Capsulatum Infection Research Articles

Laryngeal histoplasmosis in an immunocompetent patient from a non‐endemic region: case report

Histoplasma capsulatum infection involving the larynx is a rare manifestation, especially in immunocompetent individuals and a high index of suspicion is needed to establish the diagnosis correctly. We report a case of a 50-year-old Brazilian man who presented with progressive hoarseness and throat pain for 4 months. Laryngoscopy showed a supraglottic vegetant lesion, and the biopsies chronic granulomatous inflammation without any specific agent. A second laryngoscopy with biopsies was performed and after 17 days of incubation in specific medium, H. capsulatum was isolated. The patient was successfully treated with amphotericin B.

Histoplasmosis en un varón inmunocompetente manifestada 45 años después de la infección

We report a case of a lung reactivation of a latent histoplasmosis in a 68 year-old patient without immunologic dysfunction living in Barcelona (Spain). The Histoplasma capsulatum var. capsulatum infection was probably acquired in a previous stay in Equatorial Guinea 48 years before. Diagnosis of mild chronic pulmonary histoplasmosis was performed by histopathology of lung biopsy plus antibodies detection against H. capsulatum. Treatment with oral itraconazol during three months leaded to a complete clinical cure, and antibodies disappeared after four years of follow up.

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.

Interleukins 17 and 23 Influence the Host Response toHistoplasma capsulatum

Host defenses against Histoplasma capsulatum require the action of several cytokines. Here, we explored the influence of interleukin (IL)-17 and IL-23 on immunity to H. capsulatum infection in mice. In lungs, synthesis of IL-17 was up-regulated during acute infection, and the cells producing it were predominantly CD3(+). Neutralization of IL-17A blunted fungal clearance but did not promote progressive infection. Decreased inflammatory cell recruitment and increased levels of IL-6 and IL-10 were associated with impaired clearance. To determine whether the elevated cytokine levels were important in the action of IL-17A, IL-6(-/-) or IL-10(-/-) mice were treated with anti-IL-17A; neutralization of IL-17A did not alter fungal burden in either group of knockout mice. We explored the relationship between IL-17 and IL-23 because they have been reported to form a regulatory network. IL-23 transcription and protein level were increased in the lungs of infected mice. Mice producing IL-23 in the absence of IL-12 manifested prolonged survival that was IL-17 dependent. Thus, IL-17 is requisite for the generation of optimal inflammatory and protective responses. Generation of functional IL-17(+) cells is dependent on IL-6 and IL-10. Our findings also establish the existence a regulatory IL-17/IL-23 axis in histoplasmosis.

Second Case of Histoplasmosis in a Captive Mara (Dolichotis patagonum): Pathological Findings

A second case of histoplasmosis in a captive mara (Dolichotis patagonum) from a colony at the wildlife park Africam Safari, Puebla, Mexico, is described, and the mara died with disseminated clinical form of the disease, affecting mostly the large intestine and adrenal. The pathological findings of this case 2 revealed severe granulomatous typhlocolitis and moderate granulomatous gastrohepatic lymphadenitis with numerous yeast-like cells, 2-4 mum in diameter, with a clear halo surrounding them inside the cytoplasm of macrophages, suggesting the parasitic form of Histoplasma capsulatum. Adrenocortical cells had abundant similar microorganisms in their cytoplasm without any associated lesion. Gomori's methenamine silver and periodic acid Schiff stained positively these microorganisms. Immunohistochemistry, using a rabbit anti-H. capsulatum serum, and transmission electron microscopy supported the diagnosis of H. capsulatum infection.

Reconstitution inflammatory syndrome related to histoplasmosis, with a hemophagocytic syndrome in HIV infection

Immune reconstitution after initiation of antiretroviral therapy may unmask a latent infection. We report a case of disseminated Histoplasma capsulatum capsulatum infection associated with a hemophagocytic syndrome in an HIV-infected patient, three weeks after initiation of antiretroviral therapy. The immune reconstitution inflammatory syndrome might be a risk factor for hemophagocytosis.

