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ImportanceSARS-CoV-2 entry requires the TMPRSS2 cell surface protease. Antiandrogen therapies reduce expression of TMPRSS2.ObjectiveTo determine if temporary androgen suppression induced by degarelix improves clinical outcomes of inpatients hospitalized with COVID-19.Design, setting, and participantsThe Hormonal Intervention for the Treatment in Veterans With COVID-19 Requiring Hospitalization (HITCH) phase 2, placebo-controlled, double-blind, randomized clinical trial compared efficacy of degarelix plus standard care vs placebo plus standard care on clinical outcomes in men hospitalized with COVID-19 but not requiring invasive mechanical ventilation. Inpatients were enrolled at 14 Department of Veterans Affairs hospitals from July 22, 2020, to April 8, 2021. Data were analyzed from August 9 to October 15, 2021.InterventionsPatients stratified by age, history of hypertension, and disease severity were centrally randomized 2:1 to degarelix, (1-time subcutaneous dose of 240 mg) or a saline placebo. Standard care included but was not limited to supplemental oxygen, antibiotics, vasopressor support, peritoneal dialysis or hemodialysis, intravenous fluids, remdesivir, convalescent plasma, and dexamethasone.Main outcomes and measuresThe composite primary end point was mortality, ongoing need for hospitalization, or requirement for mechanical ventilation at day 15 after randomization. Secondary end points were time to clinical improvement, inpatient mortality, length of hospitalization, duration of mechanical ventilation, time to achieve a temperature within reference range, maximum severity of COVID-19, and the composite end point at 30 days.ResultsThe trial was stopped for futility after the planned interim analysis, at which time there were 96 evaluable patients, including 62 patients randomized to the degarelix group and 34 patients in the placebo group, out of 198 initially planned. The median (range) age was 70.5 (48-85) years. Common comorbidities included chronic obstructive pulmonary disorder (15 patients [15.6%]), hypertension (75 patients [78.1%]), cardiovascular disease (27 patients [28.1%]), asthma (12 patients [12.5%]), diabetes (49 patients [51.0%]), and chronic respiratory failure requiring supplemental oxygen at baseline prior to COVID-19 (9 patients [9.4%]). For the primary end point, there was no significant difference between the degarelix and placebo groups (19 patients [30.6%] vs 9 patients [26.5%]; P = .67). Similarly, no differences were observed between degarelix and placebo groups in any secondary end points, including inpatient mortality (11 patients [17.7%] vs 6 patients [17.6%]) or all-cause mortality (11 patients [17.7%] vs 7 patents [20.6%]). There were no differences between degarelix and placebo groups in the overall rates of adverse events (13 patients [21.0%] vs 8 patients [23.5%) and serious adverse events (19 patients [30.6%] vs 13 patients [32.4%]), nor unexpected safety concerns.Conclusions and relevanceIn this randomized clinical trial of androgen suppression vs placebo and usual care for men hospitalized with COVID-19, degarelix did not result in amelioration of COVID-19 severity.Trial registrationClinicalTrials.gov Identifier: NCT04397718.

The aim of this study was to determine the incidence of endobronchial lesions in patients presenting with hemoptysis. We also aimed to characterize features that would predict whether bronchoscopy would be useful.A retrospective chart review was conducted on 185 consecutive patients who presented with hemoptysis from January 1, 2006 to December 31, 2015 at Methodist Le Bonheur Healthcare-affiliated hospitals in Memphis, Tennessee. Data collection included demographic information, description of hemoptysis, imaging results, bronchoscopy results, and the final diagnosis.A total of 185 patients presented with hemoptysis during our study period. Of these, 14 patients were excluded because of age (younger than 18 years) and incomplete data (inadequate information about the procedure performed, lack of imaging studies, incorrectBronchoscopy should be strongly considered in patients presenting with hemoptysis, especially if it is frank blood, of1 week's duration, or both, because the information obtained can be vital for management. This appears to hold true even for patients who have no abnormalities seen on computed tomography chest imaging upon initial workup.

