A 21-Year-Old Woman With Persistent Fever and Malaise

Muralikrishna Gopalakrishnamoorthy, MBBS, PGY-1; Archana Bhaskaran, MBBS, PGY-1; Rajeswari Anaparthy, MBBS, PGY-1; Ted T. Lin, MS3; Syed Hasan, MBBS


September 30, 2015

Histoplasmosis is most prevalent in the United States, but it is also found in the warm climates of Central and South America, the Caribbean, Africa, and Asia. In the United States, most cases occur within the Ohio and Mississippi River valleys. Approximately 250,000-500,000 cases are reported yearly, although disseminated histoplasmosis occurs in < 0.05% of infections. Farmers, landscapers, construction workers, and people who have contact with birds or bats are especially at risk.

The occurrence of histoplasmosis in AIDS patients is 2%-5%. Other risk factors include the extremes of age; chronic obstructive pulmonary disease; primary immunodeficiency or immunosuppressing disorders; and use of immunosuppressive medications, such as corticosteroids, methotrexate, tumor necrosis factor alpha inhibitors, and antirejection therapies in solid-organ transplant recipients.

Infection follows inhalation of microconidia (spores), which germinate into yeast in the lungs. An ineffective neutrophil response against the yeast is followed by ingestion of the yeast by macrophages. Macrophages then spread the organism via the lymphatic system and the blood to the adjacent lymph nodes and throughout the reticuloendothelial system. The organisms are confined to the macrophages and are rarely seen within the tissue spaces. In patients with disseminated infection, the organisms can be seen within monocytes in the peripheral blood.

In an immunocompetent host, specific immunity develops 10-21 days after infection.[3,4,5]Patients may present shortly after exposure or years later, and they may experience asymptomatic periods interrupted by symptomatic relapses.

Progressive disseminated histoplasmosis occurs in two forms: acute and chronic, which are determined in part by the time course of the illness and by the extent of the infection. Acute infection is seen mostly in infants, immunocompromised hosts, and patients treated with tumor necrosis factor alpha inhibitors. The duration of the acute syndrome ranges from a course of 1-5 days to a prolonged course of 10-21 days of severe illness. During the acute syndrome, nonspecific symptoms of fever, myalgia, pleuritic chest pain, and nonproductive cough predominate.

Chronic infection is seen more often among older, otherwise immunocompetent adults. Pancytopenia, hepatosplenomegaly, elevated liver enzyme levels, and oropharyngeal or gastrointestinal (GI) lesions are commonly seen in presentations of chronic infection. The symptoms in chronic infection are similar to those of acute infection, but they are often less severe and may be combined with weight loss, fatigue, and night sweats. In severely immunocompromised patients and those receiving immunosuppressive medications, it may present as an overwhelming infection, with shock and multiorgan failure; in these cases, the mortality rate approaches 50%, despite treatment.

Manifestations of disseminated disease may occur in several body systems. In immunocompetent hosts, exposure to a large inoculum typically results in a severe acute pulmonary syndrome that is characterized by a prodrome of cough, chest pain, and fever, with subsequent dyspnea, hypoxemia, and coarse breath sounds on examination. In severe cases, the illness may progress to adult respiratory distress syndrome. Pericarditis may develop, either as a result of inflammation in contiguous lymph nodes or, less commonly, true infection of the pericardium. Endocarditis is uncommon in disseminated histoplasmosis, only occurring in approximately 4% of patients.

A rheumatologic syndrome of arthritis, arthralgia, and erythema nodosum is seen in approximately 10% of cases. GI symptoms may include dysphagia, abdominal pain, and GI bleeding. Adrenal involvement is very common (80%-90%), although only 10% of patients develop adrenal insufficiency (often as a manifestation of relapsing histoplasmosis years after the initial episode).

CNS histoplasmosis manifests most commonly as meningitis in 10% of patients with disseminated disease, but it rarely occurs in immunocompetent patients. The symptoms include fever, headache, and changes in mental status (if accompanied by encephalitis). Seizures and focal neurologic findings may suggest meningitis or focal brain lesions. Localized spinal cord lesions may also occur.

Local manifestations of disseminated disease may include chorioretinitis, peritonitis, pancreatitis or cholecystitis, prostatitis, panniculitis, mastitis, osteomyelitis, septic arthritis, epididymitis, or penile/vaginal involvement.[3,4]

Histoplasmosis is diagnosed using antigen testing; the Histoplasma antigen is present in the urine in 90% of cases and in the serum in 70% of cases. It is less frequently detected in other sterile body fluids (eg, cerebrospinal fluid [CSF], bronchoalveolar lavage). Histopathology may reveal organisms on hematoxylin/eosin staining of a biopsy sample from infected tissue, although silver and periodic acid/Schiff staining are superior examinations. Serologic tests are of limited value, because they often yield false-negative results in immunocompromised patients. Blood cultures are positive in 50%-70% of cases, but they yield false-negative results in 20% of disseminated cases. Bone marrow cultures are positive in up to 75% of cases, and when combined with blood cultures, markedly increase the likelihood of positive cultures.

Biopsy may be performed at any suspected site of involvement, such as the skin or oral mucosa, GI lesions, lymph nodes, adrenal glands, and liver. Chest radiographs are abnormal in 70% of cases, usually showing diffuse interstitial or reticulonodular infiltrates. CSF lymphocytic pleocytosis, protein elevation, and low glucose are suggestive of CNS involvement. Single or multiple enhancing lesions may also be seen on CT.[1,6,7]


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