Plasma Microbial Cell-Free DNA Sequencing in Immunocompromised Patients With Pneumonia: A Prospective Observational Study.

BACKGROUND: Pneumonia is a common cause of morbidity and mortality, yet a causative pathogen is identified in a minority of cases. Plasma microbial cell-free DNA sequencing may improve diagnostic yield in immunocompromised patients with pneumonia. METHODS: In this prospective, multicenter, observational study of immunocompromised adults undergoing bronchoscopy to establish a pneumonia etiology, plasma microbial cell-free DNA sequencing was compared to standardized usual care testing. Pneumonia etiology was adjudicated by a blinded independent committee. The primary outcome, additive diagnostic value, was assessed in the Per Protocol population (patients with complete testing results and no major protocol deviations) and defined as the percent of patients with an etiology of pneumonia exclusively identified by plasma microbial cell-free DNA sequencing. Clinical additive diagnostic value was assessed in the Per Protocol subgroup with negative usual care testing. RESULTS: Of 257 patients, 173 met Per Protocol criteria. A pneumonia etiology was identified by usual care in 52/173 (30.1%), plasma microbial cell-free DNA sequencing in 49/173 (28.3%) and the combination of both in 73/173 (42.2%) patients. Plasma microbial cell-free DNA sequencing exclusively identified an etiology of pneumonia in 21/173 patients (additive diagnostic value 12.1%, 95% confidence interval [CI], 7.7% to 18.0%, P < .001). In the Per Protocol subgroup with negative usual care testing, plasma microbial cell-free DNA sequencing identified a pneumonia etiology in 21/121 patients (clinical additive diagnostic value 17.4%, 95% CI, 11.1% to 25.3%). CONCLUSIONS: Non-invasive plasma microbial cell-free DNA sequencing significantly increased diagnostic yield in immunocompromised patients with pneumonia undergoing bronchoscopy and extensive microbiologic and molecular testing. CLINICAL TRIALS REGISTRATION: NCT04047719.

Challenging boundaries: Organ transplants from donors with Listeria central nervous system infections.

Pretransplant mortality rates in the US remain high and are connected to effective organ donation and utilization. Thus, there is a need to maximize the utilization of available donors. In some cases, this has been safely achieved using organs from donors with infectious complications. For example, several studies describe the use of organs from donors with bacterial meningitis due to pathogens such as Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenza, and Escherichia coli, with good outcomes. Listeria is an aerobic and facultatively anaerobic, nonspore-forming, Gram-positive rod that can affect the central nervous system, causing meningitis and meningoencephalitis. Due to its virulence, ability to cause intracellular infection, and lack of clinical data, people dying with listeria may not be evaluated for organ donation, may not have organs recovered, or may have their organs recovered but not transplanted. Herein, we describe the outcomes of 7 solid organ transplant recipients who received organs from 2 donors with Listeria monocytogenes central nervous system infection.

Solid organ transplant recipients with tuberculosis disease in California, 2010 to 2020.

Using California Tuberculosis (TB) Registry data from 2010-2020, we compared the presentation and outcomes of patients with TB aged >15 years with and without solid organ transplantation (SOT). We matched to the United Network for Organ Sharing registry for 1987-2020 and the estimated time from transplantation to the diagnosis of TB, the incidence of posttransplant TB, and the probability of death and graft failure in SOT recipients with TB, compared to those without TB. From 2010-2020, there were 148 posttransplant TB cases. Patients with posttransplant TB were more likely to have extrapulmonary disease and more than twice as likely to die as TB patients without SOT (relative risk [RR], 2.2; 95% confidence interval [CI], 1.6-2.9). The median time from transplantation to TB diagnosis was 1.2 years, with the shortest time among lung transplant recipients. The incidence of TB disease among Californians with SOT was 56.0 per 100 000 person-years. The risk of death was higher among SOT recipients with posttransplant TB than those without (adjusted hazard ratio, 2.8; 95% CI, 2.0-4.1); the risk of graft failure was higher among kidney transplant recipients with posttransplant TB than those without (adjusted hazard ratio, 3.4; 95% CI, 1.7-6.9). An increased risk of death and graft failure in SOT recipients with posttransplant TB highlights the need for enhanced pretransplant TB prevention.

COVID-19 in vaccinated versus unvaccinated hematologic malignancy patients.

