The clinical significance of Dientamoeba fragilis and Blastocystis in human stool-retrospective cohort study.

OBJECTIVES: The aim of this study was to assess the clinical significance of Dientamoeba fragilis (DF) and Blastocystis species (Bs) in human stool. METHODS: Observational study of patients ≥18 years, who were tested by stool multiplex PCR for bacteria and parasites between April 2019 and March 2022. Although DF and Bs are part of the PCR kit, these results are not routinely reported to the patient or the ordering physician. The main outcomes were the incidence of symptoms during 14 days before the referral to stool PCR test, and the incidence of several clinical outcomes during 60 days after the PCR test (symptoms, referrals to further evaluation, prescription of symptomatic, or antibiotic treatment). RESULTS: A total of 27 918 patients were tested by stool PCR during the 3 study years. A total of 6215 (22.3%) and 5337 (19.2%) were positive for DF and Bs, respectively. The incidence of symptoms before the test was similar in those positive for Bs or DF and those with all-negative PCR (adjusted OR and 95% CI of 0.87 [0.80-0.95] and 0.82 [0.76-0.88] for Bs and DF, respectively), whereas significantly higher (2.47 [2.23-2.73]) in those positive for the other multiplex PCR assay components. During the 60 days after the test, the prevalence of any of the outcomes was similar in those positive for Bs or DF and those with negative PCR (adjusted OR and 95% CI of 0.92 [0.83-1.02] and 0.89 [0.81-0.97] for symptoms, 0.84 [0.75-0.94] and 0.93 [0.85-1.01] for referrals, 0.88 [0.75-1.03] and 0.82 [0.71-0.94] for symptomatic treatment, and 0.88 [0.75-1.02] and 0.86 [0.75-0.98] for antibiotic treatment in the Bs and DF positive individuals, respectively). The PCR cycle threshold was not associated with any of the outcomes. DISCUSSION: Positive stool PCR for DF or Bs was not associated with any of the measured clinical outcomes.

Dual anti-viral treatment for persistent COVID-19 in immunocompromised hemato-oncological patients is associated with a favorable prognosis and minor side effects.

In hemato-oncological patients, COVID-19 can present as a persistent infection with ongoing symptoms and viral replication over a prolonged period of time. Data are scarce on the preferred treatment options for these patients. We describe our experience with a five-day course of dual anti-viral treatment with remdesivir and nirmatrelvir/ritonavir for hemato-oncological immunocompromised patients with persistent COVID-19. Fifteen patients with a history of lymphoma, CLL, and MM were included. Eight were male, median age was 74. All patients had an immediate clinical and virological response. In 73 % of patients, PCR for SARS-CoV-2 became negative at the end of treatment and the rest had an increase in PCR cycle threshold (CT) values, with a median increase of 6 cycles. After a follow-up of three months, 60 % of patients remained in full clinical and virological remission. None required invasive mechanical ventilation or died. The side effects we observed, neutropenia, lactatemia and elevated transaminases, were mild and almost all transient in nature. We conclude that dual anti-viral treatment appears to be a valid treatment option for persistent COVID-19.

Early Antibiotic Deescalation and Discontinuation in Patients with Febrile Neutropenia after Cellular Therapy: A Single-Center Prospective Unblinded Randomized Trial.

The optimal duration of empiric antimicrobial therapy of febrile neutropenia in patients after cellular therapy is unclear. Early deescalation has been suggested by some authorities; however, data are lacking for cellular therapy recipients. We performed a randomized controlled study of cellular therapy recipients with febrile neutropenia to evaluate the safety and noninferiority of an early deescalation and discontinuation antibiotic strategy (EDD arm) versus standard broad-spectrum antibiotic treatment until recovery of neutropenia (standard duration arm). The primary outcome was the fraction of antibiotic-free neutropenia days. We randomized 110 patients to the standard duration arm (n = 51) or EDD arm (n = 59). The fraction of antibiotic-free neutropenia days was higher in the EDD arm compared to the standard duration arm (median, .8 [interquartile range (IQR), .62 to .86] versus .51 [IQR, .17 to .86]; P = .016). This was true for the per-protocol, allogeneic hematopoietic cell transplantation (HCT), autologous HCT, and anti-CD19 chimeric antigen receptor T cell therapy subgroups. Treatment success rate, subsequent fever, death within 30 days, and other common cellular therapy-related toxicities were all similar between the 2 study arms. An EDD antibiotic strategy in patients after cellular therapy was safe and associated with a substantial reduction in broad-spectrum antibiotic utilization without compromising cellular therapy outcomes.

