Downregulation of CD45 Signaling in COVID-19 Patients Is Reversed by C24D, a Novel CD45 Targeting Peptide.

CD45, the predominant transmembrane tyrosine phosphatase in leukocytes, is required for the efficient induction of T cell receptor signaling and activation. We recently reported that the CD45-intracellular signals in peripheral blood mononuclear cells (PBMCs) of triple negative breast cancer (TNBC) patients are inhibited. We also reported that C24D, an immune modulating therapeutic peptide, binds to CD45 on immune-suppressed cells and resets the functionality of the immune system via the CD45 signaling pathway. Various studies have demonstrated that also viruses can interfere with the functions of CD45 and that patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are immune-suppressed. Given the similarity between the role of CD45 in viral immune suppression and our findings on TNBC, we hypothesized that the C24D peptide may have a similar "immune-resetting" effect on PBMCs from COVID-19 patients as it did on PBMCs from TNBC patients. We tested this hypothesis by comparing the CD45/TCR intracellular signaling in PBMCs from ten COVID-19 patients vs. PBMCs from ten healthy volunteers. Herein, we report our findings, demonstrating the immune reactivating effect of C24D via the phosphorylation of the tyrosine 505 and 394 in Lck, the tyrosine 493 in ZAP-70 and the tyrosine 172 in VAV-1 proteins in the CD45 signaling pathway. Despite the relatively small number of patients in this report, the results demonstrate that C24D rescued CD45 signaling. Given the central role played by CD45 in the immune system, we suggest CD45 as a potential therapeutic target.

Healthcare-associated Pneumocystis jirovecii Pneumonia (PJP) Infection in HIV-negative Adults: a Multicenter Study.

BACKGROUND: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection in immunocompromised patients. Clusters of PJP, especially among organ transplant recipients in clinic settings were described. Data regarding nosocomial PJP infection among inpatients are limited. OBJECTIVES: To assess the magnitude and characteristics of inpatient healthcare-associated PJP infection (HCA-PJP) in HIV-negative patients. METHODS: A retrospective chart review of hospitalized PJP patients was performed to identify HCA-PJP. The study was performed at six medical centers in Israel from 2006 to 2016. HCA-PJP was defined as cases of hospital-onset or those with documented contact with a PJP patient. We reviewed and cross-matched temporal and spatial co-locations of patients. Clinical laboratory characteristics and outcomes were compared. RESULTS: Seventy-six cases of PJP were identified. Median age was 63.7 years; 64% men; 44% hematological malignancies; 18% inflammatory diseases; and 61% steroid usage. Thirty-two patients (42%) were defined as HCA-PJP: 18/32 (23.6%) were hospitalized at onset and 14/32 (18.4%) had a previous encounter with a PJP patient. Time from onset of symptoms to diagnosis was shorter in HCA-PJP vs. community-PJP (3.25 vs. 11.23 days, P = 0.009). In multivariate analysis, dyspnea at presentation (odds ratio [OR] 16.79, 95% confidence interval [95%CI] 1.78-157.95) and a tendency toward higher rate of ventilator support (72% vs. 52%, P = 0.07, OR 5.18, 95%CI 0.7-30.3) were independently associated with HCA-PJP, implying abrupt disease progression in HCA-PJP. CONCLUSIONS: HCA-PJP was common. A high level of suspicion for PJP among selected patients with nosocomial respiratory infection is warranted. Isolation of PJP patients should be considered.

Improving urinary tract infection treatment through a multifaceted antimicrobial stewardship intervention in the emergency department.

BACKGROUND: Urinary tract infection (UTI) is frequently encountered in the emergency department (ED). We assessed an antibiotic stewardship intervention tailored for the ED. The primary objective was improving overall adherence to agent choice and treatment duration. The secondary objective was a decrease in fluoroquinolone prescription. METHODS: This pre-post study included patients discharged from the ED with a UTI diagnosis. The intensive intervention period lasted three months and involved dissemination of guidelines, short lectures, incorporation of order sets into electronic ED charts and weekly personal audit and feedback. The following 11-month phase was a booster period consisting of monthly text messages of the treatment protocol. Assessment of adherence to the protocol was compared between the three-month pre-intervention period and the last two months of the intensive intervention period, as well as with the last two months of the booster period. RESULTS: A total of 177 patients were included in the pre-intervention period, 156 in the intervention period, and 94 in the late follow-up assessing the booster period. Median age was 49 (18-94) years, 78.2% were female, 84.8% had cystitis. During the intervention period, protocol adherence with antibiotic selection and duration increased from 41% to 84% (p < 0.001). Adherence remained high in the late follow-up period (73.4% vs. 41%, p < 0.001). Fluoroquinolone use decreased from 19.1% pre-intervention, to 5% in the intervention and 7.4% in the late follow-up periods (p < 0.001). CONCLUSIONS: An antibiotic stewardship intervention in a busy ED resulted in adherence to treatment protocols, including a decrease in fluoroquinolone use. A monthly reminder preserved most of the effect for a year.

