CONTENTS
- Epidemiology
- Different forms of clinical disease:
- Diagnostic studies
- Management
- Pathophysiology
- Questions & discussion
abbreviations used in the pulmonary section:
- ABPA: Allergic bronchopulmonary aspergillosis 📖
- AE-ILD: Acute exacerbation of ILD 📖
- AEP: Acute eosinophilic pneumonia 📖
- AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
- ANA: Antinuclear antibody 📖
- ANCA: Antineutrophil cytoplasmic antibodies 📖
- ARDS: Acute respiratory distress syndrome 📖
- ASS: Antisynthetase Syndrome 📖
- BAL: Bronchoalveolar lavage 📖
- BiPAP: Bilevel positive airway pressure 📖
- CEP: Chronic eosinophilic pneumonia 📖
- COP: Cryptogenic organizing pneumonia 📖
- CPAP: Continuous positive airway pressure 📖
- CPFE: Combined pulmonary fibrosis and emphysema 📖
- CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
- CTEPH: Chronic thromboembolic pulmonary hypertension 📖
- DAD: Diffuse alveolar damage 📖
- DAH: Diffuse alveolar hemorrhage 📖
- DIP: Desquamative interstitial pneumonia 📖
- DLCO: Diffusing capacity for carbon monoxide 📖
- DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
- EGPA: Eosinophilic granulomatosis with polyangiitis 📖
- FEV1: Forced expiratory volume in 1 second 📖
- FVC: Forced vital capacity 📖
- GGO: Ground glass opacity 📖
- GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
- HFNC: High flow nasal cannula 📖
- HP: Hypersensitivity pneumonitis 📖
- IPAF: Interstitial pneumonia with autoimmune features 📖
- IPF: Idiopathic pulmonary fibrosis 📖
- IVIG: Intravenous immunoglobulin 📖
- LAM: Lymphangioleiomyomatosis 📖
- LIP: Lymphocytic interstitial pneumonia 📖
- MCTD: Mixed connective tissue disease 📖
- NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
- NSIP: Nonspecific interstitial pneumonia 📖
- NTM: Non-tuberculous mycobacteria 📖
- OP: Organizing pneumonia 📖
- PAP: Pulmonary alveolar proteinosis 📖
- PE: Pulmonary embolism 📖
- PFT: Pulmonary function test 📖
- PLCH: Pulmonary Langerhans Cell Histiocytosis 📖
- PPFE: Pleuroparenchymal fibroelastosis 📖
- PPF: Progressive pulmonary fibrosis 📖
- PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
- RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
- RP-ILD: Rapidly progressive interstitial lung disease 📖
- TNF: tumor necrosis factor
- UIP: Usual Interstitial Pneumonia 📖
geographic distribution
- Histoplasmosis is an endemic mycosis concentrated especially around the Mississippi and Ohio River valleys (map above).
- Histoplasma grows in the soil, as well as in bird/bat droppings.
- Sites of exposure may include:
- Caves (spelunking).
- Contact with bird roosts (pigeon breeders, pet birds), bird/bat guano (chicken coops).
- Soil disruption: farming, construction, landscaping.
- Old houses or barns used by birds for nesting. (34498137)
- Organic fertilizers.
- Outbreaks have been reported due to environmental disturbances (e.g., construction or tree removal). (Murray 2022)
- Establishment of latent disease with subsequent reactivation may occur. Reactivation tends to occur in the context of immunocompromise (e.g., due to initiation of biologic therapies with an anti-TNF antibodies, or due to HIV). (33516057) Reactivation may explain cases that occur outside of endemic areas. (Murray 2022)
acute pulmonary histoplasmosis is usually self-limiting
- The incubation period usually ranges from 1-3 weeks. (34498137) However, heavy exposure can result in an incubation as short as three days. (Murray 2022)
- Infection is asymptomatic in ~90% of people. (28797485)
- Spontaneous resolution usually occurs among immunocompetent patients.
symptoms of acute pulmonary histoplasmosis may include
- Common manifestations:
- Flu-like illness (fever, chills, myalgias, arthralgias, headache).
- Nonproductive cough, sometimes with dyspnea.
- Mediastinal adenitis
- Lymphadenitis may cause clinical symptoms. These are associated with radiographic lymphadenopathy (described further below).
- Severe inspiratory chest pain is common. This may help differentiate this mediastinal adenitis from other causes of mediastinal or hilar lymphadenopathy (e.g., mycobacteria). (Murray 2022)
- In the context of acute histoplasmosis, pleuritic chest pain may also be caused by pericarditis.
- Mild obstructive symptoms may result from compression of airways, esophagus, or the superior vena cava. (36836350)
- Extrapulmonary rheumatologic manifestations occur in ~5% of patients: (28797485)
- Arthralgias, arthritis.
- Erythema nodosum.
- Erythema multiforme.
- Pericarditis.
- (The combination of lymphadenopathy, arthralgias, and erythema nodosum may lead to diagnostic confusion with sarcoidosis or coccidioidomycosis.)
- Severe pneumonia may occur:
- Causes of severe pneumonia:
- (1) Massive exposure (e.g., cleaning chicken coop or attic).
- (2) Immunosuppression.
- Clinically this may cause high fevers, dyspnea, and cough. Pneumonia may progress to cause ARDS.
- Causes of severe pneumonia:
subacute pulmonary histoplasmosis
- This is a more indolent form of infection that may occur in immunocompetent patients exposed to a smaller inoculum of histoplasmosis.
- Clinical features:
- Radiologic features are similar to other patients with acute pulmonary histoplasmosis. Often focal opacities are seen in conjunction with lymphadenopathy.
