Bernard M. Kubak

Anti-IFN-γ Autoantibodies in Disseminated Nontuberculous Mycobacterial Infections

Although many patients with disseminated nontuberculous mycobacterial disease have molecular defects in the IFN-γ/IL-12 axis, recent case reports have shown autoantibodies against IFN-γ associated with severe nontuberculous mycobacterial infections. To check this finding in an independent population, we screened 35 patients with either disseminated or pulmonary nontuberculous mycobacterial infections for whom no molecular defect was known. We identified high-titer-neutralizing anti-IFN-γ IgG in the plasma of six patients. All six patients were female, parous, of East Asian descent, and had disseminated infection, predominantly with rapidly growing mycobacteria. The anti-IFN-γ IgG had in vitro biological activity on the IFN-γ-dependent phosphorylation of STAT-1 as well as on the IFN-γ-dependent up-regulation of TNF-α and IL-12. In contrast, this anti-IFN-γ Ab had no effect on IFN-α-dependent STAT-1 phosphorylation. These patients confirm a novel syndrome linking autoimmunity and immunodeficiency.

Leptospirosis, Water Sports, and Chemoprophylaxis

Recreational activities, such as water sports and adventure travel, are emerging as an important risk factor for leptospirosis, a potentially fatal zoonosis. We report the clinical course of 2 patients who acquired leptospirosis through participation in water sports. Physicians caring for patients who participate in adventure travel involving water sports should be familiar with the risk factors for and diagnosis, prevention, and treatment of leptospirosis.

Transmission of Trypanosoma cruzi by Heart Transplantation

BACKGROUND Trypanosoma cruzi infection (i.e., Chagas disease) is an unusual complication that can occur after solid-organ transplantation and that can result in severe illness or death. In 2006, there were 2 heart transplant recipients in Los Angeles, California, reported to have acute trypanosomiasis during the same month. We conducted an investigation to determine the source of these infections. METHODS We reviewed the medical, organ procurement, and donor transfusion and transplantation records of these 2 heart transplant recipients. The 2 heart transplant recipients were interviewed regarding any kind of natural exposure and were screened for parasites by obtaining blood and other tissue samples for buffy coat, culture, and polymerase chain reaction. Serum samples from the heart transplant recipients, organ donors, and blood donors were tested for T. cruzi antibodies by use of immunofluorescence assay and radioimmunoprecipitation assay. Tissue samples from the organ donors were examined by use of polymerase chain reaction and immunohistochemical staining. Other recipients of organs from the same donors were monitored for T. cruzi infection by use of polymerase chain reaction and immunofluorescence assay. RESULTS Both heart transplant recipients had no apparent risk factors for preexisting T. cruzi infection. Both were seronegative but tested positive for the parasite, indicating recent infection. Both recipients died despite medical treatment. The organ donors tested positive for T. cruzi antibodies by use of radioimmunoprecipitation assay; the blood donors were seronegative. Six other patients had received a liver or kidney from these organ donors. None showed evidence of T. cruzi infection. CONCLUSIONS To our knowledge, this is the first report of T. cruzi transmission associated with heart transplantation. Clinicians and public health authorities should be aware that manifestations of Chagas disease can occur after transplantation, requiring rapid evaluation, diagnosis, and treatment.

Diagnosis of Coccidioidomycosis with Use of the Coccidioides Antigen Enzyme Immunoassay

BACKGROUND We have previously shown antigenuria in patients with coccidioidomycosis through use of the Histoplasma antigen enzyme immunoassay (EIA), and now we have developed a specific Coccidioides antigen EIA. METHODS The Coccidioides EIA uses antibodies to Coccidioides galactomannan. The sensitivity of the Coccidioides and Histoplasma EIAs was evaluated in patients with more-severe coccidioidomycosis, and the specificity of these EIAs was evaluated in patients with nonfungal infections, in patients with other endemic mycoses, and in healthy individuals. RESULTS Among patients in the present study, antigenuria was detected in 70.8% of patients with coccidioidomycosis with use of the Coccidioides EIA and in 58.3% of patients with use of the Histoplasma EIA. Antigenuria was absent in 99.4% of healthy individuals, patients with nonfungal infections, and patients with noninfectious conditions. Cross-reactions with other endemic mycoses were observed in 10.7% of patients. CONCLUSIONS The Coccidioides EIA has potential to be useful in the rapid diagnosis of more-severe forms of coccidioidomycosis.

Treatment of Ocular Fungal Infections With Oral Fluconazole

PURPOSE We treated five patients who had ocular fungal infections with oral fluconazole to determine its safety and effectiveness. METHODS We reviewed the case histories of the five patients. One patient had coccidioidomycosis and four had endogenous Candida endophthalmitis. RESULTS The intraocular fungal infection resolved in all patients. CONCLUSION Fluconazole appears to be a safe and effective antifungal agent that can be administered orally and may be a useful agent for treating some intraocular fungal infections.

Benefit of immune monitoring in heart transplant patients using ATP production in activated lymphocytes.

