Glucocorticoids as a risk factor for infection and adverse outcomes in non-HIV and non-transplant patients with cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis (CM), an opportunistic fungal infection affecting immunocompromised hosts, leads to high mortality. The role of previous exposure to glucocorticoids as a risk factor and as an outcome modulator has been observed, but systematic studies are lacking. OBJECTIVE: The primary aim of this study is to evaluate the impact of glucocorticoid use on the clinical outcomes, specifically mortality, of non-HIV and non-transplant (NHNT) patients diagnosed with CM. METHODS: We queried a global research network to identify adult NHNT patients with CM based on ICD codes or recorded specific Cryptococcus CSF lab results with or without glucocorticoid exposure the year before diagnosis. We performed a propensity score-matched analysis to reduce the risk of confounding and analysed outcomes by glucocorticoid exposure. We used a Cox proportional hazards model for survival analysis. RESULTS: We identified 764 patients with a history of glucocorticoid exposure and 1267 patients without who developed CM within 1 year. After propensity score matching of covariates, we obtained 627 patients in each cohort. The mortality risk in 1 year was greater in patients exposed to prior glucocorticoids (OR: 1.3, CI: 1.2-2.0, p = 0.002). We found an excess of 45 deaths among CM patients with previous glucocorticoid use (7.4% increased absolute risk of dying within 1 year of diagnosis) compared to CM controls without glucocorticoid exposure. Hospitalisation, intensive care unit admission, emergency department visits, stroke and cognitive dysfunction also showed significant, unfavourable outcomes in patients with glucocorticoid-exposed CM compared to glucocorticoid-unexposed CM patients. CONCLUSIONS: Previous glucocorticoid administration in NHNT patients seems to associate with 1-year mortality after CM adjusted for possible confounders related to demographics, comorbidities and additional immunosuppressive medications. Serial CrAg screening might be appropriate for higher-risk patients on glucocorticoids after further cost-benefit analyses.

Diabetes Mellitus Type 2 as a Risk Factor and Outcome Modifier for Cryptococcosis in HIV Negative, Non-transplant Patients, a Propensity Score Match Analysis.

Cryptococcosis is an opportunistic fungal infection of worldwide distribution with significant associated morbidity and mortality. HIV, organ transplantation, malignancy, cirrhosis, sarcoidosis, and immunosuppressive medications are established risk factors for cryptococcosis. Type 2 diabetes mellitus (DM2) has been hypothesized as a risk factor and an outcome modifier for cryptococcosis. We aimed to compare outcomes among HIV-negative, non-transplant (NHNT) patients with and without DM2. We queried a global research network to identify NHNT patients (n = 3280). We performed a propensity score-matched (PSM) analysis comparing clinical outcomes among cryptococcosis patients by DM status. We also characterize adults with cryptococcosis and DM2 as the only risk factor. After PSM, NHNT patients with DM2 were more likely to develop cognitive dysfunction [9% vs. 6%, OR 1.6; 95% CI (1.1-2.3); P = 0.01] but had similar mortality, hospitalization, ICU, and stroke risk after acquiring cryptococcosis when compared to NHNT patients without DM2. Pulmonary cryptococcosis was the most common site of infection. Among 44 cryptococcosis patients with DM2 as the only identifiable risk factor for disease, the annual incidence of cryptococcosis was 0.001%, with a prevalence of 0.002%. DM2 is associated with increased cognitive dysfunction risk in NHNT patients with cryptococcosis. It is rare for DM2 to be the only identified risk factor for developing cryptococcosis. Kidney disease, hyperglycemia, and immune dysfunction can increase the risk of cryptococcosis in patients with DM2.

Bartonella quintana Infection in People Experiencing Homelessness in the Denver Metropolitan Area.

BACKGROUND: Bartonella quintana is an important cause of infection amongst people experiencing homelessness that is underdiagnosed due to its nonspecific clinical manifestations. We reviewed cases identified in the Denver metropolitan area in 2016-2021. METHODS: The electronic medical records from 2 large academic medical centers in Colorado were reviewed for demographic, clinical, and laboratory features of patients with B. quintana infection confirmed by blood culture, serologies, and/or molecular testing from July 2016 to December 2021. RESULTS: Fourteen patients with B. quintana infection were identified. The mean age was 49.5 years (SD 12.7 years) and 92.9% of patients were male. Twelve patients had history of homelessness (85.7%) and 11 were experiencing homelessness at the time of diagnosis (78.6%). Most frequent comorbidities included substance use (78.6%), of which 42.9% had alcohol use disorder. The average time to blood culture positivity was 12.1 days (SD 6.2 days). Three patients with bacteremia had negative B. quintana IgG, and 6 of 14 (42.8%) patients had evidence of endocarditis on echocardiography. CONCLUSIONS: B. quintana is an underrecognized cause of serious infection in individuals experiencing homelessness. Serologic and microbiologic testing, including prolonged culture incubation, should be considered in at-risk patients due to ongoing transmission in homeless populations.

