Central nervous system involvement in cryptococcal infection in individuals after solid organ transplantation or with AIDS

Background. Cryptococcus neoformans is an important pathogen of immunocompromised hosts. Manifestations of cryptococcal infection have not been compared between populations based on the nature of the underlying immune deficiencies. Methods. The Prospective Antifungal Therapy Alliance (PATH) is a registry that collects clinical data from patients with invasive fungal infections from medical centers in North America. Univariate analyses and group comparisons were conducted from the PATH registry for cases of infection due to Cryptococcus species occurring between March 2004 and April 2008. Results. A total 235 cases of proven infection due to Cryptococcus species were documented, all of which were due to C. neoformans (52 in solid organ transplant [SOT] recipients, 107 in patients infected with the human immunodeficiency virus [HIV], and 76 with neither HIV nor organ transplantation). A total of 140 cases manifested as meningitis (25 in SOT recipients, 88 in HIV‐positive patients, and 27 in those with neither risk factor). Of individuals with cryptococcal infection, 44.2% of SOT recipients had central nervous system (CNS) disease, while 84.1% of those with HIV infection presented with CNS involvement (P=0.0265). SOT recipients receiving calcineurin inhibitors (CNIs) were less likely to have CNS involvement in cryptococcal infection (40.1% versus 66.7%). Overall, 12‐week mortality for patients with cryptococcal infection in the PATH Alliance registry was 22.6% (21.2% for SOT, 15.9% for HIV‐infected patients, and 32.9% for patients with risk factors other than HIV infection or organ transplantation). Conclusions. In a prospectively assembled cohort of individuals with proven infection due to C. neoformans, CNS involvement was more common in individuals with HIV infection than in SOT recipients. The role of CNIs in the reduction of risk for CNS cryptococcosis remains to be defined. Overall survival of patients with cryptococcal infection in immunocompromised hosts has improved over time. Observed differences in the context of various host immune deficits provide a basis for further investigation of cryptococcosis and other opportunistic infections.     

Pulmonary cryptococcosis in solid organ transplant recipients: clinical relevance of serum cryptococcal antigen.

BACKGROUND: The role of serum cryptococcal antigen in the diagnosis and determinants of antigen positivity in solid organ transplant (SOT) recipients with pulmonary cryptococcosis has not been fully defined. METHODS: We conducted a prospective, multicenter study of SOT recipients with pulmonary cryptococcosis during 1999-2006. RESULTS: Forty (83%) of 48 patients with pulmonary cryptococcosis tested positive for cryptococcal antigen. Patients with concomitant extrapulmonary disease were more likely to have a positive antigen test result (P=.018), and antigen titers were higher in patients with extrapulmonary disease (P=.003) or fungemia (P=.045). Patients with single nodules were less likely to have a positive antigen test result than were those with all other radiographic presentations (P=.053). Among patients with isolated pulmonary cryptococcosis, lung transplant recipients were less likely to have positive cryptococcal antigen test results than were recipients of other types of SOT (P=.003). In all, 38% of the patients were asymptomatic or had pulmonary cryptococcosis detected as an incidental finding. Nodular densities or mass lesions were more likely to present as asymptomatic or incidentally detected pulmonary cryptococcosis than as pleural effusions and infiltrates (P=.008). CONCLUSIONS: A positive serum cryptococcal antigen test result in SOT recipients with pulmonary cryptococcosis appears to reflect extrapulmonary or more advanced radiographic disease.     

Cryptococcosis after living donor liver transplantation: report of three cases

Cryptococcosis is the third most common invasive fungal infection in solid organ transplantation, which usually occurs more than 6 months after the primary operation. In our series of 180 consecutive adult living-donor liver transplantation recipients, three (1.5%) had cryptococcosis and one of these patients died. The serum cryptococcal antigen examination was positive in all three patients who suffered from cryptococcosis. The serum cryptococcal antigen test might contribute to the early detection and treatment of cryptococcosis.     

Cryptococcosis mimicking cutaneous cellulitis in a patient suffering from rheumatoid arthritis: a case report

Background  

Cryptococcus neoformans is an encapsulated yeast and the most frequent cryptococcal species found in humans. Cryptococcosis is considered an opportunistic infection as it affects mainly immunosuppressed individuals. In humans, C. neoformans causes three types of infections: pulmonary cryptococcosis, cryptococcal meningitis and wound or cutaneous cryptococcosis.     