- Diagnosis may be assisted with serology, since patients seek care at a later point in their disease course (as compared to patients with more acute disease). Alternatively, since patients with subacute pulmonary histoplasmosis usually have a low organism burden, tests for histoplasma antigen have low sensitivity.
radiology of acute or subacute pulmonary histoplasmosis
- Various lung parenchymal abnormalities may be seen:
- Airspace consolidation: basilar, ill-defined, non-segmental airspace opacities may occur. This can be indistinguishable from bacterial pneumonia.
- Macronodular pattern: One or more pulmonary nodules may occur. Eventually these will often calcify.
- Micronodular pattern: A large inoculum may rarely cause a diffuse micronodular pattern (~3-5 mm)(figure below). Subsequently, nodules may coalesce into large conglomerate nodules that are surrounded by ground-glass opacification. (34498137) This is an unusual presentation that may be associated with ARDS and acute respiratory failure.
- Hilar and mediastinal lymphadenopathy:
- This usually occurs in association with parenchymal abnormalities. However, the two manifestations are not invariably linked (e.g., lymphadenopathy may occur without parenchymal disease, or parenchymal disease can occur without lymphadenopathy).
- Radiologically, lymph nodes are enlarged and solid, with homogeneous enhancement. (28797485) Calcification eventually develops in most affected nodes, but this takes years. (Murray 2022) If coalescence of lymph nodes is seen, this suggests the presence of granulomatous mediastinitis (see the section below).
- Clinically, bulky lymphadenopathy may correlate with mediastinal adenitis (discussed above).
- Overt pleural involvement is uncommon. (34498137)


basics of mediastinal granuloma
- This is an uncommon complication of acute pulmonary histoplasmosis. It may occur decades after the initial acute pulmonary infection. (28797485)
- Usually, lymphadenopathy resolves within a few months. However, some patients develop persistent lymphadenopathy (granulomatous mediastinitis). Mediastinal lymph nodes may coalesce into a semisolid mass up to 5-10 cm in size. (28797485)
symptoms of mediastinal granuloma
Lymph nodes can cause symptoms due to mass effect, or due to drainage into nearby structures (e.g., the airway, esophagus, pleural space, pericardium, or subcutaneous space in the neck). Presentations may include the following:
- Asymptomatic: Usually asymptomatic (radiographically manifesting as persistently enlarged lymph nodes).
- Compressive symptoms due to mass effect:
- Broncholithiasis: Discussed further in the section below: 📖
radiology of mediastinal granuloma
- Enlarged hilar and mediastinal lymph nodes are seen, which often show areas of calcification, necrosis, and/or septations.
- Calcification may be speckled, subcapsular, or uniform. (Murray 2022)
- Lymph nodes can coalesce into a large encapsulated lesion. This may be confused with malignancy. (28797485)
- The most common location is the right paratracheal region.
diagnostic studies in mediastinal granuloma
- Percutaneous lymph node biopsy may reveal evidence of necrosis and granulomatous inflammation, with few yeast-like organisms. (28797485)
- ⚠️ Needle biopsy via endobronchial ultrasound (EBUS) should be avoided, as this may introduce infection into the lesion, leading to bacterial mediastinitis.
- It's unusual to culture organisms from biopsy specimens.
- Serologic titers are positive in about half of patients (more on serology below: 📖). (Murray 2022)
differential diagnosis of mediastinal granuloma may include:
- (1) Other causes of broncholithiasis (listed below).
- (2) Other causes of bronchomediastinal fistula formation:(35526900)
- Malignancy (e.g., lung cancer or lymphoma).
- Tuberculosis.
- Sarcoidosis.
- Endobronchial fungal infections (e.g., aspergillosis or mucormycosis).
management of mediastinal granuloma
- Medical therapy doesn't seem to be effective (e.g., steroid or antifungal therapy). However, if it is unclear whether the patient might have mediastinal adenitis, then treatment with itraconazole may be reasonable. (Murray 2022)
- Surgery may be needed, for example:
- If lymph nodes fistulize into the airway, esophagus, or pericardium.
- If pressure is being exerted on mediastinal structures. (Murray 2022)
- As an alternative to surgery, temporary stenting has been described to maintain airway and esophageal patency. (30499720)
Broncholithiasis is defined as the presence of calcified material within the bronchial lumen. This generally results from a calcified lymph node that erodes into the bronchus. Granulomatous mediastinitis due to histoplasmosis is a common etiology, but not the sole cause.
symptoms of broncholithiasis may include:
- Cough:
- May be nonproductive.
- May be productive of calcified material (lithoptysis).
- Recurrent hemoptysis may occur (which can be massive, due to laceration of a bronchial artery or fistula formation with a systemic artery).
- Obstructive symptoms:
- Postobstructive pneumonia, and eventually bronchiectasis.
- Wheezing may mimic asthma.
- Local infection: Extrusion of the broncholith may lead to a fistula between the airway and lymph node, which may become superinfected by bacteria. (37295883)
causes of broncholithiasis
- More common:
- Fungal infections:
- Histoplasmosis.
- Cryptococcosis.
- Coccidiomycosis.
- Endobronchial aspergillosis.
- Tuberculosis, or Mycobacterium kansasii.
- Endobronchial nocardiosis.
- Fungal infections:
- Rare:
- Sarcoidosis.
- Silicosis.
- Actinomycosis. (Shepard 2019; 32033657; Rosado-de-Christenson 2022)
- 💡 Broncholithiasis may occur long after the acute infection has resolved, as a result of residual lymph node calcifications. (37295883)
CT findings
- [1] Broncholith:
- Calcified endobronchial or peribronchial lesion.