The effect of vaccination on severity of subsequent COVID-19 in patients with hematologic malignancies (HMs) is unknown. In this single-center retrospective cohort study, we found no difference in severity of COVID-19 disease in vaccinated (n = 16) versus unvaccinated (n = 54) HM patients using an adjusted multiple logistic regression model. Recent anti-B-cell therapy was associated with more severe illness.

Prevalence of carbapenemase-producing organisms among hospitalized solid organ transplant recipients, five US hospitals, 2019-2020.

BACKGROUND: Passive reporting to the Centers for Disease Control and Prevention has identified carbapenemase-producing organisms (CPOs) among solid organ transplant (SOT) recipients, potentially representing an emerging source of spread. We analyzed CPO prevalence in wards where SOT recipients receive inpatient care to inform public health action to prevent transmission. METHODS: From September 2019 to June 2020, five US hospitals conducted consecutive point prevalence surveys (PPS) of all consenting patients admitted to transplant units, regardless of transplant status. We used the Cepheid Xpert Carba-R assay to identify carbapenemase genes (blaKPC , blaNDM , blaVIM , blaIMP , blaOXA-48 ) from rectal swabs. Laboratory-developed molecular tests were used to retrospectively test for a wider range of blaIMP and blaOXA variants. RESULTS: In total, 154 patients were screened and 92 (60%) were SOT recipients. CPOs were detected among 7 (8%) SOT recipients, from two of five screened hospitals: four blaKPC , one blaNDM , and two blaOXA-23 . CPOs were detected in two (3%) of 62 non-transplant patients. In three of five participating hospitals, CPOs were not identified among any patients admitted to transplant units. CONCLUSIONS: Longitudinal surveillance in transplant units, as well as PPS in areas with diverse CPO epidemiology, may inform the utility of routine screening in SOT units to prevent the spread of CPOs.

COVID-19 in Immunocompromised Hosts: What We Know So Far.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused significant morbidity and mortality for patients and stressed healthcare systems worldwide. The clinical features and outcomes of COVID-19 among immunosuppressed patients, who are at presumed risk of more severe disease but who may also have decreased detrimental inflammatory responses, are not well characterized. We review the existing literature on COVID-19 among immunocompromised populations ranging from patients with cancer and solid-organ transplant recipients to patients with HIV and those receiving immunomodulatory therapy for autoimmune disease. Patients with malignancy and solid-organ transplant recipients may be at increased risk of severe COVID-19 disease and death, whereas for those with other types of immunocompromise, current evidence is less clear. Overall, further prospective controlled studies are needed to determine the attributable risk of immunocompromising conditions and therapies on COVID-19 disease prognosis.

Chronic lung allograft dysfunction small airways reveal a lymphocytic inflammation gene signature.

Chronic lung allograft dysfunction (CLAD) is the major barrier to long-term survival following lung transplantation, and new mechanistic biomarkers are needed. Lymphocytic bronchitis (LB) precedes CLAD and has a defined molecular signature. We hypothesized that this LB molecular signature would be associated with CLAD in small airway brushings independent of infection. We quantified RNA expression from small airway brushings and transbronchial biopsies, using RNAseq and digital RNA counting, respectively, for 22 CLAD cases and 27 matched controls. LB metagene scores were compared across CLAD strata by Wilcoxon rank sum test. We performed unbiased host transcriptome pathway and microbial metagenome analysis in airway brushes and compared machine-learning classifiers between the two tissue types. This LB metagene score was increased in CLAD airway brushes (p = .002) and improved prediction of graft failure (p = .02). Gene expression classifiers based on airway brushes outperformed those using transbronchial biopsies. While infection was associated with decreased microbial alpha-diversity (p ≤ .04), neither infection nor alpha-diversity was associated with LB gene expression. In summary, CLAD was associated with small airway gene expression changes not apparent in transbronchial biopsies in this cohort. Molecular analysis of airway brushings for diagnosing CLAD merits further examination in multicenter cohorts.

Type-1 immunity and endogenous immune regulators predominate in the airway transcriptome during chronic lung allograft dysfunction.