Very early‐onset of Cryptococcus neoformans disease following liver transplantation: Report of two cases and a review of the literature

Cryptococcosis is the third most common invasive fungal infection following solid organ transplantation, and mortality is high. Most cases occur late and are due to reactivation of latent infection; however, very early reactivation and donor‐derived transmission can occur. Routine screening pre‐transplant and antifungal prophylaxis for cryptococcosis post‐transplant in solid organ transplantation are not standard practice. We present two cases of very early‐onset Cryptococcus neoformans disease following liver transplantation to highlight the need to consider individualized pre‐transplant screening and be aware that reactivation of Cryptococcosis neoformans can occur in the immediate post‐transplant period.     

Cryptococcus neoformans pericarditis in a lung transplant recipient: Case report,literature review and pearls

A 68‐year‐old man presented for outpatient evaluation of dyspnea and new‐onset atrial fibrillation 9 months after undergoing bilateral lung transplantation. Echocardiography prior to cardioversion raised concern for tamponade. Therapeutic pericardiocentesis returned fluid containing 1875 wbc/mcl (68% pmn) and yielded Cryptococcus neoformans in culture. Cryptococcal antigen was detected in serum at a titer of 1:20. Cerebrospinal (CSF) fluid was without evidence of inflammation and without detectable cryptococcal antigen. There was no radiographic evidence of pulmonary cryptococcosis. Cultures of blood and CSF were without growth. Liposomal amphotericin B (3 mg/kg/day) was administered for 15 days. Oral fluconazole was added on day seven of amphotericin, and the patient was discharged to home 3 days later. Daily dosages of prednisone (10 mg), mycophenolate (500 mg), and tacrolimus (3 mg) at discharge were the same as at hospital admission. He was readmitted 12 days later with dyspnea and with re‐accumulation and loculation of pericardial fluid. A pericardial window was created. Pericardial fluid contained 722 wbc/mcl (35% pmn); Cryptococcus was not identified on direct examinations or cultures of pericardial fluid or tissue. Cryptococcus antigen was present in serum at 1:160. Liposomal amphotericin B was resumed and continued for 2 weeks followed by resumption of fluconazole. Mycophenolate was stopped. Prednisone and tacrolimus were continued. Restrictive pericarditis was evident 3 weeks after window creation. Colchicine was initiated, prednisone increased to 15 mg daily and pericardiectomy planned. We aim to raise awareness to Cryptococcus as a potential etiology for pericarditis in solid organ transplant recipients.     

A pilot study of the discontinuation of antifungal therapy for disseminated cryptococcal disease in patients with acquired immunodeficiency syndrome, following immunologic response to antiretroviral therapy

To determine whether microbiologic cure of acquired immunodeficiency syndrome (AIDS)-related disseminated cryptococcosis is possible in patients receiving highly active antiretroviral therapy (HAART), antifungal therapy was discontinued in 6 patients with a history of disseminated cryptococcosis who had received > or =12 months of antifungal therapy. All were asymptomatic and had absolute CD4+ T cell counts of >150 cells/microL (range, 178-525 cells/microL). Blood, cerebrospinal fluid (CSF), and urine samples were obtained for fungal culture. Serum and CSF cryptococcal antigen titers were also obtained. All 6 patients had CSF and blood cultures negative for Cryptococcus neoformans and were receiving HAART. All patients' subsequent cultures remained sterile, and all patients were clinically asymptomatic 24 months after ending antifungal therapy. Disseminated cryptococcal disease can be cured by prolonged antifungal therapy in some patients with AIDS who experience sustained CD4 lymphocyte increases while receiving HAART.     

