Histoplasma/Histoplasmosis

Histoplasmosis is an infection caused by Histoplasma capsulatum, a dimorphic fungus. The fungus exists as a mold at low temperatures and as yeast at high temperatures. H. capsulatum is the most common endemic fungal infection in the US and is most prevalent in the midwestern and central states along the Ohio and Mississippi River valleys. Transmission is through inhalation, and exposure to soils containing bird or bat droppings increases the risk of infection. Most infections are asymptomatic; however, immunocompromised individuals generally develop acute pulmonary infection, chronic infection, or even disseminated disease. Diagnosis is via different modalities, with the visualization and/or growth of the causative organism made using direct microscopy, histopathology, or culture studies. Management is dependent on disease severity. The antifungal medications that are used include amphotericin B and itraconazole.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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General Characteristics of Histoplasma

Features

  • Morphology: thermally dimorphic fungus
    • Ambient (low) temperature: mold form
    • Body (high) temperature: yeast form
  • Characteristics:
    • Obligate aerobe
    • Mold form:
      • Septate mycelium: thin and branching
      • Produce microconidia and tuberculate macroconidia
    • Yeast form:
      • Reproduce by budding
      • Slightly oval
      • 2–4 µm in diameter
      • Found exclusively in macrophages

Clinically relevant species

  • H. capsulatum var. capsulatum
  • H. capsulatum var. duboisii: exists primarily in Africa

Forms of disease

  • Pulmonary histoplasmosis:
    • Asymptomatic
    • Symptomatic
    • Acute diffuse
    • Chronic pulmonary
  • Disseminated histoplasmosis:
    • CNS
    • GI
    • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin lesions
    • Adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands

Mnemonic

Histoplasmosis is an infection caused by a dimorphic fungus. Remember the following mnemonic to recall how the fungus exists:

  • “Mold in the cold”
  • “Yeast in the heat”

Epidemiology

Frequency

  • Most common fungal infection endemic in the US
  • Incidence in the US: 500,000 new infections annually
  • Geographic prevalence:
    • US: Midwestern and Central US, Ohio and Mississippi River valleys
    • Worldwide:
      • South and Central America
      • Africa
      • India
    • Australia

Morbidity and mortality

  • Outcomes can vary depending on severity, duration, and host immune state.
  • Mild disease: typically good outcomes
  • Mortality of severe disease (despite hospitalization): 
    • 5% in children
    • 8% in adults
  • Chronic pulmonary histoplasmosis is more likely in individuals with underlying lung disease (particularly emphysema).
  • Disseminated histoplasmosis:
    • Immunocompetent adults: 1 per 2,000 cases of histoplasmosis
    • Immunocompromised individuals: 4%–27% mortality in severe cases
Map of united states areas endemic for histoplasmosis

Map of the United States illustrating the areas endemic for histoplasmosis

Image: “Map showing areas endemic for histoplasmosis in the US” by CDC. License: Public Domain

Pathogenesis

Infectious process

  • Habitat:
    • Found in soil contaminated with bird or bat droppings
    • Droppings increase nitrogen content → favorable for sporulation
    • Common sites:
      • Chicken coops
      • Farm buildings
      • Abandoned buildings
      • Caves
  • Transmission:
    • Inhalation via the respiratory tract
    • Deposition in the pulmonary alveoli
    • Exposures are seen in spelunkers and individuals involved in construction or agriculture.
  • Virulence factors:
    • Siderophores: support intracellular yeast growth
    • Melanin:
      • Found in the cell wall
      • Decreases host defense mechanisms Defense mechanisms Defense mechanisms are normal subconscious means of resolving inner conflicts between an individual's subjective moral sense and their thoughts, feelings, or actions. Defense mechanisms serve to protect the self from unpleasant feelings (anxiety, shame, and/or guilt) and are divided into pathologic, immature, mature, neurotic, and other types. Defense Mechanisms
      • Decreases the susceptibility of yeast to antifungal agents
    • Heat shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock proteins (HSPs):
      • HSP60: prevents significant activation of phagocytes
      • HSP82: role in yeast development and cellular stress
    • Yeast-phase-specific (YPS)3 gene:
      • Found in cell wall
      • Unknown function
    • Calcium-binding protein optimizes phagolysosomal conditions for yeast growth.
    • α-(1,3)-glucan: antigenic function
  • Pathogenicity and disease process:
    • Microconidia are phagocytized by macrophages.
    • Conversion to yeast form occurs.
    • Yeast multiply in alveolar macrophages.
    • Dividing yeast destroys macrophages and is then ingested by the recruited phagocytes.
    • H. capsulatum survives by capturing iron and modulating pH (to neutral), thereby decreasing the killing effect of phagolysosomes.
    • The cycle continues and allows the infection to spread to the hilar lymph nodes.
    • Macrophages help spread the organism via the lymphatic system.

