Stanley I. Martin

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.

Infectious Complications Associated with Alemtuzumab Use for Lymphoproliferative Disorders

BACKGROUND Alemtuzumab is an emerging therapy for refractory lymphoproliferative disorders. The associated long-term risks of infection remain poorly defined. METHODS From July 2001 through December 2003, all patients who received alemtuzumab for the treatment of lymphoproliferative disorders at 1 institution underwent a retrospective evaluation to document infectious complications until death or end of follow-up in October 2004. Alemtuzumab recipients who underwent allogeneic hematopoietic stem cell transplantation were compared with a concurrent cohort who also underwent allogeneic hematopoietic stem cell transplantation but did not receive alemtuzumab. RESULTS Twenty-seven patients were identified (21 with chronic lymphocytic leukemia and 6 with plasma cell disorders). The overall mortality was 37%, with 7 of 10 deaths being related to infection. Significant opportunistic infections occurred in 9 patients (43%) with chronic lymphocytic leukemia, including cytomegalovirus, progressive multifocal leukoencephalopathy, adenovirus, toxoplasmosis, and acanthamaebiasis. Thirty nonopportunistic infections in 22 patients (82%) were also identified. The 3 deaths related to nonopportunistic infections all involved Enterococcus species bacteremia. When compared with a concurrent chronic lymphocytic leukemia cohort that underwent allogeneic hematopoietic stem cell transplantation, alemtuzumab recipients had an incidence of cytomegalovirus reactivation of 66.7% (6 of 9 patients), compared with 37% in the non-alemtuzumab group (10 of 27 patients; P = .15), and an incidence of post-transplant opportunistic infections (excluding herpesviruses) of 44.4% (compared with 29.6% in the non-alemtuzumab group; P = .41). CONCLUSIONS Despite the use of herpesvirus and Pneumocystis pneumonia prophylaxis, serious infectious complications occur in patients receiving alemtuzumab for lymphoproliferative disorders. Infectious complications are more varied and diverse in patients receiving alemtuzumab than has been reported in trials to date.

Pneumocystis pneumonia in solid organ transplant recipients.

Pneumocystis spp. are thought to be ubiquitous in nature with serologic studies suggesting that exposure occurs commonly in childhood (2). Symptomatic Pneumocystis pneumonia (PCP) is generally limited to individuals with immune deficits. Animal models demonstrate both de novo infection via airborne transmission and by reactivation of previously established latent infections (3). Clusters of infection have been described in medical facilities among renal transplant recipients (4–6). Based on studies before routine implementation of prophylaxis, the overall incidence of infection among solid organ transplant recipients varied mostly in the range of 5–15% depending on organ type, transplant center and immunosuppressive regimens (7). In older reports before implementation of extensive prophylaxis, the attack rate appeared highest in lung and combined heart–lung transplant recipients with an overall incidence ranging from less than 10% to just over 40%. Among liver and kidney transplant recipients, the incidence appeared to be less at anywhere from close to 2% to 10–15% (1). The incidence overall may be decreasing with reduction in the routine use of corticosteroids in organ transplantation and the adoption of effective prophylactic measures. Table 1 outlines some risk factors for PCP among non-HIV-infected individuals.

Pneumocystis pneumonia in solid organ transplantation.

Pneumocystis jiroveci, previously P. carinii, is the quintessential opportunistic infection among immunocompromised patients (1). Despite the availability of effective prophylaxis, P. jiroveci remains an important pathogen among solid organ transplant recipients. Pneumocystis spp. are thought to be ubiquitous in nature with serologic studies suggesting exposure occurs commonly in childhood (2). The existence and degree of respiratory tract colonization by Pneumocystis is a topic of great interest (3,4). Symptomatic Pneumocystis pneumonia (PCP) is generally limited, however, to individuals with immune deficits. Animal models suggest that de novo infection via airborne transmission and reactivation of previously established infection can occur (5). Clusters of infection have been described in medical facilities among solid organ transplant recipients as well, suggesting the possibility of direct or indirect person-to-person transmission (6–11).

Histoplasmosis After Solid Organ Transplant

BACKGROUND To improve our understanding of risk factors, management, diagnosis, and outcomes associated with histoplasmosis after solid organ transplant (SOT), we report a large series of histoplasmosis occurring after SOT. METHODS All cases of histoplasmosis in SOT recipients diagnosed between 1 January 2003 and 31 December 2010 at 24 institutions were identified. Demographic, clinical, and laboratory data were collected. RESULTS One hundred fifty-two cases were identified: kidney (51%), liver (16%), kidney/pancreas (14%), heart (9%), lung (5%), pancreas (2%), and other (2%). The median time from transplant to diagnosis was 27 months, but 34% were diagnosed in the first year after transplant. Twenty-eight percent of patients had severe disease (requiring intensive care unit admission); 81% had disseminated disease. Urine Histoplasma antigen detection was the most sensitive diagnostic method, positive in 132 of 142 patients (93%). An amphotericin formulation was administered initially to 73% of patients for a median duration of 2 weeks; step-down therapy with an azole was continued for a median duration of 12 months. Ten percent of patients died due to histoplasmosis with 72% of deaths occurring in the first month after diagnosis; older age and severe disease were risk factors for death from histoplasmosis. Relapse occurred in 6% of patients. CONCLUSIONS Although late cases occur, the first year after SOT is the period of highest risk for histoplasmosis. In patients who survive the first month after diagnosis, treatment with an amphotericin formulation followed by an azole for 12 months is usually successful, with only rare relapse.