Rituximab identified as an independent risk factor for severe PJP: A case-control study.

OBJECTIVE: Pneumocystis jirovecii pneumonia (PJP) was reported among immunosuppressed patients with deficits in cell-mediated immunity and in patients treated with immunomodulatory drugs. The aim of this study was to identify risk-factors for PJP in noninfected HIV patients. METHODS: This retrospective, test negative, case-control study was conducted in six hospitals in Israel, 2006-2016. Cases were hospitalized HIV-negative patients with pneumonia diagnosed as PJP by bronchoalveolar lavage. Controls were similar patients negative for PJP. RESULTS: Seventy-six cases and 159 controls were identified. Median age was 63.7 years, 65% males, 34% had hematological malignancies, 11% inflammatory diseases, 47% used steroids and 9% received antilymphocyte monoclonal antibodies. PJP was independently associated with antilymphocyte monoclonal antibodies (OR 11.47, CI 1.50-87.74), high-dose steroid treatment (OR 4.39, CI 1.52-12.63), lymphopenia (OR 8.13, CI 2.48-26.60), low albumin (OR 0.15, CI 0.40-0.54) and low BMI (OR 0.80, CI 0.68-0.93). CONCLUSION: In conclusion, rituximab, which is prescribed for a wide variety of malignant and inflammatory disorders, was found to be significant risk-factor for PJP. Increased awareness of possible PJP infection in this patient population is warranted.

Antibiotic modification versus withhold in febrile patients without evidence of bacterial infection, unresponsive to initial empiric regimen: a multicentre retrospective study conducted in Israel.

Prescribing antibiotics for febrile patients without proof of bacterial infection contributes to antimicrobial resistance. Lack of clinical response in these patients often leads to antibiotic escalation, although data supporting this strategy are scarce. This study compared outcomes of modifying, withholding, or continuing the same antibiotic regimen for such patients. Febrile or hypothermic stable patients with suspected infection, unresponsive to empiric antibiotic treatment, admitted to one of 15 internal medicine departments in three hospitals during a 5-year study period, were included. Patients with a definitive clinical or microbiological bacterial infection, malignancy, immunodeficiency, altered mental status, or need for mechanical ventilation were excluded. Participants were divided into groups based on treatment strategy determined 72 h after antibiotic initiation: antibiotic modified, withheld or continued. Outcomes measured included in-hospital and 30-day post-discharge-mortality rates, length of hospital stay (LOS) and days of antimicrobial therapy (DOT). A total of 486 patients met the inclusion criteria: 124 in the Antibiotic modified group, 67 in the Antibiotic withheld group and 295 in the Initial antibiotic continued group. Patient characteristics were similar among groups with no differences in mortality rates in-hospital (23% vs. 25% vs. 20%, p = 0.58) and within 30 days after discharge (5% vs. 3% vs. 4%, p = 0.83). Changing antibiotics led to longer LOS (9.0 ± 6.8 vs. 6.2 ± 5.6 days, p = 0.003) and more DOT (8.6 ± 6.0 vs. 3.2 ± 1.0 days, p < 0.001) compared to withholding treatment. Withholding as compared to modifying antibiotics, in febrile patients with no clear evidence of bacterial infection, is a safe strategy associated with decreased LOS and DOT.

Estimating Risk of Venous-Thromboembolic Events in Hospitalized Medical Patients: Comparison between 2008 and 2012 Guidelines.