Candida auris uses metabolic strategies to escape and kill macrophages while avoiding robust activation of the NLRP3 inflammasome response.

Metabolic adaptations regulate the response of macrophages to infection. The contributions of metabolism to macrophage interactions with the emerging fungal pathogen Candida auris are poorly understood. Here, we show that C. auris-infected macrophages undergo immunometabolic reprogramming and increase glycolysis but fail to activate a strong interleukin (IL)-1ß cytokine response or curb C. auris growth. Further analysis shows that C. auris relies on its own metabolic capacity to escape from macrophages and proliferate in vivo. Furthermore, C. auris kills macrophages by triggering host metabolic stress through glucose starvation. However, despite causing macrophage cell death, C. auris does not trigger robust activation of the NLRP3 inflammasome. Consequently, inflammasome-dependent responses remain low throughout infection. Collectively, our findings show that C. auris uses metabolic regulation to eliminate macrophages while remaining immunologically silent to ensure its own survival. Thus, our data suggest that host and pathogen metabolism could represent therapeutic targets for C. auris infections.

Mpox Presenting as Proctitis in Men Who Have Sex With Men.

In our cohort of 70 patients of men who have sex with men (MSM) with mpox, more than one-third presented with proctitis. In two-thirds of proctitis patients, there was no typical rash upon presentation, and in one-fifth, there was no rash at all, making the diagnosis a challenge. A rectal swab for mpox polymerase chain reaction (PCR) can be diagnostic.

Thrombopoietin receptor agonist for treating bone marrow aplasia following anti-CD19 CAR-T cells-single-center experience.

Anti CD-19 chimeric antigen receptor T (CAR-T) cells demonstrate effective early anti-tumor response; however, impaired hematopoietic recovery is observed in about 30% of patients with prolonged cytopenia appearing as an unmet need for optimal treatment. All adult patients given commercially available anti CD-19 CAR-T for diffuse large B cell lymphoma (DLBCL) were screened at 21-28 days after CAR-T infusion for cytopenia. In case of severe persistent cytopenia, patients were given TPO receptor agonists. Initial dose of eltrombopag was 50 mg/day and gradually increased to a maximal dose of 150 mg/day. Romiplostim was given as subcutaneous injection once a week for 2 doses (125 mcg). Response was defined as transfusion independency along with resolution of severe neutropenia (ANC > 500 /microL) and/or platelets > 20,000/microL for three consecutive values on different days. TPO receptor agonists were tapered down when response was met. From May 2019 to December 2021, 93 patients were eligible (74%, tisagenlecleucel and 26%, axicabtagene ciloleucel). The median age was 69 (range, 19-85) years. Six patients (6.5%) (tisagenlecleucel, n = 4 or axicabtagene ciloleucel, n = 2) demonstrated prolonged severe cytopenia and were treated with TPO receptor agonists (eltrombopag, n = 4; romiplastim, n = 1, both drugs, n = 1). Median time from CAR-T infusion to initiation of TPO receptor agonist was 43 (range, 21-55) days. All patients were transfusion-dependent and were given daily GCSF prior to TPO receptor agonist administration. Response to TPO receptor agonists was seen in all 6 patients. Median time from TPO receptor agonist initiation to resolution of cytopenia was 22 (range, 8-124) days for Hb, 27 (range, 6-38) days for platelets, and 29 (range, 7-61) days for neutrophils. A complete resolution of all blood counts (ANC > 500 /microL and platelets > 20,000/microL and hemoglobin > 8 gr/dL) was seen in 5/6 patients. No toxicity was observed during the therapy course. This paper supports further investigation of TPO receptor agonists in the treatment of persistent cytopenia following CAR-T cell therapy.

Clinical features and outcomes of bacteremic and non-bacteremic Campylobacteriosis: a case-control study.

