Cohort Of Immunocompromised Patients Research Articles

Clinical characteristics and COVID-19-related outcomes of immunocompromised patients receiving tixagevimab/cilgavimab pre-exposure prophylaxis in Japan

ObjectiveTixagevimab/cilgavimab is a cocktail of two long-acting monoclonal antibodies approved for pre-exposure prophylaxis (PrEP) of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (cause of coronavirus disease 2019 [COVID-19]) in immunocompromised (IC) or high-risk patients. We investigated the patient characteristics and clinical outcomes of IC patients administered tixagevimab/cilgavimab for PrEP in real-world use in Japan. MethodsThis observational study used anonymous secondary data from Real-World Data Co., Ltd. for IC patients aged ≥12 years administered tixagevimab/cilgavimab between September 2022 and September 2023. We analyzed the baseline characteristics and event-rates of COVID-19-related clinical outcomes within 6 months of administration. ResultsData were analyzed for 397 IC patients. About half (53.4 %) were male and the median age was 71.0 (interquartile range 61.0, 77.0) years. Malignancy (97.2 %), cardiovascular disease (71.3 %), and diabetes (66.5 %) were frequent comorbidities. Systemic corticosteroids and immunosuppressants were prescribed to 87.4 % and 24.9 %, respectively. The two most common target clinical conditions were active therapy for hematologic malignancies (88.2 %) and treatment with B cell-depleting therapies (57.4 %). The event-rates per 100 person-months (95 % confidence interval; number) for medically attended COVID-19, COVID-19 hospitalization, in-hospital mortality due to COVID-19, and all-cause death were 4.14 (3.06–5.48; n = 49), 1.74 (1.09–2.64; n = 22), 0.07 (0.00–0.42; n = 1), and 0.60 (0.26–1.17; n = 8), respectively. ConclusionThis is the first report using a multicenter database to describe the clinical characteristics and COVID-19-related outcomes of IC patients administered with tixagevimab/cilgavimab in real-world settings in Japan. This cohort of IC patients who received tixagevimab/cilgavimab included many elderly patients with comorbidities.

Preclinical in vivo assessment of the activity of AZD7442 anti-SARS-CoV-2 monoclonal antibodies against Omicron sublineages

Therapeutic monoclonal antibodies have been successful in protecting vulnerable populations against SARS-CoV-2. However, their effectiveness has been hampered by the emergence of new variants. To adapt the therapeutic landscape, health authorities have based their recommendations mostly on in vitro neutralization tests. However, these do not provide a reliable understanding of the changes in the dose-effect relationship and how they may translate into clinical efficacy. Taking the example of EvusheldTM (AZD7442), we aimed to investigate how in vivo data can provide critical quantitative results and project clinical effectiveness. We used the Golden Syrian hamster model to estimate 90 % effective concentrations (EC90) of AZD7442 in vivo against SARS-CoV-2 Omicron BA.1, BA.2 and BA.5 variants. While our in vivo results confirmed the partial loss of AZD7442 activity for BA.1 and BA.2, they showed a much greater loss of efficacy against BA.5 than that obtained in vitro. We analyzed in vivo EC90s in perspective with antibody levels measured in a cohort of immunocompromised patients who received 300 mg of AZD7442. We found that a substantial proportion of patients had serum levels of anti-SARS-CoV-2 spike protein IgG above the estimated in vivo EC90 for BA.1 and BA.2 (21 % and 92 % after 1 month, respectively), but not for BA.5. These findings suggest that AZD7442 is likely to retain clinical efficacy against BA.2 and BA.1, but not against BA.5. Overall, the present study illustrates the importance of complementing in vitro investigations by preclinical studies in animal models to help predict the efficacy of monoclonal antibodies in humans.