Host risk factors

  • HIV infection HIV infection Human immunodeficiency virus (HIV), a single-stranded RNA virus belonging to the Retroviridae family, is the etiologic agent of acquired immunodeficiency syndrome (AIDS). The human immunodeficiency virus is a sexually transmitted or blood-borne infection that attacks CD4+ T lymphocyte cells, macrophages, and dendritic cells, leading to eventual immunodeficiency. HIV Infection and AIDS
  • Primary immunodeficiencies
  • Immunosuppressive disorders
  • Transplant recipients
  • Immunosuppressive drugs:
    • Most common fungal infection in patients on TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF)-α inhibitors
    • Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids
    • Antirejection therapies for solid organ transplants
  • Extremes of age
  • Heavy inoculation exposure

Clinical Presentation

General findings

Clinical presentation varies depending on host immune status and underlying risk factors.

  • Exposure to Histoplasma in endemic regions is extremely common.
  • The majority of infections are asymptomatic or subclinical.

Pulmonary histoplasmosis

  • < 5% of individuals develop symptomatic disease after low-level exposure.
  • Symptomatic pulmonary histoplasmosis:
    • Presents several weeks after exposure
    • Symptoms:
      • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
      • Chills
      • Headache
      • Myalgias
      • Anorexia
      • Cough
      • Pleuritic chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain
    • Examination:
      • Typically unremarkable
      • May exhibit rales or signs of consolidation
    • Chest X-ray: may be normal, or may show focal infiltrates with/without hilar or mediastinal lymph node involvement
  • Acute diffuse pulmonary histoplasmosis
    • Associated with large inoculum
    • Abrupt onset of symptoms
    • Chest X-ray: diffuse pulmonary infiltrates (reticulonodular)
    • ARDS ARDS Acute respiratory distress syndrome is characterized by the sudden onset of hypoxemia and bilateral pulmonary edema without cardiac failure. Sepsis is the most common cause of ARDS. The underlying mechanism and histologic correlate is diffuse alveolar damage (DAD). Acute Respiratory Distress Syndrome can develop within days.
    • Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea and fatigue may persist for months after treatment.
  • Chronic pulmonary histoplasmosis
    • Underlying lung disease ↑ risk
    • Symptoms:
      • Productive cough
      • Fatigue
      • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
      • Sweats
      • Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
    • Radiography/CT: 
      • Fibrotic apical infiltrates with cavitation
      • Can be confused for tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis
    • Areas of chronic infection have increased predisposition for:
      • Aspergilloma
      • Atypical mycobacteria Mycobacteria Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium
      • Chronic or recurrent pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
  • Broncholithiasis
    • Lymph node calcification or pulmonary granuloma calcification can occur years after the initial infection.
    • The calcification may erode into the adjacent bronchi.
    • Patient may report expectoration of:
      • Small stones
      • Gravel
      • Gritty material
    • Symptoms:
      • Chronic cough
      • Purulent sputum
      • Wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. Wheezing
      • Hemoptysis Hemoptysis Hemoptysis is defined as the expectoration of blood originating in the lower respiratory tract. Hemoptysis is a consequence of another disease process and can be classified as either life threatening or non-life threatening. Hemoptysis can result in significant morbidity and mortality due to both drowning (reduced gas exchange as the lungs fill with blood) and hemorrhagic shock. Hemoptysis
      • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
      • Chills
  • Other pulmonary manifestations:
    • Granulomatous mediastinitis Mediastinitis Mediastinitis refers to an infection or inflammation involving the mediastinum (a region in the thoracic cavity containing the heart, thymus gland, portions of the esophagus, and trachea). Acute mediastinitis can be caused by bacterial infection due to direct contamination, hematogenous or lymphatic spread, or extension of infection from nearby structures. Mediastinitis
    • Mediastinal fibrosis