Background Sepsis and septic shock are medical emergencies resulting in significant morbidity and mortality. Intravenous (IV) vitamin C, thiamine, and hydrocortisone have shown promise in reducing hospital mortality. The Memphis Veterans Affairs Medical Center (VAMC) similarly implemented this regimen, called the vitamin C protocol, for patients presenting in sepsis or septic shock in the intensive care unit (ICU). Methods This retrospective study in Veteran ICU patients with sepsis or septic shock compared outcomes of patients treated with IV vitamin C, thiamine, and hydrocortisone (treatment) with those who received IV hydrocortisone alone (control). Data was propensity matched to ensure comparability at baseline. The Sequential Organ Failure Assessment (SOFA) score was calculated at day of diagnosis (day 0) and daily for 3 subsequent days. At the 24-month follow-up, 12 months after the 1-year-intervention, survival and measures of mental and physical health were collected by telephone interviews. Results Hospital mortality, the primary outcome, did not differ significantly between groups. Secondary outcomes including ICU, 28-day, and 60-day mortality were also not different, nor were vasopressor duration or hospital length of stay. However, ICU length of stay was significantly reduced in the treatment group compared to control (7.1 vs 15.6 days, respectively, P = 0.04). Conclusions Although no significant mortality benefit was observed, the vitamin C protocol was not associated with patient harm. In this Veteran population, there was reduced ICU length of stay, suggesting possible benefit. Though further investigation is warranted, utilization of IV vitamin C, thiamine, and hydrocortisone in patients with sepsis or septic shock may be a treatment option worth considering.

BACKGROUND Candida is a leading cause of infection in the intensive care unit. Colonization versus infection remains a challenge. A Candida Score (CS) of 3 or greater has been used to target antifungal therapy in surgical patients at risk of candidemia but has not been well evaluated in medical patients with sepsis. OBJECTIVES The aim of this study was to assess utility of the CS in detecting candidemia early in patients with sepsis. METHODS This was a secondary analysis of patients with sepsis (n = 77) who were followed up for development of new infections. Patients with known fungal infection at admission were excluded. Candida colonization was defined as Candida cultured from any baseline culture, except blood, as a part of routine clinical care. RESULTS Candidemia was detected in 8 of 77 participants (10.4%; 4 [15.4%] with a CS ≥3 and 4 [7.8%] with a CS

Objectives Continuity clinics are an important aspect of pulmonary medicine fellowship training. We provide a description of a pulmonary outpatient clinic in an inner city, county-owned, university-affiliated hospital. Methods This is a descriptive study of administrative data on consecutive patient visits to the University of Tennessee Regional One Health at Memphis ambulatory clinic (Medplex) between January 2000 and August 2006. We describe demographics, socioeconomic characteristics, and the frequency of a pulmonary diagnosis of the outpatient population served by our training program. Continuous data were described by mean ± standard deviations and categorical data were described by percentage. Results The dataset included 2549 patients, 81% were African American with a mean age of 48.7 ± 13.7, 64.4% were women. Female/male body mass index was 34.6 ± 11.6 vs. 29.2 ± 10.3. Tenncare (Medicaid) covered 59.6 % of patients, whereas 11.1% were uninsured. Conclusions We provide evidence that one clinical setting may not be enough exposure to the entire lung pathology for pulmonary trainees. There is a need for further, larger, and prospective data collections to evaluate and guide changes regarding the structure of training programs.

Case Presentation A 74-year-old white male farmer was admitted from his primary care physician's office after he presented with symptoms of cough productive of clear sputum, malaise, weakness, fatigue, and shortness of breath on exertion for 3 weeks. He was an ex-smoker with a history of hypertension, hyperlipidemia, and coronary artery bypass graft surgery. He did not report any chills, night sweats, or fevers during this presentation.

Introduction: Healthcare Associated Infections (HAI) are associated with increased cost, morbidity, and mortality. Risk factors for HAI are well established; however, the independent risk associated with an exaggerated inflammatory response has not been adequately studied. Hypothesis: The objective was to investigate baseline cytokine levels (IL-6, IL-10), their polymorphisms (RS1800795, RS1800896) and environment on the development of new HAI in ICU patients admitted with sepsis. Methods: This prospective observational study evaluated 78 patients admitted to ICU with early sepsis ( Results: Seventeen HAI were identified. The final regression model included APACHE II, invasive device score, antibiotics prior to ICU, and IL6 RS1800795. Based on the multivariate model, for every 1-point increase in APACHE II score there was a 3.4% increased risk for developing HAI. Cumulative invasive device score and early antibiotic use reduced the risk of HAI. In the univariate model, the presence of IL6 polymorphism RS1800795 CC or CG resulted in a higher risk of HAI, and this risk increased in the multivariate model. Conclusions: The higher risk associated with IL-6 polymorphism RS1800795 CG and CC genotypes is consistent with higher risk associated with the C allele reported in the literature. Severity of illness is a known contributor to HAI. Sepsis guideline adherence (early antibiotics and judicious device use) may prevent HAI. We found no significant association with cytokine levels in our models. More analysis with a larger sample is needed to fully explore the relationships of these variables.