Leukotrienes Are Potent Adjuvant during Fungal Infection: Effects on Memory T Cells

Leukotrienes (LTs) are potent lipid mediators involved in the control of host defense. LTB(4) induces leukocyte accumulation, enhances phagocytosis and bacterial clearance, and increases NO synthesis. LTB(4) is also important in early effector T cell recruitment that is mediated by LTB(4) receptor 1, the high-affinity receptor for LTB(4). The aims of this study were to evaluate whether LTs are involved in the secondary immune response to vaccination in a murine model of Histoplasma capsulatum infection. Our results demonstrate that protection of wild-type mice immunized with cell-free Ags from H. capsulatum against histoplasmosis was associated with increased LTB(4) and IFN-gamma production as well as recruitment of memory T cells into the lungs. In contrast, cell-free Ag-immunized mice lacking 5-lipoxygenase(-/-), a critical enzyme involved in LT synthesis, displayed a marked decrease on recruitment of memory T cells to the lungs associated with increased synthesis of TGF-beta as well as IL-10. Strikingly, these effects were associated with increased mortality to 5-lipoxygenase(-/-)-infected mice. These data establish an important immunomodulatory role of LTs, in both the primary and secondary immune responses to histoplasmosis.

Disseminated histoplasmosis manifesting as a soft‐tissue chest wall mass in a heart transplant recipient

Soft-tissue masses are rarely associated with Histoplasma capsulatum infection. We describe a heart transplant patient who presented with a large right-sided chest wall mass as a manifestation of disseminated histoplasmosis. A successful clinical outcome was achieved upon recognition of the fungal pathogen.

The interface between virulence and host response to the pathogenic fungus Histoplasma capsulatum

Intracellular pathogens have evolved machinery to evade the immune response in order to survive within a host. Histoplasma capsulatum, one of the intracellular pathogens, is a dimorphic fungus that dodges innate and adaptive immunity; it escapes immunity presumably through virulence factors that permit fungal survival and replication within the host. This review discusses immune factors that contribute to the control of H. capsulatum infection, several host-survival mechanisms H. capsulatum uses, and new techniques that have led to the identification of several H. capsulatum virulence factors, which will most likely aid in the discovery of many more.

A Rare Case of Gastrointestinal Histoplasmosis in a 15-Year-Old Male Patient with a History of Cardiac Transplant and Diarrhea

Purpose: To report this rare finding. Methods: Case: A 15 y/o Caucasian male presents with fever of unknown origin. He has a h/o cardiac transplant in 1992 for Hypoplastic left heart syndrome. His cough symptoms did not improve with a course of azithromycin. The patient had a four-week visit with relatives in Michigan and Illinois approximately 3 months prior to the appearance of these symptoms. He now develops nausea, some vomiting, and slightly increased loose stool while hospitalized. A test for urine Histoplasma Ag was positive. A chest CT and sputum cultures showed no evidence of a fungal infection. An EGD showed several several duodenal bulb erosions. During colonoscopy, there was extensive erythema seen with superficial to deep ulcerations scattered from the cecum to sigmoid colon. Multiple pseudopolyps and inflammatory nodules were seen in the cecum. Biopsies were taken throughout which were significant for non-necrotizing granulomas. Giemsa and PAS special stains were also positive for numerous intracellular small yeast forms with focal narrow-based budding and rare hyphal forms. Duodenal biopsies were similar. These were morphologically consistent with Histoplasma capsulatum. Results: Histoplasma Capsulatum is a dimorphic fungus and found worldwide.1 In North America it is endemic in the major river valleys (Mississippi and Ohio) of the southern and central United States.2 Once the acute infection is spread hematogenously from the lungs to other organs it is generally classified as systemic. In addition to this, findings of positive blood cultures, or positive urine or serum Histoplasma antigens changes its classification to disseminated.2 Most infections are self-limited, but 1 in 2000 infections result in progressive dissemination especially in immunocompromised hosts.4 The symptoms of disseminated histoplasmosis include fever, malaise, anorexia, and weight loss. The gastrointestinal tract is commonly involved (70–90%) during disseminated infection as determined by autopsy studies.4,8 The colon is usually the most involved organ of the gastrointestinal tract followed by the small bowel. Serious gastrointestinal complications include malabsorption from severe diarrhea, ulcerations, strictures, bowel obstruction, gastrointestinal hemorrhage and perforations.7,8 Conclusion: Our case is a unique example of an immunosuppressed patient with recent travel to an endemic area which may have predisposed the duodenum and colon to a Histoplasma Capsulatum infection. Laboratory evidence of dissemination warrants endoscopic exam even when asymptomatic because the gastrointestinal tract is commonly involved. Prompt diagnosis and treatment may reduce the incidence of serious gastrointestinal complications.

