1658 PART 5 Infectious Diseases

■ ETIOLOGY

Histoplasma capsulatum, a thermal dimorphic fungus, is the etiologic

agent of histoplasmosis. In most endemic areas in North America, H.

capsulatum var. capsulatum is the causative agent. In Central and South

America, histoplasmosis is common and is caused by genetically different clades of H. capsulatum var. capsulatum. In Africa, H. capsulatum

var. duboisii is also found. Yeasts of var. duboisii are larger than those

of var. capsulatum.

Mycelia—the naturally infectious form of Histoplasma—have a

characteristic appearance, with microconidial and macroconidial

forms (Fig. 212-1). Microconidia are oval and are small enough (2–4 μm)

to reach the terminal bronchioles and alveoli. Shortly after infecting

the host, mycelia transform into the yeasts that are found inside macrophages and other phagocytes. The yeast forms are characteristically

small (2–5 μm), with occasional narrow budding (Fig. 212-2). In the

laboratory, mycelia are best grown at room temperature, whereas yeasts

are grown at 37°C on enriched media.

■ EPIDEMIOLOGY

Histoplasmosis is the most prevalent endemic mycosis in North

America. Although this fungal disease has been reported throughout the world, its endemicity is particularly notable in the Ohio and

Mississippi river valleys of North America and in certain parts of

Mexico, Central and South America (Brazil), Africa, and Asia. Histoplasmosis is increasingly reported outside of the traditionally known

endemic areas. The geographic distribution of histoplasmosis is related

to the humid and acidic nature of the soil in the endemic areas. Soil

enriched with bird or bat droppings promotes the growth and sporulation of Histoplasma. Disruption of soil containing the organism leads

to aerosolization of the microconidia and exposure of humans nearby.

Activities associated with high-level exposure include spelunking,

excavation, cleaning of chicken coops, demolition and remodeling

of old buildings, and cutting of dead trees. Most cases seen outside

of highly endemic areas represent imported disease, e.g., in Europe,

histoplasmosis is diagnosed fairly often, mostly in emigrants from or

travelers to endemic areas on other continents. The epidemiology of

histoplasmosis is changing as a result of global climate changes and

with the continued expansion of at-risk populations and the acceleration of intercontinental and international travel that brings this

infection to areas of the world that are not known to be endemic. The

population at risk for histoplasmosis continues to grow as a result of

increasing numbers of patients receiving immunosuppressive therapies

for autoimmune disorders, cancers, and organ transplants.

212

■ PATHOGENESIS AND PATHOLOGY

Infection follows inhalation of microconidia (Fig. 212-1). Once they

reach the alveolar spaces, microconidia are rapidly recognized and

engulfed by alveolar macrophages, where they transform into yeasts

(Fig. 212-2), a process that is integral to the pathogenesis of histoplasmosis and is dependent on the availability of calcium and iron inside

the phagocytes. The yeasts are capable of multiplying inside resting

macrophages. Neutrophils and then lymphocytes are attracted to the

site of infection. Before the development of cellular immunity, yeasts

use the phagosomes as a vehicle for translocation to local draining

lymph nodes, whence they spread hematogenously throughout the

reticuloendothelial system. Adequate cellular immunity develops

~2 weeks after infection. T cells produce interferon-γ to assist the

macrophages in killing the organism and controlling the progression

of disease. Interleukin 12 and tumor necrosis factor α (TNF-α) play an

essential role in cellular immunity to H. capsulatum. In the immunocompetent host, macrophages, lymphocytes, and epithelial cells eventually organize and form granulomas that contain the organisms. These

granulomas typically fibrose and calcify; calcified lung nodules, mediastinal lymph nodes, and hepatosplenic calcifications are frequently

found in healthy individuals from endemic areas. In immunocompetent hosts, infection with H. capsulatum confers protective immunity to

reinfection. In patients with impaired cellular immunity, the infection

is not properly contained and can disseminate throughout the reticuloendothelial system. Progressive disseminated histoplasmosis (PDH)

can involve multiple organs, most commonly the lungs, bone marrow,

Histoplasmosis

Chadi A. Hage, L. Joseph Wheat

FIGURE 212-1 Spiked spherical conidia of H. capsulatum (lacto-phenol cotton blue

stain) grown in the laboratory at room temperature.

A

B

3 µm

5 µm

FIGURE 212-2 A. Small (2–5 μm) narrow budding yeasts of H. capsulatum from

bronchoalveolar lavage fluid (Grocott’s methenamine silver stain). B. Intracellular

yeasts of H. capsulatum within an alveolar macrophage from a patient with AIDS

and disseminated histoplasmosis (Giemsa stain).

1659CHAPTER 212 Histoplasmosis

spleen, liver (Fig. 212-3), adrenal glands, and mucocutaneous membranes. Unlike latent tuberculosis, inactive histoplasmosis does not

reactivate. In patients with mildly impaired immune systems, active

infection may smolder and eventually worsen with further decline in

immunity.

Structural lung disease (e.g., emphysema) impairs the clearance of pulmonary histoplasmosis leading to the development of chronic pulmonary

disease. This chronic process is characterized by progressive inflammation,

tissue necrosis, and fibrosis mimicking cavitary tuberculosis.

■ CLINICAL MANIFESTATIONS

The clinical spectrum of histoplasmosis ranges from asymptomatic

infection to life-threatening illness. The attack rate and the extent and

severity of the disease depend on the intensity of exposure, the immune

status of the exposed individual, and the underlying lung architecture

of the host.

In immunocompetent individuals with low-level exposure, most

Histoplasma infections are either asymptomatic or mild and self-limited.

