View source for Histoplasma capsulatum

==Background==
===Microbiology===

*Saprophytic environmental fungus withing the family Ascomycetes
*Thermally dimorphic, existing as a mold <35ºC and a yeast at &gt;37ºC
**Mold
***Mold form is highly infectious, associated with lab-related outbreaks
***Septate hyaline mold with aerial hyphae with macroconidia, which are its identifying feature
***Two types of conidia: tuberculate macroconidia (ovoid bodies 8 to 15 μm with spikes), and microconidia (small, smooth oval bodies 2 to 5 μm)
***Two colony types, brown (B) and albino (A)
**Yeast
***Non-infectious, once hanging out in your body
***Small, 2 to 5 μm
***Demonstrates multipolar narrow-based budding
***Does not look particularly different from other yeast, but may be intracellular
*Three variants
**''H. capsulatum'' var. ''capsulatum'', which is the most common worldwide, and is further divided into various clades
**''H. capsulatum'' var. ''duboisii'' which is only present in western Africa, and has larger yeast forms
***Can take up to 7 days to grow
**''H. capsulatum'' var. ''farciminosum''

===Epidemiology===
[[File:Histoplasmosis_map.png|thumb|Distribution of histoplasmosis]]

*Endemic in many parts of the world
**Ohio and Mississippi River Valley systems (Central/Eastern US), where seroprevalence is as high as 80% in adults
**Probably up through St. Lawrence River as well
**Probably more broadly distributed, including Central and South America, South and East Asia, and Australia
**''H. capsulatum'' var. ''duboisii'' in western Africa
*Typically found in moist soil enriched with bat or bird droppings, which helps it to sporulate
**Disturbing the soil aerosolizes it, allowing the microconidia to be inhaled
**Microconidia can be transported for miles by air currents

===Risk Factors===

*HIV, solid organ transplant, hematologic transplant
*Primary immunodeficiencies: X-linked hypogammaglobulinemia

===Pathophysiology===

*Inhaled microconidia reach the alveolii and are phagocytosed by alveolar macrophages
**Innoculum size can be smaller with immunodeficiency
**Size of innoculation affects disease severity and progression
*Microconidia transform into budding yeasts, in a process that is dependent on intracellular macrophage calcium and iron
*They multiply inside macrophages, and translocate through the lymphatics
*Cellular immunity developed around 2 weeks later
**Response depends on IL-12 and TNF-α
**Organize to form granulomas to contain the infection
*Latent infection can reactivate, but rare
**Most common with [[infliximab]]
*In impaired cellular immunity, infection can become disseminated

==Clinical Manifestations==

*Spectrum of illness, related to the size of the inoculum, strain-specific virulence, and host immunity
*Often asymptomatic; in endemic areas, 50-80% of people skin-test positive or have radiographic evidence of previous infection
*Can cross tissue planes

===Acute Pulmonary Histoplasmosis===

*Fever, chill, malaise, headaches, myalgias, anorexia, cough, dyspnea, and chest pain
**Spectrum from mild to severe
**Usually self-limited, no need to treat unless longer than a month
*Pneumonitis on chest x-ray, often with adenopathy
**&quot;Buckshot&quot; appearance? (Mandell)
*Can have rheumatologic sequelae in 5-10%, with arthralgias, arthritis, and erythema nodosum
*Can have pericarditis from the inflammatory response
*Hilar adenopathy can necrotize

===Progressive Disseminated Histoplasmosis===

*Usually, though not exclusively, in immunocompromised patients
**Risk factors include CD4 &lt;200, very old or very young, and therapeutic immunosuppression ([[prednisone]], [[MMF]], [[tacrolimus]], [[methotrexate]], [[TNF-α inhibitors]], other biologics)
*Can be rapidly-progressing and acute, or more subacute

===Acute Progressive Disseminated Histoplasmosis===

*Fever, weight loss, organomegaly, thrombocytopenia
*Meningitis or focal brain lesions
*Oral and GI mucosal ulcerations
*Adrenal insufficiency

