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.

Impact of a structured interview on beta-lactam reaction documentation quality.

Incomplete documentation of ß-lactam reactions often leads to inappropriate antibiotic prescribing. The objective of this study was to evaluate the impact of a structured interview on the quality of ß-lactam reaction documentation. After 203 interviews, documentation of the core components of a ß-lactam reaction improved (48% vs 1%; P < .001).

Late onset infectious complications and safety of tocilizumab in the management of COVID-19.

BACKGROUND: Tocilizumab (TCZ) has been used in the management of COVID-19-related cytokine release syndrome (CRS). Concerns exist regarding the risk of infections and drug-related toxicities. We sought to evaluate the incidence of these TCZ complications among COVID-19 patients. METHODS: All adult inpatients with COVID-19 between 1 March and 25 April 2020 that received TCZ were included. We compared the rate of late-onset infections (>48 hours following admission) to a control group matched according to intensive care unit admission and mechanical ventilation requirement. Post-TCZ toxicities evaluated included: elevated liver function tests (LFTs), GI perforation, diverticulitis, neutropenia, hypertension, allergic reactions, and infusion-related reactions. RESULTS: Seventy-four patients were included in each group. Seventeen infections in the TCZ group (23%) and 6 (8%) infections in the control group occurred >48 hours after admission (P = .013). Most infections were bacterial with pneumonia being the most common manifestation. Among patients receiving TCZ, LFT elevations were observed in 51%, neutropenia in 1.4%, and hypertension in 8%. The mortality rate among those that received TCZ was greater than the control (39% versus 23%, P = .03). CONCLUSION: Late onset infections were significantly more common among those receiving TCZ. Combining infections and TCZ-related toxicities, 61% of patients had a possible post-TCZ complication. While awaiting clinical trial results to establish the efficacy of TCZ for COVID-19 related CRS, the potential for infections and TCZ related toxicities should be carefully weighed when considering use.

Automatic ID Consultation for Inpatients With COVID-19: Point, Counterpoint, and a Single-Center Experience.

There are many unknowns with regard to COVID-19 clinical management, including the role of Infectious Diseases Consultation (IDC). As hospitalizations for COVID-19 continue, hospitals are assessing how to optimally and efficiently manage COVID-19 inpatients. Typically, primary teams must determine when IDC is appropriate, and ID clinicians provide consultation upon request of the primary team. IDC has been shown to be beneficial for many conditions; however, the impact of IDC for COVID-19 is unknown. Herein, we discuss the potential benefits and pitfalls of automatic IDC for COVID-19 inpatients. Important considerations include the quality of care provided, allocation and optimization of resources, and clinician satisfaction. Finally, we describe how automatic IDC changed throughout the COVID-19 pandemic at a single academic medical center.

Obesity is Associated with Increased Risk for Mortality Among Hospitalized Patients with COVID-19.

OBJECTIVE: Obesity has been identified as a risk factor for severe coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 virus. This study sought to determine whether obesity is a risk factor for mortality among patients with COVID-19. METHODS: The study was a retrospective cohort that included patients with COVID-19 between March 1 and April 18, 2020. RESULTS: A total of 238 patients were included; 218 patients (91.6%) were African American, 113 (47.5%) were male, and the mean age was 58.5 years. Of the included patients, 146 (61.3%) had obesity (BMI > 30 kg/m2 ), of which 63 (26.5%), 29 (12.2%), and 54 (22.7%) had class 1, 2, and 3 obesity, respectively. Obesity was identified as a predictor for mortality (odds ratio [OR] 1.7 [1.1-2.8], P = 0.016), as was male gender (OR 5.2 [1.6-16.5], P = 0.01) and older age (OR 3.6 [2.0-6.3], P < 0.0005). Obesity (OR 1.7 [1.3-2.1], P < 0.0005) and older age (OR 1.3 [1.0-1.6], P = 0.03) were also risk factors for hypoxemia. CONCLUSIONS: Obesity was found to be a significant predictor for mortality among inpatients with COVID-19 after adjusting for age, gender, and other comorbidities. Patients with obesity were also more likely to present with hypoxemia.