AIDS-related Histoplasma capsulatum var. capsulatum infection: 25 years experience of French Guiana

Histoplasma capsulatum var. capsulatum infection is a major AIDS-defining illness in French Guiana. Although it affects South and Central American countries, the number of published cases is low. We present the largest series of AIDS-related histoplasmosis. The aim of this work is to describe clinical features and to help optimize investigations in settings where antigen detection methods are not available. Two hundred cases of AIDS-related histoplasmosis, diagnosed in the hospitals of French Guiana, were included retrospectively between 1982 and 2007. At the time of diagnosis, 92% of patients did not receive highly active antiretroviral therapy. CD4 cell count was less than 100 cells/microl for 80% of them. Most patients had fever, lymphadenopathies, and pulmonary and digestive symptoms. Neurological signs and skin/mucosal locations were less common. Other opportunistic infections were associated in 36.6% of cases (mostly tuberculosis). In most of the patients, lactic dehydrogenase was at least four times the normal value, and there was a moderate increase of aspartate aminotransaminase but not alanine aminotransaminase levels. Bone marrow aspirations were useful, but cultures of liver and lymphadenopathy specimens were the most contributive. Following treatment initiation, 17.5% died within a month. Presumptive treatment was started before diagnostic confirmation in 14.3% of the cases. In high prevalence settings, histoplasmosis often revealed AIDS in severely immunodeficient and poorly followed patients. In the absence of a quick sensitive technique, skin smear and fungal tissue cultures are contributive. Nevertheless, given the diagnostic delays and the poor prognosis, presumptive treatment with amphotericin B-containing regimens should be recommended when clinical and epidemiological contexts are evocative.

Disseminated histoplasmosis in a patient with renal allograft: A case report

Summary A case of disseminated histoplasmosis in a 25-year-old male patient with renal allograft (four years back) from Northern India is reported. The patient presented with moderate grade fever with cough, malaise and weight loss. The patient was provisionally diagnosed as a case of tuberculosis on the basis of clinical findings. Bone marrow aspirate revealed numerous intracellular globose yeast like cells and pleural fluid culture was positive for Histoplasma capsulatum . Patient was positive for cytomegalovirus (CMV) IgM antibodies. Histoplasma capsulatum infection is an opportunistic infection endemic in Ohio and Mississippi River Valleys, Central America, certain areas of South East Asia and the Mediterranean basin. This dimorphic fungus is relatively a rare entity in India. The present case highlight the fact that histoplasmosis could be an emerging opportunistic infection in India due to changing scenario in relation to immunocompromised status of the patients i.e. number of patients with malignancies, renal transplantation and HIV are on increase. Histoplasmosis should be suspected in these patients if clinical picture is suggestive.

Cutaneous cryptococcosis erroneously diagnosed as Histoplasma capsulatum infection.

Cutaneous cryptococcosis erroneously diagnosed as Histoplasma capsulatum infection.