BACKGROUND: Prophylaxis for hospitalized venous-thromboembolic events (VTEs) is frequently underutilized, in part due to lack of a simple risk assessment model (RAM). OBJECTIVES: To compare patient selection and administration of VTE prophylaxis according to the American College of Chest Physicians (ACCP) 2008 guidelines versus the newer 2012 guidelines, and assess the feasibility of developing simpler local RAMs. METHODS: We conducted a prospective assessment of VTE risk among 300 unselected consecutive patients admitted to a medical hospital ward, using the 2008 and 2012 ACCP guidelines. The frequency and relative weight of each risk factor in the 2012 ACCP guidelines were used to develop a local VTE RAM. RESULTS: VTE prophylaxis was indicated by the 2008 and 2012 ACCP guidelines in 40% and 42% of the cohort respectively, and was administered in 28% and 26% of eligible patients, respectively. Contraindication to VTE prophylaxis was found in 29% of patients according to both guidelines. In comparison to the 2008 guidelines, sensitivity and specificity of the 2012 guidelines were 96% and 88%, respectively. A local RAM based on the following concise score, comprising age, malignancy and immobility, correctly identified 99% of at-risk patients based on the 2012 guidelines, with a sensitivity and specificity of 98% and 95%, respectively. CONCLUSIONS: Both guidelines performed to a similar degree and were poorly implemented in daily practice. A simplified RAM accurately identified the vast majority of these eligible patients. The development of local RAMs is feasible and may result in higher utilization rates.

Gender-related differences in hospitalized heart failure patients.

AIMS: The burden of heart failure (HF)-related hospitalization and mortality of female patients with HF is substantial. Currently, several gender-specific distinctions have been recognized amongst HF patients, but their relationships to outcomes have not been fully elucidated. Accordingly, in the current work, we aimed to explore gender-specific clinical and echocardiographic measures and to assess their potential impact on outcome. METHODS AND RESULTS: We studied all consecutive HF patients, aged 50 or older, who had been hospitalized between January 2000 and December 2009, and had undergone at least one echocardiography study. A comparative analysis of clinical and echocardiographic findings was performed between 5228 males and 4107 females. Patients were followed for a mean of 2.8 ± 2.6 years. Females compared with males had less ischaemic heart disease, prior stroke, chronic renal failure, and COPD, and higher rates of hypertension, AF, obesity, valvular abnormalities, and pulmonary hypertension. Unadjusted 30-day and 1-year mortality rates were higher among women, while age-adjusted rates were similar. Predictors of outcomes varied between genders. Female-specific predictors of mortality included aortic stenosis, pulmonary hypertension, and malignancy, whereas diastolic dysfunction and chronic renal failure were found to be male-specific predictors. CONCLUSIONS: Age-adjusted mortality rates of male and female hospitalized HF patients are similarly high. Predictors of mortality, however, are gender distinctive, and these measures may allow a better identification of high-risk HF patients.

Risk behaviors and spectrum of diseases among elderly travelers: a comparison of younger and older adults.

BACKGROUND: Elderly travel to the developing world is increasing. Little information is available regarding risk behaviors and health during and after travel in this population. METHODS: We compared the risk factors and occurrence of travel-related diseases in two populations of Israelis, travelers aged 60 years and older and travelers in the age group of 20 to 30 years. Only people traveling for less than a month were included. Pre-travel, each person received routine counseling regarding travel-associated health risks, was immunized, and given anti-malarial prescriptions as needed. Travelers were surveyed by telephone 6 to 12 months following travel about underlying medical conditions, current medications, and travel history. Risk and preventive behaviors, compliance with anti-malarial prophylaxis, and history of illness during and after travel were assessed. RESULTS: Of patients who visited the clinic from January to June 2008, 191/208 (91%) travelers aged 60 and older and 203/291 (69%) travelers aged 20 to 30 years were contacted by phone and recruited. Fewer elderly travelers drank open drinks, compared to young travelers (8% vs 35%, p < 0.01), and fewer purchased street food compared to young travelers (16.2% vs 37.9%, p < 0.01). More elderly travelers were fully compliant with their anti-malarial chemoprophylaxis regimen (60.7% vs 33.8%, p < 0.01). More elderly travelers took organized tours (61% vs 2%, p < 0.001). Young travelers more often backpacked (50.7% vs 10.4%, p < 0.001). Illness, most commonly diarrhea, was reported by 18.8% of elderly travelers compared to 34.0% of the young travelers (p = 0.001). In a logistic regression model only travel to East Asia (OR 4.66) (95%CI 1.93-11.22) and traveling under basic conditions (OR 1.94) (95% CI 1.42-3.29) remained significantly associated with illness, irrespective of age. CONCLUSIONS: Because elderly travelers tend to comply with health-related recommendations better and use less risky travel modes, their risk for illness during travel was lower. Traveling to East Asia and travel mode are associated with illness during travel, irrespective of age.