- Most commonly involving the middle lobe or the upper lobe anterior segment bronchi. (Rosado-de-Christenson 2022)
- If prior imaging is available, it may show that calcified material has migrated into the airway. This may occur very gradually, over a period of years.
- [2] Adjacent lymphadenopathy, often with calcification.
- [3] Complications may be seen:
- Atelectasis and/or mucoid impaction.
- Postobstructive pneumonia.
- Air trapping.
- Focal bronchiectasis.
differential diagnosis may include:
- Foreign body that is calcified or metallic.
- Calcified balls of fungal hyphae.
- Endobronchial tumors that may calcify (e.g., carcinoid, airway hamartoma).
- Tracheobronchial amyloidosis.
- Tracheobronchopathia osteochondroplastica.
- Hypertrophy of the bronchial artery with protrusion into the airway. (Walker 2019)
- Mediastinal fibrosis.
management of broncholithiasis
- Asymptomatic patients can be managed conservatively, with serial observation. (37295883)
- Broncholiths may be removed bronchoscopically if they are completely free within the bronchus. However, if the broncholith is attached to the bronchial wall, attempts to remove it bronchoscopically are dangerous since this may precipitate bronchial artery laceration (attempt this only with surgical back-up). (Fishman 2023; Rosado-de-Christenson 2022)
- Surgical resection may be required for recurrent hemoptysis or for ongoing airway obstruction (often the right middle lobe is involved, which is relatively small and expendable).
basics of fibrosing mediastinitis
- Fibrosing mediastinitis is a rare complication of pulmonary histoplasmosis that involves an exuberant fibrotic response leading to entrapment of mediastinal structures.
- Fibrosing mediastinitis doesn't appear to evolve from mediastinal adenitis.
- Fibrosing mediastinitis may be either unilateral or bilateral.
epidemiology of fibrosing mediastinitis
- Typically affects people in their 20s-40s.
- It results from a hyperactive immune response, perhaps explaining its prevalence in younger people. (28797485)
clinical manifestation results from compression/entrapment of various structures
- Most patients don't report any history of acute histoplasmosis. (Murray 2022)
- Fibrosis occurs very slowly, with an average delay from initial symptoms to diagnosis of five years. (Shah 2019)
- Pulmonary:
- Compression of bronchi may cause dyspnea, cough, wheezing, atelectasis, and/or pneumonia.
- Compression of veins draining the lung may cause unilateral pulmonary edema, effusion, hemoptysis, and pulmonary hypertension (“pseudo-mitral stenosis” syndrome).
- Pulmonary emboli may occur.
- Cardiac:
- SVC syndrome (superior vena cava syndrome).
- Heart failure, constrictive pericarditis.
- Esophageal involvement: Odynophagia and/or dysphagia may occur.
- Neurological:
- Recurrent laryngeal nerve dysfunction may cause hoarseness.
- Phrenic nerve dysfunction may cause diaphragmatic weakness.
- Vagal nerve dysfunction may cause tachycardia.
- Horner syndrome may occur.
radiology of fibrosing mediastinitis
- Calcification is seen in ~80% of patients:
- Calcification due to histoplasmosis is usually focal (whereas diffuse, smooth calcification of mediastinal contours may be seen with other disorders, such as lupus, rheumatoid arthritis, or various drug reactions).
- Calcification often involves the right paratracheal lymph node.
- Calcified peripheral lung lesions are also common.
- Calcification supports a diagnosis of histoplasmosis, rather than other infiltrative diseases of the mediastinum (e.g., metastatic carcinoma or lymphoma).
- Hepatic and splenic calcifications may suggest a prior histoplasmosis infection (if seen).
- Findings may vary, depending on which structures are affected.
- If SVC (superior vena cava) syndrome occurs, this may cause collateral blood flow around obstructed veins.
- If pulmonary venous obstruction occurs, this may cause localized findings of cardiogenic pulmonary edema (e.g., thickening of interlobular septa).
differential diagnosis of mediastinal fibrosis
- Histoplasmosis accounts for >95% of all patients with fibrosing mediastinitis, but not all. Histoplasmosis causes a focal or multifocal form of fibrosing mediastinitis.
- Diffuse, infiltrative pattern on CT scan suggests an alternative diagnosis:
- Causes of diffuse mediastinal fibrosis include:
- Idiopathic fibrosing mediastinitis.
- IgG4-related disease.
- GPA (granulomatosis with polyangiitis).
- Erdheim-Chester disease.
- Radiotherapy.
- Drug-related.
- Clues to differentiate these disorders from histoplasmosis-induced fibrosis:
- Disease is more diffuse and bulkier.
- Absence of calcification.
- Fibrosis may affect extrathoracic sites, such as the retroperitoneum.
- Causes of diffuse mediastinal fibrosis include:
- Hodgkin lymphoma.
diagnostic tests for fibrosing mediastinitis
- Histoplasma serology is present in about half of patients. (Murray 2022)
- Tissue biopsy is generally unhelpful:
- There are very few histoplasma organisms in the mediastinum, so these are usually not seen on tissue biopsy. Consequently, the biopsy will simply reveal fibrotic tissue. This is a nonspecific finding, because fibrosis can be caused by other etiologies. (28797485)
- Procedural risk is high, since the fibrotic mediastinum may be more susceptible to injury during diagnostic procedures. (28797485)
diagnostic criteria for fibrosing mediastinitis
- The basic criteria include: (Murray 2022)
- (1) Invasive obstruction of pulmonary arteries or veins, superior vena cava, or airways (in nearly any combination).