Chronic lung allograft dysfunction (CLAD) remains the major complication limiting long-term survival among lung transplant recipients (LTRs). Limited understanding of CLAD immunopathogenesis and a paucity of biomarkers remain substantial barriers for earlier detection and therapeutic interventions for CLAD. We hypothesized the airway transcriptome would reflect key immunologic changes in disease. We compared airway brush-derived transcriptomic signatures in CLAD (n = 24) versus non-CLAD (n = 21) LTRs. A targeted assessment of the proteome using concomitant bronchoalveolar lavage (BAL) fluid for 24 cytokines/chemokines and alloimmune T cell responses was performed to validate the airway transcriptome. We observed an airway transcriptomic signature of differential genes expressed (DGEs) in CLAD marked by Type-1 immunity and striking upregulation of two endogenous immune regulators: indoleamine 2, 3 dioxygenase 1 (IDO-1) and tumor necrosis factor receptor superfamily 6B (TNFRSF6B). Advanced CLAD staging was associated with a more intense airway transcriptome signature. In a validation cohort using the identified signature, we found an area under the curve (AUC) of 0.77 for CLAD LTRs. Targeted proteomic analyses revealed a predominant Type-1 profile with detection of IFN-γ, TNF-α, and IL-1ß as dominant CLAD cytokines, correlating with the airway transcriptome. The airway transcriptome provides novel insights into CLAD immunopathogenesis and biomarkers that may impact diagnosis of CLAD.

Zoonotic coronavirus epidemics: Severe acute respiratory syndrome, Middle East respiratory syndrome, and coronavirus disease 2019.

OBJECTIVE: To review the virology, immunology, epidemiology, clinical manifestations, and treatment of the following 3 major zoonotic coronavirus epidemics: severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19). DATA SOURCES: Published literature obtained through PubMed database searches and reports from national and international public health agencies. STUDY SELECTIONS: Studies relevant to the basic science, epidemiology, clinical characteristics, and treatment of SARS, MERS, and COVID-19, with a focus on patients with asthma, allergy, and primary immunodeficiency. RESULTS: Although SARS and MERS each caused less than a thousand deaths, COVID-19 has caused a worldwide pandemic with nearly 1 million deaths. Diagnosing COVID-19 relies on nucleic acid amplification tests, and infection has broad clinical manifestations that can affect almost every organ system. Asthma and atopy do not seem to predispose patients to COVID-19 infection, but their effects on COVID-19 clinical outcomes remain mixed and inconclusive. It is recommended that effective therapies, including inhaled corticosteroids and biologic therapy, be continued to maintain disease control. There are no reports of COVID-19 among patients with primary innate and T-cell deficiencies. The presentation of COVID-19 among patients with primary antibody deficiencies is variable, with some experiencing mild clinical courses, whereas others experiencing a fatal disease. The landscape of treatment for COVID-19 is rapidly evolving, with both antivirals and immunomodulators demonstrating efficacy. CONCLUSION: Further data are needed to better understand the role of asthma, allergy, and primary immunodeficiency on COVID-19 infection and outcomes.

Disseminated Legionella micdadei infection in a liver transplant patient presenting as pulmonary nodules and a laryngeal lesion.

We report a liver transplant patient with disseminated Legionella micdadei infection with pulmonary, laryngeal, and suspected muscle involvement. This organism, which stains weakly acid-fast, primarily affects immunocompromised patients. The diagnosis is difficult to make; in this case, the organism was identified via molecular diagnostics on laryngeal and pulmonary biopsy tissue.

Treatment of immunocompromised COVID-19 patients with convalescent plasma.

Immunosuppressed patients such as solid organ transplant and hematologic malignancy patients appear to be at increased risk for morbidity and mortality due to coronavirus disease 2019 (COVID-19) caused by SARS coronavirus 2 (SARS-CoV-2). Convalescent plasma, a method of passive immunization that has been applied to prior viral pandemics, holds promise as a potential treatment for COVID-19. Immunocompromised patients may experience more benefit from convalescent plasma given underlying deficits in B and T cell immunity as well as contraindications to antiviral and immunomodulatory therapy. We describe our institutional experience with four immunosuppressed patients (two kidney transplant recipients, one lung transplant recipient, and one chronic myelogenous leukemia patient) treated with COVID-19 convalescent plasma through the Expanded Access Program (NCT04338360). All patients clinically improved after administration (two fully recovered and two discharged to skilled nursing facilities) and none experienced a transfusion reaction. We also report the characteristics of convalescent plasma product from a local blood center including positive SARS-CoV-2 IgG and negative SARS-CoV-2 PCR in all samples tested. This preliminary evidence suggest that convalescent plasma may be safe among immunosuppressed patients with COVID-19 and emphasizes the need for further data on the efficacy of convalescent plasma as either primary or adjunctive therapy for COVID-19.