Proinflammatory cytokines levels in sepsis and healthy volunteers, and tumor necrosis factor-alpha associated sepsis mortality: A systematic review and meta-analysis.

BACKGROUND: Sepsis is a global health challenge associated with significant morbidity and mortality. Detrimental sepsis effects are attributed to excessive inflammation or a "cytokine storm." However, anti-inflammation therapies have failed to lower sepsis mortality. We aim to characterize levels of key inflammatory cytokines in patients with sepsis and compare levels with those in healthy individuals and relate tumor necrosis factor (TNF) α levels to patient characteristics and outcomes. METHODS: We performed a systematic review and meta-analysis. Medline, Embase, Cochrane Library, and Web of Science Core Collection databases were searched between 1985 and May 2020. Analysis was restricted to studies in English. We included randomized controlled trials (RCTs), controlled trials, cohort studies, case series, and cross-sectional studies that reported mean levels of cytokines in the circulation thought to be relevant for sepsis pathogenesis. We also evaluated concentrations of these cytokines in healthy individuals. The Quality in Prognosis Studies tool was used to assess the methodological quality of included studies. We extracted summary data from published reports. Data analyses were performed using a random-effects model to estimate pooled odds ratios (OR) with 95% confidence intervals for cytokine levels and mortality. This systematic review is registered in PROSPERO (CRD42020179800). FINDINGS: We identified 3654 records, and 104 studies were included with a total of 3250 participants. The pooled estimated mean TNFα concentration in sepsis patients was 58.4 pg/ml (95% Confidence Interval or CI 39.8-85.8 pg/ml), and in healthy individuals was 5.5 pg/ml (95% CI 3.8-8.0 pg/ml). Pooled estimate means for IL-1ß and IFN-γ in sepsis patients were 21.8 pg/ml and 63.3 pg/ml, respectively. Elevated TNFα concentrations associated with increased 28-day sepsis mortality (p = 0.001). In subgroup analyses, we did not detect an association between TNFα levels and sepsis source, sepsis severity, or sequential organ failure assessment (SOFA) score. A TNF-α cutoff level ≥14.7 pg/ml separated sepsis patients from healthy individuals with a sensitivity of 82.6%, a specificity of 91.7%, and a likelihood ratio of 9.9. INTERPRETATION: Sepsis mean TNFα concentration is increased approximately 10-fold compared to mean concentration in healthy individuals, and TNFα associated with sepsis mortality but not sepsis severity. The concept that elevated cytokines cause sepsis should be revisited in the context of these data. FUNDING: None.

Cryptococcosis among hospitalised patients with COVID-19: A multicentre research network study.

It is unclear if there is an association between COVID-19 and cryptococcosis. Therefore, this study aimed to describe the clinical features, risk factors, and outcomes associated with cryptococcosis in hospitalised patients with COVID-19. The objectives of this study were to determine the incidence of and examine factors associated with cryptococcosis after a diagnosis of COVID-19. We used TriNetX to identify and sort patients 18 years and older hospitalised with COVID-19 into two cohorts based on the presence or absence of a diagnosis of cryptococcosis following diagnosis of COVID-19. Outcomes of interest included the incidence of cryptococcosis following the diagnosis of COVID-19 as well as the proportion of patients in each group who had underlying comorbidities, received immunomodulatory therapy, required ICU admission or mechanical ventilation (MV), or died. Propensity score matching was used to adjust for confounding. Among 212,479 hospitalised patients with COVID-19, 65 developed cryptococcosis. The incidence of cryptococcosis following COVID-19 was 0.022%. Patients with cryptococcosis were more likely to be male and have underlying comorbidities. Among cases, 32% were people with HIV. Patients with cryptococcosis were more likely to have received tocilizumab (p < .0001) or baricitinib (p < .0001), but not dexamethasone (p = .0840). ICU admission (38% vs 29%), MV (23% vs 11%), and mortality (36% vs 14%) were significantly higher among patients with cryptococcosis. Mortality remained elevated after adjusted propensity score matching. Cryptococcosis occurred most often in hospitalised patients with COVID-19 who had traditional risk factors, comparable to findings in patients without COVID-19. Cryptococcosis was associated with increased ICU admission, MV, and mortality.

