Urine antigen-negative disseminated histoplasmosis mimicking post-transplant lymphoproliferative disorder.

A 50-year-old woman with a history of kidney transplant presented with 2 days of abdominal pain after 6 months of recurrent streptococcal pharyngitis, fevers, weight loss and a new rash on her chest and back. Her examination was notable for a unilateral tonsillar exudate and 2-3 mm pink papules with a fine scale over her chest and back. CT of the abdomen and chest demonstrated several large lymph nodes, and laboratory investigation revealed new cytopenias and elevated transaminases. Urine antigen testing for Histoplasma capsulatum was negative, but a fungal complement fixation panel was reactive for Histoplasma antibodies. Skin biopsy revealed intracellular organisms consistent with H. capsulatum She underwent treatment with liposomal amphotericin B but due to nephrotoxicity, drug interactions and worsening transaminitis, therapy was changed to itraconazole. The diagnosis and management of disseminated histoplasmosis presents multiple challenges, which are of particular importance in patients with a history of renal transplantation.

The HIF-1α/LC3-II Axis Impacts Fungal Immunity in Human Macrophages.

The fungal pathogen Histoplasma capsulatum causes a spectrum of disease, ranging from local pulmonary infection to disseminated disease. The organism seeks residence in macrophages, which are permissive for its survival. Hypoxia-inducible factor 1α (HIF-1α), a principal regulator of innate immunity to pathogens, is necessary for macrophage-mediated immunity to H. capsulatum in mice. In the present study, we analyzed the effect of HIF-1α in human macrophages infected with this fungus. HIF-1α stabilization was detected in peripheral blood monocyte-derived macrophages at 2 to 24 h after infection with viable yeast cells. Further, host mitochondrial respiration and glycolysis were enhanced. In contrast, heat-killed yeasts induced early, but not later, stabilization of HIF-1α. Since the absence of HIF-1α is detrimental to host control of infection, we asked if large amounts of HIF-1α protein, exceeding those induced by H. capsulatum, altered macrophage responses to this pathogen. Exposure of infected macrophages to an HIF-1α stabilizer significantly reduced recovery of H. capsulatum from macrophages and produced a decrement in mitochondrial respiration and glycolysis compared to those of controls. We observed recruitment of the autophagy-related protein LC3-II to the phagosome, whereas enhancing HIF-1α reduced phagosomal decoration. This finding suggested that H. capsulatum exploited an autophagic process to survive. In support of this assertion, inhibition of autophagy activated macrophages to limit intracellular growth of H. capsulatum Thus, enhancement of HIF-1α creates a hostile environment for yeast cells in human macrophages by interrupting the ability of the pathogen to provoke host cell autophagy.

Heat Shock Proteins in Histoplasma and Paracoccidioides.

Heat shock proteins (Hsps) are highly conserved biomolecules that are constitutively expressed and generally upregulated in response to various stress conditions (biotic and abiotic). Hsps have diverse functions, categorizations, and classifications. Their adaptive expression in fungi indicates their significance in these diverse species, particularly in dimorphic pathogens. Histoplasma capsulatum and Paracoccidioides species are dimorphic fungi that are the causative agents of histoplasmosis and paracoccidioidomycosis, respectively. This minireview focuses on the pathobiology of Hsps, with particular emphasis on their roles in the morphogenesis and virulence of Histoplasma and Paracoccidioides and the potential roles of active and passive immunization against Hsps in protection against infection with these fungi.

Clinical and Laboratory Profile of Persons Living with Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome and Histoplasmosis from a Colombian Hospital.

