An international multicenter study comparing COVID-19 omicron outcomes in patients with hematological malignancies treated with obinutuzumab versus rituximab.

OBJECTIVES: Hematological malignancy (HM) patients treated with anti-CD20 monoclonal antibodies are at higher risk for severe COVID-19. A previous single-center study showed worse outcomes in patients treated with obinutuzumab compared to rituximab. We examined this hypothesis in a large international multicenter cohort. METHODS: We included HM patients from 15 centers, from five countries treated with anti-CD20, comparing those treated with obinutuzumab (O-G) to rituximab (R-G) between December 2021 and June 2022, when Omicron lineage was dominant. RESULTS: We collected data on 1048 patients. Within the R-G (n = 762, 73%), 191 (25%) contracted COVID-19 compared to 103 (36%) in the O-G. COVID-19 patients in the O-G were younger (61 ± 11.7 vs. 64 ± 14.5, p = 0.039), had more indolent HM diagnosis (aggressive lymphoma: 3.9% vs. 67.0%, p < 0.001), and most were on maintenance therapy at COVID-19 diagnosis (63.0% vs. 16.8%, p < 0.001). Severe-critical COVID-19 occurred in 31.1% of patients in the O-G and 22.5% in the R-G. In multivariable analysis, O-G had a 2.08-fold increased risk for severe-critical COVID-19 compared to R-G (95% CI 1.13-3.84), adjusted for Charlson comorbidity index, sex, and tixagevimab/cilgavimab (T-C) prophylaxis. Further analysis comparing O-G to R-G demonstrated increased hospitalizations (51.5% vs. 35.6% p = 0.008), ICU admissions (12.6% vs. 5.8%, p = 0.042), but the nonsignificant difference in COVID-19-related mortality (n = 10, 9.7% vs. n = 12, 6.3%, p = 0.293). CONCLUSIONS: Despite younger age and a more indolent HM diagnosis, patients receiving obinutuzumab had more severe COVID-19 outcomes than those receiving rituximab. Our findings underscore the need to evaluate the risk-benefit balance when considering obinutuzumab therapy for HM patients during respiratory viral outbreaks.

The development and validation of screening tools for semi-automated surveillance of surgical site infection following various surgeries.

Background: Surveillance of surgical site infections (SSIs) is essential for better prevention. We developed a screening method for SSIs in adults. Methods: The training dataset included data from patients who underwent orthopedic surgeries (N = 1,090), colorectal surgeries (N = 817), and abdominal hysterectomies (N = 523) during 2015-2018. The gold standard for the validation of the screening tool was the presence of SSI as determined by a trained infection control practitioner, via manual full medical record review, using the US Center for Disease Control and Prevention criteria. Using multivariable regression models, we identified the correlates of SSI. Patients who had at least one of these correlates were classified as likely to having SSI and those who did not have any of the correlates were classified as unlikely to have SSI. We calculated the sensitivity and specificity of this tool compared to the gold standard and applied the tool to a validation dataset (N = 1,310, years 2019-2020). Results: SSI was diagnosed by an infection control specialist in 8.2, 5.2, and 31.2% of the patients in the training dataset who underwent hysterectomies, orthopedic surgeries and colorectal surgeries, respectively, vs. 6.2, 6.6, and 25.5%, respectively, in the validation dataset. The correlates of SSI after abdominal hysterectomy were prolonged hospitalization, ordering wound or blood culture, emergency room visit and reoperation; in orthopedic surgery, emergency room visit, wound culture, reoperation, and documentation of SSI, and in colorectal surgeries prolonged hospitalization, readmission, and ordering wound or blood cultures. Area under the curve was >90%. The sensitivity and specificity (95% CI) of the screening tool were 98% (88-100) and 58% (53-62), for abdominal hysterectomy, 91% (81-96) and 82% (80-84) in orthopedic surgeries and 96% (90-98) and 62% (58-66) in colorectal surgeries. The corresponding values for the validation dataset were 89% (67-97) and 75% (69-80) in abdominal hysterectomy; 85% (72-93) and 83% (80-86) in orthopedic surgeries and 98% (93-99) and 59% (53-64) in colorectal surgeries. The number of files needed to be fully reviewed declined by 61-66. Conclusion: The presented semi-automated simple screening tool for SSI surveillance had good sensitivity and specificity and it has great potential of reducing workload and improving SSI surveillance.

Risk factors for surgical site infections following open versus laparoscopic colectomies: a cohort study.

