Psarros, Georgios MD*; Kaul, Daniel L. MD*; Kauffman, Carol A. MD*†
Fungal infections occur in 5% to 20% of solid organ ransplant recipients and are an important cause of morbidity and mortality.1,2 Many of these infections are disseminated at the time of presentation, making early recognition and initiation of appropriate therapy critical. In comparison with the opportunistic fungi, such as Candida and Aspergillus species, the endemic mycoses, histoplasmosis, blastomycosis, and coccidioidomycosis cause a small number of infections in transplant recipients.2,3 The rarity of these infections and their protean symptoms when the infection is disseminated can lead to diagnostic delays and subsequent high mortality. On the other hand, with timely and appropriate treatment, the outcomes for infection with several of these endemic fungi are generally favorable.3
Histoplasmosis, the most prevalent among the endemic mycoses, is also the most common endemic mycosis reported in solid organ transplant recipients. Most cases have been reported in kidney transplants and far fewer in liver or lung transplant recipients.3 Histoplasmosis is very uncommon in patients who undergo heart transplantation; to our knowledge, only 2 previous cases have been reported.4,5 We describe a case of disseminated histoplasmosis occurring 2 months after orthotopic heart transplantation in a patient with no obvious history of exposure. The diagnostic and therapeutic challenges presented by this case are emphasized.
A 29-year-old man, who had undergone orthotopic heart transplantation for familial dilated cardiomyopathy 2 months earlier, was admitted with high fever, rigors, mild chest pain, nonbloody diarrhea 2 to 4 times daily, and severe headache for 2 days. His medical history included mild chronic renal insufficiency, with a baseline creatinine level of 1.6 to 1.8 mg/dL. His cytomegalovirus (CMV) status was donor positive and recipient positive. Induction immunosuppression was accomplished with methylprednisolone and thymoglobulin. He had not had any episodes of rejection, and his immunosuppressive regimen on admission consisted of prednisone, 15 mg twice daily; mycophenolate mofetil, 1500 mg twice daily; and tacrolimus, dosed to keep serum levels between 5 and 7 ng/mL. Other medications included valganciclovir and trimethoprim-sulfamethoxazole for prophylaxis for CMV and Pneumocystis jirovecii, respectively.
Physical examination on admission revealed a well-nourished man whose temperature was 103.4°F; pulse rate, 94 beats/min; blood pressure, 119/70 mm Hg; respirations, 18/min; and oxygen saturation, 95% on room air. He had a well-healed sternotomy scar; there were no rashes, lymphadenopathy, or mucous membrane lesions. Cardiac, lung, and abdominal examinations were within normal limits. Neurological examination revealed no abnormalities.
On admission, the hemoglobin level was 10g/dL, white blood cell count was 3,700/μL, and platelets were 217,000/μL; serum creatinine level was 1.6 mg/dL, and liver enzymes and bilirubin level were normal. No enteric pathogens were identified in stool, and Clostridium difficile toxin was negative. Cerebrospinal fluid cell counts, protein, and glucose were unremarkable, and cerebrospinal fluid, blood, and urine yielded no growth. Chest radiograph showed no infiltrates; echocardiogram demonstrated normal left and right ventricular function and no pericardial effusion. A right heart catheterization with biopsy showed no acute rejection.
Initial empirical antibiotic therapy consisted of intravenous vancomycin and piperacillin-tazobactam. However, the patient remained febrile, and on hospital day 3, all antibiotics were discontinued. By hospital day 5, mild conversational dyspnea and a cough with occasional hemoptysis were noted. Chest radiograph revealed new diffuse interstitial and alveolar infiltrates, and computed tomography (CT) scan demonstrated diffuse parenchymal infiltrates with ill-defined nodular opacities and mild splenomegaly (Fig. 1).
Empirical administration of voriconazole 400 mg intravenously every 12 hours after an initial loading dose was initiated for possible invasive fungal infection, and bronchoalveolar lavage (BAL) was performed. Methenamine silver stain revealed no organisms, and polymerase chain reaction for P. jirovecii was negative. Serum galactomannan antigen was not elevated. Viral cultures from the BAL fluid and serum polymerase chain reaction for CMV were negative. White blood cell count had fallen to 1700/μL with 88% neutrophils, platelets were 45,000/μL, and alkaline phosphatase had risen to 506 units/mL. Aspartate aminotransferase was 62 IU/L, alanine aminotransferase was 37 IU/L, and bilirubin level was 1.2 mg/dL. The serum ferritin was 16,500 ng/mL. Valganciclovir and mycophenolate mofetil were stopped because of the pancytopenia.
