Epidemiology of Invasive Candidiasis in Patients with Hematologic Malignancy on Antifungal Prophylaxis.

The landscape of invasive Candida infections in patients with hematologic malignancy has evolved due to the adoption of anti-fungal prophylaxis, advances in oncological therapies, and developments in antifungal therapies and diagnostics. Despite these scientific gains, the morbidity and mortality caused by these infections remain unchanged, highlighting the importance of an updated understanding of its epidemiology. Non-albicans Candida species are now the predominant cause of invasive candidiasis in patients with hematological malignancy. This epidemiological shift from Candida albicans to non-albicans Candida species is partially a consequence of selective pressure from extensive azole use. Further analysis of this trend suggests other contributing factors including immunocompromise caused by the underlying hematologic malignancy and the intensity of its associated treatments, oncological practices, and regional or institution specific variables. This review characterizes the changing distribution of Candida species in patients with hematologic malignancy, describes the causes driving this change, and discusses clinical considerations to optimize management in this high-risk patient population.

Delayed mortality among solid organ transplant recipients hospitalized for COVID-19.

INTRODUCTION: Most studies of solid organ transplant (SOT) recipients with COVID-19 focus on outcomes within one month of illness onset. Delayed mortality in SOT recipients hospitalized for COVID-19 has not been fully examined. METHODS: We used data from a multicenter registry to calculate mortality by 90 days following initial SARS-CoV-2 detection in SOT recipients hospitalized for COVID-19 and developed multivariable Cox proportional-hazards models to compare risk factors for death by days 28 and 90. RESULTS: Vital status at day 90 was available for 936 of 1117 (84%) SOT recipients hospitalized for COVID-19: 190 of 936 (20%) died by 28 days and an additional 56 of 246 deaths (23%) occurred between days 29 and 90. Factors associated with mortality by day 90 included: age > 65 years [aHR 1.8 (1.3-2.4), p =<0.001], lung transplant (vs. non-lung transplant) [aHR 1.5 (1.0-2.3), p=0.05], heart failure [aHR 1.9 (1.2-2.9), p=0.006], chronic lung disease [aHR 2.3 (1.5-3.6), p<0.001] and body mass index ≥ 30 kg/m 2 [aHR 1.5 (1.1-2.0), p=0.02]. These associations were similar for mortality by day 28. Compared to diagnosis during early 2020 (March 1-June 19, 2020), diagnosis during late 2020 (June 20-December 31, 2020) was associated with lower mortality by day 28 [aHR 0.7 (0.5-1.0, p=0.04] but not by day 90 [aHR 0.9 (0.7-1.3), p=0.61]. CONCLUSIONS: In SOT recipients hospitalized for COVID-19, >20% of deaths occurred between 28 and 90 days following SARS-CoV-2 diagnosis. Future investigations should consider extending follow-up duration to 90 days for more complete mortality assessment.

Changing trends in mortality among solid organ transplant recipients hospitalized for COVID-19 during the course of the pandemic.

Mortality among patients hospitalized for COVID-19 has declined over the course of the pandemic. Mortality trends specifically in solid organ transplant recipients (SOTR) are unknown. Using data from a multicenter registry of SOTR hospitalized for COVID-19, we compared 28-day mortality between early 2020 (March 1, 2020-June 19, 2020) and late 2020 (June 20, 2020-December 31, 2020). Multivariable logistic regression was used to assess comorbidity-adjusted mortality. Time period of diagnosis was available for 1435/1616 (88.8%) SOTR and 971/1435 (67.7%) were hospitalized: 571/753 (75.8%) in early 2020 and 402/682 (58.9%) in late 2020 (p < .001). Crude 28-day mortality decreased between the early and late periods (112/571 [19.6%] vs. 55/402 [13.7%]) and remained lower in the late period even after adjusting for baseline comorbidities (aOR 0.67, 95% CI 0.46-0.98, p = .016). Between the early and late periods, the use of corticosteroids (≥6 mg dexamethasone/day) and remdesivir increased (62/571 [10.9%] vs. 243/402 [61.5%], p < .001 and 50/571 [8.8%] vs. 213/402 [52.2%], p < .001, respectively), and the use of hydroxychloroquine and IL-6/IL-6 receptor inhibitor decreased (329/571 [60.0%] vs. 4/492 [1.0%], p < .001 and 73/571 [12.8%] vs. 5/402 [1.2%], p < .001, respectively). Mortality among SOTR hospitalized for COVID-19 declined between early and late 2020, consistent with trends reported in the general population. The mechanism(s) underlying improved survival require further study.