Disseminated histoplasmosis

  • Most patients experience asymptomatic dissemination.
  • Can present acutely or years later
    • Acute: 
      • In infants and immunocompromised individuals
      • Can be rapidly fatal
    • Chronic: older patients who are immunocompetent
  • Symptoms:
    • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Malaise
    • Weight loss
  • Examination:
    • Hepatosplenomegaly
    • Lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy
    • Pallor
    • Petechiae: if pancytopenic
    • Oral ulcerations
    • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin lesions
  • Severe disease:
    • Sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock
    • Disseminated intravascular coagulation Disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation
    • Renal failure
    • Hepatic failure
    • Acute respiratory distress
  • CNS:
    • 5%–20% of cases
    • Presentation:
      • Meningitis Meningitis Meningitis is inflammation of the meninges, the protective membranes of the brain, and spinal cord. The causes of meningitis are varied, with the most common being bacterial or viral infection. The classic presentation of meningitis is a triad of fever, altered mental status, and nuchal rigidity. Meningitis
      • Isolated chronic meningitis
      • Cerebral vasculitis
      • Focal brain lesions
      • Encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis
      • Localized spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord involvement
  • GI disease:
    • Although 70% of patients have GI involvement, < 10% present clinically.
    • Can occur throughout the GI tract (most common in the ileum and colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix)
    • Manifestations:
      • Oral ulcers
      • Colonic perforation
      • Polypoid-like mass
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin:
    • 10%–15% of cases
    • More often in patients with AIDS
    • Lesions:
      • Nodules
      • Papules
      • Plaques
      • Ulcers
      • Pustules
      • Abscesses
      • Dermatitis
  • Adrenal glands Adrenal Glands The adrenal glands are a pair of retroperitoneal endocrine glands located above the kidneys. The outer parenchyma is called the adrenal cortex and has 3 distinct zones, each with its own secretory products. Beneath the cortex lies the adrenal medulla, which secretes catecholamines involved in the fight-or-flight response. Adrenal Glands:
    • Involvement is common; however, < 10% of individuals have overt insufficiency
    • Can be unilateral or bilateral
    • Perivasculitis → thrombosis → infarction of the adrenal glands
    • Adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease:
      • Electrolyte abnormalities
      • Orthostatic hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
      • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia 
  • Others: less common:
    • Cardiopulmonary: endocarditis Endocarditis Endocarditis is an inflammatory disease involving the inner lining (endometrium) of the heart, most commonly affecting the cardiac valves. Both infectious and noninfectious etiologies lead to vegetations on the valve leaflets. Patients may present with nonspecific symptoms such as fever and fatigue. Endocarditis, pericarditis Pericarditis Pericarditis is an inflammation of the pericardium, often with fluid accumulation. It can be caused by infection (often viral), myocardial infarction, drugs, malignancies, metabolic disorders, autoimmune disorders, or trauma. Acute, subacute, and chronic forms exist. Pericarditis, pleuritis Pleuritis Pleuritis, also known as pleurisy, is an inflammation of the visceral and parietal layers of the pleural membranes of the lungs. The condition can be primary or secondary and results in sudden, sharp, and intense chest pain on inhalation and exhalation. Pleuritis
    • GI/abdominal: peritonitis, pancreatitis, cholecystitis Cholecystitis Cholecystitis is the inflammation of the gallbladder (GB) usually caused by the obstruction of the cystic duct (acute cholecystitis). Mechanical irritation by gallstones can also produce chronic GB inflammation. Cholecystitis is one of the most common complications of cholelithiasis but inflammation without gallstones can occur in a minority of patients. Cholecystitis
    • Skeletal: osteomyelitis Osteomyelitis Osteomyelitis is an infection of the bone that results from the spread of microorganisms from the blood (hematogenous), nearby infected tissue, or open wounds (non-hematogenous). Infections are most commonly caused by Staphylococcus aureus. Osteomyelitis, septic arthritis Septic arthritis Septic arthritis is an infection of the joint due to direct inoculation, contiguous extension, or hematogenous spread of infectious organisms into the joint space. This process causes an acute, inflammatory, monoarticular arthritis. Septic Arthritis
    • Chorioretinitis Chorioretinitis Chorioretinitis is the inflammation of the posterior segment of the eye, including the choroid and the retina. The condition is usually caused by infections, the most common of which is toxoplasmosis. Some of these infections can affect the fetus in utero and present as congenital abnormalities. Chorioretinitis
    • Mastitis Mastitis Mastitis is inflammation of the breast tissue with or without infection. The most common form of mastitis is associated with lactation in the first few weeks after birth. Non-lactational mastitis includes periductal mastitis and idiopathic granulomatous mastitis (IGM). Mastitis
    • Thrombotic microangiopathy
    • Hemophagocytic syndrome
    • Hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia: due to calcitriol produced by macrophages