===Chronic Progressive Disseminated Histoplasmosis===

*In normal hosts
*Absent or low-grade fever
*Longer course
*Most common finding is oropharyngeal lesion: deep, well-circumscribed, unrated, and painless
**Mimics squamous cell carcinoma
*Can also have hepatosplenomegaly, chronic meningitis, or chronic granulomatous hepatitis

===Chronic Cavitary Histoplasmosis===

*Typically seen in bullous emphysema
*Productive cough, dyspnea, low-grade fever, night sweats, weight loss
**Hemoptysis is rare
**Progressive without treatment
*Chest x-ray shows upper-lobe infiltrations, vacitation, and pleural thickening, similar to tuberculosis

===Fibrosing Mediastinitis===

*Histoplasmosis is the most common cause of [[fibrosing mediastinitis]]
*Rare but serious
*Progressive fibrosis around hilar/mediastinal lymphadenopathy, wither unilateral or bilateral
**Occludes central vessels and airways
*Can present with a SVC syndrome, obstruction of pulmonary vessels, or airway obstruction
*Can also present with recurrent pneumonias, hemoptysis, or respiratory failure
*30% mortality

===Other Complications===

*Ophthalmic posterior [[uveitis]]
*Meningitis
*[[Infective endocarditis]]

===African Histoplasmosis===

*''H. capsulatum'' vars. ''capsulatum'' and ''duboisii'' coexist in Africa
*var. ''duboisii'' has more skin and skeletal manifestations
**Ulcers, nodules, or psoriaform lesions that can spontaneously resolve
***Can cause a cold abscess, without inflammation
**Osteolytic bone lesions are common (50%) of cases
***Skull and ribs most common
***Can have sinus formation and cystic bone lesions
**May not have any evidence on CXR of prior pulmonary histoplasmosis
**Can also present with progressive disseminated disease, with fevers and multiorgan involvement
***Combianation of granulomas and pus
***Larger yeast is harder for macrophages to engulf

==Diagnosis==

*Histopathology of biopsy specimens
**Caseating and non-caseating granulomas
**Mold and yeast forms depending on the temperature
***Best stain is GMS (Gomori methenamine silver)
***Seen within the macrophages
*Fungal culture of sputum (chronic cavitary), or blood or bone marrow aspirate (disseminated), or CSF (CNS histo)
**Usually grows within 7 days, and almost always within 21 days
**Need to use lysis centrifugation system to release intracellular pathogens before culture
**Yield of 15% for acute pulmonary, but cavitary is 60% and up to 90% in advanced HIV with bronchoscopy
**Bone marrow and blood cultures are 50% sensitive
**Sensitivity increases with volume and number of samples
*Serology can be done for antigen or antibody
**Serology for antibodies by complement fixation
**Serology for antibodies by agar gel precipitin test
***Anti-H is uncommon (<10% of patients), but signifies active infection
***Anti-M is common (up to 80% of patients), but signifies either active or recovered infection
**Serology may be negative in immunosuppressed patients
**Antigen of '''urine''' (best), BAL fluid, and serum if available
***Urine is best, but only 40% sensitive in cavitary, up to 95% in AIDS patients
****However, this may no longer be the case, with overall sensitivity of 80% and specificity of 90% regardless of sample source
***Cross-reacts with other endemic fungi; false-positives with antithymocyte globulin
*PCR is possible
**16S PCR

==Management==

*In general, mild infections are treated with [[Is treated by::itraconazole]] and severe infections with [[Is treated by::amphotericin B]]
**Give tablets of [[itraconazole]] with acidic drink, such as can of soda, and avoid antacids
**[[Itraconazole]] requires therapeutic drug monitoring
*[[Is treated by::Voriconazole]] is an easier-to-prescribe alternative that is likely as effective as [[itraconazole]]
*Indications for antifungal therapy
**'''Definitely:''' moderate to severe acute diffuse pulmonary infection, chronic cavitary pulmonary disease, disseminated disease, CNS infection
**'''Possibly/uncertain:''' asymptomatic, mild symptoms lasting longer than 1 month, acute focal pulmonary infection, mediastinal lymphadenitis, mediastinal granuloma
**'''Not recommended:''' mediastinal fibrosis, pulmonary nodule, broncholithiasis, presumed ocular histoplasmosis syndrome

