Case Presentation A 24 year old white male presented to the ED in Indianapolis, IN with a persistent cough for the past 4 days. Upon further questioning, he states that he has also had a mild fever (101), chills, sweats, and muscle pain. He has also noticed a rash on his lower legs.

History Meds: None Allergies: Penicillin PMHx: community acquired pneumonia 4 years ago – outpatient PSHx: Appendectomy 2 years ago Social Hx: Computer programmer for IBM, denies drugs and tobacco, significant EtOH when IU basketball dominates a big ten foe, enjoys taking pictures of bats in caves Family Hx: mom – HTN, CAD, and Type I DM; dad – HTN and prior CVA

Physical Exam GENERAL APPEARANCE:  alert, talkative, actively coughing, in no distress VITAL SIGNS:  T - 97.5, BP 110/60, respirations 22, and HR 88  HEENT: Head is normocephalic and atraumatic. Extraocular muscles are intact. Pupils are equal, round, and reactive to light and accommodation. Nares appeared normal. Mucous membranes are moist. Posterior pharynx clear of any exudate or lesions. NECK: Supple. No carotid bruits.  No lymphadenopathy or thyromegaly. LUNGS: mild tachypnea, decreased breath sounds and dullness to percussion bilaterally in middle and lower lobes, no wheeze appreciated HEART: Regular rate and rhythm without murmur. ABDOMEN: Soft, non-tender, and non-distended.  Normal bowel sounds.  No hepatosplenomegaly or palpable masses were noted. NEUROLOGIC: Cranial nerves II through XII are grossly intact, 5/5 strength in UE and LE, DTR normal SKIN: Erythematous, tender macules diffusely on both lower extremities; otherwise normal

Differential Diagnosis? Tuberculosis Pneumonia (bacterial vs viral vs fungal) Pneumocystis carinii pneumonia Histoplasmosis Blastomycosis Malignancy Need to include entities that are associated with erythema nodosum. (? Pneumocystis??)

Evaluation What labs, imaging, or procedures would be appropriate?

Labs CBC: WBC 13,000 cells/mm3, Hgb. 13.4, PLTS 350,000/mm3 BMP: Na 140, K 4.5, Cl 101, HCO3 23, BUN 20, Cr 1.5, Glucose 101 ABG: pH 7.4, pCO2 31, pO2 85 Blood cultures: pending Sputum stain: No organisms seen on stain, Cultures pending I would add appropriate units; eg /mm3, etc.

Chest PA Radiograph

Bronchoalveolar Lavage Small (2–5 nm) narrow budding yeast forms (Grocott's methenamine silver stain)

Diagnosis? Histoplasma capsulatum (picture shows environmental form)

Etiology and Epidemiology Thermal, dimorphic fungus that exist as microconidia and macroconidia Microconidia (2–4 um) are small enough to reach alveoli Shortly after infection host, conidia transform into yeast-like forms Yeast forms are 2–5 mcg, with NARROW WAISTED BUDDING Most prevalent endemic mycosis in North America Most prevalent in Mississippi and Ohio valleys This geographic pattern is due to humid and acidic nature of soil Soil enriched with bird and bat droppings promotes growth and sporulation of histoplasma Spelunking, excavation, cleaning of chicken coops, demolition and remodeling of old buildings are activities with high level of exposure

Pathogenesis Inhaled microconidia reach alveoli and are phagocytosed by alveolar macrophages within which they transform into yeast forms. Transformation is a requisite for pathogenesis Yeasts replicate within macrophages within which they are disseminated hematogenously Yeasts utilize the macrophage’s phagosome as a vehicle to translocate to hilar/mediastinal lymph nodes Histoplasma specific cellular immunity develops in immunocompetent at 2 weeks. Cells produce IFN gamma to assist macrophages in killing the organism In immunocompotent hosts, macrophages, lymphocytes, and epithelial cells organize and form granulomas that contain the organism, which typically fibrose and calcify

A, Laminated Histoplasma granuloma of the lung. B, Histoplasma capsulatum yeast forms fill phagocytes in the lung of a patient with disseminated histoplasmosis (silver stain)

Manifestations in Immunocompetent Host Most common is no manifestation = completely asymptomatic Of adults residing in endemic areas, 50–80% have skin-test and/or radiographic evidence of previous infection without clinical manifestations (incidental CXR finding is ~ 95%) Radiographs can demonstrate normal architecture OR an infiltrate with hilar/mediastinal adenopathy with focal calcifications (typically a late manifestation) Non-specific febrile illness Rheumatologic s/x Mild joint infl., ± erythema nodosum/multiforme (5-10%) Back/chest pain Weight loss if ill > 2wks Majority are self-limited

Manifestations in Immunocompromised Host In patient with an underlying cellular immunity deficiency (HIV and immunosuppressive medications), patient will not recover and can develop progressive disseminated histoplasmosis (PDH) Common risk factors include AIDS (CD4+ T cell count <200/L), extremes of age, and the use of immunosuppressive medications such as prednisone, methotrexate, and anti-TNF- agents (listen to TV commercials about rheumatoid arthritis meds… “be sure to tell your doctor if you live in areas with certain fungal infections”) Common manifestations: weight loss, fever, hepatosplenomegaly, brain lesions, oral mucosal ulcerations, GI ulcers, adrenal insufficiency, and death

Treatment Most patients will recover without therapy, however, itraconazole should be considered if the patient’s condition has not improved after 1 month In patients with a moderate to severe case of acute pulmonary histoplasmosis and PDH, a lipid emulsion of amphotericin B with glucocorticoids is given for 1- 2 weeks, then intraconazole for 12 weeks Be sure to monitor renal and hepatic function for medication side effects