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.

A study for precision diagnosing and treatment strategies in difficult-to-treat AIDS cases and HIV-infected patients with highly fatal or highly disabling opportunistic infections: Study protocol for the optimal early intervention for cryptococcal antigenemia in HIV-infected patients.

BACKGROUND: Asymptomatic cryptococcal antigenemia is a state of cryptococcal infection commonly seen in immunocompromised HIV-infected persons. Without early intervention, a proportion of HIV-infected persons with cryptococcal antigenemia may go on to develop cryptococcosis, especially cryptococcal meningitis, which is associated with high mortality. The benefits of antifungal intervention and optimal therapeutic intervention regimens for HIV-infected persons with cryptococcal antigenemia remain controversial. We therefore designed the present study in order to investigate the necessity of, and the optimal regimens for antifungal intervention in the clinical management of cryptococcal antigenemia in HIV-infected populations. METHODS/DESIGN: This study will be an open-labeled, multi-center, prospective, randomized controlled trial, and 450 eligible participants will be randomized into a control arm and 2 intervention arms at a 1:1:1 ratio, with 150 subjects in each arm. Participants in the control arm will not receive antifungal treatment during the study period. Participants in intervention arm 1 will receive oral fluconazole 800 mg/day for 2 weeks, followed by 400 mg/day for 8 weeks and 200 mg/day for 42 weeks, and participants in intervention arm 2 will receive oral fluconazole 400 mg/day for 52 weeks. The primary outcome is the incidence of CM among the 3 groups during the study period. The secondary outcomes include the differences in all-cause mortality, proportion of patients reverting to blood CrAg negativity, change of CrAg titers, and adverse events among the 3 groups during the follow-up period. DISCUSSION: We envisage that the results of this study will reveal the necessity of, and the optimal therapeutic regimens for, antifungal intervention in clinical management of HIV-infected patients with cryptococcal antigenemia. TRIAL REGISTRATION: The study was registered as one of the 12 clinical trials under a general project at the Chinese Clinical Trial Registry on February 1, 2019, and the registration number of the general project is ChiCTR1900021195.

An unusual case of tropical pyomyositis: cryptococcal pyomyositis.

The more common manifestations of cryptococcal infections are restricted to the central nervous system and lungs. A young man, suffering from idiopathic dilated cardiomyopathy with a left ventricular ejection fraction of 20%, presented with subacute, painful tender swelling in both legs initially attributed to congestive cardiac failure. No response to diuretics was achieved. Metabolically active lesions in the muscles of both lower limbs suggestive of muscle abscesses were found. A diagnosis of tropical pyomyositis was therefore made, but aspiration surprisingly revealed gram-positive yeast cells, staining of which on India ink and culture confirmed Cryptococcus. A good response to a combination of liposomal amphotericin B and flucytosine was obtained, but nevertheless the patient died from heart failure after induction of antifungal therapy.

Clinical impact of advanced chronic kidney disease in patients with non-HIV pulmonary cryptococcosis.

BACKGROUND: Pulmonary cryptococcosis is an uncommon infectious disease that can develop in both immunocompromised and immunocompetent patients. The severity of chronic kidney disease (CKD) was reported to be one of the risk factors for pulmonary cryptococcosis, but its clinical characteristics have not been fully assessed. The purpose of this study was to clarify the clinical characteristics of advanced CKD in patients with pulmonary cryptococcosis. METHODS: The present study retrospectively investigated 56 patients who had non-human immunodeficiency virus (HIV) pulmonary cryptococcosis and were treated at Saga University Hospital between 2005 and 2018. The clinical characteristics were evaluated and compared between patients with estimated glomerular filtration rate (eGFR) > 45 mL/min/1.73 m2 (n = 42, early CKD) and those with eGFR < 45 mL/min/1.73 m2 (n = 14, advanced CKD. RESULTS: Compared with patients with early CKD, those with advanced CKD had significantly higher rate of disseminated cryptococcosis (21.4% vs. 2.4%, p = 0.03); lower percentage of patients who recovered after treatment (63.6% vs. 92.5%, p = 0.02); and more frequent clinical features of fever (57.1% vs. 19.0%, p < 0.01), pleural effusion (21.4% vs. 2.4%, p = 0.03), high white blood cell count (8550/mL vs. 6150/mL, p = 0.01) and C-reactive protein (CRP) (2.1 mg/dL vs. 0.2 mg/dL, p = 0.02), and low level of serum albumin (3.0 g/dL vs. 3.8 g/dL, p < 0.01). Multivariate analysis adjusted by immunosuppressive drug use indicated the significant factors of fever (odds ratio or ß value [95% confidence interval] 6.4 [1.65-20.09], p < 0.01), high white blood cell count (1293.2 [110.2-2476.2], p = 0.03), C-reactive protein (0.89 [0.18-1.59], p = 0.01) and low level of serum albumin (- 0.34 [- 0.54 - - 0.14], p < 0.01) in patients with eGFR < 45 mL/min/1.73m2. CONCLUSION: Advanced CKD was associated with poor clinical characteristics and outcomes in patients with non-HIV pulmonary cryptococcosis. TRIAL REGISTRATION: The patients in this study were registered retrospectively.