Of adults residing in endemic areas, up to 75% have immunologic

and/or radiographic evidence of previous infection without clinical

manifestations. Asymptomatic lung nodules representing controlled

histoplasmosis are frequently found on chest CT scans obtained during screening for lung cancer in smokers from endemic areas. When

symptoms of acute histoplasmosis develop, they usually appear 1–4 weeks

after exposure. Heavy exposure leads to a flulike illness with fever,

chills, sweats, headache, myalgia, anorexia, dry cough, dyspnea, and

chest pain. Chest radiographs usually show signs of pneumonitis with

prominent hilar or mediastinal adenopathy. Pulmonary infiltrates may

be focal with light exposure or diffuse with heavy exposure. Rheumatologic symptoms of arthralgia or arthritis, often associated with

erythema nodosum, occur in 5–10% of patients with acute histoplasmosis. Pericarditis may also develop. These manifestations represent

inflammatory responses to the acute pulmonary infection rather than

extrapulmonary spread. Affected hilar or mediastinal lymph nodes

may undergo necrosis and coalesce to form large mediastinal masses

that can cause compression of great vessels, proximal airways, and

the esophagus. These necrotic lymph nodes may also rupture and

FIGURE 212-3 Intracellular yeasts (arrows) of H. capsulatum in a liver biopsy

specimen (hematoxylin and eosin stain) from a patient who developed progressive

disseminated histoplasmosis while receiving anti–tumor necrosis factor therapy for

rheumatoid arthritis.

create fistulas between mediastinal structures (e.g., bronchoesophageal

fistulas).

PDH is typically seen in immunocompromised individuals, who

account for ~70% of cases. Common risk factors include AIDS

(CD4+ T-cell count, <200/μL), extremes of age, the administration

of immunosuppressive medications to prevent or treat rejection following transplantation (e.g., prednisone, mycophenolate, calcineurin

inhibitors), and the use of methotrexate, anti-TNF-α agents, and other

biologic response modifiers for autoimmune disorders. PDH may

also occur in healthy individuals, some of whom may have rare undiagnosed genetic immunodeficiencies—workup for these conditions

should be considered in healthy subjects with PDH.

The clinical spectrum of PDH ranges from an acute, rapidly fatal

course—with diffuse interstitial or reticulonodular lung infiltrates

causing respiratory failure, shock, coagulopathy, and multiorgan failure—to

a subacute or chronic course with a focal organ distribution. Common

manifestations include fever, weight loss, hepatosplenomegaly, and

thrombocytopenia. Other findings may include meningitis or focal

brain lesions, ulcerations of the oral mucosa, gastrointestinal ulcerations and bleeding, and adrenal insufficiency. Prompt recognition of

this devastating illness is of paramount importance in patients with

severe manifestations or with underlying immunosuppression, especially that due to AIDS (Chap. 202).

Chronic cavitary histoplasmosis is seen in smokers who have structural

lung disease (e.g., bullous emphysema). This chronic illness is characterized by productive cough, dyspnea, low-grade fever, night sweats, and

weight loss. Chest radiographs usually show upper-lobe infiltrates, cavitation, and pleural thickening—findings resembling those of tuberculosis.

Without treatment, the course is slowly progressive.

Fibrosing mediastinitis is an uncommon but serious complication

of histoplasmosis. In certain patients, acute infection is followed for

unknown reasons by progressive fibrosis around the hilar and mediastinal

lymph nodes, encasing mediastinal structures with potentially devastating

consequences. Major manifestations include superior vena cava syndrome,

obstruction of pulmonary vessels, and airway obstruction. Patients may

experience recurrent pneumonia, hemoptysis, or respiratory failure.

Fibrosing mediastinitis is fatal in up to one-third of cases.

In healed histoplasmosis, calcified mediastinal nodes or lung parenchymal nodules may erode through the walls of the airways and

cause hemoptysis and expectoration of calcified material. This condition is called broncholithiasis.

The clinical features and management of histoplasmosis caused by

the genetically different clades in Central and South America are similar to those of the disease in North America. African histoplasmosis

caused by var. duboisii is clinically distinct and is characterized by

frequent skin and bone involvement.

■ DIAGNOSIS

Recommendations for the diagnosis and treatment of histoplasmosis

are summarized in Table 212-1. Once suspected, the diagnosis of histoplasmosis is usually straightforward as many diagnostic tools are now

available in the United States. This is not the case in resource-limited

endemic regions of Central America, South America, and Africa, where

the diagnosis is often delayed, with consequently poor outcomes.

Fungal culture remains the gold standard diagnostic test for histoplasmosis. However, culture results may not be known for up to 1 month,

and cultures are often negative in less severe cases. Cultures are positive

in ~75% of patients with PDH and chronic pulmonary histoplasmosis.

Cultures of bronchoalveolar lavage (BAL) fluid are positive in about half

of patients with acute pulmonary histoplasmosis causing diffuse infiltrates

and hypoxemia. In PDH, the culture yield is highest for BAL fluid, bone

marrow aspirate, and blood. Cultures of sputum or bronchial washings are

usually positive in chronic pulmonary histoplasmosis. Cultures are typically negative, however, in other forms of histoplasmosis.

Fungal stains of cytopathology or biopsy materials showing structures resembling Histoplasma yeasts are helpful in the diagnosis of

PDH, yielding positive results in about half of cases. Yeasts can be

seen in BAL fluid (Fig. 212-2) from patients with diffuse pulmonary

infiltrates, in bone marrow biopsy samples, and in biopsy specimens

1660 PART 5 Infectious Diseases

TABLE 212-1 Recommendations for the Diagnosis and Treatment of Histoplasmosis

TYPE OF HISTOPLASMOSIS DIAGNOSTIC TESTS TREATMENT RECOMMENDATIONS COMMENTS

Acute pulmonary, moderate

to severe illness or no

improvement by the time of

diagnosis

Histoplasma antigen (BAL fluid, serum, urine)

Cytopathology on and fungal culture of

BAL fluid

Histoplasma serology (ID and CF), (EIA):

IgG and IgM

Lipid AmB (3–5 mg/kg per day) ±

glucocorticoids for 1–2 weeks;

then itraconazole (200 mg bid) for

6–12 weeks. Monitor renal and

hepatic function.