Histoplasmosis is common among persons living with human immunodeficiency virus/acquired immune deficiency syndrome (PLWHA) in Latin America, but its diagnosis is difficult and often nonspecific. We conducted prospective screening for histoplasmosis among PLWHA with signs or symptoms suggesting progressive disseminated histoplasmosis (PDH) and hospitalized in Hospital La María in Medellín, Colombia. The study's aim was to obtain a clinical and laboratory profile of PLWHA with PDH. During 3 years (May 2008 to August 2011), we identified 89 PLWHA hospitalized with symptoms suggestive of PDH, of whom 45 (51%) had histoplasmosis. We observed tuberculosis (TB) coinfection in a large proportion of patients with PDH (35%), so all analyses were performed adjusting for this coinfection and, alternatively, excluding histoplasmosis patients with TB. Results showed that the patients with PDH were more likely to have Karnofsky score ≤ 30 (prevalence ratio [PR] = 1.98, 95% confidence interval [CI] = 0.97-4.06), liver compromised with hepatomegaly and/or splenomegaly (PR = 1.77, CI = 1.03-3.06) and elevation in serum of alanine aminotransferase and aspartate aminotransferase to values > 40 mU/mL (PR = 2.06, CI = 1.09-3.88 and PR = 1.53, CI = 0.99-2.35, respectively). Using multiple correspondence analyses, we identified in patients with PDH a profile characterized by the presence of constitutional symptoms, namely weight loss and Karnofsky classification ≤ 30, gastrointestinal manifestations with alteration of liver enzymes and hepatosplenomegaly and/or splenomegaly, skin lesions, and hematological alterations. Study of the profiles is no substitute for laboratory diagnostics, but identifying clinical and laboratory indicators of PLWHA with PDH should allow development of strategies for reducing the time to diagnosis and thus mortality caused by Histoplasma capsulatum.

A de novo unclassified malignant spindle cell neoplasm of liver allograft.

Spindle cell neoplasms are rarely reported in liver allografts; most are benign and associated with Epstein-Barr virus infection. We present a case of a malignant spindle cell neoplasm arising in a liver allograft. The patient underwent orthotopic liver transplant for cirrhosis secondary to nonalcoholic steatohepatitis. After 2 years, he presented with vague abdominal complaints. Imaging studies revealed a 10-cm right hepatic lobe mass. The patient underwent right-sided hepatectomy. The tumor displayed areas of broad, relatively hypocellular fascicles, whorls, and perivascular clustering; spindle cells with mild to moderate nuclear pleomorphism; and relatively abundant eosinophilic cytoplasm. Mitotic activity ranged from 2 to 4 mitotic figures per 20 high-power fields. Immunostaining displayed positivity for epithelial membrane antigen, vimentin, CD99, BCL2, cytokeratin, and human herpesvirus 8. Interphase fluorescence in situ hybridization findings were negative for a translocation involving the SS18 gene (18q11). We believe the tumor represents the first reported case of a novel unclassified spindle cell malignant neoplasm in a liver allograft.

The mycoarray as an aid for the diagnosis of an imported case of histoplasmosis in an Italian traveler returning from Brazil.

We describe an imported case of histoplasmosis, whose serological profile was established by means of a protein-based microarray platform, the recently described mycoarray. Because of its peculiarities, such a novel tool greatly facilitates the rapid and multiparametric assessment of patients' serological status and lends itself to be employed as an aid in the diagnosis of primary mycoses, especially in nonendemic countries.

Prolonged fever and splinter hemorrhages in an immunocompetent traveler with disseminated histoplasmosis.

We present a case of progressive disseminated histoplasmosis in an immunocompetent traveler. Histoplasmosis was acquired in South America; its manifestations included prolonged fever, splinter hemorrhages, erythema multiforme, arthritis, and mediastinal lymphadenopathy. To the best of our knowledge no splinter hemorrhages had previously been reported in a patient with histoplasmosis.

Analysis of outcomes for intravitreal bevacizumab in the treatment of choroidal neovascularization secondary to ocular histoplasmosis.