Pulmonary cryptococcosis complicating interstitial lung disease in a patient with systemic lupus erythematosus.

We report a case of primary pulmonary cryptococcosis in a 59-year-old female patient with a history of systemic lupus erythematosus, interstitial lung disease and glaucoma. She presented with a cough, severe fatigue, unintentional weight loss, shortness of breath (increase in home oxygen use from baseline) and pleuritic chest pain of 2 months duration. During these 2 months, her symptoms had worsened despite multiple hospital visits, empirical antibiotics and empirical increase of her steroid dosage. Cytopathology of the bronchoalveolar lavage fluid showed yeast cells with narrow-based budding and grew Cryptococcus neoformans on fungal culture. She was treated with oral fluconazole 400 mg/day for 6 months with an improvement in cough, decrease in shortness of breath (return to baseline oxygen use) and resolution of pleuritic chest pain.

Cryptococcus gattii infection complicated by immune reconstitution inflammatory syndrome in three apparently immunocompetent children.

BACKGROUND: Paediatric Cryptococcus gattii disease is rare, with only two previous cases recorded in the Northern Territory (NT) over the last 54 years. Immune reconstitution inflammatory syndrome (IRIS) is a recognised complication of C. gattii infection, even in the absence of an identified immunodeficiency syndrome; however, limited paediatric data exist. We present a series of three paediatric patients treated for C. gattii infection in the NT during 2016/2017. CASE DISCUSSIONS: All three cases were males aged 8-13 years at the time of presentation. Two were Aboriginal Australians from remote NT communities, and the third was a Timorese child from a remote district in Timor-Leste. All cases had evidence of brain cryptococcomas, and two had associated pulmonary lesions. Each child was treated with a 6-week induction phase of intravenous liposomal amphotericin and flucytosine and then continued on a 2-year course of eradication oral fluconazole. Persistent high intracranial pressure (ICP) complicated each case, requiring serial lumbar punctures and, in two cases, insertion of ventriculoperitoneal shunts. All three cases were diagnosed with IRIS between 5 and 10 weeks after commencement of antifungal treatment and were managed with high-dose corticosteroids, which were weaned slowly (6-20 months post-commencement). CONCLUSIONS: Paediatric C. gattii disease is rare, although three recent cases in the NT highlight some of the challenges involved in managing the infection, including persistent raised ICP and complications such as IRIS. There is a need for further collaborative research into paediatric C. gattii disease.

Disseminated cryptococcosis in HIV negative patient.

A 52-year-old white diabetic male with 4-weeks history of persistent cough followed by headache, drenching night sweats, low-grade fever, worsening photophobia, nausea and vomiting was presented. Examination was significant for photophobia and diminution of vision. His spinal fluid and blood cultures were positive for Cryptococcus neoformans Intravenous fluconazole were given for 2 weeks followed by oral fluconazole. There was significant improvement in systemic and ocular symptoms. HIV serology was negative, but his CD4 counts were low with inverted CD4:CD8 ratio.

CD4+ T Cells Orchestrate Lethal Immune Pathology despite Fungal Clearance during Cryptococcus neoformans Meningoencephalitis.