501. Risk Factors for Persistent Active COVID-19 Among Patients Receiving B-Cell Depleting Therapy versus Non-B-Cell Immunosuppression

Abstract Background Cases of COVID-19 characterized by prolonged replication of SARS-CoV-2 (persistent active COVID [PAC]) have been reported among immunocompromised patients, particularly those receiving B-cell depleting therapy (BCDT); however, the risk has not been quantified. We aimed to identify risk factors associated with PAC, including quantifying the risk associated with receipt of BCDT vs. other types of immunosuppression. Methods We retrospectively identified four groups of immunocompromised patients who tested positive for SARS-CoV-2 between 4/01/2020 and 4/30/2021. These groups included one group of patients who received an anti-CD20 BCDT within 1 year before a positive SARS-CoV-2 PCR and three groups who received non-BCDT which included hematopoietic cell transplant (HCT) recipients, solid organ transplant (SOT) recipients, and patients receiving chemotherapy for hematologic malignancies (HM). Chart review was performed to characterize the clinical course and development of PAC, which was defined as any of the following: (1) initial clinical improvement followed by progression of illness extending beyond 14 days, characterized by persistent fevers or progressive respiratory failure; or (2) persistent symptoms with demonstration of absent seroconversion ≥ 14 days into illness. This distinction may be supported by low crossing thresholds that occurred ≥ 14 days into illness. Logistic models were performed to identify factors associated with development of PAC and other COVID outcomes. Results We identified 67 COVID-positive patients who had received BCDT as well as 30 HM, 118 SOT, and 29 HCT patients. PAC occurred in 15/67 (22%) of patients receiving BCDT vs. 3/177 (1.7%) patients (all SOT recipients) in the non-BCTD group (SOT, HCT, HM) (Odds Ratio, 16.7; 95% confidence interval [CI] 4.7 to 60.0; p=0.00005). 30-day hospitalization and 90-day mortality were similar in BCDT and non-BCDT groups (Table 1, Figure 1) (p > 0.05). Table 1. Risk factors for specific outcomes of COVID-19 Figure 1. Proportion of patients from each cohort of immunocompromised patients who developed persistent active COVID (1A), required hospitalization within 30 days (1B), required mechanical ventilation (1C), required ICU admission (1D), or died within 90 days after diagnosis of COVID-19 (1E) Conclusion Receipt of BCDTs was significantly associated with the development of PAC in comparison to other forms of severe immunosuppression. However, rates of severe outcomes associated with COVID-19 were similar across all groups. More research is necessary to determine effective prevention or treatment strategies for PAC. Disclosures All Authors: No reported disclosures

Reduced Immune Response to Inactivated Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine in a Cohort of Immunocompromised Patients in Chile.

BackgroundInactivated SARS-CoV-2 vaccines have been widely implemented in low- and middle-income countries. However, immunogenicity in immunocompromised patients has not been established. Herein, we aimed to evaluate immune response to CoronaVac vaccine in these patients.MethodsThis prospective cohort study included 193 participants with five different immunocompromising conditions and 67 controls, receiving two doses of CoronaVac 8-12 weeks before enrollment. The study was conducted between May and August 2021, at Red de Salud UC-CHRISTUS, Chile. Neutralizing antibodies (NAb) positivity, total anti-SARS-CoV-2 IgG antibodies (TAb) concentration, and T cell response were determined.ResultsNAb positivity and median neutralizing activity were 83.1% and 51.2% for the control group versus 20.6% (p<0.0001) and 5.7% (p<0.0001) in the solid organ transplant (SOT) group, 41.5% (p<0.0001) and 19.2% (p<0.0001) in the autoimmune rheumatic diseases group, 43.3% (p=0.0002) and 21.4% (p=0.0013) in the cancer patients with solid tumors group, 45.5% (p<0.0001) and 28.7% (p=0.0006) in the HIV infected group, 64.3% (p=n.s.) and 56.6% (p=n.s.) in the hematopoietic stem cell transplantation (HSCT) group, respectively. TAb seropositivity was also lower for the SOT (20.6%, p<0.0001), rheumatic diseases (61%, p=0.0001) and HIV groups (70.9%, p=0.0032), compared to control group (92.3%). On the other hand, the number of IFN-y Spot Forming T Cells specific for SARS-CoV-2 tended to be lower but did not differ significantly between groups.ConclusionsDiverse immunocompromising conditions markedly reduce the humoral response to CoronaVac vaccine. These findings suggest a boosting vaccination strategy should be considered in these vulnerable patients.

