Fatal Scopulariopsis infection in a lung transplant recipient: lessons of organ procurement.

Seventeen days after double lung transplantation, a 56-year-old patient with idiopathic pulmonary fibrosis developed respiratory distress. Imaging revealed bilateral pulmonary infiltrates with pleural effusions and physical examination demonstrated sternal instability. Broad-spectrum antibacterial and antifungal therapy was initiated and bilateral thoracotomy tubes were placed. Both right and left pleural cultures grew a mold subsequently identified as Scopulariopsis brumptii. The patient underwent pleural irrigation and sternal debridement three times but pleural and wound cultures continued to grow S. brumptii. Despite treatment with five antifungal agents, the patient succumbed to his illness 67 days after transplantation. Autopsy confirmed the presence of markedly invasive fungal disease and pleural rind formation. The patient's organ donor had received bilateral thoracostomy tubes during resuscitation in a wilderness location. There were no visible pleural abnormalities at the time of transplantation. However, the patient's clinical course and the location of the infection, in addition to the lack of similar infection in other organ recipients, strongly suggest that Scopulariopsis was introduced into the pleural space during prehospital placement of thoracostomy tubes. This case of lethal infection transmitted through transplantation highlights the unique risk of using organs from donors who are resuscitated in an outdoor location.

Herpes simplex and varicella zoster viruses: forgotten but not gone.

Herpesvirus infections are common complications of organ transplantation. The most frequent herpesvirus infections are caused by cytomegalovirus (CMV), herpes simplex (HSV) and varicella zoster (VZV). Despite expansion of the therapeutic armamentarium, HSV and VZV continue to cause morbidity and occasional mortality in transplant recipients. Here we review the incidence and risk factors for HSV and VZV disease, their clinical presentation, effects of newer immunosuppressive regimens and prophylaxis for HSV and VZV in solid organ transplant recipients.

Varicella in a pediatric heart transplant population on nonsteroid maintenance immunosuppression.

OBJECTIVE: Varicella-zoster virus has been reported to produce serious, often life-threatening, disease in immunosuppressed patients with a variety of diagnoses. The impact of this virus on the young child after heart transplantation has not been reported. METHODS: We reviewed the charts of 28 children who were <10 years of age at heart transplantation and had at least 1 year of follow-up. The median follow-up period was 7 years (1.4-13.0 years). All were seronegative for varicella-zoster virus before transplantation. Fourteen (50%) developed varicella at a median time posttransplantation of 3.3 years. The first 7 were admitted for intravenous acyclovir for 3 days followed by oral acyclovir for 7 days. The last 7 were treated as outpatients with oral valacyclovir for 7 days (n = 6) or with oral acyclovir for 10 days (n = 1). RESULTS: Intravenous and oral regimens both were well tolerated and were without complications. No patient was receiving steroids at the time that they developed their initial episode of varicella. One patient was receiving steroids for therapy of posttransplantation lymphoproliferative disease when she developed recurrent varicella or generalized zoster. No episodes of rejection were attributed to the varicella-zoster virus infection. There were no episodes of localized zoster. All patients experienced seroconversion from undetectable to detectable antibody titers early after varicella, and 12 of the 14 patients continued to have persistent detectable titers in late follow-up. Two of the 14 who received chemotherapy or enhanced immunosuppression after retransplantation transiently lost detectable varicella-zoster virus antibodies but currently have detectable titers. CONCLUSIONS: Primary varicella-zoster infection was well tolerated in our young pediatric heart transplant recipients, with no serious complications. We now reserve inpatient/intravenous therapy for those who are unable to tolerate oral medications or those who are receiving enhanced immunosuppression.

Valacyclovir for the prevention of cytomegalovirus infection after allogeneic stem cell transplantation: a single institution retrospective cohort analysis.