<Emphasis Type="Italic">Cryptococcus neoformans</Emphasis> Abscess and Osteomyelitis in an Immunocompetent Patient with Tuberculous Lymphadenitis

Abstract Infection with Cryptococcus neoformans usually occurs in immunocompromised hosts and may occur in immunocompetent patients. Of all cryptococcal infections, 10–40% of patients have no apparent immune deficiency. Disseminated disease may occur in up to 62% of HIV-seronegative patients with cryptococcosis; however, cryptococcal osteomyelitis is rare. Here, we report an immunocompetent patient with cryptococcal vertebral osteomyelitis and concomitant tuberculous lymphadenitis. The patient received 12 weeks of fluconazole and a 1-year course of anti-tuberculous agents, with complete recovery.     

Cryptococcal infection presenting as soft tissue abscess and arthritis: Case report

Rationale:Cryptococcal infection has been documented in immunocompromised patients. AIDS and renal transplant recipients account for majority of the cases. Most cases present with central nervous system or disseminated disease, with only few presenting soft tissue, bone, and joint manifestations.Patient concerns:We present a case of soft tissue mass in a 66-year-old female renal transplant recipient and that of arthritis in a 64-year-old immunocompetent man who presented pseudogout arthropathy. Chest radiographies of both cases were negative. Biopsy revealed cryptococcal organisms. Blood culture or cerebrospinal fluid sampling indicated positive results for cryptococcal antigen.Diagnosis:Cryptococcus neoformans was recovered in the wound culture.Interventions:The patients received intravenous fluconazole and flucytosine, followed by oral fluconazole administration.Outcomes:Symptomatic improvements were achieved and no subsequent relapses were observed.Lessons:The authors experienced 2 cases of cryptococcosis with very unusual clinical presentation. Early clinical suspicion and serum cryptococcal antigen testing can help in rapid appropriate diagnosis in immunocompetent as well as immunocompromised patients even in the absence of pulmonary involvement.     

Cryptococcus gattii infection in solid organ transplant recipients: description of Oregon outbreak cases

Cryptococcus gattii was recognized as an emerging infection in the Pacific Northwest in 2004. Out of 62 total infections in Oregon since the outbreak, 11 were in solid organ transplant (SOT) recipients. SOT recipients were more likely to have disseminated disease and higher mortality than normal hosts, who mostly had isolated mass lesions. The median time from transplantation to C. gattii diagnosis was 17.8 months. The primary sites of infection were lung (n = 4), central nervous system (n = 3), or both (n = 4). The Oregon‐endemic strain, VGII (subtypes IIa and IIc) was present in 10 of 11 patients; the median fluconazole minimum inhibitory concentration (MIC) was 12 μg/mL (range 2–32 μg/mL) for this strain. We found C. gattii infection among organ transplant recipients was disseminated at diagnosis, had low cerebrospinal fluid cryptococcal antigen titers, and was associated with an elevated fluconazole MIC and high attributable mortality.     

A cluster of donor‐derived Cryptococcus neoformans infection affecting lung,liver, and kidney transplant recipients: Case report and review of literature

Donor‐derived infections (DDIs) are a very rare but potentially devastating complication of solid organ transplantation. Here we present a cluster of proven donor‐derived cryptococcal infection in the kidney, liver, and lung recipients from a single donor. Remarkably, the onset of illness in the kidney and liver recipients occurred more than 8‐12 weeks after transplantation, which is beyond the incubation period previously reported for donor‐derived cryptococcosis. DDI should always be considered in the differential diagnosis of transplant recipients admitted with febrile illness, even when presenting beyond the first month post‐transplant. Communication between reference laboratories, transplant centers, and organ procurement organizations is critical to improve outcomes.     