BACKGROUND: Surgical site infections (SSIs) are among the most common healthcare-associated infections. Evaluating risk factors for SSIs among patients undergoing laparoscopic and open colorectal resections can aid in selecting appropriate candidates for each modality. METHODS: A cohort of all consecutive patients undergoing elective colorectal resections during 2008-2017 in a single center was analyzed. SSIs were prospectively assessed by infection control personnel. Patient data were collected from electronic medical records. Risk factors for SSIs were compared between patients who underwent laparoscopic and open surgeries. A multivariate analysis was performed for significant variables. RESULTS: During the study period, 865 patients underwent elective colorectal resection: 596 laparoscopic and 269 open surgeries. Mean age was 68.2 ± 15.1 years, weight 72.5 ± 18.3 kg and 441 (51%) were men. The most common indication for surgery was malignancy, in 767 patients (88.7%) with inflammatory bowel diseases and diverticulitis following (4.5% and 3.9%, respectively). Patients undergoing laparoscopic surgery were younger, had fewer comorbidities, shorter pre-operative hospitalizations, lower risk index scores, and lower rates of SSI, compared with open surgery. Independent risk factors for SSI following laparoscopic surgery were chronic obstructive pulmonary disease [odds ratio (OR) 2.655 95% CI (1.267, 5.565)], risk index ≥ 2 [OR 2.079, 95% CI (1.041,4.153)] and conversion of laparoscopic to open surgery [OR 2.056 95%CI (1.212, 3.486)]. Independent risk factors for SSI following open surgery were immunosuppression [OR 3.378 95% CI (1.071, 10.655)], chronic kidney disease [OR 2.643 95% CI (1.008, 6.933)], and need for a second dose of prophylactic antibiotics [OR 2.519 95%CI (1.074, 5.905)]. CONCLUSIONS: Risk factors for SSIs differ between laparoscopic and open colorectal resections. Knowledge of specific risk factors may inform patient selection for these modalities.

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.

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.

Direct on-the-spot detection of SARS-CoV-2 in patients.

IMPACT STATEMENT: Humanity is currently experiencing a global pandemic with devastating implications on human health and the economy. Most countries are gradually exiting their lockdown state. We are currently lacking rapid and simple viral detections, especially methods that can be performed in the household. Here, we applied RT-LAMP directly on human clinical swabs and self-collected saliva samples. We adjusted the method to allow simple and rapid viral detection, with no RNA purification steps. By testing our method on over 180 human samples, we determined its sensitivity, and by applying it to other viruses, we determined its specificity. We believe this method has a promising potential to be applied world-wide as a simple and cheap surveillance test for SARS-CoV-2.

Economic evaluation of universal prenatal HIV screening compared with current 'at risk' policy in a very low prevalence country.

OBJECTIVES: Our objective was to economically evaluate universal HIV prenatal screening in Israel, a very low prevalence country (0.1%), compared with the current policy of testing only women belonging to high-risk (HR) groups. DESIGN: A cost-effectiveness analytical model was constructed. Life expectancies, direct medical costs and utility weights of an HIV-positive newborn and a healthy newborn were derived from the literature. Screening was assessed using fourth-generation combo tests. Structural uncertainties were discussed with leading Israeli HIV experts. Univariate and multivariate sensitivity analyses were conducted to account for uncertainty of the model's parameters. RESULTS: Under the current policy, about 2700 women are tested annually identifying 27 HIV-positive women. With the universal screening, 171 000 women would be tested yearly identifying 37 as HIV positive. The analysis included the increased life expectancy of vertically infected children based on current standards of care. Over the lifetime expectancy, universal screening is projected to grant 15 additional quality-adjusted life years and save $177 521 when compared with the current HR only policy. CONCLUSIONS: Universal prenatal HIV screening is projected to be cost saving in Israel, despite a very low HIV prevalence in the general population.

Evaluation of GS Junior and MiSeq next-generation sequencing technologies as an alternative to Trugene population sequencing in the clinical HIV laboratory.

Population HIV-1 sequencing is currently the method of choice for the identification and follow-up of HIV-1 antiretroviral drug resistance. It has limited sensitivity and results in a consensus sequence showing the most prevalent nucleotide per position. Moreover concomitant sequencing and interpretation of the results for several samples together is laborious and time consuming. In this study, the practical use of GS Junior and MiSeq bench-top next generation sequencing (NGS) platforms as an alternative to Trugene Sanger-based population sequencing in the clinical HIV laboratory was assessed. DeepChek(®)-HIV TherapyEdge software was used for processing all the protease and reverse transcriptase sequences and for resistance interpretation. Plasma samples from nine HIV-1 carriers, representing the major HIV-1 subtypes in Israel, were compared. The total number of amino acid substitutions identified in the nine samples by GS Junior (232 substitutions) and MiSeq (243 substitutions) was similar and higher than Trugene (181 substitutions), emphasizing the advantage of deep sequencing on population sequencing. More than 80% of the identified substitutions were identical between the GS Junior and MiSeq platforms, most of which (184 of 199) at similar frequency. Low abundance substitutions accounted for 20.9% of the MiSeq and 21.9% of the GS Junior output, the majority of which were not detected by Trugene. More drug resistance mutations were identified by both the NGS platforms, primarily, but not only, at low abundance. In conclusion, in combination with DeepChek, both GS Junior and MiSeq were found to be more sensitive than Trugene and adequate for HIV-1 resistance analysis in the clinical HIV laboratory.