PURPOSE: To assess the long-term outcomes of intravitreal bevacizumab (IVB) in the treatment of choroidal neovascularization (CNV) secondary to presumed ocular histoplasmosis syndrome (POHS). DESIGN: Retrospective, comparative case series. PARTICIPANTS: Interventional series of 150 eyes in 140 patients treated for subfoveal or juxtafoveal CNV secondary to POHS from January 2006 to January 2010. INTERVENTION: Intravitreal bevacizumab monotherapy or combination IVB and verteporfin photodynamic therapy (IVB/PDT). MAIN OUTCOME MEASURES: Visual acuity (VA) at 12 and 24 months was analyzed. Secondary outcome measures included the number of injections per year and treatment-free intervals. RESULTS: A total of 117 eyes received IVB monotherapy, and 34 eyes underwent combination IVB/PDT treatment. For all patients, the average pretreatment logarithm of minimum angle of resolution (logMAR) was 0.63 (Snellen equivalent 20/86) with a 12-month logMAR VA of 0.45 (Snellen equivalent 20/56) and a 24-month logMAR VA of 0.44 (Snellen equivalent 20/55). The mean follow-up was 21.1 months with an average of 4.24 IVB injections per year. There was no significant difference in initial VA, VA at 12 months, VA at 24 months, or number of eyes with a 3-line gain between the IVB monotherapy and IVB/PDT groups. Thirty-eight percent (39/104) of eyes gained 3 lines or more, and 81.2% (84/104) of subjects had maintained or improved their starting VA at 1 year. The proportion of subjects maintaining a 3-line gain in VA was relatively preserved at 2 years (29.8%, 17/57) and 3 years (30.3%, 10/32) follow-up. There was no increase in the proportion of subjects losing 3 lines or more over 3 years of follow-up. CONCLUSIONS: There is no significant difference in VA outcomes between IVB monotherapy versus IVB/PDT combination therapy. The use of IVB alone or in combination with PDT results in significant visual stabilization in the majority of patients with CNV secondary to POHS.

Intravitreal anti-vascular endothelial growth factor therapy for choroidal neovascularization secondary to ocular histoplasmosis syndrome.

BACKGROUND: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is beneficial in treating choroidal neovascularization from age-related macular degeneration, but few long-term studies have shown its efficacy in choroidal neovascularization from ocular histoplasmosis syndrome. Intravitreal anti-VEGF therapy may be effective in cases of choroidal neovascularization because of ocular histoplasmosis syndrome. METHODS: Retrospective chart review of 54 eyes treated with intravitreal anti-VEGF therapy for choroidal neovascularization in ocular histoplasmosis syndrome with >1 year of follow-up after initiation of anti-VEGF treatment was performed. Previous treatment and demographic information were recorded. Visual acuity was recorded for each injection treatment and at the last follow-up visit. The anti-VEGF agent was recorded for each injection treatment. Visual acuity was recorded at the last follow-up visit. RESULTS: Mean visual acuity improved from 20/53 to 20/26 over an average of 26.8 months. Either bevacizumab or ranibizumab were administered on an average of 4.5 injections per patient per year of follow-up. Vision loss was seen in only three eyes with loss limited to a single line of vision. Patients experienced no serious complications from treatment. CONCLUSION: Long-term intravitreal anti-VEGF therapy with bevacizumab or ranibizumab is beneficial in treatment of choroidal neovascularization in ocular histoplasmosis syndrome.

Methamphetamine enhances histoplasmosis by immunosuppression of the host.

The effect of methamphetamine on the host response to an opportunistic pathogen has not been extensively described. Methamphetamine is a major public health and safety problem in the United States. Chronic methamphetamine abuse is associated with a 2-fold higher risk of human immunodeficiency virus infection and, possibly, additional infections. Histoplasma capsulatum is a dimorphic fungus that is endemic in the Midwest of the United States and that causes respiratory and systemic disease, particularly in individuals with impaired immunity. We showed that methamphetamine abrogates normal macrophage function, resulting in an inability to control histoplasmosis. Methamphetamine decreased phagocytosis and killing of yeast by primary macrophages by alkalization of the phagosome. Furthermore, mice that received methamphetamine prior to H. capsulatum infection were immunologically impaired, with increased fungal burden, increased pulmonary inflammation, and decreased survival. Immunosuppression by methamphetamine may be associated with deregulation of cytokines in the lungs of infected mice, aberrant processing of H. capsulatum within macrophages, and immobilization of MAC-1 receptors on the surface of macrophages that are involved in phagocytosis. Additionally, methamphetamine inhibits T cell proliferation and alters antibody production, which are important components of adaptive immunity. With use of a murine model of histoplasmosis, this study establishes that methamphetamine may alter the immune system of the host and enhance fungal pathogenesis.