Chronic obstructive pulmonary disease (COPD) is characterized by progressive, irreversible airflow limitation coupled with an abnormal inflammatory process. It is associated with high morbidity and mortality. Leukotriene modifiers, approved by the United States Food and Drug Administration as treatment for asthma and allergic rhinitis, may also alleviate the abnormal inflammatory response seen in patients with COPD. To explore the outcomes of research in this area, we conducted a literature search from 1950-2007, using the PubMed database. We found no published studies that provided conclusive evidence that the available leukotriene modifiers benefit patients with COPD. However, data do suggest that leukotriene modifiers may offer benefits to patients with COPD, including effects that pertain to airflow limitation, neutrophil and lymphocyte chemotaxis, and neutrophil longevity. Added to conventional treatment, these agents appear to reduce symptoms, improve objective measures of disease, and control inflammation. Further studies are needed to determine the precise role of leukotriene modifiers in the treatment of COPD.

Background Health care-associated infections (HAIs) are the target of many well-known preventive measures in the intensive care unit (ICU); however, little is known about post-sepsis-induced immunosuppression. Objectives This study explores the relationship between baseline plasma levels of inflammatory cytokines interleukin 6 (IL-6), IL-10, and IL-6:IL-10 and subsequent development of HAIs in patients with admitted with sepsis. Methods Prospective observational study was conducted among veterans admitted to the ICU with sepsis and monitored daily through ICU discharge (up to 28 days) to investigate HAI development. Baseline plasma IL-6 and IL-10 levels were measured with a multiplex bead based assay. Exaggerated systemic inflammation was defined as the fourth quartile (IL-6 and IL-10) compared with other quartiles. Results We recruited 78 patients over 18 months, primarily older (65.5 ± 12.6 years) men (94.9%) with underlying comorbidities (93.9%) and a high severity of illness (Acute Physiologic and Chronic Health Evaluation II score 20.6 ± 6.4). Seventeen patients (21.7%) developed at least 1 HAI, and candidemia was the leading infection. Patients with exaggerated baseline systemic inflammation developed a nonsignificantly higher proportion of HAI as compared with those not developing HAI (IL-6: 31.6% vs 18.6%, P = .55; IL-10: 26.3% vs 20.3%, P = .43). Discussion Patients with exaggerated systemic inflammation had a higher severity of illness, but not a statistically significant higher incidence of HAI. A larger, more adequately powered sample with serial cytokine measures is needed. Routine surveillance cultures are needed. Health care-associated infection may occur in the absence of fever, and the emerging incidence of Candida is a concern. Immune suppression after sepsis should be recognized as a risk for HAI development. Antibiotic therapy should be targeted with prompt de-escalation of empiric therapy per established guidelines to preserve normal flora.