Integrating host response and unbiased microbe detection for lower respiratory tract infection diagnosis in critically ill adults.

Lower respiratory tract infections (LRTIs) lead to more deaths each year than any other infectious disease category. Despite this, etiologic LRTI pathogens are infrequently identified due to limitations of existing microbiologic tests. In critically ill patients, noninfectious inflammatory syndromes resembling LRTIs further complicate diagnosis. To address the need for improved LRTI diagnostics, we performed metagenomic next-generation sequencing (mNGS) on tracheal aspirates from 92 adults with acute respiratory failure and simultaneously assessed pathogens, the airway microbiome, and the host transcriptome. To differentiate pathogens from respiratory commensals, we developed a rules-based model (RBM) and logistic regression model (LRM) in a derivation cohort of 20 patients with LRTIs or noninfectious acute respiratory illnesses. When tested in an independent validation cohort of 24 patients, both models achieved accuracies of 95.5%. We next developed pathogen, microbiome diversity, and host gene expression metrics to identify LRTI-positive patients and differentiate them from critically ill controls with noninfectious acute respiratory illnesses. When tested in the validation cohort, the pathogen metric performed with an area under the receiver-operating curve (AUC) of 0.96 (95% CI, 0.86-1.00), the diversity metric with an AUC of 0.80 (95% CI, 0.63-0.98), and the host transcriptional classifier with an AUC of 0.88 (95% CI, 0.75-1.00). Combining these achieved a negative predictive value of 100%. This study suggests that a single streamlined protocol offering an integrated genomic portrait of pathogen, microbiome, and host transcriptome may hold promise as a tool for LRTI diagnosis.

Clinical outcomes and serologic response in solid organ transplant recipients with COVID-19: A case series from the United States.

The coronavirus disease 2019 (COVID-19) pandemic caused by SARS coronavirus 2 (SARS-CoV-2) has caused significant morbidity and mortality for patients and stressed healthcare systems worldwide. The clinical features, disease course, and serologic response of COVID-19 among immunosuppressed patients such as solid organ transplant (SOT) recipients, who are at presumed risk for more severe disease, are not well characterized. We describe our institutional experience with COVID-19 among 10 SOT patients, including the clinical presentation, treatment modalities, and outcomes of 7 renal transplant recipients, 1 liver transplant recipient, 1 heart transplant recipient, and 1 lung transplant recipient. In addition, we report the serologic response in SOT recipients, documenting a positive IgG response in all 7 hospitalized patients. We also review the existing literature on COVID-19 in SOT recipients to consolidate the current knowledge on COVID-19 in the SOT population for the transplant community.

Increased Risk of Infectious Complications in Older Patients With Indolent Non-Hodgkin Lymphoma Exposed to Bendamustine.

Background: Bendamustine is a potent chemotherapy agent increasingly used to treat indolent non-Hodgkin lymphoma (iNHL). While effective, it causes significant T-cell lymphopenia, which may increase risk of infection. We examined infectious complications associated with bendamustine-containing regimens among older patients with iNHL. Methods: For this Surveillance, Epidemiology, and End Results (SEER)-Medicare cohort study, we identified 9395 patients with iNHL (follicular, marginal zone, Waldenström macroglobulinemia) treated with chemotherapy from 2006 to 2013. Thirteen percent received bendamustine-containing regimens. We compared baseline characteristics and infection incidence rates between patients treated with and without bendamustine. We conducted multivariate Cox proportional hazards regression (adjusting for demographics, comorbidities, disease and treatment characteristics, risk factors for infection, and antimicrobial prophylaxis) to determine infectious risks associated with bendamustine. Results: Bendamustine was associated with an increased risk of both common infections such as bacterial pneumonia (hazard ratio [HR], 1.50 [95% confidence interval {CI}, 1.21-4.85]) and opportunistic infections such as cytomegalovirus (HR, 3.98 [95% CI, 1.40-11.26]), varicella zoster virus (HR, 1.49 [95% CI, 1.18-1.89]), histoplasmosis (HR, 3.55 [95% CI, 1.10-11.42]), and Pneumocystis jirovecii pneumonia (when administered as third-line therapy: HR, 3.32 [95% CI, 1.00-11.11]). Risk of infections was more prominent in patients receiving bendamustine as part of later (third-line and above) regimens, and independently associated with well-established factors such as neutropenia and corticosteroid exposure. Conclusions: Bendamustine is associated with an increased risk of common and opportunistic infections in patients with iNHL. Further prospective investigation into the potential role of antimicrobial prophylaxis is needed in these patients.