Histoplasmosis pulmonar diseminada (enfermedad de Darling): a propósito de un caso / Disseminated pulmonary histoplasmosis (Darling's disease): a purpose of a case

La histoplasmosis es una micosis sistémica que afecta al hombre y a los animales, causada por el Hongo Histoplasma capsulatum, se relaciona especialmente con el guano de las aves, y las cuevas habitadas por murciélagos. La infección se produce habitualmente por vía respiratoria, raramente la puerta de entrada es cutánea. El mecanismo de contagio es a través de la inhalación de esporas en el polvo del aire; la población más afectada es la que vive en zonas rurales, especialmente los granjeros; este padecimiento también se ha presentado en forma epidémica. Es una enfermedad de variada, manifestación clínica que puede ir de una simple infección respiratoria asintomática, hasta una enfermedad diseminada, caracterizada por fiebre, anemia progresiva, hepatoesplenomegalía, linfadenopatías, úlceras en el aparato digestivo y necrosis de suprarrenales. Ocurre con mayor frecuencia en individuos del sexo masculino sin distinción de raza. El tratamiento es a base de derivados del imidazol: ketoconazol, itraconazol, fluconazol y anfotericina B.

A case of laryngeal histoplasmosis mimicking carcinoma with a review of the literature.

Histoplasma capsulatum is endemic to the Ohio and Mississippi River valley regions of the United States. Infection with this fungus produces a broad range of clinical and pathologic manifestations. We report a case of laryngeal histoplasmosis, mimicking carcinoma, presenting as a manifestation of chronic disseminated histoplasmosis.

História natural da histoplasmose / Natural history of histoplasmosis

A histoplasmose é uma doença infecciosa sistêmica causada pelo fungo Histoplasma capsulatum. Sua patogenicidade está vinculada ao estado imunológico do hospedeiro e à carga fúngica inalada. O fungo apresenta distribuição cosmopolita, instalando-se em áreas de solo rico em compostos nitrogenados, habitadas por aves e morcegos. Costumeiramente, cursa com infecção assintomática ou autolimitada, porém pode evoluir para as seguintes formas: histoplasmose pulmonar aguda, histoplasmose pulmonar crônica e histoplasmose disseminada. Destaca-se, como método diagnóstico, o isolamento de forma leveduriformes em amostra de escarro, lavado broncoalveolar, biopsia de tecido pulmonar, sendo de suma importância descartar outras possibilidades diagnósticas, sobretudo, tuberculose. O tratamento depende do quadro clínico do hospedeiro e do estado imunológico, destacando-se o uso de fármacos como itraconazol, fluconazol, anfoterecina B e, eventualmente, corticosteróides como adjuvantes.

Histoplasmosis is a systemic infectious disease caused by the fungus Histoplasma capsulatum. Its pathogenicity depends on the underlying immune status of the host and the inhaled fungal burden. The fungus is found throughout the world in areas of rich nitrogenous soil, inhabited by birds and bats. The infection is mostly asymptomatic or self-limited, but severe clinical manifestations might develop with the occurrence of accute pulmonary histoplasmosis, chronic pulmonary histoplasmosis or disseminated histoplasmosis. Diagnosis is made when yeast forms are found in sputum, bronchoalveolar lavage or pulmonary tissue biopsy. Is is of the utmost importance to establish the differentials, specially tuberculosis. Treatment indicated depends on the hos clinical picture and immune status; drugs of choice are itraconazole, fluconazole, amphothericin B and corticosteroids as adjuvants.

Gastrointestinal histoplasmosis presenting as colonic pseudotumour.

We report a case of gastrointestinal histoplasmosis in a 45-year-old HIV positive man who was misdiagnosed as a case of colonic cancer. The patient presented with low-grade fever, pain in lower abdomen, anorexia and weight loss of six months duration. On examination a lump in the left iliac fossa was detected. Colonoscopy revealed stricture and ulcerated growth in the sigmoid colon. Radiological investigations suggested malignant/inflammatory mass in the sigmoid colon with luminal compromise. Patient was operated and ulcerated tissue was sent for histopathological examination, which revealed numerous intracellular, 2-4 microm, oval, narrow-based budding yeast cells suggestive of Histoplasma capsulatum. Subsequently, the patient developed fluffy opacities on X-ray chest. Examination of sputum revealed presence of acid-fast bacilli and yeast forms of H. capsulatum. Patient was started on amphotericin B but died on the seventeenth postoperative day. The diagnosis of histoplasmosis was made retrospectively. Atypical presentation and rarity of the disease led to this diagnostic pitfall. To the best of our knowledge this is the first report of gastrointestinal histoplasmosis presenting as colonic pseudotumour from India.