PURPOSE: Campylobacter bloodstream infection (C-BSI) is uncommon, and its clinical significance is unclear. The aim of the study was to determine risk factors and clinical outcomes associated with Campylobacter BSI. METHODS: We performed a single center retrospective case-control study comparing patients with C-BSI (cases) and patients with nonbacteremic Campylobacter enteritis (controls), from January 2007 through June 2020. Case and control patients were matched by age and sex at a ratio of 1:2. Demographic, clinical, and microbiological characteristics were compared between groups. RESULTS: We identified 76 patients with C-BSI and matched them with 149 nonbacteremic patients with Campylobacter enteritis. Rates of C-BSI increased tenfold in 2014 following the introduction of BacTAlert FA/FN Plus blood culture bottles. Baseline variables significantly associated with C-BSI on multivariable logistic regression were fever, absence of diarrhea and recent exposure to antibiotics. Compared with controls, C-BSI was associated with higher 30-day mortality (12% vs. 2%, P = 0.003), more frequent need for intensive care (6.6% vs. 1.2%, P = 0.032) and longer hospital stay (median, 5 days vs. 3 days, P = 0.003). There was a high proportion of immunocompromised patients in both groups (55%). CONCLUSIONS: C-BSI is identified with increasing frequency, reflecting both changes in epidemiology and improved sensitivity of blood culture systems. Our findings indicate that detection of Campylobacter spp. in blood culture is associated with significantly higher rates of death and other adverse outcomes.

Real-world safety data for the Pfizer BNT162b2 SARS-CoV-2 vaccine: historical cohort study.

OBJECTIVE: The Pfizer BNT162b2 vaccine showed a reassuring safety profile in clinical trials, but real-world data are scarce. Bell's palsy, herpes zoster, Guillain-Barré syndrome (GBS) and other neurological complaints in proximity to vaccination have received special public attention. We compared their rates among vaccinated and unvaccinated individuals. METHODS: Individuals ≥16 years vaccinated with at least one dose of BNT162b2 were eligible for this historical cohort study in a health maintenance organization insuring 1.2 million citizens. Each vaccinee was matched to a non-vaccinated control by sex, age, population sector (general Jewish, Arab, ultra-orthodox Jewish) and comorbidities. Diagnosis of Covid-19 before or after vaccination was an exclusion criterion. The outcome was a diagnosis of Bell's palsy, GBS, herpes zoster or symptoms of numbness or tingling, coded in the visit diagnosis field using ICD-9 codes. Diagnoses of Bell's palsy and GBS were verified by individual file review. RESULTS: Of 406 148 individuals vaccinated during the study period, 394 609 (97.2%) were eligible (11 539 excluded). A total of 233 159 (59.1%) were matched with unvaccinated controls. Mean follow was 43 ± 15.14 days. In vaccinated and unvaccinated individuals there were 23 versus 24 cases of Bell's palsy (RR 0.96, CI 0.54-1.70), one versus zero cases of GBS, 151 versus 141 cases of herpes zoster (RR 1.07, CI 0.85-1.35) and 605 versus 497 cases of numbness or tingling (RR 1.22, CI 1.08-1.37), respectively. DISCUSSION: No association was found between vaccination, Bell's palsy, herpes zoster or GBS. Symptoms of numbness or tingling were more common among vaccinees. This study adds reassuring data regarding the safety of the BNT162b2 vaccine.

Characteristics and recognition of early infections in patients treated with commercial anti-CD19 CAR-T cells.

The characteristics of infections following chimeric antigen receptor T (CAR-T) cells targeting CD19 in real-word population are obscure. We analyzed infections' characteristics in the first month among consecutive patients with diffuse large B-cell lymphoma (DLBCL) (n = 60, median age, 69.3 years), treated with commercial CAR-T cells. ECOG performance status (PS) was 2-3 in most patients (58%). Infections were observed in 45% of patients (16, 27%, bacterial infections, and 14, 23%, viral infections). Bacterial infection included clinically documented infection in 7 (Pneumonia, n = 5; periodontal infection, n = 1; and cellulitis, n = 1) and microbiology documented infection (MDI) in 9 patients (Gram-negative rod, n = 5; Gram-positive cocci, n = 3, bacteremia; polymicrobial, n = 1). The most common viral infection was cytomegalovirus (CMV) reactivation (n = 10, 17%) leading to initiation of anti-CMV treatment in 6 (60%) among these patients. None had CMV disease. In univariate analysis, immune effector cell-associated neurotoxicity syndrome (ICANS) was associated with higher incidence of bacterial infection (OR=4.5, P = .018), while there was a trend for lower incidence of bacterial infections in patients with chemosensitive disease to bridging therapy (OR=0.375, P = .074). Age or PS was not associated with increased risk of bacterial infection. Increase in C-reactive protein (CRP) prior to fever onset was associated with microbiologically documented infections. We conclude that infections are common in the first month following CAR-T-cell administration, however, were not increased in elderly patients or those presenting with poorer PS. Increase in CRP prior to fever onset could support infection over cytokine release syndrome.