- (2) Obstruction is caused by a mediastinal mass that usually contains calcification (ranging from punctate to highly calcified).
- (3) Absence of another etiology (e.g., malignancy, radiation).
treatment for fibrosing mediastinitis
- There is no well-defined, effective therapy.
- Stenting of compressed structures may be helpful (e.g., pulmonary arteries).
- Hemoptysis may be severe and life-threatening:
- This may be due to formation of collaterals from systemic bronchial arteries in the context of pulmonary artery compromise. In this scenario, interventional radiology embolization of collaterals is beneficial.
- Hemoptysis may be due to venous hypertension in the setting of pulmonary vein obstruction.
- Therapies to avoid:
- Antimicrobial therapy against histoplasmosis has no role. By the time patients present with fibrosing mediastinitis, viable histoplasma organisms are long gone.
- Surgery is often poorly tolerated, since the mediastinum is scarred and prone to injury. (28797485) The mortality from surgery may be up to 20%. (36836350)
prognosis
- If mediastinal structures are involved bilaterally, mortality is very high. (Murray 2022)
- Unilateral disease may eventually cause failure of the ipsilateral lung, which is often survivable.
- Bilateral disease carries a greater morbidity and mortality.
basics
- This is a chronic, progressive form of histoplasmosis that evolves over months to years. It is similar to CCPA (chronic cavitary pulmonary aspergillosis) and post-primary tuberculosis.
- Not all patients with CCPH necessarily have cavitation. However, the disease process will eventually lead to cavitation if it remains unchecked. The presence of cavitation implies more progressive and severe disease.
epidemiology
- Chronic cavitary pulmonary histoplasmosis (CCPH) is uncommon, occurring in perhaps ~8% of patients exposed.
- Risk factors for the development of chronic cavitary pulmonary histoplasmosis include: (34498137)
- Older age.
- Chronic structural lung disease (e.g., emphysema, lung cavitation due to sarcoidosis).
- Underlying immunosuppressive disorders, use of immunosuppressive medications (including steroid).
- Male sex.
symptoms
- Constitutional symptoms (fever, anorexia, weight loss).
- Cough productive of purulent sputum, or hemoptysis.
- Hemoptysis occurs only in ~10% of cases. Massive hemoptysis may suggest an aspergilloma occurring within a cavity. (34498137)
- Dyspnea.
- Pleuritic chest pain.
radiology
- Infiltrates:
- May be bilateral or unilateral, almost always in the upper lobes.
- Consolidation can resolve, but it often leads instead to cavitation.
- Eventually, extensive fibrosis may occur.
- Cavitation:
- Cavities are frequently large, and may be multiple.
- Cavitation typically involves the apical and posterior segments of the upper lobes (the same pattern as tuberculosis). However, the location can be more variable than with tuberculosis.
- Continuing necrosis in apical cavities can gradually expand and destroy the entire lung (a phenomenon described as a “marching cavity”.) (34016287)
- Calcification may be seen:
- Mediastinal and hilar lymph nodes may be calcified (although lymphadenopathy is usually absent). (28797485).
- Splenic +/- hepatic calcification may be a useful clue. Tuberculosis may also cause splenic and hepatic calcification, but calcifications due to histoplasmosis are usually more numerous. (29518379)
diagnosis
- Unlike other histoplasmosis syndromes, CCPH is a purulent infection with a high yield of sputum or bronchoalveolar lavage (as evaluated using cytopathology and culture). (32629490)
- Serology is very helpful, given the chronic duration of illness. (32629490)
epidemiology of disseminated disease
- Immunocompetent patients: Disseminated disease may occur in patients who are immunocompetent. For example, about a third of patients with CNS histoplasmosis have no identified cause of immunodeficiency (typically middle-aged or elderly men). (30921084) However, disseminated disease is more common among patients with deficient cell-mediated immunity.
- HIV patients (especially with CD4 count <100-150/uL). (34498137) Progressive disseminated disease is the most common presentation (>95%) among patients with HIV and low CD4 count. (36836350)
- Transplantation (especially solid organ transplantation). Following solid organ transplantation, donor-related infection and reactivation of latent histoplasmosis are the most common mechanisms (rather than de novo infection). Infection onset has a bimodal distribution, often occurring <6 months after transplantation or >2 years afterward. (28797485)
- Immunosuppressive medications, especially:
- Chronic steroid therapy.
- TNF inhibitors (histoplasmosis is the most common invasive fungal disease in this context). (32000281)
- Bruton tyrosine kinase inhibitors (acalabrutinib, ibrutinib, zanubrutinib).
- Lymphodepleting agents (especially alemtuzumab).
- Hematologic malignancy.
- Other immunocompromising conditions:
- Idiopathic CD4 lymphopenia.
- Common variable immunodeficiency.
- Hyper IgE syndrome (Job syndrome). (32000281)
the tempo of the disease may vary widely
- (1) Insidious consumptive process is most common:
- Immunocompetent patients tend to have an insidious onset.
- Even among immunocompromised patients, onset may be insidious.
- (2) PDH may cause a rapidly fatal sepsis syndrome that includes ARDS and DIC. Deterioration may be driven by underlying HLH (hemophagocytic lymphohistiocytosis).
manifestations may include:
- Constitutional symptoms:
- Insidious onset may cause low-grade fever, night sweats, and weight loss.
- More aggressive disease onset may cause high fevers.
- Hemophagocytic lymphohistiocytosis (HLH) 📖:
- Hepatosplenomegaly with elevated liver function tests.
