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Background Pneumocystis jirovecii is an opportunistic fungus that causes Pneumocystis pneumonia (PCP) in immunocompromised hosts. Over an 11-month period, we observed a rise in cases of PCP among kidney-transplant recipients (KTR), prompting an outbreak investigation. Methods Clinical and epidemiologic data were collected for KTR diagnosed with PCP between July 2019 and May 2020. Pneumocystis strain typing was performed using restriction fragment length polymorphism analyses and multilocus sequence typing in combination with next-generation sequencing. A transmission map was drawn, and a case-control analysis was performed to determine risk factors associated with PCP. Results Nineteen cases of PCP in KTR were diagnosed at a median of 79 months post-transplantation; 8 received monthly belatacept infusions. Baseline characteristics were similar for KTR on belatacept versus other regimens; the number of clinic visits was numerically higher for the belatacept group during the study period (median 7.5 vs 3). Molecular typing of respiratory specimens from 9 patients revealed coinfection with up to 7 P. jirovecii strains per patient. A transmission map suggested multiple clusters of interhuman transmission. In a case-control univariate analysis, belatacept, lower absolute lymphocyte count, non-White race, and more transplant clinic visits were associated with an increased risk of PCP. In multivariate and prediction power estimate analyses, frequent clinic visits was the strongest risk factor for PCP. Conclusions Increased clinic exposure appeared to facilitate multiple clusters of nosocomial PCP transmission among KTR. Belatacept was a risk factor for PCP, possibly by increasing clinic exposure through the need for frequent visits for monthly infusions.

The coronavirus disease 2019 (COVID-19) pandemic has affected many providers, but its impact on Infectious Diseases (ID) fellows in the United States is largely undescribed. In this study, we discuss key issues that emerged from the first national ID Fellows Call with respect to the ID fellow’s role during the COVID-19 pandemic, teaching/learning, and research., In this brief report, we discuss the impact of the COVID-19 pandemic on Infectious Diseases (ID) fellows in the United States, specifically with respect to the ID fellow’s role during the COVID-19 pandemic, teaching/learning, and research during fellowship.

Background Tocilizumab, an IL-6 receptor antagonist, can be used to treat cytokine release syndrome (CRS), with observed improvements in a coronavirus disease 2019 (COVID-19) case series. Research Question The goal of this study was to determine if tocilizumab benefits patients hospitalized with COVID-19. Study Design and Methods This observational study of consecutive COVID-19 patients hospitalized between March 10, 2020, and March 31, 2020, and followed up through April 21, 2020, was conducted by chart review. Patients were treated with tocilizumab using an algorithm that targeted CRS. Survival and mechanical ventilation (MV) outcomes were reported for 14 days and stratified according to disease severity designated at admission (severe, ≥ 3 L supplemental oxygen to maintain oxygen saturation > 93%). For tocilizumab-treated patients, pre/post analyses of clinical response, biomarkers, and safety outcomes were assessed. Post hoc survival analyses were conducted for race/ethnicity. Results Among the 239 patients, median age was 64 years; 36% and 19% were black and Hispanic, respectively. Hospital census increased exponentially, yet MV census did not. Severe disease was associated with lower survival (78% vs 93%; P < .001), greater proportion requiring MV (44% vs 5%; P < .001), and longer median MV days (5.5 vs 1.0; P = .003). Tocilizumab-treated patients (n = 153 [64%]) comprised 90% of those with severe disease; 44% of patients with nonsevere disease received tocilizumab for evolving CRS. Tocilizumab-treated patients with severe disease had higher admission levels of high-sensitivity C-reactive protein (120 vs 71 mg/L; P < .001) and received tocilizumab sooner (2 vs 3 days; P < .001), but their survival was similar to that of patients with nonsevere disease (83% vs 91%; P = .11). For tocilizumab-treated patients requiring MV, survival was 75% (95% CI, 64-89). Following tocilizumab treatment, few adverse events occurred, and oxygenation and inflammatory biomarkers (eg, high-sensitivity C-reactive protein, IL-6) improved; however, D-dimer and soluble IL-2 receptor (also termed CD25) levels increased significantly. Survival in black and Hispanic patients, after controlling for age, was significantly higher than in white patients (log-rank test, P = .002). Interpretation A treatment algorithm that included tocilizumab to target CRS may influence MV and survival outcomes. In tocilizumab-treated patients, oxygenation and inflammatory biomarkers improved, with higher than expected survival. Randomized trials must confirm these findings.