A retrospective single center study was performed to evaluate the safety and efficacy of valacyclovir for prevention of cytomegalovirus (CMV) infection (reactivation) after allogeneic stem cell transplantation (SCT). We compared a group of 31 patients at risk for CMV reactivation (donor, recipient or both seropositive for CMV) who received valacyclovir at an oral dose of 1 g three times a day for CMV prophylaxis with a matched cohort of 31 patients who did not receive the drug or any other form of CMV prophylaxis. Valacyclovir was used as primary prophylaxis in 12 patients and as secondary prophylaxis (after a prior CMV reactivation was effectively treated with either ganciclovir or foscarnet and without CMV antigenemia at the start of valacyclovir) in the remaining 19 patients. The two treatment groups were well matched for the donor-recipient CMV serological status and other pre-transplant characteristics. CMV reactivation was detected by blood antigenemia testing using a commercially available immunofluorescence assay for CMV lower matrix protein pp65 in circulating leukocytes. For primary prophylaxis, 3/12 patients who received valacyclovir reactivated CMV compared to 24/31 patients in the control group (P < 0.001). For secondary prophylaxis, 5/19 valacyclovir patients reactivated compared to 16/24 control patients (P < 0.05). Valacyclovir was well tolerated except for infrequent and mild gastrointestinal side-effects. There was no difference in the incidence of CMV disease in the two groups. Prophylaxis with valacyclovir appears to be safe and efficacious in preventing both primary and secondary CMV reactivation in at-risk patients after allogeneic SCT. Larger prospective randomized studies will be required to confirm these observations.

Hemorrhagic colitis due to a novel Escherichia coli serotype (O121:H19) in a transplant patient.

Infection due to enterohemorrhagic Escherichia coli (EHEC) has not been described in immunosuppressed patients. We recently saw a case of EHEC infection caused by a novel Shiga toxin II-producing Escherichia coli serotype (O121:H19) that caused hemorrhagic colitis in a patient with renal and cardiac transplants. The patient's signs, symptoms, and colon pathology were similar to reports of EHEC infection in immunocompetent patients. This case suggests that the immunosuppressed state may not alter the clinical presentation or histopathologic findings of this disorder. Assays for EHEC are not routinely done at most hospitals. Therefore, clinicians caring for transplant patients should be aware of the typical clinical presentation of EHEC infection, so that they can initiate appropriate laboratory investigation in suspected cases.

Active CMV infection before lung transplantation: risk factors and clinical implications.

BACKGROUND: Cytomegalovirus (CMV) infection is a major cause of morbidity following lung transplantation, but active CMV infection has not been described before transplantation. Since 1990, we have screened all lung-transplant recipients for CMV infection with viral urine cultures on the day of transplantation. We retrospectively reviewed the medical records of all 102 lung-allograft recipients transplanted between March 1990 and September 1998. Patients with positive urine cultures for CMV were compared to culture negative patients for age, gender, pretransplant diagnosis, time from diagnosis to transplantation, CMV serostatus, use of pretransplant immunosuppression, T-lymphocyte subsets, and presence of fever. Posttransplant outcomes assessed were duration of intubation and hospitalization, acute rejection, frequency of CMV disease, duration of Nashville rabbit antithymocyte serum or globulin (N-RATS/G) and ganciclovir, and survival. Five (5%) of 102 patients had positive urine cultures for CMV; none had symptoms of CMV infection. All 5 had idiopathic pulmonary fibrosis (IPF) (5/5 vs 27/97; p = 0.002). The age, gender, and CMV serostatus of these patients did not differ from the 97 patients in the culture negative group. Four (80%) of the 5 patients with positive cultures were receiving treatment with azathioprine or cyclophosphamide vs only 18 (19%) of the 97 patients with negative cultures (p = 0.007), and all 5 (100%) were receiving steroids compared to 50 (52%) of 97 patients with negative cultures (p = 0.06). Culture-positive IPF patients, when compared with the 27 culture-negative IPF patients, did not differ in any demographic variable or in the use of immunosuppression, but culture-positive patients were more likely to have a CD4/CD8 T-cell subset ratio <1.0 (p = 0.02). Following transplantation, 3 (60%) of 5 IPF patients with positive CMV cultures developed CMV disease compared to 3 (11%) of 27 IPF patients with negative cultures (p = 0.03). Patients with positive cultures also received more days of parenteral antiviral therapy (mean 44 +/- 11 days vs 16 +/- 10 days; p < 0.001). Utilizing pretransplant screening, we have discovered that 16% of patients with IPF had active CMV infection, which was associated with both alterations in their T-cell subsets and a greater risk for CMV disease after transplantation. This occurrence of occult CMV infection in patients with IPF has not been previously recognized, and has important implications.