BACKGROUND Balancing immunosuppression to prevent rejection while minimizing infection or drug toxicity risk is a major challenge in heart transplantation. Therapeutic drug monitoring alone is inadequate to measure the immune response. An immune monitoring (IM) assay (ImmuKnow; Cylex, Columbia, MD) performed on peripheral blood measures adenosine triphosphatase (ATP) release from activated lymphocytes and may predict the immune state. Therefore, we sought to determine the utility of IM in heart transplant recipients. METHODS Between November 2005 and July 2008, 296 heart transplant recipients had a total of 864 IM assays performed at 2 weeks to 10 years post-transplant and were correlated with infection and rejection events that occurred within 1 month after IM testing. All patients received standard triple-drug immunosuppressive therapy with tacrolimus, mycophenolate mofetil and corticosteroids, without induction therapy. RESULTS There were 38 infectious episodes and 8 rejection episodes. The average IM score was significantly lower during infection than steady state (187 vs 280 ng ATP/ml, p < 0.001). The average IM score was not significantly different during rejection when compared with steady state (327 vs 280 ng ATP/ml, p = 0.35). Interestingly, 3 of 8 rejection episodes were antibody-mediated rejections and had hemodynamic compromise and, for these, the mean IM score was significantly higher than for steady-state patients (491 vs 280 ng ATP/ml, p < 0.001). CONCLUSIONS The non-invasive IM test appears to predict infectious risk in heart transplant patients. The association between high IM scores and rejection risk is inconclusive due to the small number of rejection episodes. Further studies with larger sample sizes for rejection episodes are required.

Diagnosis of Coccidioidomycosis by Antigen Detection Using Cross-Reaction with a Histoplasma Antigen

BACKGROUND In 2005, patients with coccidioidomycosis were observed to have positive Histoplasma antigen test results. METHODS We performed a review of the records of patients with coccidioidomycosis who were under our care who underwent testing for Histoplasma antigen to determine the value of this test in the diagnosis of coccidioidomycosis. Many of the patients were immunosuppressed and critically ill. RESULTS The Histoplasma antigen test had positive results when urine samples from 11 (58%) of 19 patients who had acute or chronic coccidioidomycosis were tested. The sensitivity was highest for patients who had acute coccidioidomycosis, and antigenuria was detected in 11 (79%) of 14 patients. One patient who had chronic coccidioidomycosis but who had a negative result when a urine sample was tested had antigen detected in bronchoalveolar lavage fluid. CONCLUSIONS Physicians should be alerted that infections with Coccidioides species may cause positive Histoplasma antigen test results. There is potential for the use of this test in the diagnosis of coccidioidomycosis by taking advantage of this observed cross-reactivity. The greatest benefit appears to be in the population of seriously ill patients with acute pneumonia who live in areas that are endemic for Coccidioides infection.

Hepatitis C-positive Donors in Heart Transplantation

Hepatitis C virus (HCV) can be transmitted to heart transplant recipients by donor organs. Mid‐term results were reported using HCV‐positive donors in patients at risk of imminent death (group I, n = 10), or in patients who otherwise would not have been offered heart transplantation (group II, n = 10) because of age (9/10) or associated medical risk (1/10). Medical records pertaining to patients receiving HCV‐positive allografts between July 1994 and December 1999 were reviewed. The recipients consisted of 19 males and one female, with a median age of 54 years for group I and 66 for group II. The HCV RNA level, seroconversion of anti‐HCV antibody, biochemical liver dysfunction, and causes of death were examined. Older recipients received reduced immunosuppression. Two patients in group II were HCV positive and were also retransplants. The hospital mortality rate was 10% in group I and 20% in group II; both hepatitis C‐positive recipients died postoperatively prior to discharge. All predischarge deaths were related to multi‐system organ failure (MSOF). All 17 survivors were HCV negative prior to transplant. Of these, 4/17 seroconverted. HCV RNA was detected in two of them. At a median follow‐up of 26.4 months, 2/11 current survivors continue to test anti‐HCV positive and are RNA negative. Three‐year actual survival was 40% for group I and 70% in group II. Transplant coronary artery disease (TCAD) accounted for one postoperative death in group I. Current data show that four out of 11 survivors had developed TCAD at 3‐year follow‐up, yielding an actual freedom from TCAD rate of 12/17 (70%) at 3‐year follow‐up. Hepatitis C transmission using a donor heart as the reservoir is moderate (25%). Limited use of such donors is justified in selected patients. The risk for hepatic disease may be reduced by tailoring immunosuppression specifically for such recipients, particularly if they are at low risk of rejection. Further studies are necessary to define a possible association between HCV and TCAD.

Cluster of Cases of Invasive Aspergillosis in a Transplant Intensive Care Unit: Evidence of Person-to-Person Airborne Transmission

In October 1998, a patient developed deep surgical-site and organ-space infection with Aspergillus fumigatus 11 days after undergoing liver retransplantation; subsequently, 2 additional patients in the transplant intensive care unit had invasive pulmonary infection with A. fumigatus diagnosed. It was determined that debriding and dressing wounds infected with Aspergillus species may result in aerosolization of spores and airborne person-to-person transmission.

Mycobacterium abscessus empyema in a lung transplant recipient

Non-tuberculous mycobacteria (NTM) have emerged as important pathogens in organ transplant recipients. Because NTM pulmonary infections vary in their clinical and radiographic presentations, heightened clinical suspicion is necessary for accurate diagnosis. We report a case of Mycobacterium abscessus empyema in a lung transplant recipient. Repeated attempts at identifying the organism from a variety of clinical specimens led to the correct diagnosis and treatment.