Cryptococcal meningitis post autologous stem cell transplantation

Disseminated Cryptococcus disease occurs in patients with defective T‐cell immunity. Cryptococcal meningitis following autologous stem cell transplant (SCT) has been described previously in only 1 patient, 4 months post SCT and while off antifungal prophylaxis. We present a unique case of Cryptococcus meningitis pre‐engraftment after autologous SCT, while the patient was receiving fluconazole prophylaxis. A 41‐year‐old man with non‐Hodgkin's lymphoma underwent autologous SCT. Post‐transplant prophylaxis consisted of fluconazole 400 mg daily, levofloxacin 500 mg daily, and acyclovir 800 mg twice daily. On day 9 post transplant, he developed fever and headache. Peripheral white blood cell count (WBC) was 700/μL. Magnetic resonance imaging of the brain showed lesions consistent with meningoencephalitis. Cerebrospinal fluid (CSF) analysis revealed a WBC of 39 with 77% lymphocytes, protein 63, glucose 38, CSF pressure 20.5 cmH₂O, and a positive cryptococcal antigen. CSF culture confirmed Cryptococcus neoformans. The patient was treated with liposomal amphotericin B 5 mg/kg intravenously daily, and flucytosine 37.5 mg/kg orally every 6 h. He was switched to fluconazole 400 mg daily after 3 weeks of amphotericin therapy, with sterilization of the CSF with negative CSFCryptococcus antigen and negative CSF culture. Review of the literature revealed 9 cases of cryptococcal disease in recipients of SCT. Median time of onset was 64 days post transplant. Only 3 meningitis cases were described; 2 of them after allogeneic SCT. Fungal prophylaxis with fluconazole post autologous SCT is recommended at least through engraftment, and for up to 100 days in high‐risk patients. A high index of suspicion is needed to diagnose and treat opportunistic infections, especially in the face of immunosuppression and despite adequate prophylaxis. Infection is usually fatal without treatment, thus prompt diagnosis and therapy might be life saving.     

Investigation and control of aspergillosis and other filamentous fungal infections in solid organ transplant recipients

Filamentous fungal infections are associated with high morbidity and mortality in solid organ transplant patients, and prevention is warranted whenever possible. An increase in invasive aspergillosis was detected among solid organ transplant recipients in our institution during 1991–92. Rates of Aspergillus infection (18.2%) and infection or colonization (42%) were particularly high among lung transplant recipients. Epidemiologic investigation revealed cases to be both nosocomial and community‐acquired, and preventative efforts were directed at both sources. Environmental controls were implemented in the hospital, and itraconazole prophylaxis was given in the early period after lung transplantation. The rate of Aspergillus infection in solid organ transplant recipients decreased from 9.4% to 1.5%, and mortality associated with this disease decreased from 8.2% to 1.8%. The rate of Aspergillus infection or colonization among lung transplant recipients decreased from 42% to 22.5%; nosocomial Aspergillus infection decreased from 9% to 3.2%. Cases of aspergillosis in lung transplant recipients were more likely to be early infections in the pre‐intervention period. Early mortality in lung transplant recipients decreased from 15% to 3.2%. Two cases of dematiaceous fungal infection were detected, and no further cases occurred after environmental controls. The use of environmental measures that resulted in a decrease in airborne fungal spores, as well as antifungal prophylaxis, was associated with a decrease in aspergillosis and associated mortality in these patients. Ongoing surveillance and continuing intervention is needed for prevention of infection in high‐risk solid organ transplant patients.     

Hepatic involvement in a liver transplant recipient with disseminated cryptococcosis

Abstract: Cryptococcosis occurs primarily in immunocompromised patients such as organ transplant recipients. Central nervous system and pulmonary infections are documented most frequently; hepatic involvement is rarely reported. We report a case of early hepatic cryptococcosis in a 54-year-old male liver transplant recipient. Two weeks after orthotopic liver transplant, he was readmitted with fever, malaise, diarrhea, and progressive pulmonary infiltrates. On admission, liver-associated enzymes were decreased from those at discharge after transplantation. Blood and bronchoalveolar lavage cultures were positive for Cryptococcus neoformans . Despite treatment with amphotericin B and flucytosine, the patient developed both marked cholestasis and transaminase elevation. A liver biopsy performed 22 days after admission revealed numerous yeast-like organisms in hepatic sinusoids consistent with C. neoformans . Despite treatment, the patient died 55 days after admission and 66 days after transplantation. Our case illustrates hepatic involvement of cryptococcal infection within the first month following transplantation.     