Isoniazid hepatotoxicity in renal transplant recipients.

Tuberculosis occurs at higher rates in renal transplant recipients than in the general population. It would be desirable to use isoniazid prophylaxis in renal transplant recipients at risk for reactivation of tuberculosis; yet many transplant centers do not routinely employ INH prophylaxis because they perceive transplant recipients to be an enhanced risk of hepatotoxicity from isoniazid. Data on the risk of isoniazid in renal transplant patients receiving cyclosporine-based immunosuppression are limited. We retrospectively studied 83 renal transplant recipients (mean age 39.1 +/- 11.7 yr) who had received INH prophylaxis between 1985 and 1994. Eight patients had laboratory evidence of chronic hepatitis B or chronic hepatitis C infection. The mean duration of INH therapy was 344 +/- 163 d. The mean serum glutamate oxalacetic transferase (SGOT) at the start of INH therapy was 24.1 +/- 10.9 I.U., and 10% of patients had mildly elevated SGOTs. Mean peak SGOT during therapy was 36.4 +/- 15.3 I.U. (p < 0.001 compared to start (SGOT). In follow up, 31% of patients had an abnormal SGOT (> 40 I.U.); however, the elevations were small (the highest SGOT was 88.I.U.) and never necessitated discontinuation of INH. No patient had jaundice or other evidence of clinical hepatotoxicity. The 95% confidence interval for the observed frequency of clinical hepatitis was 0% to 4.3%. At the end of INH therapy the mean SGOT was 22.7 +/- 6.2 I.U. (p > 0.2, compared with start SGOT) and only one patient had an abnormal SGOT. In conclusion, it appears that the risk of renal transplant recipients developing serious hepatotoxicity with the administration of INH is low and not different from normal individuals.

Nocardial infections in bone marrow transplant recipients.

Infections caused by Nocardia species have been infrequently described in bone marrow transplant (BMT) recipients. We reviewed six cases of nocardiosis occurring in our population of BMT recipients and the four cases previously reported in the literature. The rate of nocardial infection at our institution was 0.2% (1 of 554) among autologous BMT recipients and 1.7% (5 of 302) among allogeneic BMT recipients (odds ratio, 9.3 [95% confidence interval, 1.1-80.1]; P = .046). All 10 patients had received immunosuppressive medications, and all but one allogeneic BMT recipient had acute or chronic graft-vs.-host disease (GVHD). Four patients had extensive exposure to soil or dust before nocardiosis developed. Seventy percent of the patients died, but death was less often due to progressive nocardial infection than to complications of GVHD and associated invasive infection with Aspergillus species. Three patients had nocardiosis despite receiving prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMZ) on an intermittent basis two or three times a week. These data show that nocardial infection is an important if infrequent complication of bone marrow transplantation and is associated with a high rate of invasive fungal infection. TMP-SMZ prophylaxis given intermittently does not reliably protect against infection.

Lactobacillus bacteremia: description of the clinical course in adult patients without endocarditis.

Lactobacillus bacteremia in the absence of endocarditis is a rare entity, and the clinical relevance of such bacteremia remains unclear. The clinical courses of lactobacillus bacteremia without endocarditis in 43 previously described patients and 12 new patients were reviewed. Bacteremia with Lactobacillus alone occurred in 34 (62%) of the patients, and 12 (22%) of the patients had bacteremia with other organisms, including Lactobacillus. Lactobacillus was isolated from another site in 18 (33%) of these patients. Intravenous catheter infections were not noted in these patients. Underlying conditions included cancer (6 patients), organ transplantation (9), diabetes mellitus (4), and recent surgery (12). Fever occurred in all patients, and eight (15%) of the patients experienced a sepsis syndrome. The mortality rate was 14%; however, only three deaths were attributed soley to lactobacillus sepsis. Lactobacillus bacteremia is an uncommon condition that usually occurs in patients with severe underlying illnesses and is frequently seen as a part of a polymicrobial infection. Blood cultures positive for Lactobacillus represent true infection and not contamination. Although resistance to commonly used antibiotics is common, the mortality rate associated with this bacteremia appears to be low.