During the COVID-19 pandemic, the antimicrobial stewardship module in our electronic medical record was reconfigured for the management of COVID-19 patients. This change allowed our subspecialist providers to review charts quickly to optimize potential therapy and management during the patient surge.

In light of the heightened risk for infection associated with solid organ and hematopoietic stem cell transplantation, rapid and accurate microbiology diagnostics are essential to the practice of transplant clinicians, including infectious diseases specialists. In the last decade, diagnostic microbiology has seen a shift toward culture-independent techniques including single-target and multiplexed molecular testing, mass-spectrometry, and magnetic resonance-based methods which have together greatly expanded the array of pathogens identified, increased processing speed and throughput, allowed for detection of resistance determinants, and ultimately improved the outcomes of infected transplant recipients. More recently, a newer generation of diagnostics with immense potential has emerged, including multiplexed molecular panels directly applicable to blood and blood culture specimens, next-generation metagenomics, and gas chromatography mass spectrometry. Though these methods have some recognized drawbacks, many have already demonstrated improved sensitivity and a positive impact on clinical outcomes in transplant and immunocompromised patients.

Interpretation of next-generation sequencing (NGS) of tumor tissue in patients with advanced Urinary Tract Cancer (UTC) is performed to guide treatment selection but may reveal pathogenic variants with germline implications. We identified three patients with UTC with unexpected germline DNA repair gene mutations. Specific testing for these was prompted by the detection of these mutations by tumor NGS. All three patients were nonsmokers with a strong family history of cancer. Two patients had upper tract UTC with age at diagnosis in the 40 s. One had a family history suggestive of hereditary breast/ovarian predisposition and a FANCA mutation detected on NGS was confirmed to be germline. The second patient had a family history suggestive of Lynch syndrome but was found to have a germline BRCA2 mutation that was suggested by NGS. The third patient had bladder cancer at an advanced age, a family history of late-onset gastrointestinal malignancies that did not meet criteria for clinical testing for a hereditary cancer predisposition syndrome. NGS identified an MUTYH mutation, and targeted testing confirmed a monoallelic germline MUTYH mutation. Detection of variants with germline implications by tumor NGS may be clinically relevant for patients and their families and warrant genetic counseling and germline genetic testing. The prevalence of germline DNA repair defects in the context of inherited predisposition to UTC merits further study.

Purpose Tumor genomic profiling helps direct therapy for advanced urothelial carcinoma (UC). In the course of clinical care, we encountered a patient with a complete loss of SMARCB1 (switch/sucrose nonfermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1), which encodes INI-1 (integrase interactor 1), as the sole detected driver of their urinary tract tumor. Our objective was the identification and genomic characterization of urinary tract neoplasia with complete SMARCB1 loss. Patients and Methods Tissue from 1287 patients with UC was assayed by hybrid capture-based comprehensive genomic profiling (CGP) in the course of clinical care to evaluate genomic alterations (GA), such as, base substitutions, insertions/deletions, amplifications, copy number alterations, fusions/rearrangements, and targeted therapy opportunities. A total of 315 genes frequently altered in cancer were assayed. Results CGP identified 10 patients with SMARCB1 alterations. Of the 10 patients, 4 (1 each with renal pelvis, ureter, bladder, and unknown primary cancer) had complete loss of SMARCB1 , and 6 had loss of heterozygosity with an unknown effect on function or heterozygous loss. Patients with complete SMARCB1 loss had few or no additional alterations. Compared with conventional UC, the tumor mutational burden was significantly lower ( P = .004). All 4 patients with complete SMARCB1-loss tumors were Conclusion The genomic profiles of the tumors from patients with UC revealed a population of tumors driven by complete loss of SMARCB1 . This previously uncharacterized subset of INI-1–deficient urinary tract tumors might constitute a new tumor category that could be sensitive to targeted therapy, including EZH2 (enhancer of zeste homolog 2) inhibition. Clinical trial testing could be challenging owing to the rarity of the disease.