[Adrenocortical function in patients with systemic mycoses]. / Función adrenocortical en pacientes con micosis sistémica.

The systemic mycoses like paracoccidioidomycosis and histoplasmosis, are the main cause of adrenal insufficiency in the countries where they arc endemic. In Venezuela an elevated frequency of these mycoses has been registered. The objective of this study was to evaluate the glucocorticoid adrenal function in patients with paracoccidioidomycosis and histoplasmosis hospitalized in the University Hospital "Ruiz y Pácz" of Ciudad Bolivar (Bolivar state) and in the Hospital "Luis Felipe Rojas Guevara", of El Tigre (Anzoátegui state), Venezuela, between January 2003 and January 2004. The test of fast stimulation with synthetic adrenocorticotrophin hormone (ACTH) was applied to a total of 12 patients with diagnosis of some of these mycoses and data of epidemiologic interest were taken. The proportion men:women was of 5:1, the average age was 35.1 +/- 0.37 years, similar to the control group. Basal plasmatic cortisol levels were within the normal rank in all the patients. After the injection of synthetic ACTH, an increase of plasmatic cortisol values in the same rank for patients with a normal adrenal function was observed, but it was significantly lower than the observed for the control group. These results suggest that there is an adrenal gland functional reserve diminution in patients with either Paracoccidioidomycosis or Histoplasmosis. In patients with systemic mycoses, it is important to evaluate the response to the test of fast stimulation with ACTH due to the frequency of impairment of the glucocorticoid adrenal function in our location.

Evaluation of minimum clinically meaningful changes in scores on the National Eye Institute Visual Function Questionnaire (NEI-VFQ) SST Report Number 19.

PURPOSE: To evaluate responsiveness of the National Eye Institute Visual Function Questionnaire (NEI-VFQ) to changes in visual acuity and to provide estimates of minimum clinically meaningful changes in NEI-VFQ scores. METHODS: Data were combined from three clinical trials of submacular surgery for subfoveal choroidal neovascularization. Patients who completed NEI-VFQ interviews and visual acuity measurements at baseline and 2 years later contributed data for analysis. Data were analyzed using anchor-based (relating 2-year change in NEI-VFQ to 2-year change in visual acuity using correlation and linear regression) and distribution-based (standardized response mean) methods. RESULTS: Of 1,015 patients enrolled, 828 patients completed NEI-VFQ interviews and had visual acuity measurements at baseline and 2 years later. Median age of patients was 75 years (range 18 to 94); all patients had subfoveal choroidal neovascularization in at least one eye. Median overall NEI-VFQ score at baseline was 69.9 (mean, 66.5). Based on anchor-based methods, a 2-line change in visual acuity of the better-seeing eye translated to a 3.4-point change in the overall NEI-VFQ score and from 2.4-point to 7.0-point changes in most subscale scores. The NEI-VFQ was sensitive to both gains and losses in visual acuity; the standardized response mean for the overall NEI-VFQ score in patients with a 2-line gain was 0.6 and for patients with 2-line loss was -0.3. In the subgroup of patients with a 2-line loss of visual acuity in the better-seeing eye, patients who had overall NEI-VFQ scores at baseline greater than the median (59.8) had an standardized response mean of -0.9 for the overall NEI-VFQ score and patients who had overall NEI-VFQ scores at baseline at or below the median had a standardized response mean of 0.2 for the overall NEI-VFQ score. A 4-point change in the overall NEI-VFQ and a 5-point change in individual subscale scores corresponded to a small clinically meaningful change. CONCLUSIONS: The NEI-VFQ was responsive to 2-year changes in visual acuity but was less responsive to changes among patients with poorer NEI-VFQ scores at baseline. Based on this analysis, a 4-point change in the overall NEI-VFQ and a 5-point change in individual subscale scores may be considered minimum clinically meaningful within-person changes in NEI-VFQ scores.