Seroepidemiology of Helicobacter pylori infection in heart transplant recipients.

We analyzed serum samples obtained from 100 heart transplant recipients before and after transplantation for the presence of IgG antibodies to Helicobacter pylori. Enzyme-linked immunosorbent assay revealed that 35 patients were seropositive before the procedure. Seropositive patients were older than seronegative patients, but the two groups did not differ in terms of cardiac diagnosis, gender, survival, or the number of admissions or rejection episodes. In addition, seropositive patients did not have more-frequent episodes of gastritis, ulcer disease, or gastrointestinal bleeding. Over a mean serological follow-up of 3.4 years, only one of 65 seronegative patients seroconverted. Of the 35 seropositive patients, 14 became seronegative for H. pylori a median of 194 days (range, 47-2,657 days) after transplantation. Seroreverters, as compared with serofast patients, had received more intravenous and total antibiotics during follow-up (P = .01), were more likely to have received a combination of antibiotics active against H. pylori (P < .025), and had received more antirejection treatment (P = .01). The incidence of H. pylori infection is not increased after heart transplantation, and many seropositive patients serorevert after transplantation when antibacterial and immunosuppressive agents are administered.

Malignant external otitis due to Aspergillus flavus with fulminant dissemination to the lungs.

Malignant external otitis secondary to aspergillus infection is rare, and only 10 cases have been reported in the literature. Nine of 10 patients responded to therapy and survived their infection. There have been no previous reports of dissemination of Aspergillus species from the ear to other organs. We describe a case of malignant external otitis due to Aspergillus flavus that disseminated hematogenously to the lungs. The result was an overwhelming, miliary pulmonary infection, which progressed very rapidly to respiratory failure and death. Pathological examination of lung tissue revealed multiple microabscesses and hyphal elements that had invaded the lung parenchyma from small pulmonary arteries.

Disseminated histoplasmosis presenting as urinary tract obstruction in a renal transplant recipient.

Disseminated histoplasmosis occasionally involves the kidney, but the infection usually does not cause either urinary symptoms or a decrease in renal function. We present a case of disseminated histoplasmosis in a renal transplant recipient who presented with urinary obstruction in the allograft from a sloughed renal papilla infected with the fungus. At the same time the patient had chronic meningitis from Histoplasma capsulatum. The literature on renal involvement with histoplasmosis is reviewed.

Single lung transplantation: a temporal look at rejection, infection, and survival.

Single lung transplantation (SLT) has emerged as routine therapy for selected patients with end-stage lung disease. This study examines the incidence of rejection, infection, and survival during the first posttransplant year. Twenty-one patients (12 male, 9 female; mean age 46 +/- 13 years) underwent 23 SLT procedures (12 left, 11 right lung). Indications were pulmonary fibrosis in six, emphysema in seven, primary pulmonary hypertension in three, Eisenmenger's syndrome in one, pulmonary veno-occlusive disease in one, a-1 antitrypsin deficiency in two, CREST syndrome in one, and retransplantation (graft failure and bronchiolitis obliterans) in two. All were maintained on triple immunotherapy. Survival at 1 year was 100%. The five patients with preoperative pulmonary hypertension had normal hemodynamics at follow up. Freedom from event at 1 year was rejection 23 per cent, all infections 6 per cent, viral 40 per cent, bacterial 55 per cent, fungal 74 per cent. At 1 year, cumulative incidence (events/patient-year) was rejection 1.61, all infections 2.18, viral 0.78, bacterial 1.12, fungal 0.28. Two of 21 patients have developed bronchiolitis obliterans at 1 and 2 years posttransplant. SLT provided safe, effective treatment for a wide variety of end-stage lung diseases. Rejection and infection, although common, may be safely treated with resolution.

Cytomegalovirus disease after heart transplantation: is acyclovir prophylaxis indicated?

