Current practices for treatment of respiratory syncytial virus and other non-influenza respiratory viruses in high-risk patient populations: a survey of institutions in the Midwestern Respiratory Virus Collaborative.

BACKGROUND: The optimal treatment for respiratory syncytial virus (RSV) infection in adult immunocompromised patients is unknown. We assessed the management of RSV and other non-influenza respiratory viruses in Midwestern transplant centers. METHODS: A survey assessing strategies for RSV and other non-influenza respiratory viral infections was sent to 13 centers. RESULTS: Multiplex polymerase chain reaction assay was used for diagnosis in 11/12 centers. Eight of 12 centers used inhaled ribavirin (RBV) in some patient populations. Barriers included cost, safety, lack of evidence, and inconvenience. Six of 12 used intravenous immunoglobulin (IVIG), mostly in combination with RBV. Inhaled RBV was used more than oral, and in the post-stem cell transplant population, patients with lower respiratory tract infection (LRTI), graft-versus-host disease, and more recent transplantation were treated at higher rates. Ten centers had experience with lung transplant patients; all used either oral or inhaled RBV for LRTI, 6/10 treated upper respiratory tract infection (URTI). No center treated non-lung solid organ transplant (SOT) recipients with URTI; 7/11 would use oral or inhaled RBV in the same group with LRTI. Patients with hematologic malignancy without hematopoietic stem cell transplantation were treated with RBV at a similar frequency to non-lung SOT recipients. Three of 12 centers, in severe cases, treated parainfluenza and metapneumovirus, and 1/12 treated coronavirus. CONCLUSIONS: Treatment of RSV in immunocompromised patients varied greatly. While most centers treat LRTI, treatment of URTI was variable. No consensus was found regarding the use of oral versus inhaled RBV, or the use of IVIG. The presence of such heterogeneity demonstrates the need for further studies defining optimal treatment of RSV in immunocompromised hosts.

Cardiac toxoplasmosis after heart transplantation diagnosed by endomyocardial biopsy.

We describe a case of cardiac toxoplasmosis diagnosed by routine endomyocardial biopsy in a patient with trimethoprim-sulfamethoxazole (TMP-SMX) intolerance on atovaquone prophylaxis. Data are not available on the efficacy of atovaquone as Toxoplasma gondii prophylaxis after heart transplantation. In heart transplant patients in whom TMP-SMX is not an option, other strategies may be considered, including the addition of pyrimethamine to atovaquone.

Acquired hypogammaglobulinemia in HIV-positive subjects after liver transplantation.

INTRODUCTION: As more solid organ transplantations are performed in patients infected with human immunodeficiency virus (HIV), post-transplant complications in this population are becoming better defined. METHODS: Using serum samples from the Solid Organ Transplantation in HIV: Multi-Site Study, we studied the epidemiology of acquired hypogammaglobulinemia (HGG) after liver transplantation (LT) in 79 HIV-infected individuals with a median CD4 count at enrollment of 288 (interquartile range 200-423) cells/µL. Quantitative immunoglobulin G (IgG) levels before and after LT were measured, with moderate and severe HGG defined as IgG 350-500 mg/dL and <350 mg/dL, respectively. Incidence, risk factors, and associated outcomes of moderate or worse HGG were evaluated using Kaplan-Meier estimator and proportional hazards (PH) models. RESULTS: The 1-year cumulative incidence of moderate or worse HGG was 12% (95% confidence interval [CI]: 6-22%); no new cases were observed between years 1 and 2. In a multivariate PH model, higher pre-transplant model for end-stage liver disease score (P = 0.04) and treated acute rejection (P = 0.04) were both identified as significant predictors of moderate or worse HGG. There was a strong association of IgG levels <500 mg/dL with non-opportunistic serious infection (hazard ratio [95% CI]: 3.5 [1.1-10.6]; P = 0.03) and mortality (3.2 [1.1-9.4]; P = 0.04). These associations held after adjustment for important determinants of infection and survival among the entire cohort. CONCLUSION: These results suggest that a proportion of HIV-positive LT recipients will develop clinically significant HGG after transplantation.

Pulmonary zygomycosis in solid organ transplant recipients in the current era.