A Case Series of Five People Living with HIV Hospitalized with COVID-19 in Chicago, Illinois.

The risk of COVID-19 among people living with HIV (PLWH) is largely unknown and there have been very few reported cases in the literature. We report a case series of five PLWH with COVID-19. We identified all patients with a diagnosis of HIV who tested positive for SARS-CoV-2 at University of Chicago Medicine between March 1, 2020, and April 7, 2020. We retrospectively collected data regarding demographics, comorbidities, medications, laboratory test results, radiology results, and outcomes associated with COVID-19. All five PLWH with COVID-19 were African American; 80% (4/5) were cisgender females. The mean age of patients was 48 years old (range 38-53). The majority of patients presented with cough, fever, and shortness of breath. Three patients had diarrhea. One patient presented with predominantly cardiac symptoms. All were taking antiretroviral therapy (ART) with CD4 count >200 cells/mm3 and suppressed HIV viral loads at the time of COVID-19 diagnosis. All five patients were hospitalized, two required supplemental oxygen, and none required mechanical ventilation. Four patients were treated with azithromycin and a cephalosporin and two were also treated with hydroxychloroquine. The median length of stay was 3 days (range 2-7). All patients recovered. More research is needed to understand the risks of COVID-19 among PLWH and the impact of ART on outcomes for patients with COVID-19.

Acquired hypogammaglobulinemia and pathogen-specific antibody depletion after solid organ transplantation in human immunodeficiency virus infection: A brief report.

Hypogammaglobulinemia (HGG) frequently occurs in recipients after types of (SOT). The incidence and significance of HGG in HIV+ recipients of SOT are just being explored. We reported that 12% of the recipients in the SOT in multi-center HIV-TR (HIV-TR) Study developed moderate or severe HGG at 1 year. In LT recipients, this was associated with serious infections and death. We have now further characterized the decreased antibodies in HIV+ SOT recipients who developed HGG. We measured the levels of pathogen-specific antibodies and poly-specific self-reactive antibodies (PSA) in relation to total IgG levels from serial serum samples for 20 HIV+ SOT recipients who developed moderate to severe HGG following SOT. Serum antibody levels to measles, tetanus toxoid, and HIV-1 were determined by EIA. Levels of PSAs were determined by incubating control lymphocytes with patient serum, staining with anti-human IgG Fab-FITC, and analysis by flow cytometry. Levels of PSA were higher compared to healthy, HIV-uninfected controls at pre-transplant baseline and increased by weeks 12 and 26, but the changes were not significant. Likewise, anti-HIV antibody levels remained unchanged over time. In contrast, antibody levels against measles and tetanus were significantly reduced from baseline by week 12, and did not return to baseline, even after 2 years. For HIV patients who develop moderate to severe HGG after transplant, the reduction in IgG levels is associated with a significant decrease in pathogen-specific antibody titers, while PSA levels and anti-HIV antibodies are unchanged. This may contribute to infectious complications and other clinical endpoints.

A case of Q fever after liver transplantation.

Coxiella burnetii, the causative agent of Q fever, is a zoonosis that causes both acute and chronic disease in humans. Few cases have been reported in solid organ transplant recipients, and this case highlights the need to include Q fever in the differential diagnosis for fever of unknown origin in solid organ transplant hosts.

Utility of Leflunomide in the Treatment of Drug Resistant Cytomegalovirus Retinitis.

