Histoplasmosis: causes, symptoms, diagnosis, treatment, and prognosis

Histoplasmosis is a highly contagious fungal infection, often transmitted through the respiratory tract, firstly invading the lungs followed by other mononuclear phagocyte systems such as liver and spleen, as well as kidney, central nervous system, and other organs.

Histoplasmosis can be divided into American histoplasmosis caused by Histoplasma capsulatum and African histoplasmosis caused by Histoplasma duboisii and Histoplasma farciminosis.


Causes

Histoplasma resides as hyphae in nature or at room temperature, but after invasion of host cell or at 37 °C, it transforms into a small yeast cell with a diameter of 1 - 5μm. Human body is infected after inhalation of the spores of Histoplasma, which are present in the soil or dust contaminated by the feces of birds or bats. Severe infections are mainly seen in extensive and prolonged exposure to environment containing spores of Histoplasma, males, infants, and patients with T cell immunodeficiency.

The lesions are predominantly in the lungs, but if the cellular immune function cannot control the infection, the infection can be disseminated in the bloodstream. Progressive disseminated histoplasmosis is an AIDS-defining opportunistic infection.


Signs and Symptoms

The vast majority of histoplasmosis is asymptomatic or with only mild symptoms, and generally patients do not need medical treatment.

Acute primary histoplasmosis is a clinical syndrome manifested by fever, cough, myalgia, and varying degrees of discomfort. Normal or diffuse nodules or miliary lesions can be seen in chest X-ray examination.

Chronic cavitary pulmonary histoplasmosis is characterized by lesions at the apex of the lung, resembling cavitary tuberculosis. Clinical manifestations are progressively aggravated cough and dyspnea, ultimately leading to respiratory failure. This illness does not disseminate. Focal cavities can be seen in chest X-ray examination.

Progressive disseminated histoplasmosis is characterized by systemic reticuloendothelial involvement, manifested by hepatosplenomegaly, lymphadenopathy, bone marrow involvement, and sometimes oral or gastrointestinal ulcers. The disease is mostly subacute or chronic, and is accompanied by non-specific symptoms such as fatigue, malaise, and discomfort, often mild. HIV-positive patients often have progressive deterioration of health without obvious causes. The disease can involve the central nervous system and is manifested by meningitis or focal cerebral lesions. The disease rarely invades the adrenal glands, and can cause Addison's disease once involved. Severe pneumonia can occur in AIDS patients, and is manifested by hypoxemia, hypotension, changes in mental status, coagulopathy, or rhabdomyolysis. Hilar lymphadenopathy accompanied by diffuse nodular exudation can be seen in chest X-ray examination.

African histoplasmosis invades mostly skin and bones. The skin lesions are initially painless papules or nodules, with mild pruritus, developing into ulcers, with curled, hyperpigmented edges, and nearby lymph nodes may be enlarged. The subcutaneous lesions are abscesses, developing into ulcers or sinus tracts after rupture. Mucosal infections are less common, often involving the tongue and buccal mucosa, and the lesions are 1 cm in size papules. The skin lesions of disseminated infection are multiple granuloma, usually healing spontaneously within 2 - 4 months, and subsequently new skin lesions occur. The disease can invade almost any bone, but predominantly the ribs and long bones, and is manifested by myeloma or sarcoidosis.

Fibrosing mediastinitis is a rare chronic histoplasmosis, and can eventually cause circulation disorders.


Histopathology

The invaded organs have basically the same pathological changes. In the early stage, central hyperplasia and more or less fungi in the phagocytes can be seen. Subsequently, tissue necrosis surrounded by granuloma changes can be observed. Finally, healing or fibrosis is present.

Primary contact histoplasmosis is manifested by non-specific inflammatory infiltration, occasionally with macrophages and necrotic areas. There are a large number of pathogens in macrophages. Histiocytes phagocytosing spores can also be found in local lymph nodes.

In disseminated and localized histoplasmosis, mucocutaneous lesions often present with superficial ulcers and necrotic foci in non-specific chronic inflammatory infiltration. There may be few giant cells. Many spores can be found in cytoplasm-rich histiocytes. Round or oval bodies with translucent halos resembling capsules can be seen in HE stain. The capsule-like appearance cannot be found in PAS stain, but red stained cell walls can be seen.


Diagnosis

Due to absent specific clinical symptoms, it is very difficult to diagnose histoplasmosis. Chest X-ray examination, histopathology, histoplasmin skin test, and serology can assist in the diagnosis.


Treatment

Acute primary histoplasmosis generally does not require antifungal treatment. If the condition does not improve spontaneously one month after onset, itraconazole 200mg orally three times daily for the first three days followed by 200mg orally once daily for 6 - 12 weeks can be administered. Fluconazole is ineffective in the treatment of this disease. Other azoles have not been well clinically evaluated, but there have been reports of successful treatment. Pulmonary histoplasmosis requires more aggressive treatment, and amphotericin B is appropriate.

Chronic histoplasmosis can be treated by itraconazole 200mg orally three times daily for the first three days followed by 200mg orally once or twice daily for 12 - 24 months. If the condition is extremely severe or does not respond to itraconazole or patients cannot tolerate itraconazole, other azoles or amphotericin B can be used.

Severe disseminated histoplasmosis can be treated by amphotericin B lipid preparations 3 mg/kg intravenously once daily for 2 weeks or until the clinical condition is stabilized, and amphotericin B 0.5 -1.0 mg/kg intravenously can also be used. After the body temperature returns to normal and does not require assisted breathing or blood pressure support, the medication can be switched to itraconazole orally 200mg 3 times daily for the first 3 days followed by 200mg twice daily for 12 months. Mild disseminated histoplasmosis can be treated by itraconazole orally 200mg 3 times daily for the first 3 days followed by 200mg twice daily for 12 months. For histoplasmosis in AIDS patients, itraconazole should be used for a long time to prevent recurrence or until the CD4 cell count > 150/μL.

Fluconazole is poorly effective, but voriconazole and posaconazole can be used for the treatment of this disease.


Prognosis

Acute primary histoplasmosis is mostly self-limiting. There are very few reports of deaths after infection, and most deaths occur in severely infected patients. Chronic cavitary histoplasmosis can cause death as a result of severe respiratory insufficiency. The mortality in untreated progressive disseminated histoplasmosis is > 90%.