- Diffuse lymphadenopathy.
- Bone marrow involvement may cause pancytopenia.
- Disseminated intravascular coagulation (DIC) may occur.
- Encephalopathy.
- Adrenal failure:
- Occurs in about half of patients.
- Adrenal crisis may be a proximal cause of death or ICU admission.
- Pulmonary:
- Pulmonary involvement may vary from no involvement to ARDS.
- Symptoms can include dyspnea and cough.
- Thoracic radiology may show:
- A miliary pattern of diffuse small nodules can occur.
- Hilar and mediastinal lymphadenopathy are often seen. (Walker 2019)
- Interstitial involvement may mimic pneumocystis jirovecii pneumonia.
- Dermatologic:
- Indurated ulcerations involving the mouth, nose, and/or larynx.
- Skin lesions may vary (including a maculopapular rash, ulceration, nodules, umbilicated lesions, pustules, or crusted lesions). (34016287)
- Neurologic: Headache, chronic meningitis (CNS manifestations explored in the section below).
- Gastrointestinal:
- Diarrhea, abdominal pain.
- Gastrointestinal ulcerations.
- Hepatitis.
- Cardiovascular: Endocarditis.

general laboratory abnormalities may include:
- Features of HLH (hemophagocytic lymphohistiocytosis) may include cytopenias, disseminated intravascular coagulation, elevated inflammatory markers including ferritin, and elevated lactate dehydrogenase. Further discussion of laboratory abnormalities HLH is here: 📖
- Features of adrenal insufficiency (e.g., hyperkalemia, hypoglycemia).
- Hypercalcemia (due to granulomatous inflammation that increases 1,25-dihydroxy vitamin D production).
diagnosis
- Urinary antigen is the most helpful test, since the organism burden is high.
- Serology may remain negative among immunocompromised patients.
basics
- CNS disease can occur in immunocompetent patients, but it is more likely in the context of immunocompromise.
- CNS involvement occurs in the context of PDH (progressive disseminated histoplasmosis). Among patients with disseminated disease, CNS involvement occurs in ~15% of cases. (31378870)
clinical features of patients with CNS involvement
- Manifestations may include:
- Brain abscess (~1/3 of patients) and/or spinal cord lesions.
- Chronic or relapsing meningitis (which may cause ischemic strokes due to small vessel vasculitis, and/or hydrocephalus).
- Encephalopathy due to hemophagocytic lymphohistiocytosis.
- Symptoms of CNS histoplasmosis:
- Fever is extremely common.
- Headache.
- Reduced level of consciousness, confusion.
- Focal cranial nerve deficits.
- Seizure, personality change, ataxia, clonus.
CSF evaluation
- Histoplasma abscess(es):
- CSF analysis is poorly sensitive and may be misleading.
- Occasionally patients may have pleocytosis or elevated protein, but CSF chemistries can be normal.
- Histoplasma meningitis:
- Generally causes a lymphocytic CSF pleocytosis, with elevated protein and low glucose.
- CSF culture may be possible, if large volumes are sampled (but this lacks sensitivity).
- CSF measurement of histoplasma antigen is highly sensitive and specific. (34016287)
other laboratory studies
- Serum antibodies are not entirely reliable.
- Urine or serum Histoplasma antigen may be detectable.
- Anemia, leukopenia, and thrombocytopenia may occur. (33516057) In this case, testing for bone marrow involvement should be considered. (Louis 2021)
imaging
- Contrast MRI may reveal abscess formation.
- Solitary or multifocal small (<2 cm), round, ring-enhancing mass lesions may be seen.
- Abscess is most often located subcortically (within the grey/white junction), or within the posterior fossa, or within the brainstem.
- Typically T1 hypointense.
- May show diffusion restriction (depending on the extent of inflammation and necrosis)
basics
- The urinary antigen test is generally superior to the serum antigen test (due to urinary concentration). In practice the urinary antigen is generally ordered alone (although some references do recommend obtaining both serum and urinary antigen tests together).
- Serial measurement of Histoplasma antigen may be used to track response to therapy. (Murray 2022) However, the antigen has a long half-life and may require several months to become undetectable – so persistence of a positive result doesn't necessarily indicate clinical failure. (32433841)
sensitivity depends on organism load in the body
- The following numbers are quoted in the literature, but the sensitivity will vary among patients depending on the severity of their individual infections.
- Acute pulmonary histoplasmosis: ~80% (28797485)
- Subacute pulmonary histoplasmosis (mild & self-limiting): ~30% (28797485)
- Chronic cavitary pulmonary histoplasmosis: ~85% (28797485)
- Progressive disseminated histoplasmosis: ~90% (28797485)
- Granulomatous mediastinitis or fibrosing mediastinitis: Extremely low sensitivity.
specificity
- Histoplasma antigen may cross-react with some other fungi:
- Blastomyces (clinically this is usually the primary diagnostic consideration).
- Coccidioides and Paracoccidioides.
- Talaromyces marneffei (penicilliosis, aka talarmycosis), Sporothrix schenckii.
- Possibly even Aspergillosis. (Murray 2022)
- Aside from other types of endemic mycoses, the rate of false-positive results is very low.
basics
- Seroconversion takes ~4-8 weeks after exposure (or ~2-6 weeks after illness onset).
- Serology may remain positive for years, so a positive result doesn't necessarily reflect active disease.
- Immunocompromised patients may fail to mount an antibody response, leading to false-negative results. (Murray 2022)
- The most commonly utilized assays are complement fixation or immunodiffusion:
complement fixation
- This yields an antibody titer.