Patients with mild cases usually recover

without therapy, but itraconazole should be

considered if the patient’s condition is not

already improving by the time the diagnosis

is established.

Chronic/cavitary pulmonary Histoplasma serology (ID and CF), (EIA):

IgG and IgM

Fungal culture of sputum or BAL fluid

Itraconazole (200 mg qd or bid to

achieve blood levels of 2–5 μg/ml) for

at least 12 months. Monitor hepatic

function.

Continue treatment until radiographic

findings show no further improvement.

Monitor for relapse after treatment is

stopped.

Progressive disseminated Histoplasma antigen (BAL fluid, serum, urine)

Histoplasma serology (ID and CF), (EIA):

IgG and IgM

Fungal culture of blood or bone

marrow aspirate

Cytopathology on biopsy of affected organ

Lipid AmB (3–5 mg/kg per day) for

1–2 weeks; then itraconazole

(200 mg qd or bid to achieve blood levels

of 2–5 μg/ml) for at least 12 months.

Monitor renal and hepatic function.

Liposomal AmB is preferred, but the AmB

lipid complex may be used because of

cost. Chronic antifungal maintenance

therapy may be necessary if the degree of

immunosuppression cannot be substantially

reduced.

Central nervous system Histoplasma antigen CSF

Histoplasma serology (ID and CF), (EIA):

IgG and IgM

Fungal culture of CSF

Liposomal AmB (5 mg/kg per day) for

4–6 weeks; then itraconazole (200 mg qd

or bid to achieve blood levels of 2-5 μg/ml)

for at least 12 months. Monitor renal and

hepatic function.

A longer course of lipid AmB is

recommended because of the high risk of

relapse. Itraconazole should be continued

until CSF or MRI abnormalities clear.

Abbreviations: AmB, amphotericin B; BAL, bronchoalveolar lavage; CF, complement fixation; CSF, cerebrospinal fluid; EIA, enzyme immunoassay; ID, immunodiffusion.

of other involved organs (e.g., liver, adrenal glands). Occasionally,

yeasts are seen within circulating phagocytes on blood smears from

patients with severe PDH. However, staining artifacts and other fungal elements sometimes stain positively and may be misidentified as

Histoplasma yeasts. Culture and pathology are no longer performed in

most patients because diagnosis is more often established by antigen

detection and/or serology, more rapidly and without subjecting the

patient to invasive procedures.

The detection of Histoplasma antigen in body fluids is extremely

useful in the diagnosis of PDH and acute diffuse pulmonary histoplasmosis. The sensitivity of this method is >95% in patients with PDH and

>80% in patients with severe acute pulmonary histoplasmosis resulting

from heavy exposure, if both urine and serum are tested. Antigen levels

correlate with severity of illness in PDH and can be used to follow disease progression, as levels predictably decrease with effective therapy.

Increased antigen levels also predict relapse. Histoplasma antigen can be

detected in cerebrospinal fluid from patients with Histoplasma meningitis

and in BAL fluid from those with pulmonary histoplasmosis. Cross-reactivity occurs with African histoplasmosis, blastomycosis, coccidioidomycosis, paracoccidioidomycosis, talaromycosis, and rarely aspergillosis.

Serologic tests, including immunodiffusion (ID), complement fixation (CF), and IgG and IgM enzyme immunoassay (EIA), are useful

for the diagnosis of histoplasmosis, especially in immunocompetent

patients. One month may be required for the detection of antibodies

after the onset of infection by ID or CF, but antibodies may be detected

earlier by more sensitive methods (EIA). IgM appears first then

declines, and IgG appears later and increases during the infection. EIA

for IgG and IgM antibodies provides a more accurate method for monitoring changes and antibody levels. Serologic tests are especially useful

for the diagnosis of chronic pulmonary histoplasmosis. Limitations of

ID and CF, however, include insensitivity early in the course of infection and reduced sensitivity in immunosuppressed patients, especially

those receiving immunosuppression for organ transplantation. Also,

antibodies may persist for several years after infection. Positive results

from past infection may lead to a misdiagnosis of active histoplasmosis

in a patient with another disease process.

TREATMENT

Histoplasmosis

Treatment is indicated for all patients with PDH or chronic pulmonary histoplasmosis as well as for most symptomatic patients

with acute pulmonary histoplasmosis who have not improved

by the time the diagnosis is established especially in those with

diffuse infiltrates and difficulty breathing. In most other cases of

pulmonary histoplasmosis, treatment is not recommended especially if the immune system of the host is intact, and the degree of

exposure is not heavy. The symptoms usually are mild, subacute,

and not progressive, and the illness resolves without therapy.

Treatment should be considered if the symptoms are not improving within a month.

The preferred treatments for histoplasmosis (Table 212-1)

include the lipid formulations of amphotericin B in severe cases

and itraconazole in others. Liposomal amphotericin B is more effective and better tolerated than the deoxycholate formulation and is

more effective in patients with AIDS and PDH. The deoxycholate

formulation of amphotericin B is an alternative to a lipid formulation for patients at low risk for nephrotoxicity and if liposomal

amphotericin B is not available. Posaconazole and isavuconazole are

alternatives for patients who cannot take itraconazole. Histoplasma

may develop resistance to fluconazole and voriconazole, and they

are not the preferred alternative to itraconazole, especially in immunocompromised patients.