Cryptococcus neoformans is a major fungal pathogen that disseminates to the central nervous system (CNS) to cause fatal meningoencephalitis, but little is known about immune responses within this immune-privileged site. CD4+ T cells have demonstrated roles in anticryptococcal defenses, but increasing evidence suggests that they may contribute to clinical deterioration and pathology in both HIV-positive (HIV+) and non-HIV patients who develop immune reconstitution inflammatory syndrome (IRIS) and post-infectious inflammatory response syndrome (PIIRS), respectively. Here we report a novel murine model of cryptococcal meningoencephalitis and a potential damaging role of T cells in disseminated cryptococcal CNS infection. In this model, fungal burdens plateaued in the infected brain by day 7 postinfection, but activation of microglia and accumulation of CD45hi leukocytes was significantly delayed relative to fungal growth and did not peak until day 21. The inflammatory leukocyte infiltrate consisted predominantly of gamma interferon (IFN-γ)-producing CD4+ T cells, conventionally believed to promote fungal clearance and recovery. However, more than 50% of mice succumbed to infection and neurological dysfunction between days 21 and 35 despite a 100-fold reduction in fungal burdens. Depletion of CD4+ cells significantly impaired IFN-γ production, CD8+ T cell and myeloid cell accumulation, and fungal clearance from the CNS but prevented the development of clinical symptoms and mortality. These findings conclusively demonstrate that although CD4+ T cells are necessary to control fungal growth, they can also promote significant immunopathology and mortality during CNS infection. The results from this model may provide important guidance for development and use of anti-inflammatory therapies to minimize CNS injury in patients with severe cryptococcal infections.IMPORTANCE CNS infection with the fungal pathogen Cryptococcus neoformans often results in debilitating brain injury and has a high mortality rate despite antifungal treatment. Treatment is complicated by the fact that immune responses needed to eliminate infection are also thought to drive CNS damage in a subset of both HIV+ and non-HIV patients. Thus, physicians need to balance efforts to enhance patients' immune responses and promote microbiological control with anti-inflammatory therapy to protect the CNS. Here we report a novel model of cryptococcal meningoencephalitis demonstrating that fungal growth within the CNS does not immediately cause symptomatic disease. Rather, accumulation of antifungal immune cells critically mediates CNS injury and mortality. This model demonstrates that antifungal immune responses in the CNS can cause detrimental pathology and addresses the urgent need for animal models to investigate the specific cellular and molecular mechanisms underlying cryptococcal disease in order to better treat treat patients with CNS infections.

The cause and effect of Cryptococcus interactions with the host.

Upon Cryptococcus neoformans infection of the host lung, the fungus enters a nutrient poor environment and must adapt to a variety of host-specific stress conditions (temperature, nutrient limitation, pH, CO2). Fungal spores enter this milieu with limited nutritional reserves, germinate, and begin proliferating by budding as yeast. Although relatively little is known about the initial stages of infection, recent work has characterized changes that occur upon germination. This program and subsequent yeast-phase proliferation progress in a dynamic environment as host nutrient immunity responds to the infection via toxic accumulation or sequestration of essential micronutrients and innate immune cells are recruited to the site of infection. Adaptation to the host environment and evasion of the immune response through pathogenicity factor expression allows proliferation and dissemination to multiple sites throughout the body, including, most significantly for human disease, the central nervous system. Here we will discuss recent insights into mechanisms underlying C. neoformans interactions with the host during infection.

Cryptococcus neoformans osteomyelitis and intramuscular abscess in a liver transplant patient.

Cryptococcus neoformans is an important pathogen that can cause severe illness and mortality in immunocompromised patients. We highlight here the case of a 53-year-old man presenting to hospital 4 years postliver transplant with fever, acute renal failure and a medial thigh lesion. Initially treated as bacterial sepsis, the patient failed to improve on broad-spectrum antibiotics. Further investigations revealed disseminated cryptococcemia complicated by patellar osteomyelitis and an intramuscular abscess. Unfortunately, although the patient initially showed signs of clinical improvement after starting standard antifungal agents, he deteriorated and died secondary to acute renal failure. Osteomyelitis is a rare manifestation of cryptococcal infection for which there is often a significant delay to diagnosis and treatment. This is the fourth reported case of cryptococcal osteomyelitis in a liver transplant patient and underlines the importance of considering fungal infections in the differential diagnosis of osseous lesions in solid organ transplant and other immunocompromised patients.

Treatment with pCramoll Alone and in Combination with Fluconazole Provides Therapeutic Benefits in C. gattii Infected Mice.