- An antibody titer of 1:32 or higher in an appropriate clinical context should suggest histoplasmosis. Lower titers (1:8 or 1:16) are less indicative, but could occur early in the course of active infection. Rising titers over time support the presence of active disease (four-fold increase over >2 weeks). (36836350)
- Overall, complement fixation is more sensitive but less specific than immunodiffusion. (32000281) Sensitivity may be ~70% in acute pulmonary histoplasmosis, or ~50% in disseminated disease. (Murray 2022)
- False-positive results may be caused by:
immunodiffusion
- This test identifies the qualitative presence of antibodies against two different antigens (H- and M-antigens):
- Antibody against H-antigen:
- Highly specific for acute disease.
- Sensitivity is low (~20%). (28797485)
- Antibody against M-antigen:
- If both anti-H and anti-M antibodies are present, that is highly suggestive of active histoplasmosis. (34498137)
sensitivity of serology depends on clinical context
- Acute pulmonary histoplasmosis:
- Sensitivity is ~70% by the sixth week. (Fishman 2023)
- Eventually, sensitivity increases to ~98%.
- CCPH (chronic cavitary pulmonary histoplasmosis):
- Sensitivity is ~95%.
- This may be the situation where serology is more useful clinically. (36836350)
- Progressive disseminated histoplasmosis:
- Sensitivity is ~70%
- However, among immunocompromised patients sensitivity may be ~50%.
- Fibrosing mediastinitis or granulomatous mediastinitis: Sensitivity is limited (e.g., ~50% in granulomatous mediastinitis).
fungal staining of bronchoalveolar lavage
- This is the most useful test to guide immediate management.
- Performance varies depending on the burden of organisms and experience of the cytologist (with a sensitivity of ~40-80%).
- In acute pulmonary histoplasmosis, sensitivity may be ~50%. (32629490)
- Specific findings:
- Histopathologic features of histoplasmosis are discussed here: 📖
- Histoplasma is a dimorphic fungus which usually takes on a yeast form within the human body. However, rarely mycelial forms may be seen in lung tissues, so this finding doesn't exclude histoplasmosis. (Murray 2022)
antigen testing of bronchoalveolar lavage fluid
- The addition of histoplasma antigen to cytology will increase the sensitivity for diagnosis (including the detection of some patients with negative urinary antigen and negative bronchoalveolar lavage cytopathology). (32000281)
- This is usually a send-out test (e.g., Mayo Clinic labs FHST).
endobronchial ultrasonography with transbronchial needle aspiration (EBUS-TBNA)
- EBUS-TBNA may be utilized to sample mediastinal lymphadenopathy (among patients with prominent lymphadenopathy).
basics
- Tissue biopsy with fungal staining may be useful in some contexts.
- Specificity is high. However, false-positive results are possible due to the presence of old, dead organisms.
- Histopathology reveals a granulomatous response that may be either necrotizing or non-necrotizing. (32000281)
site of biopsy
- For patients with disseminated disease:
- Skin lesions.
- Bone marrow biopsy has a sensitivity of ~50% in patients with hematologic findings suggestive of bone marrow involvement.
- Liver biopsy.
- For chronic cavitary pulmonary histoplasmosis, lung or lymph node biopsy may be useful.
role of culture in clinical practice
- Culture often requires 4-6 weeks to grow!
- The laboratory should be notified to use a special medium that avoids overgrowth of commensal fungi. Also, histoplasma culture requires a biosafety level 3 laboratory. (28797485)
- Given how long culture takes, the utility of culture might be limited to patients with chronic cavitary pulmonary histoplasmosis.
sensitivity depends on disease burden and specimen type
- Blood cultures should be processed using lysis centrifugation (“fungal isolator” tubes). This may have a yield of ~75% among patients with HIV and progressive disseminated histoplasmosis. Unfortunately, the yield is much lower in other contexts. (34498137)
- Respiratory cultures often have a sensitivity <50%, but sensitivity may be higher in chronic cavitary pulmonary histoplasmosis. (Murray 2022)
- Cultures from lymph nodes and pulmonary nodules are often negative. (37295884)
some general comments on antifungal activity against histoplasmosis
azole therapy for histoplasmosis:
- Itraconazole is the azole of choice for histoplasmosis, with potential utilization in mild to moderate histoplasmosis. (34016287)
- Voriconazole may be utilized as a second-line agent if itraconazole cannot be utilized (e.g., due to lack of enteral access). Data is limited, but some case reports and one case series describe successful therapy with voriconazole following the failure of standard therapy. (17438046)
- Fluconazole has a lower success rate than itraconazole, with some reports of emerging fluconazole resistance during therapy. (34364529)
acute pulmonary histoplasmosis
(1) treatment may not be needed
- Acute pulmonary histoplasmosis is generally self-limited among immunocompetent patients, so it doesn't necessarily require treatment.
(2) mild-moderate cases
- Potential indications for treatment:
- Ongoing symptoms beyond 3-4 weeks.
- Symptoms are moderate or severe.
- Immunocompromise.
- Bilateral pulmonary involvement on chest imaging. (28797485)
- Severe mediastinal adenitis with compression complications (may be treated by steroid plus itraconazole). (Murray 2022)
- Mild-to-moderate cases may be treated with itraconazole for 6-12 weeks 💉.
(3) severe cases
- Antimicrobial therapy:
- Induction therapy: Liposomal amphotericin B 3-5 mg/kg IV daily for 1-2 weeks.
