phenotypes have prognostic value with composite clinical and biomarker sub-phenotypes additionally impacting treatment response but are yet to be prospectively validated. SUMMARY: Although much progress has been made in ARDS phenotyping, implementation of precision medicine practices will depend on conducting phenotype-aware trials using rapid point of care assays or machine learning algorithms. Omics studies will enhance our understanding of biologic determinants of clinical outcomes in ARDS sub-phenotypes. Whether biologic ARDS sub-phenotypes are specific to this syndrome or rather more broadly identify endotypes of critical illness remains to be determined.

Clinical features, diagnostics, and outcomes of patients presenting with acute respiratory illness: A retrospective cohort study of patients with and without COVID-19.

BACKGROUND: Most data on the clinical presentation, diagnostics, and outcomes of patients with COVID-19 have been presented as case series without comparison to patients with other acute respiratory illnesses. METHODS: We examined emergency department patients between February 3 and March 31, 2020 with an acute respiratory illness who were tested for SARS-CoV-2. We determined COVID-19 status by PCR and metagenomic next generation sequencing (mNGS). We compared clinical presentation, diagnostics, treatment, and outcomes. FINDINGS: Among 316 patients, 33 tested positive for SARS-CoV-2; 31 without COVID-19 tested positive for another respiratory virus. Among patients with additional viral testing (27/33), no SARS-CoV-2 co-infections were identified. Compared to those who tested negative, patients with COVID-19 reported longer symptoms duration (median 7d vs. 3d, p < 0.001). Patients with COVID-19 were more often hospitalized (79% vs. 56%, p = 0.014). When hospitalized, patients with COVID-19 had longer hospitalizations (median 10.7d vs. 4.7d, p < 0.001) and more often developed ARDS (23% vs. 3%, p < 0.001). Most comorbidities, medications, symptoms, vital signs, laboratories, treatments, and outcomes did not differ by COVID-19 status. INTERPRETATION: While we found differences in clinical features of COVID-19 compared to other acute respiratory illnesses, there was significant overlap in presentation and comorbidities. Patients with COVID-19 were more likely to be admitted to the hospital, have longer hospitalizations and develop ARDS, and were unlikely to have co-existent viral infections. FUNDING: National Center for Advancing Translational Sciences, National Heart Lung Blood Institute, National Institute of Allergy and Infectious Diseases, Chan Zuckerberg Biohub, Chan Zuckerberg Initiative.

Clinical features, diagnostics, and outcomes of patients presenting with acute respiratory illness: a comparison of patients with and without COVID-19.

BACKGROUND: Emerging data on the clinical presentation, diagnostics, and outcomes of patients with COVID-19 have largely been presented as case series. Few studies have compared these clinical features and outcomes of COVID-19 to other acute respiratory illnesses. METHODS: We examined all patients presenting to an emergency department in San Francisco, California between February 3 and March 31, 2020 with an acute respiratory illness who were tested for SARS-CoV-2. We determined COVID-19 status by PCR and metagenomic next generation sequencing (mNGS). We compared demographics, comorbidities, symptoms, vital signs, and laboratory results including viral diagnostics using PCR and mNGS. Among those hospitalized, we determined differences in treatment (antibiotics, antivirals, respiratory support) and outcomes (ICU admission, ICU interventions, acute respiratory distress syndrome, cardiac injury). FINDINGS: In a cohort of 316 patients, 33 (10%) tested positive for SARS-CoV-2; 31 patients, all without COVID-19, tested positive for another respiratory virus (16%). Among patients with additional viral testing, no co-infections with SARS-CoV-2 were identified by PCR or mNGS. Patients with COVID-19 reported longer symptoms duration (median 7 vs. 3 days), and were more likely to report fever (82% vs. 44%), fatigue (85% vs. 50%), and myalgias (61% vs 27%); p<0.001 for all comparisons. Lymphopenia (55% vs 34%, p=0.018) and bilateral opacities on initial chest radiograph (55% vs. 24%, p=0.001) were more common in patients with COVID-19. Patients with COVID-19 were more often hospitalized (79% vs. 56%, p=0.014). Of 186 hospitalized patients, patients with COVID-19 had longer hospitalizations (median 10.7d vs. 4.7d, p<0.001) and were more likely to develop ARDS (23% vs. 3%, p<0.001). Most comorbidities, home medications, signs and symptoms, vital signs, laboratory results, treatment, and outcomes did not differ by COVID-19 status. INTERPRETATION: While we found differences in clinical features of COVID-19 compared to other acute respiratory illnesses, there was significant overlap in presentation and comorbidities. Patients with COVID-19 were more likely to be admitted to the hospital, have longer hospitalizations and develop ARDS, and were unlikely to have co-existent viral infections. These findings enhance understanding of the clinical characteristics of COVID-19 in comparison to other acute respiratory illnesses. .

Management and Outcomes of Critically-III Patients with COVID-19 Pneumonia at a Safety-net Hospital in San Francisco, a Region with Early Public Health Interventions: A Case Series.