Chronic Chagas Disease-the Potential Role of Reinfections in Cardiomyopathy Pathogenesis.

PURPOSE OF THE REVIEW: Chagas disease is a neglected anthropozoonosis of global importance with significant cardiovascular-associated mortality. This review focuses on the Trypanosoma cruzi reinfections' role in chronic Chagas cardiomyopathy pathogenesis. We discuss and summarize the available data related to pathology, pathogenesis, diagnosis, and treatment of reinfections. RECENT FINDINGS: Reinfections influence the genetic and regional diversity of T. cruzi, tissue tropism, modulation of the host's immune system response, clinical manifestations, the risk for congenital infections, differences in diagnostics performances, response to antiparasitic therapy, and the natural history of the disease. Animal models suggest that reinfections lead to worse outcomes and increased mortality, while other studies showed an association between reinfections and lower parasitemia levels and subsequent infection protection. In some regions, the human risk of reinfections is 14% at 5 years. Evidence has shown that higher anti-T. cruzi antibodies are correlated with an increased rate of cardiomyopathy and death, suggesting that a higher parasite exposure related to reinfections may lead to worse outcomes. Based on the existing literature, reinfections may play a role in developing and exacerbating chronic Chagas cardiomyopathy and are linked to worse outcomes. Control efforts should be redirected to interventions that address structural poverty for the successful and sustainable prevention of Chagas disease.

Hantavirus Infection with Renal Failure and Proteinuria, Colorado, USA, 2019.

In North America, hantaviruses commonly cause hantavirus pulmonary syndrome (HPS). Clinical descriptions of hantavirus-associated renal disease in the Americas are scarce. Herein, we discuss the case of a 61-year-old man whose predominant manifestations were acute kidney injury and proteinuria. Clinical recognition of renal signs in hantavirus infections can reduce risk for death.

Cutaneous Mycobacterial Infections.

Humans encounter mycobacterial species due to their ubiquity in different environmental niches. In many individuals, pathogenic mycobacterial species may breach our first-line barrier defenses of the innate immune system and modulate the activation of phagocytes to cause disease of the respiratory tract or the skin and soft tissues, sometimes resulting in disseminated infection. Cutaneous mycobacterial infections may cause a wide range of clinical manifestations, which are divided into four main disease categories: (i) cutaneous manifestations of Mycobacterium tuberculosis infection, (ii) Buruli ulcer caused by Mycobacterium ulcerans and other related slowly growing mycobacteria, (iii) leprosy caused by Mycobacterium leprae and Mycobacterium lepromatosis, and (iv) cutaneous infections caused by rapidly growing mycobacteria. Clinically, cutaneous mycobacterial infections present with widely different clinical presentations, including cellulitis, nonhealing ulcers, subacute or chronic nodular lesions, abscesses, superficial lymphadenitis, verrucous lesions, and other types of findings. Mycobacterial infections of the skin and subcutaneous tissue are associated with important stigma, deformity, and disability. Geography-based environmental exposures influence the epidemiology of cutaneous mycobacterial infections. Cutaneous tuberculosis exhibits different clinical phenotypes acquired through different routes, including via extrinsic inoculation of the tuberculous bacilli and dissemination to the skin from other sites, or represents hypersensitivity reactions to M. tuberculosis infection. In many settings, leprosy remains an important cause of neurological impairment, deformity, limb loss, and stigma. Mycobacterium lepromatosis, a mycobacterial species related to M. leprae, is linked to diffuse lepromatous leprosy of Lucio and Latapí. Mycobacterium ulcerans produces a mycolactone toxin that leads to subcutaneous tissue destruction and immunosuppression, resulting in deep ulcerations that often produce substantial disfigurement and disability. Mycobacterium marinum, a close relative of M. ulcerans, is an important cause of cutaneous sporotrichoid nodular lymphangitic lesions. Among patients with advanced immunosuppression, Mycobacterium kansasii, the Mycobacterium avium-intracellulare complex, and Mycobacterium haemophilum may cause cutaneous or disseminated disease. Rapidly growing mycobacteria, including the Mycobacterium abscessus group, Mycobacterium chelonei, and Mycobacterium fortuitum, are increasingly recognized pathogens in cutaneous infections associated particularly with plastic surgery and cosmetic procedures. Skin biopsies of cutaneous lesions to identify acid-fast staining bacilli and cultures represent the cornerstone of diagnosis. Additionally, histopathological evaluation of skin biopsy specimens may be useful in identifying leprosy, Buruli ulcer, and cutaneous tuberculosis. Molecular assays are useful in some cases. The treatment for cutaneous mycobacterial infections depends on the specific pathogen and therefore requires a careful consideration of antimicrobial choices based on official treatment guidelines.