To determine the efficacy of acyclovir prophylaxis in preventing cytomegalovirus (CMV) disease after heart transplantation, the clinical course of 103 patients (ages, 0.1 to 62 years; mean age, 41.8 years; 87 males, 16 females) was analyzed. Active CMV infection (defined as a positive culture from any site or a fourfold increase in immunoglobulin G antibody titers) occurred in 64% (66/103) and clinical CMV disease (defined as pathologic evidence of CMV in tissue biopsy or a typical CMV syndrome with fever and two of the following: leukopenia, thrombocytopenia, atypical lymphocytes, and elevated liver function test results in a patient with CMV infection) occurred in 25% (26/103). Independent variables studied included acyclovir prophylaxis, duration of acyclovir use, duration and type of induction therapy, donor and recipient CMV status, total steroid dose at 3 and 6 months, azathioprine dose and cyclosporine level at 3 months, age, and sex. In a multivariate regression analysis, acyclovir prophylaxis was independently associated with freedom from CMV disease (p = 0.029). Positive donor CMV status (p = 0.025), higher total steroid dose at 3 months (p = 0.036), and lower azathioprine dose at 3 months (p = 0.047) were associated with higher occurrence of CMV disease. The use of antilymphocyte induction therapy was associated with an increased occurrence of active CMV infection (p = 0.022) but not CMV disease. The prophylactic administration of acyclovir reduced the occurrence of CMV disease after heart transplantation.

Therapeutic use of ganciclovir for invasive cytomegalovirus infection in cadaveric renal allograft recipients.

Between November 1987 and September 1989, 419 cadaveric renal transplants were performed at our university. Of the patients 36 (8.6%) had invasive cytomegalovirus infection documented by gastric or duodenal mucosal biopsy in 23 (64%), bronchoalveolar lavage in 12 (33%), allograft biopsy or nephrectomy specimen in 5 (14%) and/or liver biopsy in 1 (3%). Cytomegalovirus severity was defined as mild in 27 patients, moderate in 6 and severe in 3. Ganciclovir [9-(1,3-dihydroxy-2-propoxymethyl)-guanine] was begun once the diagnosis was confirmed by histology or culture at a median of 56 days from transplantation (range 28 to 133 days). Duration of ganciclovir therapy was a minimum of 7 days or until fever was absent for 5 consecutive days (mean 12.2 +/- 3.5 days, range 4 to 21). Ganciclovir was well tolerated and side effects were limited to de novo neutropenia (7 patients), thrombocytopenia (2) and rash (1). Initial clinical improvement was observed in all patients. Two patients had recurrent cytomegalovirus infections that responded to a second course of ganciclovir. The 1-year actuarial patient survival was 100%. At a mean followup of 12.7 +/- 6.2 months 19 patients retained allograft function with a mean serum creatinine of 2.5 mg./dl. (range 1.2 to 4.6). Ganciclovir appears to be a safe and effective drug for the treatment of tissue invasive cytomegalovirus infection in cadaver renal transplant recipients. Prompt institution of this drug at diagnosis of invasive cytomegalovirus may lower the mortality rate formerly associated with this disease.

Posttransplant lymphoproliferative disease in thoracic organ transplant patients: ten years of cyclosporine-based immunosuppression.

Lymphoproliferative disease developed in 15 heart and five lung transplant recipients during a decade of heart and lung transplantation from 1980 through 1989. The overall incidence of posttransplant lymphoproliferative disease in patients who survived more than 30 days is 4%. The incidence after heart transplantation is 3.4% and after lung transplantation is 7.9% (p = 0.08). The peak occurrence of posttransplant lymphoproliferative disease is 3 to 4 months after transplantation. However, posttransplant lymphoproliferative disease occurring early versus late (defined as before or after 1 year after transplantation) appears to have different clinical outcomes. The mortality of early onset of posttransplant lymphoproliferative disease as a result of lymphoma is 36%; response to reduction in immunotherapy occurs in 89% and presentation with disseminated disease occurs in 23%. The mortality of late onset of posttransplant lymphoproliferative disease as a result of lymphoma is 70%; no patient responded to reduction in immunotherapy and presentation with disseminated disease occurs in 86% of patients. Epstein-Barr virus primary infection was present in 14 and secondary Epstein-Barr virus infection was present in three of the 20 patients with posttransplant lymphoproliferative disease. The other three patients were positive for Epstein-Barr virus also but had no pretransplant sera for comparison. There is no correlation with immunoprophylaxis or maintenance immunosuppression and the development of posttransplant lymphoproliferative disease in our series.