Background: Following early implementation of public health measures, San Francisco has experienced a slow rise and a low peak level of coronavirus disease 2019 (COVID-19) cases and deaths. Methods and Findings: We included all patients with COVID-19 pneumonia admitted to the intensive care unit (ICU) at the safety net hospital for San Francisco through April 8, 2020. Each patient had ≥15 days of follow-up. Among 26 patients, the median age was 54 years (interquartile range, 43 to 62), 65% were men, and 77% were Latinx. Mechanical ventilation was initiated for 11 (42%) patients within 24 hours of ICU admission and 20 patients (77%) overall. The median duration of mechanical ventilation was 13.5 days (interquartile range, 5 to 20). Patients were managed with lung protective ventilation (tidal volume ≤8 ml/kg of ideal body weight and plateau pressure ≤30 cmH2O on 98% and 78% of ventilator days, respectively). Prone positioning was used for 13 of 20 (65%) ventilated patients for a median of 5 days (interquartile range, 2 to 10). Seventeen (65%) patients were discharged home, 1 (4%) was discharged to nursing home, 3 (12%) were discharged from the ICU, and 2 (8%) remain intubated in the ICU at the time of this report. Three (12%) patients have died. Conclusions: Good outcomes were achieved in critically ill patients with COVID-19 by using standard therapies for acute respiratory distress syndrome (ARDS) such as lung protective ventilation and prone positioning. Ensuring hospitals can deliver sustained high-quality and evidence-based critical care to patients with ARDS should remain a priority.

Feasibility of Direct Sputum Molecular Testing for Drug Resistance as Part of Tuberculosis Clinical Trials Eligibility Screening.

A rapid diagnosis of drug-resistant tuberculosis (TB) is critical for early initiation of effective therapy. Molecular testing with line probe assays (MTBDRplus and MTBDRsl) on culture isolates has been available for some time and significantly reduces the time to diagnosis of drug resistance. However, routine use of this test directly on sputum is less common. As part of enrollment screening procedures for tuberculosis clinical trials conducted in Hanoi, Vietnam, we evaluated the feasibility and performance of line probe assay (LPA) testing directly on sputum samples from 315 participants with no prior history of TB treatment. Test performance characteristics for the detection of rifampin (RIF) and isoniazid (INH) drug resistance as compared to culture-based drug susceptibility testing (DST) reference standard were calculated. LPA demonstrated high sensitivity and specificity for the diagnosis of drug resistance. Scaling up molecular testing on sputum as part of time-sensitive clinical trial screening procedures in high TB burden settings is feasible and will reduce both time to initiation of appropriate therapy and the risk of late exclusions due to microbiologic ineligibility.

Adherence interventions and outcomes of tuberculosis treatment: A systematic review and meta-analysis of trials and observational studies.

BACKGROUND: Incomplete adherence to tuberculosis (TB) treatment increases the risk of delayed culture conversion with continued transmission in the community, as well as treatment failure, relapse, and development or amplification of drug resistance. We conducted a systematic review and meta-analysis of adherence interventions, including directly observed therapy (DOT), to determine which approaches lead to improved TB treatment outcomes. METHODS AND FINDINGS: We systematically reviewed Medline as well as the references of published review articles for relevant studies of adherence to multidrug treatment of both drug-susceptible and drug-resistant TB through February 3, 2018. We included randomized controlled trials (RCTs) as well as prospective and retrospective cohort studies (CSs) with an internal or external control group that evaluated any adherence intervention and conducted a meta-analysis of their impact on TB treatment outcomes. Our search identified 7,729 articles, of which 129 met the inclusion criteria for quantitative analysis. Seven adherence categories were identified, including DOT offered by different providers and at various locations, reminders and tracers, incentives and enablers, patient education, digital technologies (short message services [SMSs] via mobile phones and video-observed therapy [VOT]), staff education, and combinations of these interventions. When compared with DOT alone, self-administered therapy (SAT) was associated with lower rates of treatment success (CS: risk ratio [RR] 0.81, 95% CI 0.73-0.89; RCT: RR 0.94, 95% CI 0.89-0.98), adherence (CS: RR 0.83, 95% CI 0.75-0.93), and sputum smear conversion (RCT: RR 0.92, 95% CI 0.87-0.98) as well as higher rates of development of drug resistance (CS: RR 4.19, 95% CI 2.34-7.49). When compared to DOT provided by healthcare providers, DOT provided by family members was associated with a lower rate of adherence (CS: RR 0.86, 95% CI 0.79-0.94). DOT delivery in the community versus at the clinic was associated with a higher rate of treatment success (CS: RR 1.08, 95% CI 1.01-1.15) and sputum conversion at the end of two months (CS: RR 1.05, 95% CI 1.02-1.08) as well as lower rates of treatment failure (CS: RR 0.56, 95% CI 0.33-0.95) and loss to follow-up (CS: RR 0.63, 95% CI 0.40-0.98). Medication monitors improved adherence and treatment success and VOT was comparable with DOT. SMS reminders led to a higher treatment completion rate in one RCT and were associated with higher rates of cure and sputum conversion when used in combination with medication monitors. TB treatment outcomes improved when patient education, healthcare provider education, incentives and enablers, psychological interventions, reminders and tracers, or mobile digital technologies were employed. Our findings are limited by the heterogeneity of the included studies and lack of standardized research methodology on adherence interventions. CONCLUSION: TB treatment outcomes are improved with the use of adherence interventions, such as patient education and counseling, incentives and enablers, psychological interventions, reminders and tracers, and digital health technologies. Trained healthcare providers as well as community delivery provides patient-centered DOT options that both enhance adherence and improve treatment outcomes as compared to unsupervised, SAT alone.

Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

Genitourinary exam skills training curriculum for medical students: a follow-up study of comfort and skill utilization.

PURPOSE: We developed a genitourinary skills training (GUST) curriculum for incoming third year medical students (MS3) and performed a follow-up study of comfort with and utilization of these skills. MATERIALS AND METHODS: GUST consisted of a didactic lecture followed by skills sessions including standardized patient testicular examination (TE) and digital rectal examination (DRE), male and female Foley catheter (MFC and FFC) placement training, suture-knot tying, and a faculty-directed small group learning session. Precourse and postcourse, and 6 and 18 months after the course, MS3 rated comfort with each skill (Likert scale 0-5), and quantified skill usage. Results were compared with 4th year students (MS4) who had not undergone GUST. RESULTS: Participants were 281 MS3 GUST students and 44 MS4. Post-GUST, mean comfort on a Likert scale (0=uncomfortable) increased for all four skills (88.2%-96.9% vs 8.3%-18.5%, P<0.0001). This was maintained at the 6-month and 18-month follow up time points (P<0.0001). At 18 months, MS3 trended toward higher comfort with TE compared with MS4 (74 vs 54%, P=0.068), while with the other skills, both groups showed equal comfort. MS4 learned exam skills from faculty and MFC and FFC from nurses on the wards. Eleven percent of MS4 were never formally taught TE or DRE. MS3 and MS4 performed TE and/or DRE on <8% of newly admitted patients. CONCLUSIONS: MS3 described improved comfort with the GU skills at all time points during follow-up. This was particularly important because both MS3 and MS4 reported using their skills infrequently during their clinical training years.

Nontuberculous mycobacteria among patients who are suspected for multidrug-resistant tuberculosis-need for earlier identification of nontuberculosis mycobacteria.

BACKGROUND: In this study, we intended to find the prevalence of nontuberculosis mycobacteria (NTM) among patients who are referred as suspected multidrug-resistant tuberculosis (MDR-TB) cases to the only referral center in Iran. METHODS: All patients referred to our center in 2002-2006 as MDR-TB with histories of treatment with standard and CAT II World Health Organization regimens were included in the study. Sputum smear and culture for acid-fast bacilli were performed for all patients 3 times. Sputum polymerase chain reaction was also performed for all patients. Mycobacterial identification was performed via polymerase chain reaction and routine identification tests for all culture-positive cases. RESULTS: Of the 105 patients in the study, 12 (11.43%) were identified to have NTM infection. The identified mycobacteria were classified in order of prevalence as Chelonae (8 cases), Simiae (2 cases), Aloei (1 case), and Farcinogen (1 case). Based on radiologic findings, most of the cases demonstrated bilateral nodularity (83.3%) and also multifocal bronchiectasis (75%). Notably, cavitary lesions were present in 41.7% of the cases. CONCLUSION: Based on the findings of this study, it is essential that such cases be identified before commencing MDR-TB treatment.

Representative drug susceptibility patterns for guiding design of re-treatment regimens for multidrug-resistant tuberculosis in Iran.

BACKGROUND AND OBJECTIVE: The prevalence of multidrug-resistant tuberculosis (MDR-TB) has increased substantially in the past 20 years, however, there are no data specific to Iran. This study investigated patients suspected to have MDR-TB, attending the TB referral hospital in Iran. METHODS: All patients suspected of having MDR-TB on hospital admission in the period 2003-2005 were included in this study. Sputum from all patients was tested for smear and culture, and drug sensitivity testing was performed using the proportion method. Patients were categorized into three groups based on their history of medical treatment. Group I consisted of patients with CAT I regimen failure; Group II consisted of patients with a history of CAT II regimen failure and Group III comprised patients with a history of more than two courses of irregular CAT I anti-TB regimen. RESULTS: There were 105 patients recruited; 32 in Group I, 53 in Group II and 20 in Group III. There were no significant differences between the three groups in their resistance to first-line anti-TB drugs. Fifty-five patients were diagnosed with MDR-TB. The prevalence of MDR-TB was 56% (18 cases) in group I, 49% (26 cases) in group II and 55% (11 cases) in group III. No significant difference in the pattern of drug resistance was observed between the three groups. CONCLUSION: The prevalence of MDR-TB was high in this study. The lack of response of MDR-TB patients to CAT II treatment indicates that antibiotic sensitivity testing is essential in patients with CAT I treatment failure.