Fifty-eight solid organ transplant recipients with zygomycosis were studied to assess the presentation, radiographic characteristics, risks for extra-pulmonary dissemination and mortality of pulmonary zygomycosis. Pulmonary zygomycosis was documented in 31 patients (53%) and developed a median of 5.5 months (interquartile range, 2-11 months) posttransplantation. In all, 74.2% (23/31) of the patients had zygomycosis limited to the lungs and 25.8% (8/31) had lung disease as part of disseminated zygomycosis; cutaneous/soft tissue (50%, 4/8) was the most common site of dissemination. Pulmonary disease presented most frequently as consolidation/mass lesions (29.0%), nodules (25.8%) and cavities (22.6%). Patients with disseminated disease were more likely to have Mycocladus corymbifer as the causative pathogen. The mortality rate at 90 days after the treatment was 45.2%. In summary, pulmonary zygomycosis is the most common manifestation in solid organ transplant recipients with zygomycosis, and disseminated disease often involves the cutaneous/soft tissue sites but not the brain.

Pre-transplant ganciclovir and post transplant high-dose valacyclovir reduce CMV infections after alemtuzumab-based conditioning.

Alemtuzumab (Campath-1H)-based conditioning regimens are effective in preventing GVHD, but are associated with very high rates of cytomegalovirus (CMV) infection, a major limitation to their use. We evaluated 85 patients receiving conditioning with fludarabine 30 mg/m2/day (day -7 to day -3), alemtuzumab 20 mg/day (day -7 to day -3), and melphalan 140 mg/m2 on day -2. The initial patients received post transplant CMV prophylaxis with high-dose acyclovir. A very high incidence of CMV viremia was observed as has been commonly reported after alemtuzumab-based conditioning. Sixty-seven subsequent patients received pre-transplant ganciclovir and high-dose valacyclovir after engraftment. The cumulative incidence of CMV infection in the valacyclovir cohort was 29%. This compared favorably to the cumulative incidence of 53% in patients receiving only acyclovir (P = 0.004) and to literature data. CMV prophylaxis with pre-transplant ganciclovir and high-dose valacyclovir after engraftment appears effective in preventing the excessive incidence of CMV infection after alemtuzumab-based conditioning regimens.

Low incidence of CMV viremia and disease after allogeneic peripheral blood stem cell transplantation. Role of pretransplant ganciclovir and post-transplant acyclovir.

To establish the incidence of CMV viremia after allogeneic blood stem cell transplantation, we studied 51 consecutive allogeneic peripheral blood stem cell (PBSC) transplant recipients. A total of 12 recipients were at moderate risk for CMV disease and 39 were at high risk. Conditioning regimens varied, but GvHD prophylaxis consisted of tacrolimus and mini-methotrexate in all patients. All patients received prophylactic ganciclovir from admission until day -2 and prophylactic acyclovir from day -1 until day 180 after transplantation. CMV viremia was treated with ganciclovir. Using a PCR-based technique, the cumulative incidence of CMV viremia was 31+/-14% by day 100 and 35+/-14% by day 150. Donor type, CMV risk group, underlying disorder, conditioning regimen, GvHD, and steroid use were not associated with the risk for CMV viremia. No cases of CMV disease occurred. We hypothesize that the low rate of CMV viremia and the absence of CMV disease in this cohort of PBSCT transplant recipients, which contrasts with other reports, may be related to the prophylactic use of high-dose acyclovir and possibly to pretransplant use of ganciclovir.

Active immunization in HIV-infected patients.

Patients infected with human immunodeficiency virus (HIV) are at risk for various viral and bacterial infections. Active immunization with currently available vaccines may reduce the risk of some vaccine-preventable diseases in this population. Based on available data, most vaccines used in the United States are safe in HIV-infected adults and children. Their clinical efficacy in these individuals is not well defined, although it appears that patients in the earlier stages of infection are more likely to mount a protective antibody response than those in the later stages. Current guidelines for vaccination in HIV-infected children and adults in the United States have been recommended by the Advisory Committee on Immunization Practices.

Cunninghamella bertholletiae infection in a bone marrow transplant patient: amphotericin lung penetration, MIC determinations, and review of the literature.

Infections caused by Cunninghamella bertholletiae, an opportunistic fungal organism, have an extremely high mortality rate. A fatal case of C. bertholletiae fungal pneumonia occurred in a man who had received an allogeneic bone marrow transplant. Aggressive debridement and high-dose liposomal amphotericin B failed to eradicate the infection. Right lung tissue samples obtained during lobectomy were assayed for amphotericin B concentrations by high-performance liquid chromatography, and minimum inhibitory concentration (MIC) determinations of amphotericin B against C. bertholletiae were determined by the macrobroth dilution method. The MIC for the isolate of C. bertholletiae was 4 microg/ml. Amphotericin B lung concentrations averaged 9.5 microg/ml (range 3.7-13.8 microg/ml), with a corresponding serum trough concentration of 0.9 microg/ml. To our knowledge, this is the first reported case of amphotericin B concentrations measured at the site of infection in a patient with a pulmonary Cunninghamella infection, together with a corresponding MIC of the organism. The patient's death, which occurred despite aggressive debridement and high amphotericin B lung concentrations, highlights the need for novel strategies to treat infections caused by invasive molds such as C. bertholletiae.