Diagnosis

Diagnostic approach

  • Diagnosis cannot be made on clinical information alone.
  • The approach will vary depending on presentation and test limitations.
  • Multiple tests including culture, direct microscopy, and histopathology can help in diagnosis.
    • Time consuming (> 14 days)
    • Variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables sensitivity
    • Culture is most effective when the fungal burden is high.
  • Histopathology:
    • KOH prep
    • Stains:
      • Methenamine silver (GMS)
      • PAS
    • Biopsy findings:
      • 2–4-µm narrow, budding yeast cells
      • Granulomas
      • Lymphohistiocytic aggregates
      • Diffuse mononuclear cell infiltrates
  • Culture:
    • Medium: Sabouraud’s dextrose agar
    • Growth: 2–6 weeks
    • Sources:
      • Tissue
      • Sputum and/or bronchoalveolar lavage (BAL)
      • Blood
      • Bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow
  • Antigen detection:
    • ELISA for antigen testing
    • Allows for rapid diagnosis, particularly in disseminated disease
    • Sensitivity increases with disease severity (most sensitive test in disseminated disease).
    • False positives can occur with other fungal diseases.
    • Sources:
      • Urine
      • Serum
      • BAL
      • CSF
  • Direct microscopy:
    • Wright’s stained smear (blood)
    • Least expensive
    • Can allow for rapid and confirmatory diagnosis
    • Limited by low sensitivity (< 10%)
  • Others:
    • Antibody tests (immunodiffusion test and complement fixation test)
    • PCR

Imaging

  • Chest X-ray and chest CT:
    • Can be normal
    • Findings:
      • Focal infiltrates
      • Hilar and/or mediastinal lymphadenopathy
      • Calcified granulomas
      • Pulmonary nodules
      • Diffuse interstitial or reticulonodular infiltrates
      • Cavitary lesions (rare)
      • Pleural effusions
  • CT (other areas):
    • Head CT:
      • Can be useful to detect cerebral histoplasmosis
      • Should be performed prior to lumbar puncture
    • Abdominal CT:
      • Can demonstrate adrenal involvement, if suspected
      • The findings typically demonstrate adrenal enlargement.
Chest_x-ray_acute_pulmonary_histoplasmosis

Chest X-ray:
Diffuse pulmonary infiltration due to acute pulmonary histoplasmosis caused by Histoplasma capsulatum

Image: “This chest film shows diffuse pulmonary infiltration due to acute pulmonary histoplasmosis caused by H. capsulatum” by CDC/M. Renz. License: Public Domain

Management

Principles

  • Treatment varies depending on disease severity.
  • Most cases are self-limiting and do not require treatment.
  • Individuals with large inoculum exposure and patients who are immunocompromised usually require treatment.
  • Antifungal drugs are the mainstay of treatment.
Table: Treatment of histoplasmosis
Condition Treatment
Moderate pulmonary disease or symptoms lasting > 4 weeks Itraconazole
Moderately severe to severe pulmonary disease Amphotericin B + itraconazole
Chronic pulmonary histoplasmosis Itraconazole
Mild disseminated histoplasmosis: mild symptoms with single focus (no CNS involvement) Itraconazole
Severe disseminated histoplasmosis without CNS involvement Amphotericin B + itraconazole
CNS involvement Amphotericin B (prolonged) + itraconazole