Redefining the Clinical Spectrum of Chronic Pulmonary Histoplasmosis

Chronic pulmonary histoplasmosis is a disorder caused by Histoplasma capsulatum infection that is classically described as cavitary disease in male smokers with underlying chronic obstructive pulmonary disease (COPD). This clinical description relies on previous studies conducted mainly on cohorts from tuberculosis sanatoriums and United States Department of Veterans Affairs hospitals. Patients in earlier series were often selected either after being suspected of having Mycobacteria tuberculosis or by the presence of cavitary disease on chest radiograph. These early studies therefore may overrepresent the true proportion of males, smokers, and the percentage with cavitary disease in the general population. We sought to define the clinical spectrum of chronic pulmonary histoplasmosis in a mixed-sex inpatient and outpatient population. We conducted a retrospective chart review from 1976 to 2000 on all adults with a diagnosis of histoplasmosis with symptoms suggestive of pulmonary histoplasmosis for > or =6 weeks and either significantly positive serum H. capsulatum antibody titers or positive cultures (without evidence of disseminated disease). Participants included 46 patients, with a median age of 56 years. Notable differences were found between our study population and those in previously reported studies. First, nearly half of our patients were women (48%), and one-quarter were life-long nonsmokers (27%). Only 39% had cavitary disease and only 20% had COPD. It is noteworthy that there were no positive cultures from those patients who had never smoked. Major differences existed between male and female participants. Female patients had a lower presence of cavities, a decreased number of smokers and extent of smoking exposure, a decreased number of positive cultures, and an absence of underlying COPD. To our knowledge, this study is the first to report on a large number of outpatients with chronic pulmonary histoplasmosis. In contrast to previous studies, the current study included 48% female patients, 27% never smokers, and only 39% of patients with cavitary disease, representing a noticeably different spectrum of disease compared to previous studies.

Tumor Necrosis Factor Blockade: Mechanism of Action

Modulation of the immune response with tumor necrosis factor (TNF) blockers is not a new treatment strategy for many inflammatory disorders; however, relatively little is known about their specific mechanism of action. Understanding the mode of action, pharmacology, and pharmacokinetics of the monoclonal TNF antibodies, infliximab and adalimumab, and the soluble TNF receptor, etanercept, may therefore enable us to account for their differing clinical profiles. The aim of this supplement is to explore the roles and mechanisms of TNF and TNF blockade using in vitro pharmacological and in vivo animal modeling experiments, and in vivo studies of the effects of etanercept on the inflammatory cascade in patients with psoriasis.

The PD-1/PD-L costimulatory pathway plays a key role in Histoplasma capsulatum pathogenesis (B122)

Abstract The PD-1 costimulatory receptor negatively regulates T cell receptor signaling upon interacting with its ligands PDL1 and PDL2 expressed on antigen presenting cells (APCs) and has a key role in maintaining self-tolerance. In the present study we examined the role of PD-1 in Histoplasma capsulatum (Hc) infection. Hc is a human pathogenic dimorphic fungus that replicates within macrophages in vivo. To characterize immune responses in murine histoplasmosis, macrophages, as well as splenocytes were analyzed after intranasal infection with Hc. qRT-PCR and FACS analysis showed significant, IFN-γ-mediated up-regulation of PDL1 on both macrophages and splenocytes. The role of the PD-1 pathway in Hc pathogenesis is further demonstrated by the significant (100%) survival of PD-1 deficient mice infected with a lethal dose of Hc. Although initially inflammatory reactions developed in the lungs, the mice were disease free by day 10, as shown by histological analysis and cfu values. Also, when Hc infected C57BL/6 mice were treated with blocking anti-PD-1 monoclonal antibody, there was a significant increase in the survival of the animals (70%), whereas all untreated mice died. Our results show for the first time the importance of the PD-1/PDL pathway in anti-fungal immunity, and offer novel strategies for immunotherapy in clinical histoplasmosis.