Lacunar Stroke in Cryptococcal Meningitis: Clinical and Radiographic Features.

OBJECTIVE: Cryptococcal meningitis carries a high mortality, and survivors are left with considerable neurologic sequelae and marked disability. We lack a clear understanding of the pathogenesis of neurologic sequelae and description of stroke features in this population. We aim to describe clinical and radiographic features and predictors of stroke in a cohort of patients with cryptococcal meningitis. METHODS: We collected key information on patients diagnosed with cryptococcal meningitis at the University of Colorado Hospital between 2000 and 2018 (n = 42). Of those, 32 had neuroimaging studies available. Bivariate and risk ratio estimates regression models were performed to identify predictors of stroke. RESULTS: We found a 26% ischemic stroke complication rate in individuals with cryptococcal meningitis. Most strokes were acute (75%), lacunar (100%), multiple (88%), bilateral (63%), and involving the basal ganglia (75%). Presence of malignancy (38% versus 8%, P = .085) was higher in stroke in individuals with cryptococcal meningitis, although not statistically significant. Every unit decrease in hemoglobin and serum sodium were predictors for 1.35 and 1.14 times increase in the risk of ischemic stroke, respectively. The presence of hyponatremia carried a RR of 5.7 (95% confidence interval, 1.7-34, P = .005). Cryptococcal meningitis lead to death in 19% of patients and a considerable rate of neurologic sequela among survivors. CONCLUSIONS: Cryptococcal meningitis carries a high risk of lacunar stroke, particularly in the basal ganglia. Cryptococcal meningitis-associated stroke is common and frequently associated with neurologic disability among survivors. We need to understand the possible role of malignancy, anemia, and hyponatremia in the onset of ischemic stroke.

Cryptococcus gattii Complex Infections in HIV-Infected Patients, Southeastern United States.

Cryptococcus gattii traditionally infects immunocompetent hosts and causes devastating pulmonary or central nervous system disease. However, this infection rarely occurs in patients infected with HIV. We report 3 cases of HIV-associated C. gattii complex infections in the southeastern United States. Detection of C. gattii in HIV-infected patients in this region warrants increased awareness of this threat to ensure appropriate diagnosis and treatment to optimize patient outcomes.

Treatment of cryptococcosis in non-HIV immunocompromised patients.

PURPOSE OF REVIEW: Cryptococcosis has become a common opportunistic infection among non-HIV immunocompromised hosts. Recent reports have shown the incidence of Cryptococcosis among HIV-negative immunocompromised patients reaches close to half of the overall cases reported in the USA. Management of this infection in this population carries unique challenges. We aim to review relevant and recent research findings to develop treatment recommendations for this type of population. RECENT FINDINGS: Most of the recommendations for the management of non-HIV immunocompromised host are extrapolated from HIV studies. Cryptococcosis among non-HIV patients is common but often overlooked. Some clinical factors, when present, may increase the risk of Cryptococcosis among HIV-negative patients and appropriate screening and assessment for the disease is necessary. Treating clinicians should consider a longer duration of induction with Amphotericin B depending on the type of host, immunocompromised state, antifungal response and presence of neurological complications. Baseline fluconazole resistance can reach up to 12%, which is an important consideration for cryptococcal meningitis relapses or suboptimal responses to therapy. SUMMARY: Cryptococcus spp. conveys a high disease burden among immunocompromised hosts. Clinicians must consider numerous variables and factors in a dynamic way to offer the best possible treatment and to monitor their response to therapy. Due to the high cost and associated toxicities, we still need new affordable therapies and studies among non-HIV immunocompromised patients.

Cryptococcosis and cryptococcal meningitis: New predictors and clinical outcomes at a United States academic medical centre.

