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Objectives To demonstrate the successful use of pharmacogenomic testing to specifically tailor antifungal treatment to the phenotype of a patient with human immunodeficiency virus (HIV) and disseminated histoplasmosis who had clinical progression while on itraconazole and subsequently had insufficient therapeutic drug levels of voriconazole. Case summary We present the case of a patient with HIV and disseminated histoplasmosis with a persistently elevated serum Histoplasma capsulatum antigen and subtherapeutic levels of voriconazole. Pharmacogenomic testing revealed he was a CYP2C19 rapid metabolizer, thus explaining his persistent, subtherapeutic levels of voriconazole and prompting a change in therapy. Practice implications Our case illustrates the importance of pharmacogenomic testing as a tool to evaluate subtherapeutic itraconazole or voriconazole levels, especially in patients with failed clinical or Histoplasmosis Ag response despite reporting full adherence to prescribed therapy.

The diagnosis of progressive disseminated histoplasmosis is often a challenge to clinicians, especially due to the low sensitivity and long turnaround time of the classic diagnostic methods. In recent years, studies involving a variety of non-culture-based diagnostic tests have been published in the literature. We performed a systematic review by selecting studies evaluating non-culture-based diagnostic methods for progressive disseminated histoplasmosis. We searched for articles evaluating detection of antibody, antigens, as well as DNA-based diagnostic methods. A comprehensive PUBMED, Web of Science, and Cochrane Library search was performed between the years 1956 and 2016. Case reports, review articles, non-human models and series involving less than 10 patients were excluded. We found 278 articles and after initial review 18 articles were included: (12) involved antigen detection methods, (4) molecular methods, and (2) antibody detection methods. Here we demonstrate that the pursuit of new technologies is ultimately required for the early and accurate diagnosis of disseminated histoplasmosis. In particular, urinary antigen detection was the most accurate tool when compared with other diagnostic techniques. Keywords: Disseminated histoplasmosis, Non-culture, Enzyme immunoassay, Diagnostic tests

Hemophagocytic lymphohistiocytosis (HLH) is a rare and aggressive disease involving immune system over-activation leading to hemophagocytosis. HLH requires early diagnosis and prompt treatment initiation, especially in patients with Acquired Immunodeficiency Syndrome (AIDS). We present a case of a middle-aged male with AIDS and renal failure, who developed HLH secondary to disseminated histoplasmosis. Etoposide chemotherapy as recommended by the HLH 2004 Guidelines was deferred and treatment focused instead on anti-fungal therapy. Anti-retroviral therapy followed thereafter. Keywords: Hemophagocytic lymphohistiocytosis, Histoplasmosis, AIDS, Fungal infection

This case report describes an atypical presentation of a relatively common opportunistic infection, without documented exposure to areas known at the time to be endemic, resulting in catastrophic complications. The patient presented with a two month progressive history of vomiting, diarrhea, productive cough, and shortness of breath, on the background of poorly-controlled HIV. There was a low index of suspicion for infection with histoplasmosis, particularly given the large differential diagnosis and the lack of travel or endemic precedence. The case was complicated by the development of disseminated intravascular coagulation (DIC) prior to identification of the pathogen. Ultimately, the patient’s goals of care transitioned to palliation, and treatments were discontinued. It is our hope that in the future, such outcomes might be prevented by considering disseminated histoplasmosis in systemically unwell patients with HIV, regardless of endemic exposure or specific presentation.

Introduction Histoplasma capsulatum is rarely found in nose and sinuses in immunocompetent and even in immunosupressed patients. A literature review revealed rare cases of H. capsulatum sinusitis and the case we describe in this paper is the first case of H. capsulatum sinusitis in Morocco. The purpose of our work is to present a rare case of H. capsulatum sinusitis and a literature review.

Early human immunodeficiency virus (HIV) infection leads to transient immunosuppression followed by a quasi-homeostatic state with slow progression towards AIDS. Histoplasmosis has never been reported in early HIV. We present a case of disseminated histoplasmosis with documented recent seroconversion and review the literature regarding other opportunistic infections in early HIV.

Histoplasmosis of the gallbladder is an extremely rare condition. We present the case of cholecystitis due to progressive, disseminated histoplasmosis in an immunocompetent woman. Keywords: Histoplasmosis, Gallbladder

We describe an immunocompromised HIV patient with disseminated histoplasmosis, cerebral toxoplasmosis, Pneumocystis jirovecii pneumonia (PJP) with cytomegalovirus (CMV) and Human Herpes virus 8 (HHV8) viraemia complicated by severe thrombocytopenia and hypocalcaemia. During a prolonged inpatient admission at our infectious disease (ID) high care unit (HCU), he represented a diagnostic challenge and management dilemma involving a variety of medical specialties. We aim to explore the difficulties surrounding the diagnosis and management of disseminated histoplasmosis especially in view of other concurrent opportunistic infections (OIs). We aim to elaborate on how this rare case provided new insight into the management of multiple OIs in a severely immunocompromised HIV individual and why we need specialist ID high dependency units.