Epidemiology of fungal infections in solid organ transplant patients

The epidemiology of fungal infection in solid organ transplant patients is of concern due to the high mortality associated with this complication. Rates of fungal infections vary by type of transplant recipient. Most of these infections occur two to six months after transplantation. Liver transplant recipients are more likely to have early fungal infection which is often due to Candida species. Exogenous and endogenous Candida infection may occur in the immunosuppressed patient in the intensive care unit. Patients with chronic rejection are more likely to have late infection (after six months) which may be due to Aspergillus or endemic fungi such as Cryptococcus. Lung and heart–lung transplant recipients are more predisposed to infection with Aspergillus and other filamentous fungi, due to exposure of the transplanted organ to the external environment. Preventative measures such as environmental controls and chemoprophylaxis may be beneficial in high-risk patients. Emerging fungal pathogens such as the dematiaceous fungi may cause skin or soft tissue infection, or more serious systemic infections. Fungal infection should be ruled out in the solid organ transplant patient with early brain abscess. Characteristic risk factors in high-risk types of solid organ transplant recipients should be recognized for early diagnosis and treatment of these infections associated with high morbidity and mortality.     

Invasive Trichosporon infection in solid organ transplant patients: a report of two cases identified using IGS1 ribosomal DNA sequencing and a review of the literature

Trichosporon species are rare etiologic agents of invasive fungal infection in solid organ transplant (SOT) recipients. We report 2 well‐documented cases of Trichosporon inkin invasive infection in SOT patients. We also conducted a detailed literature review of Trichosporon species infections in this susceptible population. We gathered a total of 13 cases of Trichosporon species infections. Any type of organ transplantation can be complicated by Trichosporon infection. Bloodstream infections and disseminated infections were the most common clinical presentations. Liver recipients with bloodstream or disseminated infections had poor prognoses. Although the most common species was formerly called Trichosporon beigelii, this species name should no longer be used because of the changes in the taxonomy of this genus resulting from the advent of molecular approaches, which were also used to identify the strains isolated from our patients. Antifungal susceptibility testing highlights the possibility of multidrug resistance. Indeed, Trichosporon has to be considered in cases of breakthrough infection or treatment failure under echinocandins or amphotericin therapy. Voriconazole seems to be the best treatment option.     

Pulmonary cryptococcosis in nonimmunocompromised patients

BACKGROUND: Cryptococcus neoformans can cause serious systemic infections requiring systemic antifungal therapy in immunocompromised hosts. However, isolated pulmonary cryptococcosis in nonimmunocompromised hosts has been reported to resolve spontaneously without treatment. STUDY OBJECTIVE:s: To determine the role of antifungal therapy in the management of isolated pulmonary cryptococcosis in nonimmunocompromised hosts. DESIGN: Retrospective study. SETTING: Tertiary care, referral medical center PATIENTS: Thirty-six nonimmunocompromised subjects with isolated pulmonary cryptococcosis who received diagnoses at the Mayo Clinic (Rochester, MN) from 1976 to 2001. INTERVENTIONS: None. Measurements and results: Of 42 nonimmunocompromised subjects with cryptococcal infections, 36 (86%) had isolated pulmonary cryptococcosis. The mean (+/- SD) age of these 36 patients was 61 +/- 15 years (range, 14 to 88 years), and the groups included 17 men (47%) and 19 women (53%). Twenty-four patients (67%) were symptomatic, and 12 patients (33%) were asymptomatic. The most common presenting symptoms were cough, dyspnea, and fever. Cultures of sputum and bronchial washings most commonly yielded the diagnosis. Cerebrospinal fluid examination was performed in 11 patients (31%) and was negative in all of them. Follow-up information was available on 25 patients (69%) with a median duration of 19 months (range, 1 to 330 months). Twenty-three of these patients (92%) had resolution of their disease (no treatment, 8 patients; surgical resection only, 6 patients; and antifungal therapy, 9 patients). The condition of the two remaining patients had improved. There was no documented treatment failure, relapse, dissemination, or death in any of these 25 patients. CONCLUSIONS: Our findings suggest that an initial period of observation without the administration of antifungal therapy is a reasonable option for nonimmunocompromised subjects with pulmonary cryptococcosis in the absence of systemic symptoms or evidence of dissemination, as well as after surgical resection for focal cryptococcal pneumonia.     