Coronavirus Disease 2019 in Solid Organ Transplant: A Multicenter Cohort Study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has led to significant reductions in transplantation, motivated in part by concerns of disproportionately more severe disease among solid organ transplant (SOT) recipients. However, clinical features, outcomes, and predictors of mortality in SOT recipients are not well described. METHODS: We performed a multicenter cohort study of SOT recipients with laboratory-confirmed COVID-19. Data were collected using standardized intake and 28-day follow-up electronic case report forms. Multivariable logistic regression was used to identify risk factors for the primary endpoint, 28-day mortality, among hospitalized patients. RESULTS: Four hundred eighty-two SOT recipients from >50 transplant centers were included: 318 (66%) kidney or kidney/pancreas, 73 (15.1%) liver, 57 (11.8%) heart, and 30 (6.2%) lung. Median age was 58 (interquartile range [IQR] 46-57), median time post-transplant was 5 years (IQR 2-10), 61% were male, and 92% had ≥1 underlying comorbidity. Among those hospitalized (376 [78%]), 117 (31%) required mechanical ventilation, and 77 (20.5%) died by 28 days after diagnosis. Specific underlying comorbidities (age >65 [adjusted odds ratio [aOR] 3.0, 95% confidence interval [CI] 1.7-5.5, P < .001], congestive heart failure [aOR 3.2, 95% CI 1.4-7.0, P = .004], chronic lung disease [aOR 2.5, 95% CI 1.2-5.2, P = .018], obesity [aOR 1.9, 95% CI 1.0-3.4, P = .039]) and presenting findings (lymphopenia [aOR 1.9, 95% CI 1.1-3.5, P = .033], abnormal chest imaging [aOR 2.9, 95% CI 1.1-7.5, P = .027]) were independently associated with mortality. Multiple measures of immunosuppression intensity were not associated with mortality. CONCLUSIONS: Mortality among SOT recipients hospitalized for COVID-19 was 20.5%. Age and underlying comorbidities rather than immunosuppression intensity-related measures were major drivers of mortality.

COVID-19 in hospitalized lung and non-lung solid organ transplant recipients: A comparative analysis from a multicenter study.

Lung transplant recipients (LTR) with coronavirus disease 2019 (COVID-19) may have higher mortality than non-lung solid organ transplant recipients (SOTR), but direct comparisons are limited. Risk factors for mortality specifically in LTR have not been explored. We performed a multicenter cohort study of adult SOTR with COVID-19 to compare mortality by 28 days between hospitalized LTR and non-lung SOTR. Multivariable logistic regression models were used to assess comorbidity-adjusted mortality among LTR vs. non-lung SOTR and to determine risk factors for death in LTR. Of 1,616 SOTR with COVID-19, 1,081 (66%) were hospitalized including 120/159 (75%) LTR and 961/1457 (66%) non-lung SOTR (p = .02). Mortality was higher among LTR compared to non-lung SOTR (24% vs. 16%, respectively, p = .032), and lung transplant was independently associated with death after adjusting for age and comorbidities (aOR 1.7, 95% CI 1.0-2.6, p = .04). Among LTR, chronic lung allograft dysfunction (aOR 3.3, 95% CI 1.0-11.3, p = .05) was the only independent risk factor for mortality and age >65 years, heart failure and obesity were not independently associated with death. Among SOTR hospitalized for COVID-19, LTR had higher mortality than non-lung SOTR. In LTR, chronic allograft dysfunction was independently associated with mortality.

Universal molecular Clostridioides difficile screening and overtreatment in solid organ transplant recipients.

BACKGROUND: Screening for Clostridioides difficile (CD) colonization can be performed using molecular testing to identify the presence of microbial DNA of the toxin gene. Colonization rates for hospitalized patients are as high as 20% and may be considerably higher in solid organ transplant (SOT) recipients. Treatment for CD should be based on clinical disease and not colonization, yet clinicians may misinterpret a positive CD screen resulting in overtreatment. OBJECTIVES: The objective of this analysis is to determine how often positive CD screens resulted in inappropriate treatment with oral vancomycin. METHODS: Clostridioides difficile screens were performed using the Xpert C difficile assay (Cepheid), a nucleic acid amplification testing method utilizing polymerase chain reaction (PCR), on peri-rectal swabs for newly admitted patients. This was a single-center cohort study of adult patients with CD screens hospitalized between July 2015 and November 2018. The primary outcome was the rate of inappropriate oral vancomycin treatment in all patients and in SOT recipients, defined as therapy in the absence of diarrhea. RESULTS: Of the 47 076 total CD screens reviewed, 1,921 were positive. In the SOT cohort, 58 of 329 screens were positive (4.1% vs 17.9%, P < .01). Of all patients with a positive CD screen, 20.1% (386/1921) were treated with oral vancomycin within 48 hours of swab collection. In the SOT cohort, 39.6% (23/58) with positive CD screens were treated with oral vancomycin within 48 hours. Of the SOT patients who received oral vancomycin, 39% (9/23) did not have true CD infection. CONCLUSION: Solid organ transplant recipients were more likely to have CD colonization detected by peri-rectal screening than the general inpatient population. SOT and non-SOT patients were treated with oral vancomycin at similar rates in response to the positive screen. Nearly half of the oral vancomycin use in SOT recipients was likely overtreatment, but this finding is limited by the low number of patients in this cohort.