PURPOSE: To describe leflunomide use in the treatment of drug resistant cytomegalovirus retinitis. Leflunomide has been shown to be effective in the treatment of systemic CMV viremia. METHODS: Retrospective chart review of patients with CMV retinitis treated with leflunomide. RESULTS: Two HIV-negative organ transplant recipients with UL 97 mutation resistant-genotype CMV were identified. Patient 1 developed CMV viremia post-kidney transplant and subsequently bilateral CMV retinitis. Retinitis progressed, despite intravitreal injection of ganciclovir and foscarnet, and IV foscarnet and oral valganciclovir. Retinitis control was achieved with the addition of oral leflunomide. Disease remained inactive for 22 months. Patient 2 developed CMV retinitis after lung transplant. Disease progressed despite intravitreal foscarnet injections and oral valganciclovir. Control of retinitis was achieved with addition of oral leflunomide, allowing cessation of intravitreal therapy. Disease remained inactive until his death. CONCLUSIONS: Leflunomide may be considered as a treatment option for resistant CMV retinitis.

Cobicistat Significantly Increases Tacrolimus Serum Concentrations in a Renal Transplant Recipient with Human Immunodeficiency Virus Infection.

Cobicistat is a pharmacokinetic booster in several fixed-dose combination products for treatment of human immunodeficiency virus (HIV) infection. As a potent inhibitor of cytochrome P450 (CYP) 3A enzymes, significant drug-drug interactions are expected between cobicistat and medications that are metabolized primarily through the CYP3A pathway, including calcineurin inhibitors (e.g., tacrolimus and cyclosporine). We describe a case of tacrolimus toxicity due to supratherapeutic tacrolimus concentrations when Stribild (elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate) was initiated for newly diagnosed HIV infection in a 50-year-old renal transplant recipient who was previously receiving a stable tacrolimus regimen. Drug-drug interaction via CYP3A inhibition was acknowledged, and weekly labs were ordered to allow for close monitoring of renal function and tacrolimus serum concentrations as recommended by Stribild prescribing information. The patient reported headache, insomnia, stomachache, and decreased urine output within 1 week of starting Stribild and was found to have acute kidney injury (serum creatinine [Scr ]concentration increasing from 1.5-2.3 mg/dl) and a serum tacrolimus concentration of 111.2 ng/ml at 1 week follow-up (goal trough level 4-6 ng/ml). Both tacrolimus and Stribild were withheld. In 15 days, the patient's tacrolimus serum concentration returned to goal. In the interim, he required twice/week clinic visits for laboratory assessments and an emergency department visit for management of hyperkalemia (potassium 6.5 mEq/L). Triumeq (abacavir, dolutegravir, and lamivudine) was started about 4 weeks later after Scr returned to baseline, and his tacrolimus serum trough concentrations subsequently remained stable. To our knowledge, this is the first case report describing the extent, significance, and onset of cobicistat and tacrolimus drug-drug interaction in clinical practice. As more fixed-dose combination products including cobicistat as a pharmacokinetic booster come to market, clinicians should be reminded of its multitude of clinically significant drug-drug interactions.

Use of leflunomide in renal transplant recipients with ganciclovir-resistant/refractory cytomegalovirus infection: a case series from the University of Chicago.

INTRODUCTION: Although antiviral prophylaxis for cytomegalovirus (CMV) is widely used, CMV infection remains common in renal transplant recipients with adverse consequences. METHODS: We report 5 cases of renal transplant recipients with resistant CMV infection who were successfully managed with leflunomide at the University of Chicago Medical Center. RESULTS: Five renal transplant recipients (2 simultaneous pancreas/kidney transplants, 3 deceased donor kidney transplants) were diagnosed with GCV-resistant CMV infection from 2003 to 2011. Of the 4 patients who had resistance genotype testing, 3 showed a UL97 mutation and 1 patient had a clinically resistant CMV infection. All patients received CMV prophylaxis with valganciclovir for 3 months. The number of days from the date of transplant to viremia ranged from 38 to 458 days (median 219). All 5 patients received other antiviral agents (e.g. ganciclovir, foscarnet), and in 4 patients, viremia was cleared before leflunomide was initiated as consolidation (or maintenance) therapy. CONCLUSION: Leflunomide was well tolerated and successful in preventing recurrence of viremia in renal transplant recipients with resistant CMV infection. The beneficial effect of leflunomide in this setting warrants further investigation.