Hematopoietic and solid organ transplant recipients are at increased risk of opportunistic infections and infections usually are severe due to impaired cell mediated immunity. We report an unusual case of disseminated histoplasmosis in a renal transplant recipient manifesting with a chronic progressive course over several years. After starting treatment with itraconazole, the patient showed marked improvement in his symptoms and had clinical resolution Keywords: Chronic progressive disseminated histoplasmosis, Renal transplant, Fever of unknown origin, Pancytopenia, Histoplasma antigen

Histoplasma infection of vascular grafts is extremely rare. To our knowledge, there are only 4 cases reported with Histoplasma capsulatum infection of the aortic graft. All had previous disseminated histoplasmosis and atherosclerotic peripheral vascular disease. They were treated surgically with explantation of the infected graft and reimplantation of new graft in extra-anatomic uninfected site. The authors present a new case of H capsulatum infection of aortofemoral bypass graft, but unlike the other cases, this case was managed without surgical intervention.

• The thick blood smear is a useful, rapid, and low cost technique for the diagnosis of disseminated histoplasmosis.

We present a case of disseminated histoplasmosis in a domestic cat imported from the USA to Austria. Histopathological examination revealed a systemic mycosis with most severe involvement of the lungs suggestive of Histoplasma (H.) capsulatum-infection. Molecular confirmation was based on polymerase chain reaction (PCR) and sequence analysis of a fungal culture from liver samples. This is the first case of feline histoplasmosis proven by molecular diagnostic technique in Europe and reported in Austria, etc.

We present a case of a 64-year-old man with a prolonged history of fatigue, weight loss, fever, and kidney failure. Kidney biopsy showed severe granulomatous interstitial nephritis with numerous giant cells. Silver stains identified fungal micro-organisms consistent with Histoplasma species. Despite antifungal treatment, the patient died of overwhelming infection a few weeks later. This report emphasizes the importance of diagnosing histoplasmosis early. A high degree of suspicion is required to make the diagnosis of histoplasmosis in a case of granulomatous interstitial nephritis.

Highlights • Tumor necrosis factor (TNF) inhibitors are associated with risks of invasive infections. • Disseminated histoplasmosis can be easily mistaken for a pneumonia. • Confounding comorbidities and travel-associated risk factors may delay diagnoses. • Liposomal amphotericin b, may or may not have altered the course of this patient’s illness., Tumor necrosis factor (TNF) inhibitors are widely used in the treatment of inflammatory conditions and are associated with risks of invasive infections. We present a diagnostically challenging patient with unique comorbidities and travel history. A 53-year-old man with a history of polysubstance abuse and psoriasis on adalimumab presented to our hospital directly from the airport with fever, dyspnea, and cough. He had been living in Costa Rica and engaged in many outdoor activities. Within 6 hours and a limited history, he was intubated; vasopressors and antimicrobials were promptly administered. An extensive infectious disease investigation was undertaken, considering potential travel-related exposures and his immunosuppressive state. However, multi-organ failure with worsening disseminated intravascular coagulation ensued, and within four days of admission, the patient passed away. Five days after his death, the urine Histoplasma antigen resulted positive. Disseminated histoplasmosis should be suspected in a patient on anti-TNF therapy, with a severe febrile illness and pneumonia refractory to antibacterial therapy. A high index of suspicion is necessary to make the diagnosis and initiate prompt treatment.

Histoplasmosis is an endemic fungal infection that can involve any organ when disseminated. Although oral, pharyngeal, laryngeal, and endobronchial involvement have been described, direct tracheal involvement has not been reported. We describe the first case of disseminated histoplasmosis with direct involvement of the trachea. The endobronchial manifestations of histoplasmosis are reviewed.

Resumen Presentamos un caso de histoplasmosis diseminada en un paciente ecuatoriano de 33 anos, con sida y recuento de linfocitos CD4 de 39 celulas/μl. Al llegar a nuestro hospital referia fiebre prolongada y tos, fue diagnosticado de sindrome hemofagocitico con fallo multiorganico y fallecio a los 18 dias del ingreso. El diagnostico se completo post-mortem, con el aislamiento de Histoplasma capsulatum en las muestras de sangre y biopsia medular. En la revision de los casos de histoplasmosis diseminada en infectados por el VIH publicados en Espana desde 1988, encontramos 22 pacientes. Todos excepto dos eran varones menores de 50 anos. Diecinueve habian nacido o vivido en areas endemicas. El diagnostico de histoplasmosis se realizo por cultivo de biopsia de medula osea en 10 casos. Diez de los trece pacientes que sobrevivieron habian sido tratados con anfotericina B y, posteriormente, con itraconazol como segundo farmaco.