In severe cases requiring hospitalization, a lipid formulation of

amphotericin B is used first, followed by itraconazole. In patients

with meningitis, a lipid formulation of amphotericin B should be

given for 4–6 weeks before switching to itraconazole. In immunosuppressed patients, the degree of immunosuppression should be

reduced if possible, although immune reconstitution inflammatory

syndrome (IRIS) may ensue. Antiretroviral treatment improves the

outcome of PDH in patients with AIDS and is recommended; however, whether antiretroviral treatment should be delayed to avoid

IRIS is unknown.

Blood levels of itraconazole should be monitored to ensure adequate drug exposure, with target concentrations of the parent drug

and its hydroxy metabolites measuring 2–5 μg/mL. Drug interactions should be carefully assessed; itraconazole not only is cleared

by cytochrome P450 metabolism but also inhibits cytochrome

P450. This profile causes interactions with many other medications.

The duration of treatment for acute pulmonary histoplasmosis is

6–12 weeks, while that for PDH and chronic pulmonary histoplasmosis is at least 1 year. Antigen levels in urine and serum should

be monitored during and for at least 1 year after therapy for PDH.

Stable or rising antigen levels suggest treatment failure or relapse

and should raise concerns regarding proper intake of itraconazole

(capsule formulation with food), adherence to treatment, itraconazole serum concentrations, and drug interactions.

1661CHAPTER 213 Coccidioidomycosis

■ DEFINITION AND ETIOLOGY

Coccidioidomycosis, commonly known as Valley fever (see “Epidemiology,” below), is caused by dimorphic soil-dwelling fungi of the genus

Coccidioides. Genetic analysis has demonstrated the existence of two

species, C. immitis and C. posadasii. These species are indistinguishable

with regard to the clinical disease they cause and their appearance on

routine laboratory media. Thus, the organisms will be referred to simply as Coccidioides for the remainder of this chapter.

■ EPIDEMIOLOGY

Coccidioidomycosis is confined to the Western Hemisphere between

the latitudes of 40°N and 40°S. In the United States, areas of high

endemicity include the San Joaquin Valley of California (hence the

sobriquet “Valley fever”) and the south-central region of Arizona.

However, infection may be acquired in other areas of the southwestern

United States, including the southern coastal counties in California,

southern Nevada, southwestern Utah, southern New Mexico, and western Texas (including the Rio Grande Valley). Cases where infection

was acquired well outside the recognized endemic areas, including in

eastern Washington state and in northeastern Utah, have been recently

described, suggesting that the endemic region may be expanding.

Outside the United States, coccidioidomycosis is endemic to northern

Mexico as well as to localized regions of Central America. In South

America, there are endemic foci in Colombia, Venezuela, northeastern

Brazil, Paraguay, Bolivia, and north-central Argentina.

The risk of infection is increased by direct exposure to soil harboring Coccidioides. Because of difficulty in isolating Coccidioides from

environmental sites, the precise characteristics of potentially infectious

soil are not known. In the United States, several outbreaks of coccidioidomycosis have been associated with soil from archeologic excavations of Amerindian sites both within and outside of the recognized

213 Coccidioidomycosis

Neil M. Ampel

Rupturing

spherule

Host

Environment

Maturing

spherule

Early

spherule

Arthroconidium

~ 5 µm

Endospore

Spherule stage

Mycelial stage

FIGURE 213-1 Life cycle of Coccidioides, including the mycelial phase in the

environment and the spherule phase in the host.

Lifelong itraconazole maintenance therapy is recommended for

patients with persistently suppressed immunity but not for those

with immune recovery—e.g., patients with AIDS who complete at

least 1 year of itraconazole and show no signs of active infection

including Histoplasma antigen levels <2 ng/mL respond well to

antiretroviral treatment with CD4+ T-cell counts of at least 150/μL

(preferably >250/μL) and HIV viral load <50 copies/mL. Similarly,

maintenance therapy may not be necessary in other immunocompromised patients if the clinical findings have cleared, antigen levels

are <2 ng/mL, and immunosuppression is substantially reduced.

Fibrosing mediastinitis, which represents a chronic fibrotic reaction to past mediastinal histoplasmosis rather than an active infection, does not respond to antifungal therapy. Often patients with

mediastinal granuloma have chronic or progressive courses and

receive treatment with itraconazole and corticosteroids to reduce

disease progression.

■ FURTHER READING

Azar MM et al: Clinical perspectives in the diagnosis and management of histoplasmosis. Clin Chest Med 38:403, 2017.

Azar MM et al: Current concepts in the epidemiology, diagnosis, and

management of histoplasmosis. Semin Respir Crit Care Med 41:13,

2020.

Bahr NC et al: Histoplasmosis infections worldwide: Thinking outside

of the Ohio River valley. Curr Trop Med Rep 2:70, 2015.

Hage CA et al: A multicenter evaluation of tests for diagnosis of histoplasmosis. Clin Infect Dis 53:448, 2011.

endemic region. These cases often involved alluvial soils in regions of

relative aridity with moderate temperature ranges. When found,

Coccidioides is isolated 2–20 cm below the surface; it is not found at

greater depths, nor is it usually isolated from cultivated soil.

In endemic areas, most cases of coccidioidomycosis occur without

obvious soil or dust exposure, and it is presumed that infection occurs

through inhalation of airborne fungal particles. Climatic factors may

increase the infection rate in these regions. In particular, periods of

aridity following rainy seasons have been associated with marked

increases in the number of symptomatic cases. From 2011−2017, there

were 95,371 cases of coccidioidomycosis reported in the United States.