Safety and Immunogenicity of the BNT162b2 mRNA COVID-19 Vaccine in Patients after Allogeneic HCT or CD19-based CART therapy-A Single-Center Prospective Cohort Study.

Data are scarce regarding both the safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients undergoing immune cell therapy; thus, we prospectively evaluated these two domains in patients receiving this vaccine after allogeneic hematopoietic cell transplantation (HCT; n = 66) or after CD19-based chimeric antigen receptor T cell (CART) therapy (n = 14). Overall, the vaccine was well tolerated, with mild non-hematologic vaccine-reported adverse events in a minority of the patients. Twelve percent of the patients after the first dose and 10% of the patients after the second dose developed cytopenia, and there were three cases of graft-versus-host disease exacerbation after each dose. A single case of impending graft rejection was summarized as possibly related. Evaluation of immunogenicity showed that 57% of patients after CART infusion and 75% patients after allogeneic HCT had evidence of humoral and/or cellular response to the vaccine. The Cox regression model indicated that longer time from infusion of cells, female sex, and higher CD19+ cells were associated with a positive humoral response, whereas a higher CD4+/CD8+ ratio was correlated with a positive cellular response, as confirmed by the ELISpot test. We conclude that the BNT162b2 mRNA COVID-19 vaccine has impressive immunogenicity in patients after allogeneic HCT or CART. Adverse events were mostly mild and transient, but some significant hematologic events were observed; hence, patients should be closely monitored.

BNT162b2 Vaccine Effectiveness in Preventing Asymptomatic Infection With SARS-CoV-2 Virus: A Nationwide Historical Cohort Study.

BACKGROUND: There is strong evidence regarding the efficacy and effectiveness of the BNT162b2 vaccine in preventing symptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There is a relative paucity of data regarding its effectiveness in the prevention of asymptomatic infection. METHODS: In this real-world observational study, we identified a subpopulation of individuals in a large health maintenance organization who were repeatedly tested for SARS-CoV-2 infection by polymerase chain reaction (PCR). We included these individuals in the study cohort and compared those who were vaccinated with BNT162b2 mRNA vaccine to unvaccinated individuals. A positive SARS-CoV-2 PCR test result was used as the outcome. The follow-up period was from January 1, 2021, until February 11, 2021. RESULTS: A total of 6286 individuals were included in the cohort. Seven days after the second vaccine dose, a rate of 6 positive PCR tests per 10 000 person-days was recorded, compared with a rate of 53 positive tests per 10 000 person-days for the unvaccinated group. The estimated vaccine effectiveness against infection with SARS-CoV-2 virus after 2 vaccine doses was 89% (95% CI, 82%-94%). The estimated effectiveness 2 weeks after the first vaccine dose was 61% (95% CI, 49%-71%). CONCLUSIONS: In this study, vaccination with BNT162b2 reduced infection rates among individuals who underwent screening by frequent SARS-CoV-2 PCR testing. Using a cohort of frequently tested individuals reduced the indication bias for the PCR testing, which enabled estimation of infection rates.

Single Dose of Doxycycline for the Prevention of Tick-borne Relapsing Fever.

The current postexposure prophylaxis regimen for tick-borne relapsing fever (TBRF) consists of 5 days' doxycycline. In this observational study of 77 spelunkers at high risk for TBRF, a single dose of 100 mg doxycycline taken up to 72 hours after exposure to ticks was 100% effective in preventing the disease.

Delayed diagnosis of colorectal sexually transmitted diseases due to their resemblance to inflammatory bowel diseases.

OBJECTIVE: Sexually transmitted diseases (STDs), mainly lymphogranuloma venereum (LGV), induce colorectal symptoms that may be misdiagnosed as inflammatory bowel disease (IBD). This study describes patients who presented with STDs masquerading as IBD in order to improve understanding of missed diagnosis of colorectal STDs and their association with LGV in Israel. METHODS: This retrospective, descriptive study characterized the clinical, endoscopic, and pathological findings of 16 patients who were diagnosed with a colorectal STD after erroneously being diagnosed with IBD. Molecular genotyping was used to characterize some of the Chlamydia trachomatis isolates. RESULTS: All patients were men who have sex with men (MSM), mostly HIV-1-positive, and had clinical and endoscopic findings compatible with IBD. The STD was diagnosed 1-36 months after the initial diagnosis: 14 were positive for Chlamydia trachomatis, of which three were of the LGV2b (ST58) serotype and one was ST 108 serotype. Five were positive for gonorrhea and four were positive for syphilis. Several pathogens were diagnosed in six episodes. CONCLUSIONS: Colorectal STDs may resemble IBD and therefore their diagnosis may be delayed. IBD symptoms in MSM who engage in non-protected anal sex should prompt at least syphilis and anal PCR for STD testing. If C. trachomatis is diagnosed but LGV subtyping cannot be done, doxycycline 100mg twice daily for 21days should be recommended.