Genomic presence of recombinant porcine endogenous retrovirus in transmitting miniature swine

The replication of porcine endogenous retrovirus (PERV) in human cell lines suggests a potential infectious risk in xenotransplantation. PERV isolated from human cells following cocultivation with porcine peripheral blood mononuclear cells is a recombinant of PERV-A and PERV-C. We describe two different recombinant PERV-AC sequences in the cellular DNA of some transmitting miniature swine. This is the first evidence of PERV-AC recombinant virus in porcine genomic DNA that may have resulted from autoinfection following exogenous viral recombination. Infectious risk in xenotransplantation will be defined by the activity of PERV loci in vivo.

Effect of body mass index and device type on infection in left ventricular assist device support beyond 30 days

Infection as a complication of long-term left ventricular assist device (LVAD) support leads to significant morbidity and mortality. Obesity, a possible risk factor for other postoperative cardiovascular surgical site infections, is an increasingly prevalent condition among recipients of LVAD devices. We retrospectively analyzed 145 LVADs that remained in place beyond 30 days over a nine-year period at a single medical institution. Statistical analysis was carried out using univariate and multivariable logistic regression and chi(2)-testing where indicated. Body mass index (BMI) had no effect on the incidence of infectious outcomes regardless of age, gender, underlying pathogen or device type. This included the morbidly obese population as well (BMI >or=40). Independent of BMI, device type did have an effect, with the HeartMate XVE increasing the risk for infections [odds ratio (OR) 4.3 with 95% confidence interval (CI) 2.1-8.8, P=0.0001] and the HeartMate II reducing the risk (OR 0.21 with 95% CI 0.09-0.50, P=0.0001). The risk for infection after LVAD placement for long-term support is likely to be a multi-factorial phenomenon. BMI, including morbid obesity, does not appear to be a statistically significant relevant factor in determining that risk. Device type may have an effect, however, on risk of infection in long-term support.

Monitoring infection with Epstein-Barr virus among seromismatch adult renal transplant recipients.

Patients who undergo Epstein–Barr virus (EBV) seromismatch (D+/R−) transplants have a higher risk for the development of post‐transplant lymphoproliferative disorder (PTLD). Adult renal transplant recipients at a single institution were prospectively monitored for EBV during the first year post‐transplant. Over a 2‐year period, 34 patients (7.78%) were identified as being EBV D+/R−recipients. Patients who developed symptoms or had persistent viremia were pre‐emptively administered rituximab. Six recipients were discharged without monitoring on the protocol. Of those six, three (50%) developed PTLD and all three lost their grafts. Twenty (60.6%) of the 34 recipients developed viremia during the first year post‐transplant. Of the recipients who became viremic, six (30%) received rituximab. None of the six who received rituximab‐developed PTLD. We found that recipients who were not monitored on the protocol were more likely to have PTLD and graft loss compared to those who were (p = 0.008). Post‐transplant monitoring of adults who undergo EBV D+/R−kidney transplants for viremia and symptoms associated with EBV infection may prompt intervention which reduces the incidence of PTLD within the first year. Use of rituximab in preventing PTLD among patients with primary EBV infection requires further prospective study to determine its overall safety and efficacy.

Multidrug-resistant Acinetobacter baumannii Pneumonia in Lung Transplant Recipients

We present 6 cases of multidrug-resistant (MDR) Acinetobacter baumannii pneumonia in lung transplant recipients. All cases were treated with imipenem and/or non-traditional antibiotics, such as tigecycline and colistimethate, and had different microbiologic and clinical outcomes. Prior treatment with broad-spectrum anti-microbial therapy was the single most likely risk factor for the development of infection due to MDR Acinetobacter baumannii. Ideal preventive and therapeutic strategies for this pathogen in lung transplant recipients require further study.

Successful Management of Immunosuppression in a Patient With Severe Hyperammonemia After Lung Transplantation

Hyperammonemia after lung transplantation is a rare complication of unknown etiology. Its management is largely supportive and outcomes have been variable. More disconcerting is its immunosuppressive management because the precipitating factors leading to this potentially lethal entity are unknown, but are suspected to be drug-related. We describe the successful management of a lung transplant recipient with severe hyperammonemia.