During this time, there has been a general increase in the incidence

of disease. In California, this increase has occurred both within the

established endemic area of the San Joaquin Valley and in the areas

contiguous to it. The factors associated with this increase have not

been elucidated but likely include an influx of older individuals without

prior coccidioidal infection into endemic areas, construction activity,

increased reporting, and changing climatic conditions.

■ PATHOGENESIS, PATHOLOGY, AND IMMUNE

RESPONSE

On agar media and in the environment, Coccidioides organisms exist

as filamentous molds. Within this mycelial structure, individual filaments (hyphae) elongate and branch, some growing upward. Alternating cells within the hypha degenerate, leaving barrel-shaped viable

elements called arthroconidia. Measuring ~2 μm by 5 μm, individual

arthroconidia may dislodge and become airborne for extended periods. When inhaled by a susceptible host, their small size allows them

to evade initial mechanical mucosal defenses and reach deep into the

bronchial tree, where infection is initiated.

Once within a susceptible host, the arthroconidia enlarge, become

rounded, and develop internal septations. The resulting structures,

called spherules (Fig. 213-1), may attain sizes up to 200 μm and

are unique to Coccidioides. The septations encompass uninuclear

elements called endospores. Spherules may rupture and release packets of endospores that can themselves develop into spherules, thus

1662 PART 5 Infectious Diseases

Clinical dissemination of infection outside the thoracic cavity occurs

in <1% of infected individuals. Dissemination is more likely to occur

in male patients, particularly those of African-American or Filipino

ancestry, and in persons with depressed cellular immunity, including

patients with HIV infection and peripheral-blood CD4+ T-cell counts

of <250/μL, those receiving chronic glucocorticoid therapy, those with

allogeneic solid-organ transplants, and those being treated with tumor

necrosis factor α antagonists. Women who acquire new coccidioidal

infection during the second or third trimester of pregnancy or postpartum also are at risk for disseminated disease. Common sites for dissemination include the skin, bones, joints, soft tissues, and meninges.

Dissemination may follow symptomatic or asymptomatic pulmonary

infection and may involve only one site or multiple anatomic foci.

When it occurs, clinical dissemination is usually evident within the

first 6 months after primary pulmonary infection.

Of the disseminated syndromes, coccidioidal meningitis is the most

dire and, if untreated, is uniformly fatal. Patients usually present with

a persistent headache, often accompanied by lethargy and confusion.

Nuchal rigidity, if present, is not severe. Examination of cerebrospinal fluid (CSF) demonstrates lymphocytic pleocytosis with profound

hypoglycorrhachia and elevated protein levels. CSF eosinophilia is

occasionally observed. With or without appropriate therapy, patients

may develop hydrocephalus, either communicating or noncommunicating, which presents clinically as a marked decline in mental status,

often with gait disturbances.

■ DIAGNOSIS

Serology plays an important role in establishing a diagnosis of coccidioidomycosis. Several techniques are available, including the traditional

tube-precipitin (TP) and complement-fixation (CF) assays, immunodiffusion TP and CF (IDTP and IDCF), and enzyme immunoassay

(EIA) to detect IgM and IgG antibodies. TP and IgM antibodies are

found in serum soon after infection and persist for weeks to months.

They are not useful for gauging severity of disease. The CF and IgG

antibodies occur later in the course of the disease and persist longer

than TP and IgM antibodies. Rising CF titers are associated with clinical progression, and the presence of CF antibody in CSF is indicative

of coccidioidal meningitis. Antibodies disappear over time in persons

whose clinical illness resolves.

Because of its commercial availability, the coccidioidal EIA is frequently used as a screening tool for coccidioidal serology. There has

been concern that the IgM EIA is occasionally falsely positive, particularly in asymptomatic individuals. In addition, while the sensitivity and

specificity of the IgG EIA appear to be higher than those of the CF and

IDCF assays, the optical density obtained in the EIA does not correlate

with the serologic titer of either of the latter tests.

Coccidioides grows within 3–7 days at 37°C on a variety of artificial

media, including blood agar. Therefore, it is always useful to obtain

samples of sputum or other respiratory fluids and tissues for culture

in suspected cases of coccidioidomycosis. The clinical laboratory

should be alerted to the possibility of this diagnosis, since Coccidioides

poses a significant laboratory hazard if it is inadvertently inhaled.

The organism can also be identified directly. While treatment of

samples with potassium hydroxide is rarely fruitful in establishing

the diagnosis, examination of sputum or other respiratory fluids

after Papanicolaou, Gomori methenamine silver, or calcofluor white

staining reveals spherules in a significant proportion of patients with

pulmonary coccidioidomycosis. For fixed tissues (e.g., those obtained

from biopsy specimens), spherules with surrounding inflammation

can be demonstrated with hematoxylin-eosin or Gomori methenamine

silver staining.

A commercially available test for coccidioidal antigenuria and

antigenemia has been developed and appears to be particularly useful

in immunosuppressed patients with severe or disseminated disease.

It appears to be useful when the CSF is assayed in cases of suspected

coccidioidal meningitis. False-positive results may occur in cases of

histoplasmosis or blastomycosis. Some laboratories offer genomic

detection by polymerase chain reaction; this assay does not appear to

be more sensitive than culture but can be more rapid.

propagating infection locally. If returned to artificial media or the soil,

the fungus reverts to its mycelial stage.

Clinical observations and data from animal studies strongly support

the critical role of a robust cellular immune response in the host’s

control of coccidioidomycosis. Necrotizing granulomas containing

spherules are typically identified in patients with resolved pulmonary

infection. In disseminated disease, granulomas are generally poorly

formed or do not develop at all, and a polymorphonuclear leukocyte

response occurs frequently. In patients who are asymptomatic or in

whom the initial pulmonary infection resolves, delayed-type hypersensitivity to coccidioidal antigens has been routinely documented.