Recurrent pulmonary cryptococcosis during chronic HBV infection: A case report

Rationale:Pulmonary cryptococcosis is one of the important opportunistic infections and has a wide range of symptoms depending on the underlying conditions. Here, we reported a case living with chronic hepatitis B virus infection who had a recurrent pulmonary cryptococcosis.Patient concerns:A 51-year-old male patient was admitted to our center because of cough, fatigue, and shortness of breath for 2 weeks.Diagnosis:Pulmonary infection was suggested by chest computed tomography. Most lab examinations for infection were negative and only cryptococcal antigen testing was positive. Therefore, a clinical diagnosis of pulmonary cryptococcosis was made.Interventions:Fluconazole (200 mg/day) and bicyclol (50 mg/day) was given orally.Outcomes:During the follow-up of 3 and 6 months, his conditions improved, and he recovered fully. Moreover, cryptococcal antigen level was 12.57 ng/mL. During the 2-year follow-up, no recurrence occurred.Lessons:This case highlights the importance of the awareness of opportunistic infections during chronic hepatitis B virus infection, especially the potential of recurrence.     

Immune reconstitution inflammatory syndrome mimicking relapsing cryptococcal meningitis in a renal transplant recipient

T. Legris, M. Massad, R. Purgus, H. Vacher‐Coponat, S. Ranque, N. Girard, Y. Berland, V. Moal. Immune reconstitution inflammatory syndrome mimicking relapsing cryptococcal meningitis in a renal transplant recipient.
Transpl Infect Dis 2011: 13: 303–308. All rights reserved Abstract: Immune reconstitution inflammatory syndrome (IRIS) is a rare entity that has been described recently in solid organ transplant (SOT) recipients. IRIS is characterized by an exuberant and dysregulated immune response following treatment of opportunistic infections. We describe here the case of a kidney transplant recipient who developed cryptococcal meningitis that was efficiently treated with antifungal therapy and decreased immunosuppression regimen. Eight months later, a paradoxical worsening of neurological symptoms and neuroradiological findings led to the diagnosis of IRIS. A short course of high‐dose steroid therapy allowed complete resolution of neurological symptoms. This report highlights the challenge for physicians to distinguish IRIS from a relapsing cryptococcal infection. Clinical improvement of cryptococcosis‐associated IRIS by anti‐inflammatory drugs needs to be confirmed among SOT recipients.     

Pulmonary cryptococcosis: comparison of clinical and radiographic characteristics in immunocompetent and immunocompromised patients

STUDY OBJECTIVES: We compared the clinical characteristics and imaging findings between immunocompetent and immunocompromised patients in whom pulmonary cryptococcosis had been diagnosed to define the role of serum cryptococcal antigen (sCRAG) and radiographs during a follow-up period of up to 1 year. DESIGN: Retrospective cohort study. SETTING: University hospital. PATIENTS: The clinical records, chest radiographs, and CT scan findings of 13 immunocompetent and 16 immunocompromised patients with a diagnosis based on cerebrospinal fluid (CSF) culture, sCRAG titers, and cytologic or histologic confirmation of the presence of pulmonary cryptococcosis were reviewed during the course of the study. Two thoracic radiologists reviewed chest radiographs and CT scans for morphologic characteristics and the distribution of parenchymal abnormalities, and a final reading was reached by consensus. The correlation between serial radiographs and sCRAG titers was examined in 9 immunocompetent and 10 immunocompromised patients. MEASUREMENTS: Serum or CSF cryptococcal antigen. RESULTS: The most common clinical symptom was cough, which was present in 24 patients (82.8%). Pulmonary nodules were the most frequent radiologic abnormality. Cavitation within nodules and parenchymal consolidation were significantly less common in immunocompetent patients compared to immunocompromised patients (p = 0.02 and p = 0.05, respectively). Immunocompromised patients tended to have a larger extent of pulmonary involvement than immunocompetent patients, the changes seen on their serial radiographs were more variable, and their corresponding sCRAG titers were higher (> 1:256). In the immunocompetent patients, the radiographic characteristics of lesions usually improved with a corresponding decrease in sCRAG titers over time. CONCLUSIONS: Our study suggests that pulmonary cryptococcosis usually follows a benign clinical course in immunocompetent patients. Immunocompromised patients often undergo an evolution to cavitary lesions that represent a more aggressive disease nature. Serial radiographic changes and changes in sCRAG titers reliably reflect disease progression and the response to therapy.