Treatment of thoracolumbar spinal cord compression associated with Histoplasma capsulatum infection in a cat

A 7-year-old domestic shorthair cat with a 2-month history of decreased appetite and weight loss was examined because of paraparesis of 1 week's duration that had progressed to paraplegia 3 days earlier. Neurologic examination revealed normo- to hyperreflexia and absence of deep pain sensation in the hind limbs and thoracolumbar spinal hyperesthesia. Neuro-anatomically, the lesion was located within the T3 through L3 spinal cord segments. Biochemical analysis and cytologic examination of CSF revealed no abnormalities. Radiography revealed narrowing of the T11-12 intervertebral disk space and intervertebral foramen suggestive of intervertebral disk disease. Myelography revealed an extradural mass centered at the T12-13 intervertebral disk space with extension over the dorsal surfaces of T11-13 and L1 vertebral bodies. A right-sided hemilaminectomy was performed over the T11-12, T12-13, and T13-L1 intervertebral disk spaces, and a space-occupying mass was revealed. Aerobic bacterial culture of samples of the mass yielded growth of a yeast organism after a 10-day incubation period; histologically, Histoplasma capsulatum was identified. Treatment with itraconazole was initiated. Nineteen days after surgery, superficial pain sensation and voluntary motor function were evident in both hind limbs. After approximately 3.5 months, the cat was ambulatory with sling assistance and had regained some ability to urinate voluntarily. In cats with myelopathies that have no overt evidence of fungal dissemination, differential diagnoses should include CNS histoplasmosis. Although prognosis associated with fungal infections of the CNS is generally guarded, treatment is warranted and may have a positive outcome.

Gr-1 + cells play an essential role in an experimental model of disseminated histoplasmosis

Recent studies have shown the participation of Gr-1 + cells in many types of infections; however, the role played by these cells in the immune response to fungal pathogens is controversial. In this study we determined whether Gr-1 + cells are involved in the protective immune response in systemic Histoplasma capsulatum infection. Depletion of Gr-1 + cells using the monoclonal antibody (MAb) RB6-8C5 increased histoplasmosis severity and inhibited the subsequent development of a protective immune response. In addition to the increased fungal burden in lungs and spleens, the Th1 response was found to be unbalanced in these mice and the suppression of the cellular immune response seemed to be associated with increased nitric oxide production. Taken together, these results indicate that Gr-1 + cell depletion at the beginning of infection allows yeast multiplication and increases mice mortality. This study improves the understanding of the role of Gr-1 + cells on the protective immunity in histoplasmosis.

Characterization of theHistoplasma capsulatum-Induced Granuloma

Rising rates of Histoplasma capsulatum infection are an emerging problem among the rapidly growing population of immune-compromised individuals. Although there is a growing understanding of systemic immunity against Histoplasma, little is known about the local granulomatous response, which is an important component in the control of infection. The focus of this article is the characterization of Histoplasma-induced granulomas. Five days after i.p. infection, infected macrophage appear in the liver and lung; however, no granulomas are apparent. Two days later, well-formed sarcoid granulomas are abundant in the lung and liver of infected mice, which contain all visible Histoplasma. Granulomas are dominated by macrophage and lymphocytes. Most of the Histoplasma and most of the apoptotic cells are found in the center of the lesions. We isolated liver granulomas at multiple time points after infection and analyzed the cellular composition, TCR gene usage, and cytokine production of granuloma-infiltrating cells. The lesions contain both CD4+ and CD8+ T cell subsets, and T cells are the primary source of IFN-gamma and IL-17. The main source of local TNF-alpha is macrophage. Chemokines are produced by both infiltrating macrophage and lymphocytes. Dendritic cells are present in granulomas; however, T cell expansion seems to occur systemically because TCR usage is very heterogeneous even at the level of individual lesions. This study is the first direct examination of host cellular responses in the Histoplasma-induced granuloma representing the specific interface between host and pathogen. Our studies will allow further analysis of key elements of host Histoplasma interactions at the site of chronic infection.

Histoplasmosis: a review for clinicians from non‐endemic areas

Histoplasmosis is an important systemic mycosis in the Americas, Asia, and Africa. Increasingly cases are recognised in nonendemic areas. Proper management requires recognition of the clinical syndromes caused by Histoplasma capsulatum infection, familiarity with the uses and limitations of the diagnostic tests, an understanding of the indications for treatment and role of specific antifungal agents. This review will address these issues with the goal of providing physicians in non-endemic areas sufficient information to suspect, diagnose, and treat patients with histoplasmosis.