■ CLINICAL AND LABORATORY MANIFESTATIONS

After infection, 60% of individuals remain completely asymptomatic.

The other 40% have symptoms that are related primarily to pulmonary

infection, including fever, cough, and pleuritic chest pain. Symptoms

generally occur from several days to 2 weeks after inhalation of infectious spores. The risk of symptomatic illness increases with age.

There are several manifestations of primary pulmonary coccidioidomycosis that are due to an immunologic response rather than directly

to infection. Most prominent among these are cutaneous reactions. A

diffuse, erythematous maculopapular rash, known as toxic erythema,

has been noted in some cases. In addition, erythema nodosum (see

Fig. A1-39)—typically over the lower extremities—and erythema

multiforme (see Fig. A1-24)—usually in a necklace distribution—

may occur. Lesions consistent with Sweet’s syndrome have also been

reported (Chap. 19). Cutaneous manifestations are especially common

in women. Symmetrical arthralgias (“desert rheumatism”) may also

occur with or without cutaneous manifestations.

Primary pulmonary coccidioidomycosis is often misdiagnosed as

community-acquired bacterial pneumonia. However, the diagnosis of

primary pulmonary coccidioidomycosis is strongly suggested by the

findings of rash and symmetrical arthralgias in a patient with an appropriate exposure history in a patient with pneumonia. The finding of

any of the following is also strongly suggestive of coccidioidomycosis: a

history of night sweats, marked fatigue, peripheral-blood eosinophilia,

failure to improve with antibacterial therapy, and hilar or mediastinal

lymphadenopathy on chest imaging.

In most patients, primary pulmonary coccidioidomycosis usually

resolves without sequelae over several weeks. However, several pneumonic complications may arise. Pulmonary nodules are residua of

primary pneumonia. Generally single, frequently located in the upper

lobes, and ≤4 cm in diameter, nodules are often discovered on a routine

chest radiograph in an asymptomatic patient. Calcification is uncommon. Coccidioidal pulmonary nodules can be difficult to distinguish

radiographically from pulmonary malignancies. Like malignancies,

coccidioidal nodules often enhance on positron emission tomography.

However, unlike malignancies, routine CT often demonstrates multiple nodules in coccidioidomycosis, and there may be satellite lesions,

smaller nodules surrounding the larger one. These findings are not

specific, and biopsy may be required to distinguish between these two

entities.

Pulmonary cavities occur when a nodule extrudes its contents

into the bronchial tree, resulting in a thin-walled shell. Frequently

asymptomatic, these cavities can be associated with persistent cough,

hemoptysis, and pleuritic chest pain. Rarely, a cavity may rupture into

the pleural space, causing pyopneumothorax. In such cases, patients

present with acute dyspnea, and the chest radiograph reveals a collapsed lung with a pleural air-fluid level. Chronic or persistent pulmonary coccidioidomycosis manifests with prolonged fever, cough, and

weight loss and is radiographically associated with pulmonary scarring,

fibrosis, and cavities. It occurs most commonly in patients who already

have chronic lung disease due to other etiologies.

In some cases, primary pneumonia presents as a diffuse reticulonodular pulmonary process on plain chest radiography in association

with dyspnea and fever. Primary diffuse coccidioidal pneumonia may

occur in settings of intense environmental exposure or profoundly

suppressed cellular immunity (e.g., in patients with AIDS), with unrestrained fungal growth that is frequently associated with fungemia.

1663CHAPTER 213 Coccidioidomycosis

TABLE 213-1 Clinical Presentations of Coccidioidomycosis,

Their Frequency, and Recommended Initial Therapy for the

Immunocompetent Host

CLINICAL

PRESENTATION FREQUENCY, % RECOMMENDED THERAPY

Asymptomatic infection 60 None

Primary pneumonia

(focal)

40 In most cases, nonea

Diffuse pneumonia <1 Amphotericin B followed by

prolonged oral triazole therapy

Pulmonary sequelae 5

Nodule None

Cavity In most cases, noneb

Chronic pneumonia Prolonged triazole therapy

Disseminated disease ≤1

 Skin, bone, joint, soft

tissue disease

Prolonged triazole therapyc

Meningitis Lifelong triazole therapyd

a

Treatment is indicated for hosts with depressed cellular immunity as well as for

those with prolonged symptoms and signs of increased severity, including night

sweats for >3 weeks, weight loss of >10%, a complement-fixation titer of >1:16,

and extensive pulmonary involvement on chest radiography. b

Treatment (usually

with the oral triazoles fluconazole and itraconazole) is recommended for persistent

symptoms. c

In severe cases, some clinicians would use amphotericin B as initial

therapy. d

Intraventricular or intrathecal amphotericin B is recommended in cases of

triazole failure. Hydrocephalus may occur, requiring a cerebrospinal fluid shunt.

Note: See text for dosages and durations.

TREATMENT

Coccidioidomycosis

Currently, two main classes of antifungal agents are useful for

the treatment of coccidioidomycosis (Table 213-1). While once

prescribed routinely, amphotericin B in all its formulations is now

reserved for only the most severe cases of dissemination and for

intrathecal or intraventricular administration to patients with coccidioidal meningitis in whom triazole antifungal therapy has failed.

The original formulation of amphotericin B, which is dispersed

with deoxycholate, is usually administered intravenously in doses

of 0.7–1.0 mg/kg either daily or three times per week. The newer

lipid-based formulations are associated with less renal toxicity but

have not been demonstrated to lead to better improvement than the

deoxycholate formulation in coccidioidomycosis. The lipid dispersions are administered intravenously at doses of 3–5 mg/kg daily or

three times per week.