As the diagnosis of cryptococcosis is challenging in low-prevalence settings, uncovering predictive factors can improve early diagnosis and timely treatment. The aim of the study was to relate clinical outcomes to predictive variables for the presence of cryptococcosis. A retrospective case-control study matched by collection date, age and gender at a 1:2 ratio (55 cases and 112 controls) was performed in case patients diagnosed with Cryptococcus infection at the University of Colorado Hospital between 2000 and 2017 (n = 167). A bivariate and a forward, stepwise multivariable logistic regression model were performed to identify predictors of cryptococcosis infection. In an adjusted multivariable model, cryptococcal infection was significantly associated with the presence of respiratory symptoms, hyponatremia, lung disease or corticosteroids. Additionally, cryptococcal meningitis was associated with headaches, corticosteroids or increased CSF protein. Conversely, a reduced risk of cryptococcosis was associated with hypertension or peripheral monocytosis. Cryptococcal meningitis leads to subsequent hearing impairment (16% vs 4% (control), P = .013), muscle weakness (40% vs 20%, P = .021), cognitive deficits (33% vs 6%, P = .0001) or any adverse outcome (84% vs 29%, P = .0001). We uncovered novel clinical predictors for the presence of cryptococcal infection or cryptococcal meningitis. This study in patients at a low-prevalence US medical centre underscores the importance of early diagnosis in this population.

Effect of the 2014 Clinical and Laboratory Standards Institute urine-specific breakpoints on cefazolin susceptibility rates at a community teaching hospital.

BACKGROUND: Enterobacteriaceae, which include Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, are identified as the infectious etiology in the majority of urinary tract infections (UTIs) in community hospitals across the United States. The minimum inhibitory concentration (MIC) is a useful tool when choosing an appropriate antibacterial agent. Recent changes to the 2014 Clinical and Laboratory Standards Institute (CLSI) guidelines included reporting a urine-specific cefazolin breakpoint for enterobacteriaceae (susceptible ≤16 mcg/mL). The purpose of this study was to determine the clinical and financial impact of implementing the 2014 CLSI urine-specific breakpoints for cefazolin in a community-based teaching hospital in the Southern U.S.A. METHODS: A retrospective review of patients hospitalized from January 1, 2010 through October 1, 2014 was performed. Patients that met inclusion criteria had a documented initial clinical isolate of E. coli, K. pneumoniae, or P. mirabilis from urine cultures during each year. Descriptive statistics and two-proportion test of hypothesis were used in the analysis to compare susceptibility rates before and after implementation of the updated CLSI breakpoints for cefazolin. RESULTS: A total of 190 clinical isolates from patients were included in the study. E. coli was the most common organism isolated (63.7%), followed by K. pneumoniae (22.1%), and P. mirabilis (14.2%). 86% of the included isolates were susceptible to cefazolin using the 2010 breakpoints. Implementation of the 2014 breakpoints did not significantly impact susceptibility results for E. coli, K. pneumoniae, or P. mirabilis. CONCLUSION: Modification of breakpoints did not significantly impact susceptibility rates of cefazolin. Substituting cefazolin may decrease the overall drug cost by 77.5%. More data is needed to correlate in vitro findings with clinical outcomes using cefazolin for UTIs.

Leprosy in the 21st century.

Despite significant improvements in leprosy (Hansen's disease) treatment and outlook for patients since the introduction of multidrug therapy (MDT) 3 decades ago, the global incidence remains high, and patients often have long-term complications associated with the disease. In this article, we discuss recent findings related to genetics, susceptibility, and disease reservoirs and the implications of these findings for Hansen's disease control and health outcomes for patients. We describe the continued difficulties associated with treatment of inflammatory episodes known as "leprosy reactions," which cause much of the disability associated with the disease and can affect people for many years after MDT is complete. We also discuss some of the contemporary challenges for physicians and patients, including international and internal migration of people affected by the disease. We suggest some important areas of focus for future Hansen's disease research.

Unsolved matters in leprosy: a descriptive review and call for further research.

Leprosy, a chronic mycobacterial infection caused by Mycobacterium leprae, is an infectious disease that has ravaged human societies throughout millennia. This ancestral pathogen causes disfiguring cutaneous lesions, peripheral nerve injury, ostearticular deformity, limb loss and dysfunction, blindness and stigma. Despite ongoing efforts in interrupting leprosy transmission, large numbers of new cases are persistently identified in many endemic areas. Moreover, at the time of diagnosis, most newly identified cases have considerable neurologic disability. Many challenges remain in our understanding of the epidemiology of leprosy including: (a) the precise mode and route of transmission; (b) the socioeconomic, environmental, and behavioral factors that promote its transmission; and