A Randomized Controlled Study Assessing Convalescent Immunoglobulins versus Convalescent Plasma for Hospitalized COVID-19 Patients.

BACKGROUND: It is unknown whether convalescent immunoglobulins (cIgG) are better than convalescent plasma (CP) for COVID-19 patients. METHODS: In this randomized trial we assigned high risk COVID-19 with ≤10 days of symptoms, to receive cIgG or CP. The primary endpoint was improvement on day 14 according to the WHO scale. Secondary endpoints were survival on day 14, and improvement, survival, and percent of ventilated patients on day 28 and treatment response in unvaccinated and vaccinated patients. RESULTS: 319 patients were included; 166 received cIgG, and 153 CP. Median age was 64-66 years. 112 patients (67.5%) in the cIgG and 103 patients (67.3%) in the CP group reached the primary endpoint. Difference between groups was 0.1 (95%CI -10.1-10.4, p=0.026), failing to reach non-inferiority. More patients receiving cIgG improved by day 28 [136 patients (81.9%) and 108 patients (70.6%), respectively, 95% CI 1.9-20.7, p<0.001, for superiority p=0.018)]. 17 patients in the cIgG group (10.2%) and 25 patients (16.3%) in the CP group required mechanical ventilation (p=0.136). 16 (9.6%) and 23 (15%) patients respectively died (p=0.172). More unvaccinated patients improved by day 28 in the cIgG group (84.1% vs. 66.1%, p<0.024) and survival was better in the cIgG group (89.9% vs. 77.4% p=0.066). CONCLUSIONS: cIgG failed to reach the primary non-inferiority endpoint on day 14 but was superior to CP on day 28. Survival and improvement by day 28 in unvaccinated patients treated with cIgG were better. In the face of new variants, cIgG is a viable option for treating COVID-19. TRIAL REGISTRATION NUMBER: My Trials MOH_2021-01-14_009667.

Hospitalized patients with severe COVID-19 during the Omicron wave in Israel - benefits of a fourth vaccine dose.

BACKGROUND: Waning vaccine-immunity and an increased incidence of COVID-19 during the Omicron outbreak led the Israeli Ministry of Health to recommend a fourth dose of BNT162b2 for high-risk individuals. This study assessed the effect of that dose for hospitalized patients with severe/critical, breakthrough COVID-19. METHODS: In this multi-center retrospective cohort study of hospitalized adults with severe/critical COVID-19 in Israel, from 01/15/2022-01/31/2022, cases were divided according to the number of vaccinations received. Poor outcome was defined as mechanical ventilation or in-hospital death, and was compared between 3- and 4-dose vaccinees using logistic regression. RESULTS: Included were 1,049 patients, median age 80 years (IQR 69-87), 51% males. Among them, 394 were unvaccinated, 386 had received 3 doses and 88 4 doses. The 3-dose group was older, had more males and immunosuppression, but with similar outcomes, 49% vs. 51% compared to unvaccinated patients (p = 0.72). Patients after 4 doses were similarly older and immunosuppressed, but had better outcomes compared to unvaccinated patients, 34% vs. 51% (p < 0.01). We examined independent predictors for poor outcome in patients with either 3 or 4 doses, received a median of 161 (IQR 147-168) or 14 (IQR 10-18) days before diagnosis, respectively. Receipt of the fourth dose was associated with protection: OR 0.51 (95%CI 0.3-0.87), as was Remdesivir OR 0.65 (95%CI 0.44-0.96). Male sex, chronic renal failure and dementia were associated with poor outcomes. CONCLUSIONS: Among hospitalized patients with severe/critical breakthrough COVID-19, a recent fourth dose was associated with significant protection against mechanical ventilation or death, compared to three doses.

Invasive Fungal Diseases in Hospitalized Patients with COVID-19 in Israel: A Multicenter Cohort Study.

Highly variable estimates of COVID-19-associated fungal diseases (IFDs) have been reported. We aimed to determine the incidence of clinically important fungal diseases in hospitalized COVID-19 patients during the first year of the pandemic. We performed a multicenter survey of IFDs among patients hospitalized with COVID-19 in 13 hospitals in Israel between February 2020 and May 2021. COVID-19-associated pulmonary mold disease (PMD) and invasive candidiasis (IC) were defined using ECMM/ISHAM and EORTC/MSG criteria, respectively. Overall rates of IC and PMD among patients with critical COVID-19 were 10.86 and 10.20 per 1000 admissions, respectively, with significant variability among medical centers. PMD rates were significantly lower in centers where galactomannan was a send-out test versus centers with on-site testing (p = 0.035). The 30-day mortality rate was 67.5% for IC and 57.5% for PMD. Treatment with an echinocandin for IC or an extended-spectrum azole for PMD was associated with significantly lower mortality rates (adjusted hazard ratio [95% confidence interval], 0.26 [0.07-0.91] and 0.23 [0.093-0.57], respectively). In this multicenter national survey, variable rates of PMD were associated with on-site galactomannan testing, suggesting under-detection in sites lacking this capacity. COVID-19-related IFDs were associated with high mortality rates, which were reduced with appropriate antifungal therapy.