Risk of systemic fungal infections after exposure to wildfires: a population-based, retrospective study in California.

BACKGROUND: Large-scale wildfires in California, USA, are increasing in both size and frequency, with substantial health consequences. The capacity for wildfire smoke to displace microbes and cause clinically significant fungal infections is poorly understood. We aimed to determine whether exposure to wildfire smoke was associated with an increased risk of hospital admissions for systemic fungal infections. METHODS: In this population-based, retrospective study, we used hospital administrative data from 22 hospitals in California, USA, to analyse the association between wildfire smoke exposure and monthly hospital admissions for aspergillosis and coccidioidomycosis. We included hospitals that were members of the Vizient Clinical Data Base or Resource Manager during the study and excluded those that did not have complete reporting into Vizient during the study period. Smoke exposure was estimated using satellite-imaged smoke plumes in the hospital county. Incident rate ratios were calculated for all infection types 1 month and 3 months after smoke exposure. FINDINGS: Between Oct 1, 2014, and May 31, 2018, there were a median of 1638 annual admissions per hospital in the study sample. Individual patient demographics were not collected. We did not observe an association between smoke exposure and rate of hospital admission for aspergillosis. However, hospital admission for coccidioidomycosis increased by 20% (95% CI 5-38) in the month following any smoke exposure. Hospital admission increased by 2% (0-4) for every day that there had been smoke exposure in the previous month, after adjustment for temperature and temporal trend. Similar results were obtained with smoke exposure data from the 3 months before admission. INTERPRETATION: In the months following wildfire smoke exposure, California hospitals saw increased coccidioidomycosis infections. Given the projected increase in California wildfires and their expansion in endemic territories of soil-dwelling fungi, the ability for wildfire smoke to carry microbes and cause human disease warrants further research. FUNDING: None.

Duration of neurological deficit and outcomes in the surgical treatment of spinal coccidioidomycosis.

OBJECTIVE: Vertebral osteomyelitis is a rare complication of coccidioidomycosis infection. Surgical intervention is indicated when there is failure of medical management or presence of neurological deficit, epidural abscess, or spinal instability. The relationship between timing of surgical intervention and recovery of neurological function has not been previously described. The purpose of this study was to investigate if the duration of neurological deficits at presentation affects neurological recovery after surgical intervention. METHODS: This was a retrospective study of all patients diagnosed with coccidioidomycosis involving the spine at a single tertiary care center between 2012 and 2021. Data collected included patient demographics, clinical presentation, radiographic information, and surgical intervention. The primary outcome was change in neurological examination after surgical intervention, quantified according to the American Spinal Injury Association Impairment Scale. The secondary outcome was the complication rate. Logistic regression was used to test if the duration of neurological deficits was associated with improvement in the neurological examination after surgery. RESULTS: Twenty-seven patients presented with spinal coccidioidomycosis between 2012 and 2021; 20 of these patients had vertebral involvement on spinal imaging with a median follow-up of 8.7 months (IQR 1.7-71.2 months). Of the 20 patients with vertebral involvement, 12 (60.0%) presented with a neurological deficit with a median duration of 20 days (range 1-61 days). Most patients presenting with neurological deficit (11/12, 91.7%) underwent surgical intervention. Nine (81.2%) of these 11 patients had an improved neurological examination after surgery and the other 2 had stable deficits. Seven patients had improved recovery sufficient to improve by 1 grade according to the AIS. The duration of neurological deficits on presentation was not significantly associated with neurological improvement after surgery (p = 0.49, Fisher's exact test). CONCLUSIONS: The duration of neurological deficits on presentation should not deter surgeons from operative intervention in cases of spinal coccidioidomycosis.