1024. Using DOOR-MAT to Theoretically Compare Three Rapid Diagnostic Tests for Gram-Negative Bloodstream Infections in Immunocompromised Patients

BackgroundMolecular rapid diagnostic tests (RDTs) for bloodstream infections (BSI) utilize a variety of technologies and differ substantially in organisms and resistance mechanisms detected. RDT platforms decrease time to optimal antibiotics; however, data on RDTs in special populations, such as immunocompromised are extremely limited. This study aimed to compare theoretical changes in antibiotics based on differences in panel identification of organisms and resistance targets among three commercially available RDT panels.MethodsRetrospective cohort of immunocompromised patients treated for gram-negative BSI at University of Maryland Medical Center from January 2018 to September 2020. Immunocompromised was defined as active hematologic or solid tumor malignancy at time of BSI diagnosis, history of hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT), or absolute neutrophil count (ANC) < 1000 cells/mm3 at any time 30 days prior to BSI diagnosis. Verigene BC-GN was performed as standard of care. GenMark ePlex BCID and BioFire FilmArray BCID 2 results were assigned based on respective identifiable organism panels. An infectious diseases clinician blinded to final antimicrobial susceptibility testing (AST) results used RDT results to assign antibiotic treatments for each platform. Decisions were referenced against a priori DOOR-MAT matrices. A partial credit scoring system (0 to 100) was applied to each decision based on final AST results. The mean and standard deviation (SD) were compared across panels using One-Way Repeated Measures ANOVA with modified Bonferroni for multiple comparisons.ResultsA total of 146 patients met inclusion. Baseline characteristics are summarized in Table 1. The mean (SD) DOOR-MAT scores for the three RDT panels were: 86.1 (24.4) Verigene BC-GN vs. 88.5 (22.2) GenMark BCID vs. 87.2 (24.4) BioFire BCID 2. There was no statistically significant difference between the panels for DOOR-MAT score (P=0.6). Table 1. Baseline Patient Characteristics and Organism Identification ConclusionWithin an immunocompromised patient population, differences in organism identification between three commercially available RDT panels did not impact theoretical antibiotic prescribing. Disclosures J. Kristie Johnson, PhD, D(ABMM), GenMark (Speaker’s Bureau) Kimberly C. Claeys, PharmD, GenMark (Speaker’s Bureau)

Albumin replacement therapy in immunocompromised patients with sepsis - Secondary analysis of the ALBIOS trial.

The best fluid replacement strategy and the role of albumin in immunocompromised patients with sepsis is unclear. We performed a secondary analysis of immunocompromised patients enrolled in the ALBIOS trial which randomized patients with severe sepsis or septic shock to receive either 20% albumin (target 30g per liter or more) and crystalloid or crystalloid alone during ICU stay. Of 1818 patients originally enrolled, 304 (16.4%) were immunocompromised. One-hundred-thirty-nine (45.7%) patients were randomized in the albumin while 165 (54.2%) in the crystalloid group. At 90days, 69 (49.6%) in the albumin group and 89 (53.9%) in the crystalloids group died (hazard ratio - HR - 0.94; 95% CI 0.69-1.29). No differences were observed with regards to 28-day mortality, SOFA score (and sub-scores), length of stay in the ICU and in the hospital, proportion of patients who had developed acute kidney injury or received renal replacement therapy, duration of mechanical ventilation. Albumin was not independently associated with a higher or lower 90-day mortality (HR 0.979, 95% CI 0.709-1.352) as compared to crystalloid. Albumin replacement during the ICU stay, as compared with crystalloids alone, did not affect clinical outcomes in a cohort of immunocompromised patients with sepsis.