Hospitalised patients with breakthrough COVID-19 following vaccination during two distinct waves in Israel, January to August 2021: a multicentre comparative cohort study.

BackgroundChanging patterns of vaccine breakthrough can clarify vaccine effectiveness.AimTo compare breakthrough infections during a SARS-CoV-2 Delta wave vs unvaccinated inpatients, and an earlier Alpha wave.MethodsIn an observational multicentre cohort study in Israel, hospitalised COVID-19 patients were divided into three cohorts: breakthrough infections in Comirnaty-vaccinated patients (VD; Jun-Aug 2021) and unvaccinated cases during the Delta wave (ND) and breakthrough infections during an earlier Alpha wave (VA; Jan-Apr 2021). Primary outcome was death or ventilation.ResultsWe included 343 VD, 162 ND and 172 VA patients. VD were more likely older (OR: 1.06; 95% CI: 1.05-1.08), men (OR: 1.6; 95% CI: 1.0-2.5) and immunosuppressed (OR: 2.5; 95% CI: 1.1-5.5) vs ND. Median time between second vaccine dose and admission was 179 days (IQR: 166-187) in VD vs 41 days (IQR: 28-57.5) in VA. VD patients were less likely to be men (OR: 0.6; 95% CI: 0.4-0.9), immunosuppressed (OR: 0.3; 95% CI: 0.2-0.5) or have congestive heart failure (OR: 0.6; 95% CI: 0.3-0.9) vs VA. The outcome was similar between all cohorts and affected by age and immunosuppression and not by vaccination, variant or time from vaccination.ConclusionsVaccination was protective during the Delta variant wave, as suggested by older age and greater immunosuppression in vaccinated breakthrough vs unvaccinated inpatients. Nevertheless, compared with an earlier post-vaccination period, breakthrough infections 6 months post-vaccination occurred in healthier patients. Thus, waning immunity increased vulnerability during the Delta wave, which suggests boosters as a countermeasure.

Critical Stepwise Decline of Antibodies against SARS-CoV-2 among Chronic Hemodialysis Patients 180 Days Post Comirnaty Vaccine.

BACKGROUND: The reduced immune response of maintenance hemodialysis patients to coronavirus disease 2019 (COVID-19) vaccines is a major concern. OBJECTIVES: To analyze the late (6 months after full vaccination) antibody response and compare it to early post-vaccination titer. METHODS: We conducted a multicenter prospective study of 13 hemodialysis units in Israel. RESULTS: We demonstrated that the low titers observed among ESRD patients 2-3 months after vaccination with the Comirnaty vaccine (median 63.8 AU/ml) declined to critically lower values 6 months after full vaccination. (Mediananti S antibodies, 31 AU/ml). Seropositivity significantly declined among hemodialysis patients from 89% to 74% (P < 0.0001), although it did not significantly change among controls. CONCLUSIONS: We recommend all patients on hemodialysis receive a booster COVID-19 vaccine 6 months after the second dose.

Diminished and waning immunity to COVID-19 vaccination among hemodialysis patients in Israel: the case for a third vaccine dose.

BACKGROUND: Humoral responses to coronavirus disease 2019 (COVID-19) vaccines in hemodialysis (HD) patients can direct vaccination policy. METHODS: We compared 409 COVID-19-naïve HD patients from 13 HD units in Israel to 148 non-dialysis-dependent COVID-19-naïve controls. Twenty-four previously infected (antinucleocapsid positive) HD patients were analysed separately. Blood samples were obtained ≥14 days post-vaccination (BNT162b2, Pfizer/BioNTech) to assess seroconversion rates and titers of anti-spike (anti-S) and neutralizing antibodies. RESULTS: The median time from vaccination to blood sample collection was 82 days [interquartile range (IAR) 64-87] and 89 days (IQR 68-96) for HD patients and controls, respectively. Seroconversion rates were lower in HD patients compared with controls for both anti-S and neutralizing antibodies (89% and 77% versus 99.3%, respectively; P < 0.0001). Antibody titers were also significantly lower in HD patients compared with controls {median 69.6 [IQR 33.2-120] versus 196.5 [IQR 118.5-246], P < 0.0001; geometric mean titer [GMT] 23.3 [95% confidence interval (CI) 18.7-29.1] versus 222.7 [95% CI 174-284], P < 0.0001, for anti-S and neutralizing antibodies, respectively}. Multivariate analysis demonstrated dialysis dependence to be strongly associated with lower antibody responses and antibody titers waning with time. Age, low serum albumin and low lymphocyte count were also associated with lower seroconversion rates and antibody titers. HD patients previously infected with sudden acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had no difference in their seroconversion rates or antibody titers compared with COVID-19-naïve patients. CONCLUSION: This study demonstrates diminished and waning humoral responses following COVID-19 vaccination in a large and diverse cohort of HD patients, including those previously infected with SARS-CoV-2. Considering these results and reduced vaccine effectiveness against variants of concern, in addition to continued social distancing precautions, a third booster dose should be considered in this population.