Does local matter? Evaluating susceptibility variations between hospital-wide and hematology-oncology unit antibiograms.

Antibiograms are important for guiding empiric antibiotics for febrile neutropenia. However, hospital-wide antibiograms may not capture complexities of patients with hematologic malignancies. We created a hematology-oncology unit-specific antibiogram and found higher resistance among Escherichia coli, Klebsiella pneumonia, and Enterococcus isolates compared to hospital-wide data.

Efficacy of booster doses in augmenting waning immune responses to COVID-19 vaccine in patients with cancer.

Anti-COVID-19 immunity dynamics were assessed in patients with cancer in a prospective clinical trial. Waning of immunity was detected 4-6 months post-vaccination with significant increases in anti-spike IgG titers after booster dosing, and 56% of seronegative patients seroconverted post-booster vaccination. Prior anti-CD20/BTK inhibitor therapy was associated with reduced vaccine efficacy.

Bacterial infections in lung transplantation.

Lung transplantation has lower survival rates compared to other than other solid organ transplants (SOT) due to higher rates of infection and rejection-related complications, and bacterial infections (BI) are the most frequent infectious complications. Excess morbidity and mortality are not only a direct consequence of these BI, but so are subsequent loss of allograft tolerance, rejection, and chronic lung allograft dysfunction due to bronchiolitis obliterans syndrome (BOS). A wide variety of pathogens can cause infections in lung transplant recipients (LTRs), including a number of nosocomial pathogens and other multidrug-resistant (MDR) pathogens. Although pneumonia and intrathoracic infections predominate, LTRs are at risk of a number of types of infections. Risk factors include altered anatomy and function of airways, impaired immunity, the microbial flora of the donor and recipient, underlying medical conditions, and genetic factors. Further work on immune monitoring has the potential to improve outcomes. The infecting agents can be derived from the donor lung, pre-existing recipient flora, or acquired from the environment over time. Certain infections may preclude lung transplantation, but this varies from center to center, and more recent studies suggest fewer patients should be disqualified. New molecular methods allow microbiome studies of the lung, gut, and other sites that may further our knowledge of how airway colonization can result in infection and allograft loss. Surveillance, early diagnosis, and aggressive antimicrobial therapy of BI is critical in LTRs. Antibiotic resistance is a major barrier to successful management of these infections. The availability of new agents for MDR Gram-negatives may improve outcomes. Other new therapies, such as bacteriophage therapy, show promise for the future. Finally, it is important to prevent infections through peri-transplant prophylaxis, vaccination, and infection control measures.

Cytomegalovirus skin disease in a kidney transplant patient.

A 44-year-old man with a history of renal transplantation presented with right lower abdominal wall swelling, redness and pain. A bacterial abscess was drained, and he was discharged home with oral antibiotics. After failing to improve, he returned to the hospital, where he was briefly treated with intravenous antibiotics and discharged home again. The patient returned 5 days later, reporting worsening right groin swelling that extended into the ipsilateral scrotum. Imaging revealed a persistent fluid collection in the region, and he was taken for surgical debridement. Tissue immunochemistry and histopathological evaluation identified cytomegalovirus infection. Plasma quantitative PCR for cytomegalovirus demonstrated high viraemia. The patient was successfully treated with intravenous ganciclovir, followed by oral valganciclovir, with resolution of the skin changes. Persistent hydrocele with epididymitis on imaging suggests that this process may have been the source of the cutaneous cytomegalovirus infection.

Early and Significant Reduction in C-Reactive Protein Levels After Corticosteroid Therapy Is Associated With Reduced Mortality in Patients With COVID-19.