[Metabolic bone disorders in HIV patients].

The life expectancy of HIV patients has increased dramatically since the introduction of combination antiretroviral therapy. This led to an increase in the incidence of non-AIDS related diseases, such as liver diseases, malignancies and metabolic disorders. Increased incidence of osteoporosis and bone fractures was found in HIV patients compared to the general population. The causes were multifactorial, combining traditional risk factors (such as age, sex, low weight, smoking, steroid treatment, vitamin D deficiency), with risk factors associated with the viral infection itself (increased bone loss and decreased bone formation), and to a lesser extent from the antiretroviral treatment itself. An association between bone density loss and antiviral drugs such as Tenofovir, and different protease inhibitors, was found in several studies, but no definite evidence of an increased risk of bone fractures was found. Current American guidelines recommend screening for low bone density only HIV patients who are over 50 years of age with a risk factor for osteoporosis. European guidelines recommend screening all HIV patients older than 50 years. HIV patients at risk for fractures should be treated according to local guidelines in the general population. Currently, no recommendations exist to change any specific antiretroviral therapy in case of osteoporosis, unless there are specific circumstances.

A nationwide surveillance of invasive pneumococcal disease in adults in Israel before an expected effect of PCV7.

Pneumococcal infections in adults vary in severity and incidence is affected by childhood vaccination policy. Here, we try to define the host determinants and the interaction with specific serotypes that result in invasive pneumococcal disease (IPD) before an expected effect of pneumococcal conjugate vaccines. A nationwide active surveillance was initiated on July 2009, at the time of national implementation of PCV7 in Israel. The surveillance included all 27 laboratories and medical centers performing blood cultures in Israel, providing all blood and CSF pneumococcal isolates from persons ≥18y. Capture-recapture method assured that >95% of all cases were reported. IPD outcome and medical history were recorded and isolates were serotyped. Four hundred and sixty IPD cases were reported (annual incidence [/100,000] of 9.25). Incidence increased with age, from 2.6 among 18-34y to 66.8 among ≥85y. The most common diagnosis was pneumonia (72.4%), followed by bacteremia with no apparent focus (20.2%). Case fatality rate increased with age and number of comorbidities (34.5% for ≥75y or those with ≥3 comorbidities vs. 9.2-11.2% among <65y or those with no comorbidities; p=0.015). Variables independently associated with mortality were: age ≥75, chronic renal failure, malignancy, neurosurgery, alcohol abuse, multi-lobar pneumonia and sepsis with no apparent focus. The predominant serotypes in patients 18-49y were 1, 5, 8, 7F and 9V (constituting 56.3% in this age-group vs. 11.9% in ≥75y; p<0.01). The predominant serotypes among patients ≥75y were 3, 19A, 23F and 14 (40.3% of this age-group vs. 12.9% of 18-49y; p<0.01). Overall, PCV7 and PCV13 covered 25.6% and 63.7% of isolates, respectively, and 30.9% and 67.9% of isolates in mortality cases respectively. This nationwide active surveillance provides the baseline incidence, mortality rates and risk group distributions of IPD in adults before expected PCV effect.

Men who have sex with men, risk behavior, and HIV infection: integrative analysis of clinical, epidemiological, and laboratory databases.

BACKGROUND: Centralized data collection and analytic tools facilitate tracing HIV transmission trends at the patient-population level with increasing resolution, complementing behavioral studies while avoiding sampling biases. By several measures, the rate of HIV infection among men who have sex with men (MSM) in Israel increased in the past several years more rapidly than was expected. We describe features of the data that connect this increase to behavioral changes. METHODS: We retrospectively analyzed data from the national HIV reference laboratory and the national HIV and sexually transmitted infections registries. We examined changes in selected epidemiologic and clinical parameters and in the pattern of drug-resistant virus transmission among MSM in Israel. In particular, virus isolates from 296 MSM (23.8% of all MSM who received a diagnosis) were genotyped, drug-resistance conferring mutations were characterized, and phylogenetic trees were constructed. RESULTS: Compared with earlier years, during 2007-2009 MSM were more often infected with drug-resistant virus before treatment initiation, were coinfected with syphilis, and received a diagnosis during acute retroviral syndrome. Phylogenetic analysis suggested frequent transmission of drug-resistant HIV by drug-treated individuals to >1 partner. Secondary transmission of resistant virus by drug-naive patients is also consistent with the phylogenetic patterns. In addition, non-B HIV subtypes began to appear among MSM. CONCLUSIONS: Together, our findings suggest that the sexual behavior of MSM, both HIV-infected and uninfected, has become riskier, contributing to the number of those seeking early clarification of status, to syphilis comorbidity, and to the spread of drug resistance. These findings call for action by public health planners and community-based organizations aimed at increasing awareness of the risks, bringing a change in attitude and establishing safe sex norms.

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.