Cryptococcus gattii is one of the main causative agents of cryptococcosis in immunocompetent individuals. Treatment of the infection is based on the use of antimycotics, however, the toxicity of these drugs and the increase of drug-resistant strains have driven the search for more effective and less toxic therapies for cryptococcosis. pCramoll are isolectins purified from seeds of Cratylia mollis, a native forage plant from Brazil, which has become a versatile tool for biomedical application. We evaluated the effect of pCramoll alone and in combination with fluconazole for the treatment of mice infected with C. gatti. pCramoll alone or in combination with fluconazole increased the survival, reduced the morbidity and improved mice behavior i.e., neuropsychiatric state, motor behavior, autonomic function, muscle tone and strength and reflex/sensory function. These results were associated with (i) decreased pulmonary and cerebral fungal burden and (ii) increased inflammatory infiltrate and modulatory of IFNγ, IL-6, IL-10, and IL-17A cytokines in mice treated with pCramoll. Indeed, bone marrow-derived macrophages pulsed with pCramoll had increased ability to engulf C. gattii, with an enhanced production of reactive oxygen species and decrease of intracellular fungal proliferation. These findings point toward the use of pCramoll in combination with fluconazole as a viable, alternative therapy for cryptococcosis management.

Fungal colonization of the brain: anatomopathological aspects of neurological cryptococcosis.

Brain infection by the fungus Cryptococcus neoformans results in an estimated 500,000 human deaths per annum. Colonization of the central nervous system (CNS) by C. neoformans causes different clinical syndromes that involve interaction of a number of fungal components with distinct brain cells. In this manuscript, our literature review confirmed the notion that the Cryptococcus field is expanding rapidly, but also suggested that studies on neuropathogenesis still represent a small fraction of basic research activity in the field. We therefore discussed anatomical and physiological aspects of the brain during infection by C. neoformans, in addition to mechanisms by which brain resident cells interact with the fungus. This review suggests that multiple efforts are necessary to improve the knowledge on how C. neoformans affects brain cells, in order to enable the generation of new therapeutic tools in a near future.

How histopathology can contribute to an understanding of defense mechanisms against cryptococci.

Invasive fungal infections, particularly those considered opportunistic, have become a common and significant complication of procedures performed in advanced contemporary medicine. Among such infections, cryptococcosis, which is usually caused by infection with Cryptococcus neoformans and Cryptococcus gattii, is particularly problematic because this fungal infection occurs in immunocompromised and apparently immunocompetent individuals. It has been largely accepted that Cryptococcus species are recognized by cellular receptors and that Th1-type immune responses play an important role in defense mechanisms against the yeast. However, the interaction between the yeast and host tissue varies depending on the characteristics of the yeast and the immune status of the host. To gain a better understanding of the pathophysiology of cryptococcosis, we wish to emphasize the usefulness of histopathological examinations, because it allowed more detailed information of an extremely complex interaction between the causative yeasts and tissue response. In the present review, we describe the pathophysiology of cryptococcosis as largely revealed in our previous histopathological investigations of the experimental infection.

Effect of virulence factors on the photodynamic inactivation of Cryptococcus neoformans.

Opportunistic fungal pathogens may cause an array of superficial infections or serious invasive infections, especially in immunocompromised patients. Cryptococcus neoformans is a pathogen causing cryptococcosis in HIV/AIDS patients, but treatment is limited due to the relative lack of potent antifungal agents. Photodynamic inactivation (PDI) uses the combination of non-toxic dyes called photosensitizers and harmless visible light, which produces singlet oxygen and other reactive oxygen species that produce cell inactivation and death. We report the use of five structurally unrelated photosensitizers (methylene blue, Rose Bengal, selenium derivative of a Nile blue dye, a cationic fullerene and a conjugate between poly-L-lysine and chlorin(e6)) combined with appropriate wavelengths of light to inactivate C. neoformans. Mutants lacking capsule and laccase, and culture conditions that favoured melanin production were used to probe the mechanisms of PDI and the effect of virulence factors. The presence of cell wall, laccase and melanin tended to protect against PDI, but the choice of the appropriate photosensitizers and dosimetry was able to overcome this resistance.