- Maintenance therapy: Itraconazole for at least 12 weeks (longer duration therapy may be needed in patients with immunosuppression). (34498137)
- Steroid:
- Among patients with ARDS, a combination of steroid plus antifungal therapy may be beneficial (e.g., 40-60 mg/day prednisone, or methylprednisolone 0.5-1 mg/kg/day). (28797485; Murray 2022, 36836350)
- If mediastinal adenitis is causing obstruction of vital structures, a combination of steroid plus antifungal therapy may be utilized. (34016287)
chronic cavitary pulmonary histoplasmosis
- Treatment is necessary in all cases.
- In severe cases, treatment may begin with amphotericin, with subsequent transition to a prolonged course of itraconazole. However, most patients can be treated on a solely outpatient basis with itraconazole for 1-2 years. (Fishman 2023)
progressive disseminated histoplasmosis
immunosuppression reduction
- If possible, any immunosuppressive medications or conditions should be reduced or treated (e.g., HIV therapy).
induction therapy for severe disease
- ⚠️ Paradoxical reactions may cause deterioration following initiation of therapy. (36836350)
- Induction therapy may be indicated for moderately severe to severe disease (including CNS involvement). This usually involves 1-2 weeks of IV amphotericin. 💉
- CNS involvement: Induction therapy usually involves 4-6 weeks of high-dose liposomal amphotericin B (5 mg/kg daily). (28797485) Surgical excision of abscesses is usually not necessary. (31378870)
- ARDS management: For patients with ARDS, adjunctive steroids may be utilized during the first 1-2 weeks of treatment (similarly to acute pulmonary histoplasmosis above).
- Adrenal insufficiency management: for patients with adrenal involvement. 📖
- Hypercalcemia management: for patients with hypercalcemia due to elevated 1,25-dihydroxy vitamin D levels. 📖
- Hemophagocytic lymphohistiocytosis management: for patients with obvert HLH, additional therapies might be considered (although caution is required, as these therapies may cause immunosuppression). 📖
maintenance therapy
- Itraconazole 💉 may subsequently be used as step-down therapy. (28797485)
- The treatment duration is often 1-2 years. (Fishman 2023) Some patients with immunosuppression may require lifelong suppressive therapy.
monitoring treatment response
- Following antigen levels may help monitor control of disease. For patients with HIV who clinically deteriorate, monitoring antigen levels may help distinguish between treatment failure versus IRIS (immune reconstitution inflammatory syndrome). (28797485)
- Histoplasmosis is a dimorphic fungus:
- In nature, it grows as a mold.
- Within the human body, it grows as a yeast.
- Histoplasmosis is phagocytized by macrophages. It survives and multiplies within macrophages, using the macrophages to travel around the body. This explains the proclivity of histoplasmosis for lymphoid tissue (e.g., liver, spleen, lymph nodes).
- A few weeks after infection, cell-mediated immunity develops. This involves CD4+ T-cells that activate macrophages via release of interferon gamma, leading to killing of intracellular histoplasma organisms. Ultimately, this may lead to caseous granulomas that eventually calcify in various organs (e.g., spleen and liver).
- Like other endemic fungi, the outcome of exposure depends on three factors:
- (1) The size of the inoculum (e.g., intense exposure may cause ARDS).
- (2) The patient's immune system (especially cellular immunity).
- (3) The presence of any underlying structural lung disease.
To keep this page small and fast, questions & discussion about this post can be found on another page here.
Guide to emoji hyperlinks 
= Link to online calculator.
= Link to Medscape monograph about a drug.
= Link to IBCC section about a drug.
= Link to IBCC section covering that topic.
= Link to FOAMed site with related information.
- 📄 = Link to open-access journal article.
= Link to supplemental media.
References
- 28797398 Patterson J, Graham D, George A, Will M, Sutter D. Right Middle Lobe Collapse and Pleural Effusion in an 18-Year-Old Man. Chest. 2017 Aug;152(2):e33-e38. doi: 10.1016/j.chest.2017.04.187 [PubMed]
- 28797485 Azar MM, Hage CA. Clinical Perspectives in the Diagnosis and Management of Histoplasmosis. Clin Chest Med. 2017 Sep;38(3):403-415. doi: 10.1016/j.ccm.2017.04.004 [PubMed]
- 29518379 Gafoor K, Patel S, Girvin F, Gupta N, Naidich D, Machnicki S, Brown KK, Mehta A, Husta B, Ryu JH, Sarosi GA, Franquet T, Verschakelen J, Johkoh T, Travis W, Raoof S. Cavitary Lung Diseases: A Clinical-Radiologic Algorithmic Approach. Chest. 2018 Jun;153(6):1443-1465. doi: 10.1016/j.chest.2018.02.026 [PubMed]
