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Specific fungal infections

Histoplasmosis

Histoplasmosis

  • Histoplasmosis is caused by inhalation of dust-borne microconidia of the dimorphic fungus Histoplasma capsulatum.
  • In the United States, most disease is localized along the Ohio and Mississippi river valleys.

Clinical Presentation

  • In the vast majority of patients, low-inoculum exposure to H. capsulatum results in mild or asymptomatic pulmonary histoplasmosis. The course of disease is generally benign, and symptoms usually abate within a few weeks of onset. Patients exposed to a higher inoculum during a primary infection or reinfection may experience an acute, self-limited illness with flulike pulmonary symptoms, including fever, chills, headache, myalgia, and nonproductive cough.
  • Chronic pulmonary histoplasmosis generally presents as an opportunistic infection imposed on a preexisting structural abnormality such as lesions resulting from emphysema. Patients demonstrate chronic pulmonary symptoms and apical lung lesions that progress with inflammation, calcified granulomas, and fibrosis. Progression of disease over a period of years, seen in 25% to 30% of patients, is associated with cavitation, bronchopleural fistulas, extension to the other lung, pulmonary insufficiency, and often death.
  • In patients exposed to a large inoculum and in immunocompromised hosts, progressive illness, disseminated histoplasmosis, occurs. The clinical severity of the diverse forms of disseminated histoplasmosis (Table Clinical Manifestations and Therapy of Histoplasmosis) generally parallels the degree of macrophage parasitization observed.
  • Acute (infantile) disseminated histoplasmosis is seen in infants and young children and (rarely) in adults with Hodgkin's disease or other lymphoproliferative disorders. It is characterized by unrelenting fever; anemia; leukopenia or thrombocytopenia; enlargement of the liver, spleen, and visceral lymph nodes; and gastrointestinal symptoms, particularly nausea, vomiting, and diarrhea. Untreated disease is uniformly fatal in 1 to 2 months.
  • Most adults with disseminated histoplasmosis demonstrate a mild, chronic form of the disease. Untreated patients are often ill for 10 to 20 years, with long asymptomatic periods interrupted by relapses.
  • Adult patients with AIDS demonstrate an acute form of disseminated disease that resembles the syndrome seen in infants and children.
TABLE. Clinical Manifestations and Therapy of Histoplasmosis
Type of Disease and Common Clinical Manifestations Approximate Frequency (%)a Therapy/Comments
Nonimmunosuppressed Host
Acute pulmonary histoplasmosis
Asymptomatic or mild disease 50-99 Asymptomatic, mild, or symptoms <4 wk: No therapy generally required

Symptoms >4 weeks: Itraconazole 200 mg once daily x 6-12 weeksb

Self-limited disease 1-50 Self-limited disease: Amphotericin Bc 0.3-0.5 mg/kg/day x 2-4 weeks (total dose 500 mg) or ketoconazole 400 mg orally daily x 3-6 months may be beneficial in patients with severe hypoxia following inhalation of large inocula

Antifungal therapy generally not useful for arthritis or pericarditis; NSAIDsd or corticosteroids may be useful in some cases

Mediastinal granulomas 1-50 Most lesions resolve spontaneously; surgery or antifungal therapy with amphotericin B 40-50 mg/day x 2-3 weeks or itraconazole 400 mg/day orally x 6-12 months may be beneficial in some severe cases; mild to moderate disease may be treated with itraconazole for 6-12 months
Severe diffuse pulmonary disease Amphotericin B 0.7 mg/kg/day, for a total dose of ≤35 mg/kg (or 3 mg/kg/day of one of the lipid preparations) + prednisone 60 mg daily tapered over 2 weeks,e followed by itraconazole 200 mg twice daily for 6-12 weeks; in patients who do not require hospitalization, itraconazole 200 mg once or twice daily for 6-12 weeks can be used
Inflammatory/fibrotic disease 0.02 Fibrosing mediastinitis: The benefit of antifungal therapy (itraconazole 200 mg twice daily x 3 months) is controversial but should be considered, especially in patients with elevated ESRf or CFg titers 1:32; surgery may be of benefit if disease is detected early; late disease may not respond to therapy