How compassionate use enabled Israel to deliver the Pfizer-BioNTech COVID-19 vaccination to vulnerable children aged 12-15 years before regulatory approval.

AIM: This paper describes the emergency, compassionate use of the COVID-19 vaccination for high-risk adolescents aged 12-15 years prior to approval by the American Food and Drugs Administration in May 2021. The target audience had underlying health conditions associated with severe disease and multisystem inflammatory syndrome in children (MIS-C) or severely immunosuppressed household members. METHODS: An orderly approval system was established in Israel for adolescents aged 12-15 years, based on a professional position paper and compassionate treatment regulations. From 12 February 2021, eligible adolescents were referred to the Israeli Ministry of Health for permission to vaccinate, via four health maintenance organisations. Data were collected about adverse events after vaccinations and the incidence of any cases of COVID-19. RESULTS: By 15 March 2021, the vaccine had been approved for 607 adolescents: 333 had received one dose, and 92 had received two doses. The median age was 14.6 years, and the major indication was obesity. Only one child tested positive for the virus, 4 days after vaccination, and no adverse effects were recorded. CONCLUSION: The emergency use of COVID-19 vaccination for 333 adolescents aged 12-15, 92 of them with 2 doses, based on a position paper and compassionate treatment regulations, did not result in any adverse effects. Since 27 July 2021, the same process was further applied in Israel among younger children, aged 5-11, preceding formal release of the clinical trial.

Oropharyngeal shedding of herpesviruses before and after BNT162b2 mRNA vaccination against COVID-19.

INTRODUCTION: Concerns were raised over an increase in Bell's palsy, herpes simplex and herpes zoster after BNT162b2 vaccination, all are manifestations of herpesviruses reactivation. As herpesviruses commonly reactivate in the oropharynx, we have hypothesized that oropharyngeal shedding of herpesviruses will increase after vaccination. METHODS: Immune-competent Adults, excluding those using topical steroids or manifesting symptomatic herpesvirus infection, were sampled before BNT162b2 vaccination and one week after. Herpesviruses 1-7 shedding was tested with a multiplexed PCR. RESULTS: In 103 paired samples the prevalence of herpesviruses was similar before and after vaccination: HSV1, 3.9% vs. 5.8% (p = 0.75); HSV2, 0% vs. 1% (p = not applicable, NA); VZV, 0% vs. 0% (p = NA); EBV, 14.6% vs. 17.5% (p = 0.63); CMV, 0% vs. 0% (p = NA); HHV6, 4.9% vs. 7.8% (p = 0.55); HHV7, 71.8% vs. 72.8% (p = 1); any herpesvirus, 73.8% vs. 74.8% (p = 1). DISCUSSION: We did not find evidence for increased oropharyngeal reactivation of herpesviruses one week after BNT162b2.

Delayed respiratory syncytial virus epidemic in children after relaxation of COVID-19 physical distancing measures, Ashdod, Israel, 2021.

Following low incidence of respiratory syncytial virus (RSV) infections in 2020 during the COVID-19 pandemic, we noted a resurgence in hospitalised children in spring/summer 2021 following relaxation of public health measures. We compared this outbreak to previous autumn/winter seasons. We found higher weekly case numbers and incidence rates, more cases from urban neighbourhoods with lower socioeconomic status, and similar clinical presentation and severity. Public health implications include the re-evaluation of palivizumab administration and the need for surge capacity planning.

BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully vaccinated hospitalized COVID-19 patients in Israel.