BACKGROUND: Corticosteroids may be beneficial in a subset of patients with coronavirus disease 2019 (COVID-19), but predictors of therapeutic response remain unknown. C-reactive protein (CRP) is a routinely measured biomarker, and reduction in its levels after initiation of therapy may predict inpatient mortality. METHODS: In this retrospective cohort study, the charts of patients who were admitted to Montefiore Medical Center between March 10, 2020, and May 2, 2020 for the management of COVID-19 were examined. Of all patients who met inclusion criteria, patients who received corticosteroid treatment were categorized as CRP responders (≥50% CRP level reduction) and CRP nonresponders (<50% CRP level reduction) based on change in CRP within 72 hours of corticosteroid treatment initiation. The outcomes of interest were two-fold: (1) CRP response after treatment with corticosteroid, and (2) differences in mortality among patients with CRP response compared those without. RESULTS: Of 2,707 patients admitted during the study period, 324 received corticosteroid treatment. Of patients who received corticosteroid treatment, CRP responders had reduced risk of death compared with risk among CRP nonresponders (25.2% vs 47.8%; unadjusted odds ratio [OR], 0.37; 95% CI, 0.21-0.65; P <.001). This effect remained strong and significant after adjustment for potential confounders (adjusted OR, 0.27; 95% CI, 0.14-0.54; P <.001). CONCLUSION: Reduction in CRP by 50% or more within 72 hours of initiating corticosteroid therapy potentially predicts inpatient mortality. This may serve as an early biomarker of response to corticosteroid therapy in patients with COVID-19.

Seroconversion rates following COVID-19 vaccination among patients with cancer.

As COVID-19 adversely affects patients with cancer, prophylactic strategies are critically needed. Using a validated antibody assay against SARS-CoV-2 spike protein, we determined a high seroconversion rate (94%) in 200 patients with cancer in New York City that had received full dosing with one of the FDA-approved COVID-19 vaccines. On comparison with solid tumors (98%), a significantly lower rate of seroconversion was observed in patients with hematologic malignancies (85%), particularly recipients following highly immunosuppressive therapies such as anti-CD20 therapies (70%) and stem cell transplantation (73%). Patients receiving immune checkpoint inhibitor therapy (97%) or hormonal therapies (100%) demonstrated high seroconversion post vaccination. Patients with prior COVID-19 infection demonstrated higher anti-spike IgG titers post vaccination. Relatively lower IgG titers were observed following vaccination with the adenoviral than with mRNA-based vaccines. These data demonstrate generally high immunogenicity of COVID-19 vaccination in oncology patients and identify immunosuppressed cohorts that need novel vaccination or passive immunization strategies.

Patterns of leukocyte recovery predict infectious complications after CD19 CAR-T cell therapy in a real-world setting.

BACKGROUND: Adoptive immunotherapy using CD19-targeted Chimeric antigen receptor T cells (CAR-T) has revolutionized the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Data is limited on the propensity of infections and lymphohematopoietic reconstitution after Day 30 (D30) following CAR-T cell therapy. In this study, we evaluated the prevalence and nature of infectious complications in an expanded cohort of DLBCL patients treated with CD19 CAR-T therapy and its association with the dynamics of leukocyte subpopulation reconstitution post-CAR-T cell therapy. METHODS: We conducted a retrospective study including 19 patients who received axicabtagene ciloleucel and investigated associations between cytopenia and infectious complications after D30. RESULTS: Nineteen patients were included, consisting of 42% Hispanic, 32% Caucasian, 21% African-American, and 5% Asian subjects. Post-D30 of CAR-T infusion, 47% patients (n=9) developed an infection and 53% (n=10) remained infection-free. The most common infection type observed was viral (7 patients) followed by bacterial (5 patients) and fungal (3 patients). Of 25 total infectious events, 56% were grade 1 or 2 and 44% were grade 3 with 10 being viral in etiology. To determine the kinetics of lymphohematopoietic reconstitution and its association with infection risk, we evaluated the relationship between cytopenias and rates of infection after D30. Notably, compared to non-infection group, infection group had a higher median absolute lymphocyte count (ALC) (1,000/µL vs. 600/µL, P<0.05), a lower median absolute neutrophil count (ANC)/ALC ratio (1.6 vs. 3.1, P<0.05) and a lower median AMC/ALC at D30 (0.37 vs. 1.67, P<0.05). In addition, we observed that only 22% of patients had recovered ANC >1,500/µL in the infection group as opposed to 70% in the non-infection group at D90 (P<0.05). Fifty-eight percent of the patients (11/19) with relapsed refractory DLBCL achieved a complete response with a median follow-up of 233 days (7.7 months). CONCLUSIONS: Although CAR-T cell therapy is highly effective, infectious complications remain an important cause of morbidity and mortality. Low ANC/ALC and AMC/ALC ratios at D30 are potential novel predictors of infection and can be considered in future prophylactic strategies.