To test the hypothesis that the interaction between nuclear factor-kappaB (NF-kappaB) and glucocorticoid receptor alpha (GRalpha) is a key pathogenetic mechanism regulating the progression of systemic and pulmonary inflammation in sepsis and acute respiratory distress syndrome (ARDS), we used an ex vivo model of systemic inflammation. Naive peripheral blood leukocytes (PBL) were exposed to longitudinal (days 1-10) plasma samples from ARDS patients divided into three groups based on physiological improvement and clinical outcome by days 7-10: improvers, nonimprovers-survivors, and nonimprovers-nonsurvivors. In a separate group of nonimprovers-survivors, we correlated the severity of lung histopathology with the intensity of NF-kappaB and GRalpha nuclear staining in immunohistochemistry analysis of lung tissue obtained by open lung biopsy. We found that exposure of naive cells to longitudinal plasma samples led to divergent directions in NF-kappaB and GRalpha activation that reflected the severity of systemic inflammation. Plasma samples from improvers with declining cytokine levels over time elicited a progressive increase in all measured aspects of glucocorticoid (GC)-induced GRalpha-mediated activity (p = 0.0001) and a correspondent reduction in NF-kappaB nuclear binding (p = 0.0001) and transcription of TNF-alpha and IL-1beta (regulated, GRalpha-driven response). In contrast, plasma samples from nonimprovers with sustained elevation in cytokine levels over time elicited only a modest longitudinal increase in GC-GRalpha-mediated activity (p = 0.04) and a progressive increase in NF-kappaB nuclear binding over time (p = 0.0001) that was most striking in nonsurvivors (dysregulated, NF-kappaB-driven response). By days 3-5, no overlap was observed between groups for NF-kappaB and GC-GRalpha nuclear binding. In immunohistochemistry analyses, lung tissues of patients with severe versus mild ARDS had a higher intensity of NF-kappaB nuclear staining (13 +/- 1.3 vs. 7 +/- 2.9; p = 0.01) and a lower ratio of GRalpha:NF-kappaB in nuclear staining (0.5 +/- 0.2 vs. 1.5 +/- 0.2; p = 0.007). In conclusion, we demonstrated that the ability of GC-GRalpha to downregulate NF-kappaB activation is critical for the resolution of systemic and pulmonary inflammation in ARDS. The findings provide a rationale for the use of prolonged GC treatment in early ARDS.

Histoplasmosis is considered to be the most prevalent endemic mycosis in United States that can present as a disseminated infection. The initial presentation of Disseminated Histoplasmosis (DH) can be atypical. We report three cases with such atypical presentation. Our first patient presented with bowel perforation, the second with left-sided pleural effusion and the third with submandibular abscess. Blood cultures as well as biopsy of perforation site, culture of pleural fluid and submandibular abscess were positive for Histoplasma Capsulatum (HC). We encourage clinicians to look for HC even in uncommon sites as dictated by the presenting symptoms and signs, especially in immunocompromised patients in endemic areas.

To test the hypothesis that the interaction between nuclear factor-kappaB (NF-kappaB) and glucocorticoid receptor alpha (GRalpha) is a key pathogenetic mechanism regulating the progression of systemic and pulmonary inflammation in sepsis and acute respiratory distress syndrome (ARDS), we used an ex vivo model of systemic inflammation. Naïve peripheral blood leukocytes (PBL) were exposed to longitudinal (days 1-10) plasma samples from ARDS patients divided into three groups based on physiological improvement and clinical outcome by days 7-10: improvers, nonimprovers-survivors, and nonimprovers-nonsurvivors. In a separate group of nonimprovers-survivors, we correlated the severity of lung histopathology with the intensity of NF-kappaB and GRalpha nuclear staining in immunohistochemistry analysis of lung tissue obtained by open lung biopsy. We found that exposure of naïve cells to longitudinal plasma samples led to divergent directions in NF-kappaB and GRalpha activation that reflected the severity of systemic inflammation. Plasma samples from improvers with declining cytokine levels over time elicited a progressive increase in all measured aspects of glucocorticoid (GC)-induced GRalpha-mediated activity (p = 0.0001) and a correspondent reduction in NF-kappaB nuclear binding (p = 0.0001) and transcription of TNF-alpha and IL-1beta (regulated, GRalpha-driven response). In contrast, plasma samples from nonimprovers with sustained elevation in cytokine levels over time elicited only a modest longitudinal increase in GC-GRalpha-mediated activity (p = 0.04) and a progressive increase in NF-kappaB nuclear binding over time (p = 0.0001) that was most striking in nonsurvivors (dysregulated, NF-kappaB-driven response). By days 3-5, no overlap was observed between groups for NF-kappaB and GC-GRalpha nuclear binding. In immunohistochemistry analyses, lung tissues of patients with severe versus mild ARDS had a higher intensity of NF-kappaB nuclear staining (13 +/- 1.3 vs. 7 +/- 2.9; p = 0.01) and a lower ratio of GRalpha:NF-kappaB in nuclear staining (0.5 +/- 0.2 vs. 1.5 +/- 0.2; p = 0.007). In conclusion, we demonstrated that the ability of GC-GRalpha to downregulate NF-kappaB activation is critical for the resolution of systemic and pulmonary inflammation in ARDS. The findings provide a rationale for the use of prolonged GC treatment in early ARDS.