Elite controller CD8+ T cells exhibit comparable viral inhibition capacity, but better sustained effector properties compared to chronic progressors.

Mechanisms modulating HIV-specific CD8+ T cell-mediated viral inhibition are not well defined. To delineate features of effective control, we compared the ability of CD8+ T cells from HIV ECs and CPs to inhibit HIV ex vivo. ECs showed superior inhibition compared to HAART-treated or untreated CPs in a typical VIA in which CD8+ T cells are rested 3 d before use (P = 0.025). In contrast, comparable antiviral activity was observed in freshly thawed cells. Rested CD8+ T cells underwent apoptosis with preferential loss of HIV-specific cells. EC CD8+ T cells showed greater capacity to sustain polyfunctionality ex vivo compared with those of CPs, and incubation of CD8+ T cells with IL-15 augmented inhibition. These results indicate that superior ex vivo inhibition of viral replication by CD8+ T cells from ECs is associated with enhanced retention of functional qualities and that in vitro antiviral function is enhanced by IL-15.

Fluoroquinolones or macrolides alone versus combined with ß-lactams for adults with community-acquired pneumonia: Systematic review and meta-analysis.

Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality. This review compared two of the main treatment alternatives: quinolone or macrolide monotherapy versus their combination with ß-lactams. A systematic review and meta-analysis of randomised controlled trials (RCTs) including adult inpatients and outpatients with CAP that compared treatment with any respiratory fluoroquinolone or macrolide administered as single agent with combination therapy of a ß-lactam plus either a fluoroquinolone or a macrolide (four separate comparisons) were conducted. The primary outcome was all-cause 30-day mortality. Secondary outcomes included clinical and microbiological failure, treatment discontinuation and adverse events. A comprehensive search was conducted with no date, language or publication status restrictions. Pooled risk ratios (RRs) with 95% confidence intervals are reported. Sixteen RCTs randomising 4809 patients were included. All but one included hospitalised patients. Mortality was low, and no differences between groups were observed in all comparisons. Quinolone monotherapy resulted in significantly less clinical failures [RR=0.72 (0.57-0.91)], treatment discontinuations [RR=0.65 (0.54-0.78)] and diarrhoea [RR=0.13 (0.05-0.34)] compared with ß-lactam/macrolide combinations (nine trials). Addition of a ß-lactam to quinolones did not improve outcomes (three trials). In all comparisons, treatment discontinuation and diarrhoea were more frequent in patients receiving combination therapy with a ß-lactam. Overall, there is no evidence for a benefit of ß-lactam/macrolide or ß-lactam/quinolone combination therapies over monotherapy with a respiratory fluoroquinolone. The ecological implications of selecting fluoroquinolone or ß-lactam monotherapy as the preferred regimen for hospitalised CAP among adults should be further investigated.

ß-glycosphingolipids ameliorated non-alcoholic steatohepatitis in the Psammomys obesus model.

Liver steatosis is a common characteristic of obesity and type 2 diabetes, and fatty liver disease is increasingly recognized as a major health burden. Accumulating evidence suggests that ß-glycosphingolipids play an important role in insulin sensitivity and thus could affect hepatic steatosis. To determine the effect associated with ß-glycosphingolipid-mediated amelioration of liver injury, seven groups of Psammomys obesus on a high-energy diet were studied. Animals were treated with daily injections of ß-glucosylceramide, ß-lactosylceramide, or a combination of both. ß-glycosphingolipids ameliorated the hepatic injury manifested by decreased liver enzymes, liver weight, and hepatic fat, and improved liver histology. Administration of both ß-glucosylceramide and ß-lactosylceramide also decreased interferon (IFN)-γ serum levels. These effects were associated with improved serum cholesterol and triglyceride levels. These data suggest that ß-glycosphingolipids ameliorate liver injury in an animal model of nonalcoholic steatohepatitis.