Triazole antifungals are the principal drugs now used to treat

most cases of coccidioidomycosis. Clinical trials have demonstrated

the usefulness of both fluconazole and itraconazole. Evidence indicates that itraconazole is more effective against bone and joint disease. Fluconazole has been the triazole of choice for the treatment

of coccidioidal meningitis, but itraconazole also is effective. For

both drugs, a minimal oral adult dosage of 400 mg/d should be

used. The maximal dose of itraconazole is 200 mg three times daily,

but higher doses of fluconazole may be given. The newer triazole

antifungals, voriconazole and posaconazole, are useful for all types

of clinical disease, including meningitis, and should be considered

in cases where fluconazole or itraconazole therapy has failed. To

date, isavuconazole has been used in limited circumstances in

coccidioidomycosis. High-dose triazole therapy may be teratogenic

during the first trimester of pregnancy; thus, if antifungal therapy is

needed, amphotericin B should be considered in pregnant women

during this period.

Most patients with focal primary pulmonary coccidioidomycosis

do not require antifungal therapy. Patients for whom antifungal

therapy should be considered include those with underlying cellular

immunodeficiencies and those with prolonged symptoms and signs

of extensive disease. Specific criteria include symptoms persisting

for ≥2 months, night sweats occurring for >3 weeks, weight loss of

>10%, a serum CF antibody titer of >1:16, and extensive pulmonary

involvement apparent on chest radiography. When antifungal therapy is used, either fluconazole or itraconazole at 400 mg daily for up

to 6 months is considered appropriate.

Diffuse pulmonary coccidioidomycosis represents a special

situation. Because most patients with this form of disease are

profoundly hypoxemic and critically ill, many clinicians favor

beginning therapy with an amphotericin B formulation combined

with an oral triazole antifungal. The triazole antifungal therapy is

continued alone once clinical improvement occurs and should be

continued for 6 months to 1 year.

The nodules that may follow primary pulmonary coccidioidomycosis do not require treatment. As noted above, these nodules are not easily distinguished from pulmonary malignancies by

means of radiographic imaging. Close clinical follow-up and biopsy

may be required to distinguish between these two entities. Most

pulmonary cavities do not require therapy. Antifungal treatment

should be considered in patients with persistent cough, pleuritic

chest pain, and hemoptysis. Occasionally, pulmonary coccidioidal

cavities become secondarily infected. This development is often

manifested by an air-fluid level within the cavity. Bacterial flora or

Aspergillus species are commonly involved, and therapy directed

at these organisms should be considered. Surgery is sometimes

required in cases of persistent productive cough and hemoptysis. In

addition, cavities >4 cm in diameter are unlikely to resolve spontaneously, and surgical extirpation should be considered. Surgery is

always required to reexpand the lung in cases of pyopneumothorax.

For chronic pulmonary coccidioidomycosis, prolonged antifungal

therapy—lasting for at least 1 year—is usually required, with monitoring of symptoms, radiographic changes, sputum cultures, and

serologic titers.

Most cases of disseminated coccidioidomycosis require prolonged antifungal therapy. Duration of treatment is based on clinical improvement in conjunction with a significant decline in serum

CF antibody titer. Such therapy routinely is continued for at least

several years. Relapse occurs in 15–30% of individuals once therapy

is discontinued.

Coccidioidal meningitis poses a special challenge. While most

patients with this form of disease respond to treatment with oral

triazoles, 80% experience relapse when therapy is stopped. Thus,

lifelong therapy is recommended. In cases of triazole failure, intrathecal or intraventricular amphotericin B may be used. Installation

requires considerable expertise and should be undertaken only by

an experienced health care provider. Shunting of CSF in addition

to appropriate antifungal therapy is required in cases of meningitis

complicated by hydrocephalus. It is prudent to obtain expert consultation in all cases of coccidioidal meningitis.

■ PREVENTION

There are no proven methods to reduce the risk of acquiring coccidioidomycosis among residents of an endemic region, but avoidance of

direct contact with uncultivated soil or with visible dust-containing

soil is a reasonable measure. For individuals with suppressed cellular

immunity, the risk of developing symptomatic coccidioidomycosis is

greater than that in the general population. Among those about to

undergo allogeneic solid-organ transplantation, antifungal therapy is

appropriate when there is evidence of active or recent coccidioidomycosis. Some transplant centers in the endemic region are providing universal antifungal prophylaxis for 6 months to 1 year after solid-organ

transplantation. Several cases of donor-transmitted coccidioidomycosis have occurred during transplantation. If possible, donors from

an endemic region should be screened for coccidioidomycosis before

transplantation. Data on the use of antifungal agents for prophylaxis in

other situations are limited. The administration of prophylactic antifungals is not recommended for HIV-1-infected patients who live in an

endemic region. Most experts would administer a triazole antifungal

to patients with a history of active coccidioidomycosis or a positive

1664 PART 5 Infectious Diseases

coccidioidal serology in whom therapy with tumor necrosis factor α

antagonists is being initiated.

■ FURTHER READING

Benedict K et al: Surveillance for coccidioidomycosis–United States,

2011-2017. Morbid Mortal Wkly Rep 68:1, 2019.

Galgiani JN et al: 2016 Infectious Diseases Society of America (IDSA)

clinical practice guideline for the treatment of coccidioidomycosis.

Clin Infect Dis 63:e112, 2016.

Kahn A et al: Universal fungal prophylaxis and risk of coccidioidomycosis in liver transplant recipients living in an endemic area. Liver

Transpl 21:353, 2015.