Serologic evidence for reactivation of cryptococcosis in solid-organ transplant recipients.

Cryptococcosis is a significant infection with a high mortality in solid-organ transplant recipients. Nonetheless, the pathogenesis of this disease is poorly understood. It has been hypothesized that cryptococcosis may result from either primary infection or reactivation of a latent infection. Sera were obtained from transplant recipients prior to transplantation and at the time they developed cryptococcosis. Control sera were obtained before and after transplant from patients who did not develop cryptococcosis. Sera were tested for antibodies against Cryptococcus neoformans by using an immunoblot assay. Antibody responses were also compared with those observed in sera from rats with experimental pulmonary cryptococcosis. In all, 52% of the transplant recipients who developed cryptococcosis exhibited serologic evidence of cryptococcal infection before transplantation. These patients developed cryptococcosis significantly earlier after transplant than patients without preexisting reactivity did (5.6 +/- 3.4 months compared to 40.6 +/- 63.8 months, respectively [P = 0.0011]). The results from our study suggest that a substantial proportion of transplant-associated cryptococcosis cases result from the reactivation of a latent infection. These findings also highlight the potential utility of serologic studies in identifying patients at risk for the development of cryptococcosis after transplantation.

Invasive pulmonary aspergillosis complicating neoplastic disease.

Invasive pulmonary aspergillosis is a necrotizing pneumonia that is most frequently seen in association with profound granulocytopenia as a consequence of cytotoxic chemotherapy that is used to treat hematologic neoplasms. There is considerable evidence that the incidence of this infection is increasing over the past decade as a result of improved medical support used in the management of "at risk" patients. Heightened clinical awareness coupled with advances in diagnostic techniques have led to earlier treatment and improved outcomes of this once uniformly fatal infection. Amphotericin B remains the treatment of choice; however, newer therapeutics (azoles) and strategies (combination chemotherapy, biological response modifiers) show promise as alternative regimens. Novel approaches in preventing the acquisition of pulmonary aspergillosis in the "at risk" patient are being explored.

Aspergillus species colonization and invasive disease in patients with AIDS.

Invasive aspergillosis is an uncommon infectious complication in patients with AIDS. Of the 972 patients with AIDS who were observed at our institution over a 10-year period, Aspergillus species were isolated from the respiratory sites of 45 patients before death. Invasive aspergillosis was documented at autopsy in four of these patients and was strongly suspected in an additional patient on whom an autopsy was not performed. A fifth case was documented at autopsy (no antemortem respiratory sample was obtained from this patient). Traditional risk factors for the development of invasive disease (neutropenia, hematologic malignancy, and/or corticosteroid use) were present in all of our patients with invasive aspergillosis. A review of the literature revealed reports of an additional 13 cases of invasive aspergillosis in patients with AIDS. Therapy with amphotericin B should be considered for neutropenic patients with AIDS who have pneumonia of uncertain etiology and from whom Aspergillus species have been isolated from a respiratory specimen.

Impaired phagocyte respiratory burst responses to opportunistic fungal pathogens in transplant recipients: in vitro effect of r-metHuG-CSF (Filgrastim).

Phagocyte respiratory burst capacity in response to pathogenic fungi and the in vitro effects of granulocyte colony-stimulating factor (G-CSF) were examined in 15 normal volunteers and 39 transplant recipients (4 autologous and 4 allogeneic bone marrow, 3 heart, 10 liver, 8 lung, and 10 kidney). Chemiluminescence was measured for reaction mixtures of diluted whole blood, opsonized fungi, and luminol, with and without in vitro incubation with r-metHuG-CSF (Filgrastim). Transplant patients exhibited significantly impaired respiratory burst responses to conidia and yeast compared with controls, but this was reversed with Filgrastim. Responses to hyphae were low for both groups, and G-CSF had little or no effect. There was excellent correlation between responses to fungi and responses to opsonized zymosan. In vitro respiratory burst capacity is impaired in transplant recipients. This may predict susceptibility to invasive fungal infections. G-CSF can reverse impaired phagocyte function and is of potential benefit in the prevention and/or treatment of fungal infection in transplant patients.

Delayed recognition memory span in HIV-1 infection.