Epidemiology of hepatitis E virus infection in a cohort of 4023 immunocompromised patients

ObjectivesThe prevalence of active, chronic, and former hepatitis E virus (HEV) infections was investigated in a cohort of immunocompromised patients. The association with transfusion transmitted HEV was evaluated, and the HEV seroprevalence was compared with that in healthy blood donors. Study design and methodsSerum samples from 4023 immunocompromised patients at Rigshospitalet, Denmark were retrospectively tested for HEV RNA and anti-HEV IgG. HEV RNA-positive patients were followed up by HEV testing, clinical symptoms, and transfusion history. Factors associated with anti-HEV were explored by multivariable logistic regression analysis. Samples from 1226 blood donors were retrospectively tested for anti-HEV IgG. ResultsHEV RNA was detected in six patients (0.15%) with no indications of chronic HEV infection. HEV RNA prevalence rates among recipients of allogeneic haematopoietic stem cell transplantation (allo-HSCT) and solid organ transplantation (SOT) were 0.58% and 0.21%, respectively. Transfusion transmitted infections were refuted, and transfusion history was not associated with anti-HEV positivity. The difference in HEV seroprevalence between patients (22.0%) and blood donors (10.9%) decreased when adjusting for age and sex (odds ratio 1.20, 95% confidence interval 0.97–1.48). ConclusionsHEV viremia among allo-HSCT and SOT recipients suggests that clinicians should be aware of this diagnosis. The lack of association of blood transfusion with anti-HEV positivity supports food-borne transmission as the main transmission route of HEV common to both patients and blood donors.

223. Predicting Mortality Among Immunocompromised Patients Who Present With Bloodstream Infection

BackgroundThe revised definition of sepsis (Sepsis-3) uses Sequential Organ Failure Assessment (SOFA) and quick SOFA (qSOFA) to identify patients with sepsis instead of systemic inflammatory response syndrome (SIRS) criteria. Subsequent studies revealed contradictory results pertaining to qSOFA, and limited data are available for immunocompromised patients. The objectives of this study were to (1) evaluate the performance of Sepsis -3 in a cohort of immunocompromised patients with microbiologically-proven sepsis, defined as having received antibiotics and having bloodstream infection (BSI); and (2) to compare its performance in the BSI cohort to its performance in immunocompromised patients who received antibiotics but did not have BSI (Non-BSI cohort).MethodsAdult patients with hematologic malignancy or solid transplant recipients admitted to Michigan Medicine between 2012–2017 with suspected infection were included based on criteria used in the Sepsis-3 study: having both a body fluid culture and having received intravenous antibiotics. SOFA, qSOFA and SIRS components within 1 day of the index date (culture date or antibiotic date, whichever came first) were extracted from the medical record. For each group, a baseline risk model for mortality was created including age, gender, race, and Charlson comorbidity index. Each score (SOFA ≥ 2, qSOFA ≥ 2, SIRS ≥ 2) was added to the baseline risk model as a dichotomous variable and AUROC values were calculated.Results2822 patients with a mean age of 56.8±15.6 were included. 349 (12.4%) had BSI. The most common immune compromising conditions were solid-organ transplantation (47%), lymphoma (21.3%) and acute leukemia (17%). 14% of patients in the BSI cohort died during hospitalization compared with 6.6% in the non-BSI cohort (P < 0.001). For the BSI cohort, when SOFA ≥ 2, qSOFA ≥ 2, SIRS ≥ 2 scores were added to the model, the AUROC values were less than those for the non-BSI cohort (table). The addition of SOFA ≥6 to the baseline risk model produced the highest AUROC values in both the BSI and non-BSI cohorts (figure).ConclusionAmong immunocompromised patients, an SOFA score ≥6 was the strongest predictor of mortality. Surprisingly, sepsis scores performed better in the non-BSI cohort than in the BSI cohort. Disclosures All authors: No reported disclosures.

Safety of Foscarnet (FOS) Treatment for Human Herpesviruses (HHV) in a Contemporary Cohort of Immunocompromised Patients

Safety of Foscarnet (FOS) Treatment for Human Herpesviruses (HHV) in a Contemporary Cohort of Immunocompromised Patients

Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease.