We report the rare finding of Strongyloides stercoralis rhabditiform larvae in biliary fluid, here associated with cholecystitis and near total portal vein thrombosis. The role of S. stercoralis leading to atypical clinical presentations and difficulty diagnosing strongyloidiasis in such patients with appropriate geographic exposure is discussed.

Background Abiraterone acetate has been approved for metastatic castration-resistant prostate cancer (mCRPC). Coadministration with prednisone has been recommended to prevent the toxicity from secondary mineralocorticoid excess, such as hypertension, hypokalemia, and edema. However, the use of prednisone is often not desired by patients because of the potential for detrimental effects of long-term therapy with corticosteroids, especially in those with comorbidities such as diabetes or who have received previous immunotherapeutic agents. Eplerenone is a nonsteroidal mineralocorticoid antagonist demonstrated to abrogate mineralocorticoid excess. In the present retrospective study, we report our real-world experience with the use of eplerenone with abiraterone in men with mCRPC who wished to avoid concomitant prednisone therapy. Patients and Methods The incidence and grade (Common Terminology Criteria for Adverse Events, version 4) of mineralocorticoid excess toxicities, baseline demographics, disease characteristics, and progression-free survival (PFS) were collected retrospectively. The patient population included men with mCRPC treated with abiraterone, who were not willing to receive corticosteroids, and thus received eplerenone. Their data were compared with the data from those treated with abiraterone and prednisone during the same period. Continuous variables were assessed using the Wilcoxon rank sum test or Student t test, and categorical variables were assessed using Fischer's exact test or χ 2 test, as appropriate. PFS was compared using the Kaplan-Meier method. Results Of the 106 men treated with abiraterone, 40 received eplerenone and 66 received prednisone. The baseline and disease characteristics, incidence and grade of adverse events related to the syndrome of mineralocorticoid excess, and the median PFS were similar in both cohorts. Conclusion In a real-world population of men with mCRPC treated with abiraterone, corticosteroids can be avoided by concomitant treatment with eplerenone. These data require further validation.

Human herpesviruses cause diseases of considerable morbidity and mortality, ranging from encephalitis to hematologic malignancies. As evidence emerges about the role of innate immunity and natural killer (NK) cells in the control of herpesvirus infection, evidence of viral methods of innate immune evasion grows as well. These methods include interference with the ligands on infected cell surfaces that bind NK cell activating or inhibitory receptors. This paper summarizes the most extensively studied NK cell receptor/ligand pairs and then describes the methods of NK cell evasion used by all eight herpesviruses through these receptors and ligands. Although great strides have been made in elucidating their mechanisms, there is still a disparity between viruses in the amount of knowledge regarding innate immune evasion. Further research of herpesvirus innate immune evasion can provide insight for circumventing viral mechanisms in future therapies.

Prenatal inflammation prevents normal lung morphogenesis and leads to bronchopulmonary dysplasia (BPD), a common complication of preterm birth. We previously demonstrated in a bacterial endotoxin mouse model of BPD that disrupting fibronectin localization in the fetal lung mesenchyme causes arrested saccular airway branching. In this study we show that expression of the fibronectin receptor, integrin alpha8beta1 is decreased in the lung mesenchyme in the same inflammation model suggesting it is required for normal lung development. We verified a role for integrin alpha8beta1 in lung development using integrin alpha8-null mice, which develop fusion of the medial and caudal lobes as well as abnormalities in airway division. We further show in vivo and in vitro that alpha8-null fetal lung mesenchymal cells fail to form stable adhesions and have increased migration. Thus we propose that integrin alpha8beta1 plays a critical role in lung morphogenesis by regulating mesenchymal cell adhesion and migration. Furthermore, our data suggest that disruption of the interactions between extracellular matrix and integrin alpha8beta1 may contribute to the pathogenesis of BPD.