We administered a spatial version of the Delayed Recognition Span Test (DRST), a working memory task performed abnormally by patients with basal ganglia disease, to a group of 96 HIV-seropositive and 83 seronegative subjects with a high prevalence of substance abuse. For comparison purposes, we also administered the Symbol-Digit Modalities Test (SDMT) and the Trail Making Test (TMT), measures which detect HIV-related mental slowing efficiently in gay men but are nonspecifically impaired in subjects with a history of substance abuse. As predicted, scores on the TMT and the SDMT did not discriminate the groups, but HIV-seropositive subjects had significantly shorter spatial spans (p < .007) and DRST total scores (p < .005). These effects could not be attributed to differences in age, education, estimated intelligence, or psychological distress, because the groups were well matched on these variables. The DRST is a promising measure of HIV-related cognitive dysfunction in substance abusers, who are often nonspecifically impaired on psychomotor tasks. These preliminary data also indicate that working memory function should be studied further in HIV-seropositive subjects.

Information processing and antiretroviral therapy in HIV-1 infection.

Computerized reaction time (RT) tasks are sensitive measures of subclinical HIV-related mental slowing. We previously reported that nondemented HIV-seropositive patients on antiretroviral therapy at the time of testing had faster choice RTs compared to matched untreated seropositive participants. In the present study, we evaluated the performance of 163 nondemented HIV-seropositive participants on a reaction time version of the Stroop task as a function of antiretroviral status. Persons on antiretroviral therapy at the time of testing had significantly faster reaction times than untreated individuals, although treated asymptomatic participants showed significantly less Stroop interference than treated symptomatic participants. These effects could not be attributed to differences in demographic variables, disease status, substance abuse, or psychological distress. These data indicate that central information processing is faster for patients treated with antiretroviral compounds compared to untreated patients, and suggest that reaction time tasks may have significant potential utility in clinical trials of neuroprotective compounds.

Reaction times are faster in HIV-seropositive patients on antiretroviral therapy: A preliminary report.

We evaluated subclinical mental and motor slowing in 142 HIV-seropositive patients without dementia, using computerized simple and choice reaction time tasks and self-report measures of psychological distress. Patients on antiretroviral therapy at the time of testing (n = 79) had significantly faster choice reaction times (p < 0.05), indicating faster mental processing speed, than untreated patients (n = 63). These faster RTs could not be attributed to differences in age, education, risk factors, degree of immunosuppression, substance abuse history, peripheral neuropathy, or psychological distress. Reaction time tasks should be investigated further as potential outcome measures in clinical trials, particularly for subjects with few or no overt cognitive deficits.

A cluster of four cases of Mycobacterium haemophilum infection.

Four cases of infection with Mycobacterium haemophilum occurred at a single hospital in a seven-month period. Only 22 cases have been reported since 1976. All four patients were immunocompromised; two had AIDS and two were the first known recipients of allogeneic bone marrow transplants (BMT) to develop the infection. One BMT recipient died of Mycobacterium haemophilum pneumonia. The organism requires hemin or ferric ammonium citrate and incubation of media at 30 degrees C for optimum growth. Clinicians and microbiologists should consider infection with Mycobacterium haemophilum, particularly when specimens are from immunocompromised patients with unexplained illness and/or when acid-fast bacilli are seen on smear.

Working memory deficits in HIV-seropositive drug users.

We studied the integrity of working memory operations in 38 HIV-seropositive and 20 seronegative drug users, using a modified version of the Tower of London task. This new task, the Tower of London-Working Memory version (TOL-WM), includes a delayed-response component in addition to the planning required for successful performance of the standard TOL. Symptomatic HIV-seropositive participants solved significantly fewer TOL-WM problems compared to matched seronegative controls. However, seropositive and seronegative subjects showed similar overall levels of planning efficiency, suggesting that the TOL-WM deficit may be associated primarily with failure to encode or maintain an adequate online memory representation. The results of this study confirm our previous report of a possible working memory deficit in HIV-1 infection and suggest that measures of working memory have particular utility in the evaluation of HIV-related cognitive deficits.

Verbal working memory in HIV-seropositive drug users.

Recent evidence suggests that HIV-seropositive drug users are impaired on tasks of visuospatial working memory compared with drug users seronegative for HIV. In the current study we evaluated the performance of 30 HIV-seropositive male drug users and 30 risk-matched seronegative controls on two measures of verbal working memory, the Listening Span and the verbal Self Ordered Pointing Task. Impaired working memory performance was significantly more common among HIV-seropositive persons compared to controls, with the highest incidence of deficit among symptomatic participants. These findings indicate that working memory deficits in persons with HIV are not domain-specific and can be demonstrated reliably in drug users.