Human immunodeficiency virus and coinfection with hepatitis B and C.

In HIV-infected individuals, coinfection with HBV and/or HCV is common because of shared modes of transmission. It is known that HIV accelerates progression of liver disease and results in increased morbidity and mortality associated with viral hepatitis, but it is less clear if viral hepatitis has a direct effect on HIV. Treatment of viral hepatitis improves outcomes and should be considered in all HIV-infected patients. Treatment of HBV without concurrent treatment of HIV is risky because resistance can occur in both viruses if regimens are not carefully chosen.

BK Virus and Its Role in Hematopoietic Stem Cell Transplantation: Evolution of a Pathogen.

We reviewed the literature regarding disease induced by BK virus (BKV) in the hematopoietic stem cell transplant (HSCT) population, particularly hemorrhagic cystitis (HC) and nephritis. The association between BKV and HC has been reported over the past four decades. BKV has been clinically implicated and widely accepted as an etiologic agent of HC and nephritis in HSCT and nephropathy in renal transplant patients. We discuss the potential benefit of early initiation of therapy in patients who fail supportive care alone as well as the different treatment strategies for HC induced by BKV. Treatments that have been used such as cidofovir and leflunomide are accompanied by risks, and the benefits are not as concrete as with other viral illness in the HSCT population.

Infectious complications of stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) is an accepted treatment for a variety of hematologic malignancies. The profound immunosuppression these patients experience adversely affects their risk of infection. This risk is much higher than in the general population and requires aggressive diagnostic and therapeutic interventions. The chapter will outline the major infections after HSCT.

Geographic differences in disease expression of cryptococcosis in solid organ transplant recipients in the United States.

BACKGROUND: Whether there are geographic differences in clinical presentation of cryptococcosis in solid organ transplant (SOT) recipients in the United States (US) is not known. MATERIAL/METHODS: Patients comprised a cohort of 120 SOT recipients from US transplant centers who fulfilled the EORTC/MSG criteria for cryptococcal disease. RESULTS: Central nervous system, pulmonary, and cutaneous cryptococcal disease were observed in 51% (61/120), 64% (77/120), and 15% (18/120) of the patients, respectively. Cutaneous disease was documented in 9% (3/32) of the patients from South Atlantic region, 19% (6/32) from Mid Atlantic, 26% (6/23) from Southern, 7% (2/29) from Midwestern, and in 1 of 4 patients from the Northwestern region of the US. When controlled for age, immunosuppressive regimen, type of transplant, and renal failure at baseline, patients from the Southern compared with other regions of the US were significantly more likely to have cutaneous cryptococcal disease (OR 3.8, 95% CI 1.1-14, P=0.045). CONCLUSIONS: Post-transplant cryptococcosis is more likely to present with cutaneous disease in the Southern region compared with other regions in the US. This predilection for cutaneous cryptococcosis could not be explained on the basis of differences in immunosuppression or the type of transplant. Whether our findings are related to strain-related variations in characteristics of the yeast or other transplant variables remains to be determined.

Unrecognized pretransplant and donor­derived cryptococcal disease in organ transplant recipients.