Multicentric Castleman disease (MCD) describes a heterogeneous group of disorders involving systemic inflammation, characteristic lymph node histopathology, and multi-organ dysfunction because of pathologic hypercytokinemia. Whereas Human Herpes Virus-8 (HHV-8) drives the hypercytokinemia in a cohort of immunocompromised patients, the etiology of HHV-8-negative MCD is idiopathic (iMCD). Recently, a limited series of iMCD cases in Japan sharing a constellation of clinical features, including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O) has been described as TAFRO syndrome. Herein, we report clinicopathological findings on 25 patients (14 males and 11 females; 23 Japanese-born and two US-born), the largest TAFRO syndrome case series, including the first report of cases from the USA. The median age of onset was 50 years old (range: 23-72). The frequency of each feature was as follows: thrombocytopenia (21/25), anasarca (24/25), fever (21/25), organomegaly (25/25), and reticulin fibrosis (13/16). These patients frequently demonstrated abdominal pain, elevated serum alkaline phosphatase levels, and acute kidney failure. Surprisingly, none of the cases demonstrated marked hypergammoglobulinemia, which is frequently reported in iMCD. Lymph node biopsies revealed atrophic germinal centers with enlarged nuclei of endothelial cells and proliferation of endothelial venules in interfollicular zone. 23 of 25 cases were treated initially with corticosteroids; 12 patients responded poorly and required further therapy. Three patients died during the observation period (median: 9 months) because of disease progression or infections. TAFRO syndrome is a unique subtype of iMCD that demonstrates characteristic clinicopathological findings. Further study to clarify prognosis, pathophysiology, and appropriate treatment is needed.

Respiratory Virus Detection in Immunocompromised Patients with FilmArray Respiratory Panel Compared to Conventional Methods

Respiratory virus infections cause significant morbidity and mortality in immunocompromised patients. Timely diagnosis is needed to provide optimal clinical care. Diagnostic tests routinely available at most institutions are limited by poor sensitivity and a slow turnaround time. We collected 90 respiratory samples from 87 immunocompromised patients (56 bronchoalveolar lavage and 34 nasopharyngeal aspirate samples) in order to compare the performance of routine respiratory virus testing available at our institution to the FilmArray respiratory panel assay, a novel diagnostic tool which utilizes multiplex PCR to test for 21 respiratory pathogens with a 1-h turnaround time. Samples with discordant results and 13 samples with concordant results underwent further verification testing by laboratory-developed real-time PCR. The FilmArray assay identified viral pathogens in more samples than did clinical testing (30/90 versus 16/90; McNemar P = 0.001). Most of the additional viral pathogens identified by the FilmArray respiratory panel assay that were confirmed by verification testing were pathogens not assessed by routine clinical tests, including rhinovirus/enterovirus, human metapneumovirus, and coronavirus. The FilmArray respiratory panel assay allowed for increased identification of respiratory viral pathogens in this cohort of immunocompromised patients.

BAL Neutrophils, Serum Procalcitonin, and C-Reactive Protein To Predict Bacterial Infection in the Immunocompromised Host

Bacterial pulmonary infection is a common life-threatening complication in immunocompromised patients. The results of BAL cultures are not immediately available, and their microbiological yield might be limited by empiric antibiotic prescriptions. We evaluated clinical signs and symptoms, leukocyte counts, C-reactive protein (CRP) levels, procalcitonin levels, and BAL fluid neutrophil percentages as potential markers for bacterial infection in a cohort of immunocompromised patients with pulmonary complications. One hundred seven consecutive patients who had been referred for bronchoscopy due to suspected pulmonary infection were included in this study. Based on clinical, laboratory, radiologic, microbiological, and histologic results, patients were classified as having proven bacterial infection (n = 27), possible bacterial infection (n = 11), and no bacterial infection (n = 69). Most common underlying conditions were hematologic malignancy (n = 62) and solid organ transplantation (n = 20). Clinical parameters were similar in patients with and without bacterial infection (difference was not significant). The percentage of BAL fluid neutrophils had the highest area under the curve (0.818; 95% confidence interval [CI], 0.700 to 0.935; p < 0.001), followed by absolute neutrophil counts (0.797; 95% CI, 0.678 to 0.916; p < 0.001), procalcitonin level (0.746; 95% CI, 0.602 to 0.889; p = 0.001), and CRP level (0.688; 95% CI, 0.555 to 0.821; p = 0.015) to predict proven bacterial infection (in opposition to no or possible bacterial infection) in the receiver operating characteristic analysis. Conversely, neither infiltrates (p = 0.123) nor leukocyte counts (p = 0.429) were useful in diagnosing bacterial infection. The percentage of BAL fluid neutrophils and procalcitonin level were independent predictors of bacterial infection in the multivariate regression. Neutrophil percentage in BAL fluid, procalcitonin level, and CRP level might be potentially useful to differentiate bacterial infection from nonbacterial conditions in immunocompromised hosts with pulmonary complications.