OBJECTIVES: The mRNA coronavirus disease 2019 (COVID-19) vaccines have shown high effectiveness in the prevention of symptomatic COVID-19, hospitalization, severe disease and death. Nevertheless, a minority of vaccinated individuals might become infected and experience significant morbidity. Characteristics of vaccine breakthrough infections have not been studied. We sought to portray the population of Israeli patients, who were hospitalized with COVID-19 despite full vaccination. METHODS: A retrospective multicentre cohort study of 17 hospitals included patients fully vaccinated with Pfizer/BioNTech's BNT162b2 vaccine who developed COVID-19 more than 7 days after the second vaccine dose and required hospitalization. The risk for poor outcome, defined as a composite of mechanical ventilation or death, was assessed. RESULTS: A total of 152 patients were included, accounting for half of hospitalized fully vaccinated patients in Israel. Poor outcome was noted in 38 patients and mortality rate reached 22% (34/152). Notably, the cohort was characterized by a high rate of co-morbidities predisposing to severe COVID-19, including hypertension (108; 71%), diabetes (73; 48%), congestive heart failure (41; 27%), chronic kidney and lung diseases (37; 24% each), dementia (29; 19%) and cancer (36; 24%), and only six (4%) had no co-morbidities. Sixty (40%) of the patients were immunocompromised. Higher viral load was associated with a significant risk for poor outcome. Risk also appeared higher in patients receiving anti-CD20 treatment and in patients with low titres of anti-Spike IgG, but these differences did not reach statistical significance. CONCLUSIONS: We found that severe COVID-19 infection, associated with a high mortality rate, might develop in a minority of fully vaccinated individuals with multiple co-morbidities. Our patients had a higher rate of co-morbidities and immunosuppression compared with previously reported non-vaccinated hospitalized individuals with COVID-19. Further characterization of this vulnerable population may help to develop guidance to augment their protection, either by continued social distancing, or by additional active or passive vaccinations.

Purpurona: A Novel Report of COVID-19-Related Henoch-Schonlein Purpura in a Child.

The coronavirus disease 2019 global pandemic is reshaping our understanding of medicine, including the diagnostic approach to common medical presentations. We describe a novel case of a 3-year-old male with a clinical diagnosis of Henoch-Schonlein Purpura vasculitis with concurrent SARS-CoV-2 infection. This case highlights a potentially newly described presentation of coronavirus disease 2019 infection.

Detection and infectivity potential of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) environmental contamination in isolation units and quarantine facilities.

OBJECTIVES: Environmental surfaces have been suggested as likely contributors in the transmission of COVID-19. This study assessed the infectivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contaminating surfaces and objects in two hospital isolation units and a quarantine hotel. METHODS: SARS-CoV-2 virus stability and infectivity on non-porous surfaces was tested under controlled laboratory conditions. Surface and air sampling were conducted at two COVID-19 isolation units and in a quarantine hotel. Viral RNA was detected by RT-PCR and infectivity was assessed by VERO E6 CPE test. RESULTS: In laboratory-controlled conditions, SARS-CoV-2 gradually lost its infectivity completely by day 4 at ambient temperature, and the decay rate of viral viability on surfaces directly correlated with increase in temperature. Viral RNA was detected in 29/55 surface samples (52.7%) and 16/42 surface samples (38%) from the surroundings of symptomatic COVID-19 patients in isolation units of two hospitals and in a quarantine hotel for asymptomatic and very mild COVID-19 patients. None of the surface and air samples from the three sites (0/97) were found to contain infectious titres of SARS-Cov-2 on tissue culture assay. CONCLUSIONS: Despite prolonged viability of SARS-CoV-2 under laboratory-controlled conditions, uncultivable viral contamination of inanimate surfaces might suggest low feasibility for indirect fomite transmission.

Compassionate use of convalescent plasma for treatment of moderate and severe pneumonia in COVID-19 patients and association with IgG antibody levels in donated plasma.

BACKGROUND: We assessed outcome of patients with moderate and severe COVID-19 following treatment with convalescent plasma (CP) and the association with IgG levels in transfused CP. METHODS: A prospective cohort study. Primary outcome was improvement at day 14 defined as alive, not on mechanical ventilation, and moderate, mild, or recovered from COVID-19. Antibody levels in CP units were unknown at the time of treatment. IgG against the spike protein S1 was subsequently measured by ELISA. Neutralizing antibodies titers were determined in a subset. Outcome was assessed in relation to the mean antibody level transfused to the patients (≤4.0 versus >4.0). FINDINGS: Of 49 patients, 11 (22.4%) had moderate, 38 (77.6%) had severe disease, 28 were ventilated. At day 14, 24 (49.0%) patients improved, 9 (18.4%) died, and 13 (26.5%) were ventilated. In 14/98 (14.3%) CP units IgG was < 1.1 (cutoff calibration) and in 60 (61.2%) ≤4.0. IgG level and neutralizing antibody titer were correlated (0.85 p < 0.001). In patients receiving ≤4.0 antibody levels, 11/30 improved (36.7%) versus 13/19 (68.4%) in patients receiving >4.0 odds ratio (OR) 0.267 [95% confidence interval (CI) 0.079-0.905], P = 0.030. In patients diagnosed >10 days prior to treatment, 4/14 (22.4%) improved in the ≤4.0 antibody group, versus 6/7 (85.7%) in the >4.0 antibody group, OR 0.048 (95% CI, 0.004-0.520), P = 0.007. No serious adverse events were reported. INTERPRETATION: Treatment with CP with higher levels of IgG against S1 may benefit patients with moderate and severe COVID-19. IgG against S1 level in CP predicts neutralization antibodies titers.