BACKGROUND: Cryptococcosis occurring ≤30 days after transplantation is an unusual event, and its characteristics are not known. METHODS: Patients included 175 solid-organ transplant (SOT) recipients with cryptococcosis in a multicenter cohort. Very early-onset and late-onset cryptococcosis were defined as disease occurring ≤30 days or >30 days after transplantation, respectively. RESULTS: Very early-onset disease developed in 9 (5%) of the 175 patients at a mean of 5.7 days after transplantation. Overall, 55.6% (5 of 9) of the patients with very early-onset disease versus 25.9% (43 of 166) of the patients with late-onset disease were liver transplant recipients (P = .05). Very early cases were more likely to present with disease at unusual locations, including transplanted allograft and surgical fossa/site infections (55.6% vs 7.2%; P < .001). Two very early cases with onset on day 1 after transplantation (in a liver transplant recipient with Cryptococcus isolated from the lung and a heart transplant recipient with fungemia) likely were the result of undetected pretransplant disease. An additional 5 cases involving the allograft or surgical sites were likely the result of donor‐acquired infection. CONCLUSIONS: A subset of SOT recipients with cryptococcosis present very early after transplantation with disease that appears to occur preferentially in liver transplant recipients and involves unusual sites, such as the transplanted organ or the surgical site. These patients may have unrecognized pretransplant or donor-derived cryptococcosis.

Outcomes from pandemic influenza A H1N1 infection in recipients of solid-organ transplants: a multicentre cohort study.

BACKGROUND: There are few data on the epidemiology and outcomes of influenza infection in recipients of solid-organ transplants. We aimed to establish the outcomes of pandemic influenza A H1N1 and factors leading to severe disease in a cohort of patients who had received transplants. METHODS: We did a multicentre cohort study of adults and children who had received organ transplants with microbiological confirmation of influenza A infection from April to December, 2009. Centres were identified through the American Society of Transplantation Influenza Collaborative Study Group. Demographics, clinical presentation, treatment, and outcomes were assessed. Severity of disease was measured by admission to hospital and intensive care units (ICUs). The data were analysed with descriptive statistics. Proportions were compared by use of chi(2) tests. We used univariate analysis to identify factors leading to pneumonia, admission to hospital, and admission to an ICU. Multivariate analysis was done by use of a stepwise logistic regression model. We analysed deaths with Kaplan-Meier survival analysis. FINDINGS: We assessed 237 cases of medically attended influenza A H1N1 reported from 26 transplant centres during the study period. Transplant types included kidney, liver, heart, lung, and others. Both adults (154 patients; median age 47 years) and children (83; 9 years) were assessed. Median time from transplant was 3.6 years. 167 (71%) of 237 patients were admitted to hospital. Data on complications were available for 230 patients; 73 (32%) had pneumonia, 37 (16%) were admitted to ICUs, and ten (4%) died. Antiviral treatment was used in 223 (94%) patients (primarily oseltamivir monotherapy). Seven (8%) patients given antiviral drugs within 48 h of symptom onset were admitted to an ICU compared with 28 (22.4%) given antivirals later (p=0.007). Children who received transplants were less likely to present with pneumonia than adults, but rates of admission to hospital and ICU were similar. INTERPRETATION: Influenza A H1N1 caused substantial morbidity in recipients of solid-organ transplants during the 2009-10 pandemic. Starting antiviral therapy early is associated with clinical benefit as measured by need for ICU admission and mechanical ventilation. FUNDING: None.

Significant CD4, CD8, and CD19 lymphopenia in peripheral blood of sarcoidosis patients correlates with severe disease manifestations.