Mixed cytomegalovirus glycoprotein B genotypes in immunocompromised patients.

On the basis of sequence variation in the UL55 gene that encodes glycoprotein B (gB), human cytomegalovirus (CMV) can be classified into 4 gB genotypes. The goal of the present study was to determine the distribution of CMV gB genotypes and the effect of gB type on clinical outcomes in a cohort of immunocompromised patients, including both transplant recipients and nonrecipients. The distribution of gB genotypes was as follows: gB1, 28.9% of patients; gB2, 19.6%; gB3, 23.7%; gB4, 2.0%; and mixed infection, 25.8%. In contrast to patients infected with a single gB genotype, patients infected with multiple gB genotypes developed progression to CMV disease, had an increased rate of graft rejection, had higher CMV loads, and were significantly more often infected with other herpesviruses. The presence of multiple gB genotypes, rather than the presence of a single gB genotype, could be a critical factor associated with severe clinical manifestations in immunocompromised patients.

Contamination of central venous catheters in immunocompromised patients: a comparison between two different types of central venous catheters

Catheters impregnated with silver have been proposed as a means of reducing catheter-related infection. We therefore performed a prospective randomized study to compare a new silver-impregnated central venous catheter (CVC) with a commercially available CVC in a cohort of immunocompromised patients. We studied 157 patients of whom 97 could be analysed. The median indwelling time in the study group (SC) was 10.5 days and 11 days in the control group (CC). The incidence of contamination in the SC group was 15.6 vs 24.6 in the CC group referring to 1000 catheter days. In both groups, we found 6% of catheter-related infections according to the definitions of a published scoring system. The differences between the two groups were not significant. We conclude that the SC decrease the incidence of catheter contamination and may have a positive effect on the reduction of CVC-related infections.

Cerebral infection complicating systemic aspergillosis in acute leukemia: clinical and radiographic presentation.

Cerebral fungal infection is becoming an increasingly recognized entity in immunocompromised patients on post-mortem examination. In order to determine the frequency of clinically significant cerebral fungal infection and define its clinical characteristics in a cohort of immunocompromised patients at high risk of fungal infection, the records of 118 patients with acute leukemia were examined for 57 clinical and laboratory features. The characteristics of 26 patients with systemic aspergillosis and acute leukemia were compared to 92 patients with acute leukemia in a control group. Eight of 118 patients (7%) had cerebral infection (seven Aspergillus, on Candida). Patients with systemic aspergillosis were more likely than patients in the control group to have focal neurologic findings (p = 0.02), confusion (p = 0.04), and abnormal computerized tomography (CT) of the brain characterized by single or multiple, enhancing or non-enhancing hypodense lesions (p = 0.02). Patients with systemic aspergillosis were more likely to die in complete remission than patients in the control group (p = 0.003); three of six patients with aspergillosis who died in remission expired as a consequence of cerebral infection. Cerebral infection complicated systemic Aspergillus infection in seven of 26 patients (27%), versus one of 16 patients with systemic Candida infection (6%) (p = NS). The authors conclude, therefore, that systemic aspergillosis complicating acute leukemia is more likely to be associated with confusion, focal neurologic findings, and abnormal CT scan of the brain, and that these findings suggest the presence of cerebral infection. In addition, cerebral infection commonly complicates the course of systemic aspergillosis, and is a significant cause of morbidity and mortality in patients with acute leukemia. A high index of suspicion is needed to insure early diagnosis and appropriate therapy, particularly in those who achieve remission of their leukemia.