{| class="wikitable"
!Syndrome
!Treatment
|-
| colspan="2" |'''Acute pulmonary histoplasmosis'''
|-
| Mild, self-resolving
|If resolves within a month, no need to treat
|-
| Mild, ongoing symptoms
|[[Itraconazole]] 200 mg po TID x3d then itra 200 mg po daily or BID for 6-12 weeks
|-
| Moderate to severe
|[[Liposomal amphotericin B]] 3-5 mg/kg/d for 1-2 weeks, followed by [[itraconazole]] 200 mg TID x3d then [[itraconazole]] 200 mg BID x12wk<br />[[Methylprednisolone]] 0.5-1 mg/kg IV daily for first 1-2 weeks if respiratory complications
|-
|Chronic cavitary pulmonary histoplasmosis
|[[Itraconazole]] 200 mg TID x3d then daily or BID for at least 1 year (18-24 months may have lower relapse)
|-
| colspan="2" |'''Complications'''
|-
| Pericarditis
|NSAIDs if mild<br />[[Prednisone]] 0.5-1 mg/kg daily then taper over 1-2 weeks, plus [[itraconazole]] (as above) for 6-12 weeks if hemodynamic compromise<br />May need therapeutic pericardiocentesis
|-
| Rheumatologic
|NSAIDs if mild, [[prednisone]] and [[itraconazole]] (as for pericarditis) if severe
|-
| Mediastinal lymphadenitis
|Usually no treatment. Follow guide for acute pulmonary histoplasmosis.
|-
| Mediastinal granuloma
|Usually no treatment. Standard [[itraconazole]] protocol for 6-12 weeks if symptomatic.
|-
| [[Fibrosing mediastinitis|Mediastinal fibrosis]]
|Antifungals not recommended. Treat only if there is suspicion of mediastinal granuloma. May need stenting of obstructed pulmonary vessels.
|-
| Broncholithiasis
|Antifungals not recommended. May need surgery.
|-
|'''Progressive disseminated histoplasmosis'''
|Follow antigen levels during therapy and for 12 months after to monitor for relapse
|-
| Mild to moderate
|[[Itraconazole]] for 12 months
|-
| Moderately severe to severe
|[[Liposomal amphotericin B]] 3 mg/kg for 1-2 weeks then oral [[itraconazole]] for at least 12 months
|-
| Immunosuppressed
|May need lifelong suppressive therapy with [[itraconazole]] 200 mg po daily
|-
|CNS histoplasmosis
|[[Liposomal amphotericin B]] 5 mg/kg daily for 4-6 weeks (total 175 mg/kg) followed by itraconazole for at least 1 year, until resolution of CSF abnormalities
|-
|Pregnancy
|[[Liposomal amphotericin B]] 3-5 mg/kg for 4-6 weeks
|-
|Children
|As per above guidelines, with [[amphotericin B deoxycholate]] 1 mg/kg and [[itraconazole]] 2.5-5 mg/kg bid (max 400 mg daily)
|-
|Prophylaxis
|[[Itraconazole]] 200 mg po daily recommended if [[HIV]] with CD4 &lt;150 and more than 10 cases per 100 patient-years
|}

*'''Note:''' therapeutic drug level monitoring is recommended for itraconazole
*'''Source:''' IDSA guidelines 2007

==Prevention==

===Lab Safety===

*[[Biosafety risk groups|Biosafety risk group 3]] organism, so needs BSL 3
*Should be suspected with any white mold

===Prophylaxis===

*May be indicated for endemic areas in patients with advanced HIV and low CD4 count
{{DISPLAYTITLE:''Histoplasma capsulatum''}}
[[Category:Dimorphic fungi]]