BACKGROUND: Sarcoidosis is a poorly understood chronic inflammatory condition. Infiltration of affected organs by lymphocytes is characteristic of sarcoidosis, however previous reports suggest that circulating lymphocyte counts are low in some patients with the disease. The goal of this study was to evaluate lymphocyte subsets in peripheral blood in a cohort of sarcoidosis patients to determine the prevalence, severity, and clinical features associated with lymphopenia in major lymphocyte subsets. METHODOLOGY/PRINCIPAL FINDINGS: Lymphocyte subsets in 28 sarcoid patients were analyzed using flow cytometry to determine the percentage of CD4, CD8, and CD19 positive cells. Greater than 50% of patients had abnormally low CD4, CD8, or CD19 counts (p<4x10(-10)). Lymphopenia was profound in some cases, and five of the patients had absolute CD4 counts below 200. CD4, CD8, and CD19 lymphocyte subset counts were significantly correlated (Spearman's rho 0.57, p = 0.0017), and 10 patients had low counts in all three subsets. Patients with severe organ system involvement including neurologic, cardiac, ocular, and advanced pulmonary disease had lower lymphocyte subset counts as a group than those patients with less severe manifestations (CD4 p = 0.0043, CD8 p = 0.026, CD19 p = 0.033). No significant relationships were observed between various medical therapies and lymphocyte counts, and lymphopenia was present in patients who were not receiving any medical therapy. CONCLUSIONS/SIGNIFICANCE: Significant lymphopenia involving CD4, CD8, and CD19 positive cells was common in sarcoidosis patients and correlated with disease severity. Our findings suggest that lymphopenia relates more to disease pathology than medical treatment.

Cutaneous cryptococcosis in solid organ transplant recipients.

Clinical manifestations, treatment, and outcomes of cutaneous cryptococcosis in solid organ transplant (SOT) recipients are not fully defined. In a prospective cohort comprising 146 SOT recipients with cryptococcosis, we describe the presentation, antifungal therapy, and outcome of cutaneous cryptococcal disease. Cutaneous cryptococcosis was documented in 26/146 (17.8%) of the patients and manifested as nodular/mass (34.8%), maculopapule (30.4%), ulcer/pustule/abscess (30.4%), and cellulitis (30.4%) with 65.2% of the skin lesions occurred in the lower extremities. Localized disease developed in 30.8% (8/26), and disseminated disease in 69.2% (18/26) with involvement of the central nervous system (88.9%, 16/18), lung (33.3%, 6/18), or fungemia (55.6%, 10/18). Fluconazole (37.5%) was employed most often for localized and lipid formulations of amphotericin B (61.1%) for disseminated disease. Overall mortality at 90 days was 15.4% (4/26) with 16.7% in disseminated and 12.5% in localized disease (P = 0.78). SOT recipients who died were more likely to have renal failure (75.0% vs. 13.6%, P = 0.028), longer time to onset of disease after transplantation (87.5 vs. 22.6 months, P = 0.023), and abnormal mental status (75% vs. 13.6%, P = 0.028) than those who survived. Cutaneous cryptococcosis represents disseminated disease in most SOT recipients and preferentially involves the extremities. Outcomes with appropriate management were comparable between SOT recipients with localized and disseminated cryptococcosis.

Identifying predictors of central nervous system disease in solid organ transplant recipients with cryptococcosis.

BACKGROUND: Cerebrospinal fluid (CSF) analysis is often deferred in patients with cryptococcal disease, particularly in the absence of neurologic manifestations. We sought to determine whether a subset of solid organ transplant (SOT) recipients with high likelihood of central nervous system (CNS) disease could be identified in whom CSF analysis must be performed. METHODS: Patients comprised a multicenter cohort of SOT recipients with cryptococcosis. RESULTS: Of 129 (88%) of 146 SOT recipients with cryptococcosis who underwent CSF analysis, 80 (62%) had CNS disease. In the overall study population, abnormal mental status, time to onset of cryptococcosis more than 24 months posttransplantation (late-onset disease), serum cryptococcal antigen titer more than 1:64, and fungemia were independently associated with an increased risk of CNS disease. Of patients with abnormal mental status, 95% had CNS cryptococcosis. When only patients with normal mental status were considered, three predictors (serum antigen titer >1:64, fungemia, and late-onset disease) independently identified patients with CNS cryptococcosis; the risk of CNS disease was 14% if none, 39% if one, and 94% if two of the aforementioned predictors existed (chi for trend P<0.001). CONCLUSIONS: CSF analysis should be strongly considered in SOT recipients with cryptococcosis who have late-onset disease, fungemia, or serum cryptococcal antigen titer more than 1:64 even in the presence of normal mental status.