- 30499720 Sala MA, Celli D, Yeldandi A, Gillespie CT, Argento AC. A Young Man with Fevers and an Invasive Mediastinal Mass. Ann Am Thorac Soc. 2018 Dec;15(12):1477-1482. doi: 10.1513/AnnalsATS.201806-378CC [PubMed]
- 32000281 Azar MM, Loyd JL, Relich RF, Wheat LJ, Hage CA. Current Concepts in the Epidemiology, Diagnosis, and Management of Histoplasmosis Syndromes. Semin Respir Crit Care Med. 2020 Feb;41(1):13-30. doi: 10.1055/s-0039-1698429 [PubMed]
- 32033657 Venkatnarayan K, Raj R, Krishnaswamy UM, Ramachandran P, Devaraj U, Crasta J, Aijaz T. A 51-Year-Old Woman With Pellets in the Sputum. Chest. 2020 Feb;157(2):e25-e29. doi: 10.1016/j.chest.2019.09.037 [PubMed]
- 32433841 Armstrong KA, Cohen JV, Shepard JO, Folch EE, Mansour MK, Stefely JA. Case 16-2020: A 47-Year-Old Woman with Recurrent Melanoma and Pulmonary Nodules. N Engl J Med. 2020 May 21;382(21):2034-2043. doi: 10.1056/NEJMcpc1916258 [PubMed]
- 32629490 Azar MM, Malo J, Hage CA. Endemic Fungi Presenting as Community-Acquired Pneumonia: A Review. Semin Respir Crit Care Med. 2020 Aug;41(4):522-537. doi: 10.1055/s-0040-1702194 [PubMed]
- 34016287 Araúz AB, Papineni P. Histoplasmosis. Infect Dis Clin North Am. 2021 Jun;35(2):471-491. doi: 10.1016/j.idc.2021.03.011 [PubMed]
- 34364529 Thompson GR 3rd, Le T, Chindamporn A, Kauffman CA, Alastruey-Izquierdo A, Ampel NM, Andes DR, Armstrong-James D, Ayanlowo O, Baddley JW, Barker BM, Lopes Bezerra L, Buitrago MJ, Chamani-Tabriz L, Chan JFW, Chayakulkeeree M, Cornely OA, Cunwei C, Gangneux JP, Govender NP, Hagen F, Hedayati MT, Hohl TM, Jouvion G, Kenyon C, Kibbler CC, Klimko N, Kong DCM, Krause R, Lee Lee L, Meintjes G, Miceli MH, Rath PM, Spec A, Queiroz-Telles F, Variava E, Verweij PE, Schwartz IS, Pasqualotto AC. Global guideline for the diagnosis and management of the endemic mycoses: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology. Lancet Infect Dis. 2021 Dec;21(12):e364-e374. doi: 10.1016/S1473-3099(21)00191-2. Epub 2021 Aug 6. Erratum in: Lancet Infect Dis. 2021 Nov;21(11):e341 [PubMed]
- 34498137 Tobón AM, Gómez BL. Pulmonary Histoplasmosis. Mycopathologia. 2021 Oct;186(5):697-705. doi: 10.1007/s11046-021-00588-4 [PubMed]
- 34723760 Contreras-Rodríguez FJ, Alba MA, Rivera-Rosales RM, Flores-Suárez LF. An Immunocompetent Woman with Pulmonary Granulomatous Vasculitis. Ann Am Thorac Soc. 2021 Nov;18(11):1907-1911. doi: 10.1513/AnnalsATS.202101-066CC [PubMed]
- 35526900 Singh H, Benn BS, Jani CT, Abdalla M, Fredeen TS, Kurman JS. A 31-Year-Old Man With Fever, Atypical Chest Pain, and Mediastinal Mass. Chest. 2022 May;161(5):e299-e304. doi: 10.1016/j.chest.2021.12.644 [PubMed]
- 36836350 Barros N, Wheat JL, Hage C. Pulmonary Histoplasmosis: A Clinical Update. J Fungi (Basel). 2023 Feb 10;9(2):236. doi: 10.3390/jof9020236 [PubMed]
- 37031985 Datta A, Mohapatra PR, Mishra P, Goud MS. A 54-Year-Old Woman With Rheumatoid Arthritis, Low-Grade Fever, and Cough. Chest. 2023 Apr;163(4):e151-e155. doi: 10.1016/j.chest.2022.11.047 [PubMed]
- 37295883 Han Y, Guan W, Zhao L, Liu M, Zhou G, Ren Y, Dai H. A 56-Year-Old Man With Cough, Bloody Sputum, and Lithoptysis. Chest. 2023 Jun;163(6):e255-e258. doi: 10.1016/j.chest.2022.12.025 [PubMed]
- 37295884 Schroeder B, Asad H, Aboudara MC. A 40-Year-Old Man With Multiple Pulmonary Nodules and Mediastinal Lymphadenopathy With Positive Anti-Neutrophil Cytoplasmic Antibody Reveals an Unexpected Diagnosis. Chest. 2023 Jun;163(6):e259-e263. doi: 10.1016/j.chest.2023.01.005 [PubMed]
Books:
- Shah, P. L., Herth, F. J., Lee, G., & Criner, G. J. (2018). Essentials of Clinical pulmonology. In CRC Press eBooks. https://doi.org/10.1201/9781315113807
- Shepard, JO. (2019). Thoracic Imaging The Requisites (Requisites in Radiology) (3rd ed.). Elsevier.
- Walker C & Chung JH (2019). Muller’s Imaging of the Chest: Expert Radiology Series. Elsevier.
- Palange, P., & Rohde, G. (2019). ERS Handbook of Respiratory Medicine. European Respiratory Society.
- Rosado-De-Christenson, M. L., Facr, M. L. R. M., & Martínez-Jiménez, S. (2021). Diagnostic imaging: chest. Elsevier.
- Murray & Nadel: Broaddus, V. C., Ernst, J. D., MD, King, T. E., Jr, Lazarus, S. C., Sarmiento, K. F., Schnapp, L. M., Stapleton, R. D., & Gotway, M. B. (2021). Murray & Nadel’s Textbook of Respiratory Medicine, 2-Volume set. Elsevier.
- Fishman's: Grippi, M., Antin-Ozerkis, D. E., Cruz, C. D. S., Kotloff, R., Kotton, C. N., & Pack, A. (2023). Fishman’s Pulmonary Diseases and Disorders, Sixth Edition (6th ed.). McGraw Hill / Medical.