Despite treatment with voriconazole, daily fevers persisted; increasing hypoxia and rising serum creatinine required transfer to the intensive care unit. By hospital day 10, the urine Histoplasma antigen assay was reported strongly positive at 51.57 units/mL. Histoplasma capsulatum complement fixation antibody returned later showing 1:16 (yeast phase) and 1:8 (mycelial phase); immunodiffusion was negative.
A presumptive diagnosis of disseminated histoplasmosis was made. Voriconazole was discontinued after 5 days, and liposomal amphotericin B, 5 mg/kg daily, was initiated. Within 24 hours, the patient became afebrile. Progressive renal failure required temporary hemodialysis. After 7 days, liposomal amphotericin B was stopped, and itraconazole solution-200 mg orally 3 times daily for 3 days and then 200 mg twice daily-was initiated. The creatinine level returned to normal, and the patient was discharged on the 23rd hospital day. The day after discharge, cultures from the BAL fluid yielded a mold that was proved to be H. capsulatum. One month later, CT scan of the thorax showed complete resolution of the diffuse airspace opacities, and urine Histoplasma antigen had decreased to 21 units/mL. He remains on itraconazole solution, 200 mg orally twice daily; all symptoms, signs, and laboratory abnormalities have resolved, with the exception of the urine Histoplasma antigen, which remains positive.
The true incidence of histoplasmosis in solid organ transplant recipients is not known. Recent data from 25 transplant centers in the United States (TransNet) noted that the incidence in those 11 centers that were within the endemic area was 1.6/1000 transplants performed.6 Although the number of cases was highest among kidney transplants, the incidence was only 1/1000 transplants for this group. The incidence rate was highest for liver transplants, 3.8/1000 transplants. These rates can be influenced greatly in the presence of an outbreak; before the large Indianapolis outbreak, histoplasmosis was noted in only 0.5% of kidney transplant recipients but increased to 2.1% during the outbreak.7 Similarly, Freifeld et al8 reported that the incidence of histoplasmosis in solid organ transplant recipients in the 5 years from January 1997 to December 2001 was 0.11% but rose 17-fold to 1.9% from January 2002 to June 2004, reflecting an overall increase in cases of histoplasmosis in the community. Most reports of individual cases of histoplasmosis are in kidney transplant recipients, and only a few have been noted in recipients of liver, lung, or heart transplants.4,5,7-26 Our patient is only the third heart transplant recipient reported with histoplasmosis. The other 2 patients, one from Cleveland and one from Brazil, developed histoplasmosis 8 months and 5 years after transplantation, respectively4,5 (Table 1).
Histoplasmosis in solid organ transplant recipients most often results from exogenous infection by inhalation of conidia from the environment but can also occur with reactivation of quiescent disease or from transmission by the transplanted organ. Our patient developed illness within 2 months of transplantation. Although it is most likely that he was exposed to H. capsulatum in the immediate posttransplant period when immunosuppression was high, no obvious exposure could be elicited on repeated questioning. He had lived in Detroit all of his life and repeatedly denied any exposure to rural settings, construction sites, or bird or bat roosts in the pretransplant or posttransplant periods.
This raises the question as to whether H. capsulatum could have been transmitted with the donor heart. The heart, not part of the reticuloendothelial system, would seem an unusual organ to contain H. capsulatum; it is not commonly involved when dissemination occurs.27 The few well-documented cases of transfer with the transplanted organ have occurred in kidney and liver transplant recipients.10,19-21,26 Somewhat surprisingly, most of these cases presented 6 to 9 months after transplantation, rather than within a few weeks of the transplant. However, infection occurring within 2 weeks of transplantation has been reported in 3 recipients of organs from 1 donor who later had H. capsulatum documented in splenic tissue at the time of his death.26 In addition to the heart received by our patient, another patient received a kidney and the liver, and a third patient received the other kidney from the same donor. All organ recipients received their transplants at the University of Michigan; thus, we were able to assess whether the other 2 organ recipients had an illness suggestive of histoplasmosis. Follow-up has shown no evidence for histoplasmosis in either of these 2 organ recipients.
Our patient initially presented without symptoms, signs, or radiographic findings, suggesting pulmonary involvement. Only after a few days did dyspnea and hypoxemia occur. By then, diffuse pulmonary infiltrates had become prominent and led to initiation of empirical treatment of a presumed fungal infection. A similar delayed onset of pulmonary findings has been noted before in transplant recipients,11 but other reports emphasize the prominence of pulmonary symptoms and signs.8
Progressive pancytopenia, noted in our patient and in the other 2 heart transplant recipients, was initially thought to be because of medications used for immunosuppression and CMV prophylaxis. Pancytopenia is a valuable clue to disseminated granulomatous infections, especially histoplasmosis and tuberculosis. However, its importance in transplant patients may be overlooked because these patients are often on drugs that have bone marrow suppression as a common side effect, and the pancytopenia is ascribed to a side effect of the drugs.