Cytomegalovirus infection and survival in lung transplant recipients.

Fifty-nine patients who survived more than 30 days after lung transplantation (52 heart-lung, seven double lung, and two single lung) were studied for mortality and morbidity related to cytomegalovirus (CMV) infection. CMV infection developed in 32 patients (54%) and was more common in the preoperatively CMV seropositive group (95%) as compared with the seronegative group (38%). Symptomatic infections, pneumonitis, and CMV-related mortality, however, were higher in the seronegative (primary infection) group and actuarial survival was worse in these patients (40% and 23% at 1 and 5 years, respectively). Transplantation of CMV-seropositive donor organs was associated with a significantly higher incidence of primary infection and use of seronegative blood products led to a decrease in the primary CMV infection rate. The mortality of primary CMV infection was 54% and this was associated with a significantly higher rate of pulmonary superinfections in the first year after transplantation. The incidence of late pulmonary infections was associated with the development of chronic rejection rather than CMV status. We conclude that primary CMV infection has a major impact on the outcome after lung transplantation. The high mortality of primary infections justifies an aggressive approach to prevention and treatment in the at-risk seronegative group.

Herpes simplex virus hepatitis after solid organ transplantation in adults.

Twelve patients developed herpes simplex (HSV) hepatitis a median of 18 days after solid organ transplantation. This is earlier than cytomegalovirus hepatitis, which usually occurs 30-40 days after transplantation. Eight recipients (67%) died, and in seven, the diagnosis was made at autopsy or less than 48 h before death. Clinical manifestations associated with mortality were hypotension, disseminated intravascular coagulation (DIC), metabolic acidosis, gastrointestinal bleeding, and bacteremia. Laboratory abnormalities at diagnosis associated with mortality were high creatinine, low platelet counts, prolonged partial thromboplastin time, and a high percentage of band forms on the blood smear. Disseminated HSV disease was noted in four of six patients who had an autopsy and included involvement of lungs in three and the gastrointestinal tract in three. Five recipients developed DIC and all died. Pathologically, HSV hepatitis has two forms, focal and diffuse. All three patients with diffuse liver pathology died. However, three of seven with focal liver pathology survived with antiviral therapy, which suggests that early diagnosis and treatment may be lifesaving. None of these patients had received prophylactic acyclovir. It is possible that acyclovir prophylaxis may be able to prevent this disease.

Cytomegalovirus serologic status and postoperative infection correlated with risk of developing chronic rejection after pulmonary transplantation.

Twenty-seven patients received pulmonary transplants during the period since we began routine use of cytomegalovirus-seronegative blood products for CMV-seronegative recipients. Preoperative serologic status of the recipient and the occurrence of cytomegalovirus infection in the postoperative period were correlated with development of obliterative bronchiolitis (OB) as diagnosed by transbronchial biopsy (TBB). Patients included 20 heart-lung and 7 double-lung recipients. OB occurred in 18 of 27 patients. All 3 CMV seronegative recipients receiving lungs from a seropositive donor and 9 of 10 CMV recipients seropositive at the time of transplantation developed OB compared with only 6 of 14 CMV seronegative patients receiving seronegative grafts (P = 0.018). CMV infection occurred in 10/27 patients, of whom 5 were asymptomatic; 90% of these patients developed OB. Donor-specific alloreactivity, based on primed lymphocyte testing (PLT) of bronchoalveolar lavage cells was found at the time of diagnosis of OB in 23 of 27 patients. A positive PLT was significantly associated with the presence of OB (P = 0.017). We conclude that preoperative seropositive status for CMV, grafting of organs from seropositive donors, and postoperative CMV infection are significant risk factors for developing OB. That OB is, in part, an immunologically mediated form of injury and represents chronic rejection is supported by the presence of donor-specific alloreactivity in BAL lymphocytes from all recipients with OB.