Tratamiento satisfactorio de una neurocriptococosis por Cryptococcus gattii en una niña inmunocompetente de 5 años de edad, procedente de la Guyana francesa, Amazonia / Successful treatment of Cryptococcus gattii neurocryptococcosis in a 5-year-old immunocompetent child from the French Guiana Amazon region

Comparado con la incidencia en pacientes adultos, la criptococosis es una infección excepcional entre niños. Describimos un caso de neurocriptococosis debida a Cryptococcus gattii en una niña de 5 años de edad, sin factores de riesgo identificados, que vivía en la Guyana francesa. La cirugía neurológica combinada con un tratamiento antimicótico prolongado con anfotericina B y flucitosina (5-fluorocitosina) resolvieron satisfactoriamente la infección. La caracterización molecular posterior del aislamiento de Cryptococcus reveló que la infección se debió al genotipo AFLP6B/cepa VGIIb de C. gattii (AU)

Compared to the incidence in adults, cryptococcosis is rare among children. We report a case of neurocryptococcosis due to Cryptococcus gattii in a five-year-old girl without identified risk factors living in French Guiana. Neurological surgery in combination with long-term antifungal treatment with amphotericin B and 5-flucytosine successfully resolved the cryptococcal infection. Subsequent molecular characterization of the Cryptococcus isolate revealed that the infection was caused by a C. gattii genotype AFLP6B/VGIIb strain(AU)

Immune modulation mediated by cryptococcal laccase promotes pulmonary growth and brain dissemination of virulent Cryptococcus neoformans in mice.

C. neoformans is a leading cause of fatal mycosis linked to CNS dissemination. Laccase, encoded by the LAC1 gene, is an important virulence factor implicated in brain dissemination yet little is known about the mechanism(s) accounting for this observation. Here, we investigated whether the presence or absence of laccase altered the local immune response in the lungs by comparing infections with the highly virulent strain, H99 (which expresses laccase) and mutant strain of H99 deficient in laccase (lac1Δ) in a mouse model of pulmonary infection. We found that LAC1 gene deletion decreased the pulmonary fungal burden and abolished CNS dissemination at weeks 2 and 3. Furthermore, LAC1 deletion lead to: 1) diminished pulmonary eosinophilia; 2) increased accumulation of CD4+ and CD8+ T cells; 3) increased Th1 and Th17 cytokines yet decreased Th2 cytokines; and 4) lung macrophage shifting of the lung macrophage phenotype from M2- towards M1-type activation. Next, we used adoptively transferred CD4+ T cells isolated from pulmonary lymph nodes of mice infected with either lac1Δ or H99 to evaluate the role of laccase-induced immunomodulation on CNS dissemination. We found that in comparison to PBS treated mice, adoptively transferred CD4+ T cells isolated from lac1Δ-infected mice decreased CNS dissemination, while those isolated from H99-infected mice increased CNS dissemination. Collectively, our findings reveal that immune modulation away from Th1/Th17 responses and towards Th2 responses represents a novel mechanism through which laccase can contribute to cryptococcal virulence. Furthermore, our data support the hypothesis that laccase-induced changes in polarization of CD4+ T cells contribute to CNS dissemination.

Cost of invasive fungal infections in the era of new diagnostics and expanded treatment options.

STUDY OBJECTIVE: To determine the true institutional cost of treating invasive fungal infections in light of recent advances in diagnostic techniques and antifungal therapies for both treatment and prophylaxis of these infections. DESIGN: Economic analysis. SETTING: Academic medical center. PATIENTS: A total of 200 patients discharged from the hospital during 2004-2005 with a diagnosis of proven, probable, or possible aspergillosis, cryptococcosis, invasive candidiasis, or zygomycosis (cases). Patients were matched in a 1:1 fashion with patients having similar underlying disease states but no invasive fungal infections (controls). MEASUREMENTS AND MAIN RESULTS: Data on demographic and clinical characteristics were collected from patients' medical records. In addition, information concerning each patient's hospitalization was recorded. Resource utilization data for a patient's entire hospitalization were collected from the hospital's charge databases and converted to costs. These data were compared between the cases and the controls. After adjusting for race-ethnicity, sex, age, and comorbid illnesses, mean total hospital cost for cases was $32,196 more than for controls (p<0.0001). Nonpharmacy costs accounted for the majority (63%) of this difference, and an additional $3996 was attributed to systemic antifungal drugs. The mean length of hospital stay was longer for cases than controls (25.8 vs 18.4 days). CONCLUSION: Treatment of patients with invasive fungal infections was associated with a significantly higher inpatient hospital cost compared with controls. However, due to new diagnostic techniques and effective antifungal therapy, the relative cost of these infections appears to be at least stable compared with the previous decade. These findings can help assess the utility of cost-avoidance strategies such as antifungal prophylaxis and application of appropriate treatment.