The high serum ferritin noted in our patient, in retrospect, could have been a hint pointing toward the diagnosis of disseminated histoplasmosis. One of the other 2 heart transplant recipients also had an extremely high serum ferritin (82,876 ng/mL).4 High serum ferritin levels have been noted before in acquired immune deficiency syndrome (AIDS) patients who have disseminated histoplasmosis, and the levels seem to correlate with disease activity.28,29 In several AIDS patients and in the other heart transplant recipient with extremely high ferritin levels, the reactive hemophagocytic syndrome was also present.4,28
The positive Histoplasma antigen assay gave the first evidence of histoplasmosis in our patient. Antigen can be detected in the urine of approximately 90% of the patients and in the serum of 70% of the patients who have AIDS and disseminated histoplasmosis.30 Fewer data are available for non-AIDS patients who have disseminated disease, but it is likely that the sensitivity of the assay is similar.31 The antigen assay is the most rapid diagnostic modality for histoplasmosis, with the exception of histopathologic examination of involved tissues.
Growth of H. capsulatum from tissues or body fluids remains the most important confirmatory test but is rarely rapid enough to aid in the diagnosis of disseminated infection in patients who are immunosuppressed. Serological studies are often negative or show only low titers, as was the case in our patient and others reported in the literature.9 Although suggestive of exposure to H. capsulatum and likely to raise the diagnosis possibility of histoplasmosis, complement fixation titers of 1:8 or 1:16 are not adequate to firmly make a diagnosis of histoplasmosis without other evidence.
The decision to use amphotericin B formulations in patients who have preexisting renal dysfunction is a difficult one; however, this case illustrates the exquisite responsiveness of H. capsulatum to amphotericin B. The 2007 revised Infectious Diseases Society of America Guidelines for the treatments of histoplasmosis strongly favor the use of amphotericin B for moderately severe to severe disseminated histoplasmosis, even in the face of renal dysfunction.32 Often, renal function improves as the infection is brought under control. Our patient's renal function initially deteriorated; the temporary use of hemodialysis allowed liposomal amphotericin B to be given for 7 days, which was adequate to bring the infection under control. After changing to itraconazole solution, the patient's renal function returned to baseline.
The role of voriconazole in the treatment of histoplasmosis has not been defined. Transplant recipients have been successfully treated on a compassionate basis,8,33 and a few other patients have also received voriconazole for histoplasmosis.34,35 However, there are no large series or controlled trials defining the effectiveness of this agent for histoplasmosis. Our patient had no response when this agent was used, albeit for a short period, as initial empirical therapy for possible fungal infection, but he responded rapidly to liposomal amphotericin B. Itraconazole remains the azole of choice for treatment of histoplasmosis.32
In addition to treatment with specific antifungal agents, reduction of immunosuppression is important for successful treatment of disseminated fungal infections in solid organ transplant recipients. This involves balancing the risk of rejection with that of not controlling the infection. Our patient tolerated discontinuation of mycophenolate mofetil and a decrease in the dosage of tacrolimus, but the risk of rejection was deemed too high to reduce the prednisone dosage. In contrast to the situation in heart transplant recipients, reduction of immunosuppression is more feasible in kidney transplant recipients in whom dialysis is an option if organ rejection occurs.
All 3 heart transplant recipients who had histoplasmosis survived. All were treated with amphotericin B initially; 2 had their regimen changed to itraconazole, and the patient from Brazil remained on amphotericin B deoxycholate for the entire course of the therapy. In their 1999 review of renal transplant recipients who were reported to have histoplasmosis, Jha et al25 noted that 15 (34%) of 44 recipients died. The mortality rate did not improve after the advent of azole therapy for histoplasmosis in the mid-1980s. Admittedly, itraconazole was not approved until 1992, and it is clearly superior to ketoconazole, the only oral azole available in the mid-1980s. Marked improvement in survival has been noted in the last several years. The preliminary report of 33 cases from 2001 to 2003 in the TransNet database noted a mortality rate of only 12%.6 Whether this is because of improved diagnostic techniques or of the more frequent use of lipid formulation amphotericin B is not clear, and the numbers are too small to make meaningful comparisons with cases reported from prior decades.
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