Acute pulmonary histoplasmosis

  • No treatment for:
    • Asymptomatic individuals
    • Individuals with mild symptoms
  • Prolonged symptoms (> 4 weeks) or moderate pulmonary disease:
    • Itraconazole for 6–12 weeks (loading dose for the 1st 3 days)
    • Monitor response with chest imaging.
    • Monitor for relapse (several years).
  • Moderately severe to severe pulmonary disease:
    • Amphotericin B for 1–2 weeks, followed by itraconazole for 12 weeks
    • Methylprednisone for 1–2 weeks for ARDS ARDS Acute respiratory distress syndrome is characterized by the sudden onset of hypoxemia and bilateral pulmonary edema without cardiac failure. Sepsis is the most common cause of ARDS. The underlying mechanism and histologic correlate is diffuse alveolar damage (DAD). Acute Respiratory Distress Syndrome

Chronic pulmonary histoplasmosis

  • Treatment is indicated for all patients.
  • Itraconazole for 1 year (loading dose for the 1st 3 days)

Disseminated histoplasmosis

  • If mild clinical symptoms and single focus of disease (without CNS involvement): itraconazole for 1 year (loading dose for the 1st 3 days)
  • All other cases:
    • Amphotericin B for 1–2 weeks (with CNS involvement: 4–6 weeks)
    • Itraconazole for at least 1 year (loading dose for the 1st 3 days)

Suppressive therapy

  • Relapse can occur if immune recovery is not maintained with antiretroviral therapy Antiretroviral therapy Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs in patients with AIDS.
  • Itraconazole is effective in preventing up to 95% of cases.
  • For patients with HIV having CD4 counts < 150 cells/µL → long-term itraconazole