Untreated histoplasmosis is life threatening, especially in immunosuppressed patients. In French Guiana, South America, it is one of the most common opportunistic infections in AIDS patients. Twenty-one cases of disseminated histoplasmosis were diagnosed in 2004 in the mycology laboratory of Cayenne hospital. Culture samples for histoplasmosis diagnosis is simple, sensitive, and specific, but it is a lengthy process. Management of the disease is then dangerously delayed. In this work, we tested a polymerase chain reaction (PCR) method on 40 samples from patients with suspected disseminated histoplasmosis. The recently described Hcp100 nested PCR method was used to detect Histoplasma capsulatum DNA in these samples. All of the positive cultures for H. capsulatum were also positive with PCR method. Tested on other fungi or negative culture, it also showed high specificity. Furthermore, it allows treating patients more rapidly. Culture remains necessary, but histoplasmosis PCR offers great prospects, on a clinical point of view.

Histoplasmosis is an endemic mycosis. Histoplasma capsulatum, and duboisii are the pathogenic agents in humans. The disease is reported as endemic in more than 30 countries. Three clinical forms are distinguished; acute, chronic and disseminated. Oral lesions may take on different clinical aspects which are often associated with disseminated histoplasmosis. Disseminated histoplasmosis is frequently diagnosed in immunocompromised hosts. High risk of mortality dictates rapid diagnosis and treatment.

s S237 patients. These results suggest that allosensitization should be considered in the lung allocation score. Patient data; ritux-rituximab; MMF-mycophenolate mofetil; PLEX-plasmapheresis Patient Age Gender Diagnosis Pre-desensitization cPRA Desensitization regimen Postdesensitization cPRA Outcome 1 68 F COPD 89 Ritux, IVIG 82 Transplanted, BOS 0 at 19m 2 60 M ILD 92 Ritux, IVIG 83 Transplanted, DSA, BOS 0p at 33m 3 63 M ILD 82 Ritux, IVIG 75 Transplanted, BOS 0 at 37m 4 59 F COPD 98 Ritux, IVIG 98 Died on waiting list 5 42 F ILD 98 Ritux, IVIG, MMF, PLEX 49 Transplanted, BOS 0 at 36m 6 52 M ILD 83 Ritux, IVIG, MMF, PLEX 81 Transplanted, DSA, BOS 0p at 35m 7 21 F CF 97 IVIG 97 Disease improved, re-listed 30m later, still waiting 8 56 F COPD 98 Ritux, IVIG, MMF, PLEX 98 Died on waiting list 9 38 F ILD 81 Ritux, IVIG, MMF, PLEX 61 Disseminated histoplasmosis, waiting 10 59 M ILD 97 Ritux, IVIG, MMF, PLEX 62 Transplanted, BOS 0 at 19m 11 30 F CF 98 Ritux, IVIG, PLEX 99 Listed, still waiting

We describe a patient who developed multi-organ failure with reactive hemophagocytic syndrome secondary to disseminated histoplasmosis 8 months after orthotopic heart transplantation. The patient responded fully to a prolonged course of therapy with amphotericin B and remains free of recurrence. Disseminated histoplasmosis and reactive hemophagocytic syndrome have rarely been described in the setting of cardiac transplantation and never before in combination.

Disseminated histoplasmosis was diagnosed in a 4·75-year-old, captive female sea otter ( Enhydra lutris ). At necropsy, the liver was found to be markedly swollen, with many nodules (4–12 mm in diameter). Histologically, macrophages containing numerous intracellular yeast-like organisms were noted in the liver, spleen, lung and kidney. These organisms were labelled immunohistochemically with anti-histoplasma yeast antibody. Ultrastructurally, the yeast-like organisms, 2–4 μm in diameter, were found within membranous structures in the cytoplasm of macrophages. This is the first confirmed report of disseminated histoplasmosis in sea otters.

Resumen La histoplasmosis es una micosis sistemica, endemica en varios paises de America, producida por un hongo dimorfo, denominado Histoplasma capsulatum var capsulatum. Las formas diseminadas de la enfermedad afectan a los pacientes inmunocomprometidos y son la consecuencia de la reactivacion de una infeccion latente. Presentamos un paciente con sida que desarrollo una histoplasmosis laringea como unica manifestacion clinica de la enfermedad. El diagnostico se confirmo por la histopatologia de las lesiones con la presencia de levaduras compatibles con Histoplasma capsulatum. El tratamiento con anfotericina B seguida de itraconazol se asocio con una remision completa de las lesiones laringeas. En nuestro conocimiento este seria el tercer caso de histoplasmosis de laringe en un paciente con sida.

• Disseminated histoplasmosis with CNS involvement is not only seen in immunocompromised patients