Kusne S et al: Coccidioidomycosis transmission through organ transplantation: A report of the OPTN Ad Hoc Disease Transmission

Advisory Committee. Am J Transplant 16:3562, 2016.

Litvintseva AP et al: Valley fever: Finding new places for an old disease: Coccidioides immitis found in Washington state soil associated

with recent human infection. Clin Infect Dis 60:e1, 2015.

■ DEFINITION

Blastomycosis is a pyogranulomatous disease that follows the inhalation of Blastomyces conidia or hyphal fragments. Typically, Blastomyces

causes pulmonary infection; however, a subset of patients will have

disseminated disease that involves organs such as the skin, bone, brain,

or genitourinary system. Blastomycosis is considered a primary fungal infection because it affects persons with either intact or impaired

immune systems. A delay in diagnosis is common because blastomycosis mimics other diseases such as bacterial pneumonia, tuberculosis,

and malignancy. Diagnosis involves culture- and nonculture-based

tests. Amphotericin B formulations and triazoles are the drugs of

choice for treatment.

■ ETIOLOGY

Blastomyces is a species complex comprising B. dermatitidis, B. gilchristii, B. helicus, B. percursus, B. emzantsi, B. silverae, and B. parvus.

B. silverae and B. parvus are not known to commonly infect humans.

Blastomyces species exhibit thermal dimorphism, which involves the

ability to convert between hyphal and yeast morphologies in response

to temperature. In the soil (22–25o

C), Blastomyces grows as septate

hyphae that produce infectious conidia. Among the Blastomyces species, B. helicus is unique because its hyphae grow in a coiled pattern and

it does not sporulate under in vitro growth conditions. In organs and

tissues (37o

C), Blastomyces grows as a pathogenic yeast (Fig. 214-1)

that elicits pyogranulomatous inflammation. The yeast form of all Blastomyces species grows as broad-based budding yeast cells, with subtle

differences in size among the different species (4–29 μm).

■ EPIDEMIOLOGY

Although the majority of Blastomyces infections occur in North America,

blastomycosis is a systemic fungal infection of global importance, with

infections also occurring in Africa and Asia. In the United States, the

traditional geographic range for Blastomyces includes the Mississippi

and Ohio River basins, the St. Lawrence River basin, states bordering

the Great Lakes, and southeastern states. In Canada, the traditional

geographic range includes the provinces of Saskatchewan, Manitoba,

Ontario, and Quebec. In North America, B. dermatitidis is located

throughout the traditional geographic range. B. gilchristii is geographically restricted to Minnesota, Wisconsin, Canada, and areas along

the St. Lawrence River. B. dermatitidis and B. gilchristii are thought to

have diverged 1.9 million years ago during the Pleistocene epoch, with

214 Blastomycosis

Gregory M. Gauthier, Bruce S. Klein

FIGURE 214-1 Blastomyces yeast at 37o

C, with broad-based budding between

mother and daughter cells (arrow). Bar = 10 μm. (Gregory M. Gauthier, MD, MS)

B. gilchristii restricted to formerly glaciated areas. B. dermatitidis is found

in glaciated and nonglaciated areas. In the environment, B. dermatitidis

and B. gilchristii are not uniformly distributed; rather, they grow in ecologic niches often referred to as microfoci, which are characterized by

acidic, sandy soils that are found near water and that contain decaying

organic matter such as vegetation or wood. B. helicus infections have

been reported in the western United States (California, Montana, Idaho,

Colorado, Nebraska, Texas) and Canada (Saskatchewan, Alberta); their

ecologic niche has yet to be defined. The geographic range and ecologic

niche for B. parvus and B. silverae are unknown.

Outside of North America, blastomycosis has been reported in

Africa (more than 100 cases), India (fewer than 10 cases), and Israel. On

the basis of morphologic analysis, nearly all clinical isolates of Blastomyces in Africa were originally thought to be B. dermatitidis. However,

molecular phylogenetic analysis of human clinical isolates has demonstrated that multiple Blastomyces species exist in Africa, including B.

dermatitidis, B. gilchristii, B. percursus, and B. emzantsi. A combination

of internal transcribed spacer (ITS) sequencing, multilocus sequence

typing (MLST), and whole-genome sequencing was used to identify a

new species, B. emzantsi, and to differentiate B. percursus from other

Blastomyces species. MLST has identified a B. dermatitidis isolate from

Rwanda and B. gilchristii from Zimbabwe and South Africa. Analysis of

20 isolates from South Africa collected over a 40-year period identified

them as either B. emzantsi or B. percursus. The geographic distribution and ecologic niche of the four Blastomyces species in Africa are

unknown. In India, there have been fewer than 10 autochthonous cases

of blastomycosis, with the majority identified by morphologic analysis.

One autochthonous case (caused by B. percursus) with molecular confirmation has been reported from Israel.

Epidemiologic information about blastomycosis derives primarily

from passive laboratory surveillance, retrospective studies, and outbreak investigations. The lack of sensitive skin testing and serologic

testing, along with difficulty in isolating Blastomyces from the environment by culture or molecular methods, has limited an in-depth

epidemiologic understanding of blastomycosis. In North America,

blastomycosis is reportable in 5 U.S. states (Minnesota, Wisconsin,

Michigan, Arkansas, and Louisiana) and two Canadian provinces

(Manitoba, Ontario). The annual incidence of blastomycosis in the traditional endemic area ranges from 0.11 to 2.17 cases/100,000 persons.

In older persons (Medicare beneficiaries, 1999–2008), the nationwide

annual incidence of blastomycosis was 0.7/100,000, with the highest

rates in the Midwest and Southern regions of the United States. In