Differential Diagnosis

  • Opportunistic fungal infections: a group of infections that occur in patients with weakened immune systems (especially individuals with CD4 counts < 200 cells/μL). Healthy individuals with normal immune systems are typically not affected. The general signs and symptoms can be similar to those of histoplasmosis. Exposure history, microscopy, and culture of sputum or BAL to identify specific organisms can help differentiate fungal infections.
  • Community-acquired pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia: the typical symptoms (cough, fever, pleuritic chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain) are usually of a shorter duration than those seen in histoplasmosis pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia. A chest X-ray will typically demonstrate lobar consolidation (typical) or bilateral interstitial infiltrates (atypical). Gram staining of the sputum and culture often reveals neutrophils and bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview that are not part of the normal flora. Antibiotics are the general mainstay of treatment.
  • Sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis: an autoimmune disorder that can present with clinical findings similar to those of histoplasmosis. The common findings include diffuse pulmonary infiltrates, mediastinal lymphadenopathy, erythema nodosum Erythema nodosum Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum, splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly, and non-caseating granulomas. Although ↑ ACE levels are seen in both diseases, the elevation is classically associated with sarcoidosis.
  • Blastomycosis Blastomycosis Blastomycosis is an infection caused by inhalation of the spores of the fungus, Blastomyces. Blastomyces species thrive in moist soil and decaying material and are common in the Ohio and Mississippi River valleys and the Great Lakes regions of the United States and Canada. Although most patients are asymptomatic, some can develop pneumonia. Blastomyces/Blastomycosis: a pulmonary disease caused by inhaling the spores of Blastomyces Blastomyces Blastomycosis is an infection caused by inhalation of the spores of the fungus, Blastomyces. Blastomyces species thrive in moist soil and decaying material and are common in the Ohio and Mississippi River valleys and the Great Lakes regions of the United States and Canada. Although most patients are asymptomatic, some can develop pneumonia. Blastomyces/Blastomycosis. Patients can develop pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia or disseminated extrapulmonary disease. Clinically, pulmonary manifestations can be difficult to distinguish from histoplasmosis. Unlike in histoplasmosis, the skin is the most common site of dissemination in blastomycosis. Blastomyces Blastomyces Blastomycosis is an infection caused by inhalation of the spores of the fungus, Blastomyces. Blastomyces species thrive in moist soil and decaying material and are common in the Ohio and Mississippi River valleys and the Great Lakes regions of the United States and Canada. Although most patients are asymptomatic, some can develop pneumonia. Blastomyces/Blastomycosis is endemic to the regions of the Great Lakes and the Ohio and Mississippi River valleys. Diagnosis is made by cultures and imaging.
  • TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis: an infectious disease caused by bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview of the Mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis complex. Like histoplasmosis, TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis usually infects the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs but can also spread to other parts of the body. Both TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis and histoplasmosis are associated with a period of latency and can present with similar signs and symptoms. Look for a history of exposure to an environment with TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis prevalence (healthcare setting, homeless shelters, etc.). A CD4 count of < 300 cells/μL is typically associated with TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis. The diagnosis is established with a tuberculin skin test, blood tests, sputum culture, and lung imaging.
  • Coccidioidomycosis Coccidioidomycosis Coccidioidomycosis, commonly known as San Joaquin Valley fever, is a fungal disease caused by Coccidioides immitis or Coccidioides posadasii. When Coccidioides spores are inhaled, they transform into spherules that result in infection. Coccidioidomycosis is also a common cause of community-acquired pneumonia and can cause severe disease in the immunocompromised. Coccidioides/Coccidioidomycosis: a pulmonary or hematogenously spread fungal disease caused by Coccidioides Coccidioides Coccidioidomycosis, commonly known as San Joaquin Valley fever, is a fungal disease caused by Coccidioides immitis or Coccidioides posadasii. When Coccidioides spores are inhaled, they transform into spherules that result in infection. Coccidioidomycosis is also a common cause of community-acquired pneumonia and can cause severe disease in the immunocompromised. Coccidioides/Coccidioidomycosis species. Like histoplasmosis, coccidioidomycosis is acquired through inhalation. The endemic regions for Coccidioides Coccidioides Coccidioidomycosis, commonly known as San Joaquin Valley fever, is a fungal disease caused by Coccidioides immitis or Coccidioides posadasii. When Coccidioides spores are inhaled, they transform into spherules that result in infection. Coccidioidomycosis is also a common cause of community-acquired pneumonia and can cause severe disease in the immunocompromised. Coccidioides/Coccidioidomycosis are distinct from Histoplasma and include southern California, Arizona, New Mexico, and West Texas.

References

  1. Baddley, J.W. (2021). Diagnosis and treatment of histoplasmosis in patients with HIV. UpToDate. Retrieved June 18, 2021, from https://www.uptodate.com/contents/diagnosis-and-treatment-of-histoplasmosis-in-patients-with-hiv
  2. Guimarães, A.J., Nosanchuk, J.D., Zancopé-Oliveira, R.M. (2006). Diagnosis of histoplasmosis. Braz J Microbiol 37, 1–13.
  3. Kauffman, C.A. (2020). Histoplasmosis: A clinical and laboratory update. Clin Microbiol Rev 20, 115–132.
  4. Kauffman, C.A. (2021). Diagnosis and treatment of pulmonary histoplasmosis. UpToDate. Retrieved June 18, 2021, from https://www.uptodate.com/contents/diagnosis-and-treatment-of-pulmonary-histoplasmosis
  5. Kauffman, C.A. (2021). Pathogenesis and clinical features of pulmonary histoplasmosis. UpToDate. Retrieved June 18, 2021, from https://www.uptodate.com/contents/pathogenesis-and-clinical-features-of-pulmonary-histoplasmosis
  6. Kauffman, C.A. (2021). Pathogenesis and clinical manifestations of disseminated histoplasmosis. UpToDate. Retrieved June 18, 2021, from https://www.uptodate.com/contents/pathogenesis-and-clinical-manifestations-of-disseminated-histoplasmosis
  7. Linder, K.A., Kauffman, C.A. (2019). Histoplasmosis: Epidemiology, diagnosis, and clinical manifestations. Curr Fungal Infect Reports 13, 120–128.
  8. Mihu, M.R., Nosanchuk, J.D. (2012). Histoplasma virulence and host responses. Int J Microbiol 2012, 268123.

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