Sarcoid-like: nonsteroidal anti-inflammatory drugs or corticosteroids may be of benefit for some patients

Pericarditis: Severe disease: corticosteroids 1 mg/kg/day or pericardial drainage procedure

Chronic pulmonary histoplasmosis 0.05 Antifungal therapy generally recommended for all patients to halt further lung destruction and reduce mortality

Mild-moderate disease: Itraconazole 200-400 mg PO daily x 6-24 months is the treatment of choice

Itraconazole and ketoconazole (200-800 mg/day orally for 1 year) are effective in 74% to 86% of cases, but relapses are common; fluconazole 200-400 mg daily is less effective (64%) than ketoconazole or itraconazole, and relapses are seen in 29% of responders

Severe disease: Amphotericin B 0.7 mg/kg/day for a minimum total dose of 35 mg/kg is effective in 59% to 100% of cases and should be used in patients who require hospitalization or are unable to take itraconazole because of drug interactions, allergies, failure to absorb drug, or failure to improve clinically after a minimum of 12 weeks of itraconazole therapy

Immunosuppressed Host
Disseminated histoplasmosis 0.02-0.05 Disseminated histoplasmosis: Untreated mortality 83% to 93%; relapse 5% to 23% in non-AIDS patients; therapy is recommended for all patients
Acute (Infantile) Nonimmunosuppressed patients: Ketoconazole 400 mg/day orally x 6-12 months or amphotericin B 35 mg/kg intravenous
Subacute Immunosuppressed patients: (non-AIDS) or endocarditis or central nervous system disease: Amphotericin B >35 mg/kg x 3 months followed by fluconazole or itraconazole 200 mg orally twice daily x 12 months
Progressive histoplasmosis (immunocompetent patients and immunosuppressed patients without AIDS) Life-threatening disease: Amphotericin B 0.7-1 mg/kg/day intravenous for a total dosage of 35 mg/kg over 2-4 months; once the patient is afebrile, able to take oral medications, and no longer requires blood pressure or ventilatory support, therapy can be changed to itraconazole 200 mg orally twice daily for 6-18 months
Non-life-threatening disease: Itraconazole 200-400 mg orally daily for 6-18 months; fluconazole therapy 400-800 mg daily) should be reserved for patients intolerant to itraconazole, and the development of resistance may lead to relapses
Progressive disease of AIDS 25-50h Amphotericin B 15-30 mg/kg (1-2 g over 4-10 weeks)i or itraconazole 200 mg 3 times daily for 3 days then twice daily for 12 weeks, followed by lifelong suppressive therapy with itraconazole 200-400 mg orally daily; a study is in progress to determine whether itraconazole therapy can be discontinued after one year if CD4+ counts are >150 cells/mm3
aAs a percentage of all patients presenting with histoplasmosis.

bItraconazole plasma concentrations should be measured during the second week of therapy to ensure that detectable concentrations have been achieved. If the concentration is below 1 mcg/mL, the dose may be insufficient or drug interactions may be impairing absorption or accelerating metabolism, requiring a change in dosage. If plasma concentrations are greater than 10 mcg/mL, the dosage may be reduced.

cDesoxycholate amphotericin B.

dNonsteroidal anti-inflammatory drugs.

eEffectiveness of corticosteroids is controversial.

fErythrocyte sedimention rate.

gComplement fixation.

hAs a percentage of AIDS patients presenting with histoplasmosis as the initial manifestation of their disease.

iLiposomal amphotericin B (AmBisome) may be more appropriate for disseminated disease.

Diagnosis

  • Identification of mycelial isolates from clinical cultures can be made by conversion of the mycelium to the yeast form (requires 3 to 6 weeks) or by the more rapid (2-hour) and 100% sensitive DNA probe that recognizes ribosomal DNA.
  • In most patients, serologic evidence remains the primary method in the diagnosis of histoplasmosis. Results obtained from complement fixation, immunodiffusion, and latex antigen agglutination antibody tests are used alone or in combination.
  • In the AIDS patient with progressive disseminated histoplasmosis, the diagnosis is best established by bone marrow biopsy and culture, which yield positive cultures in 90% of patients.

Treatment

  • Recommended therapy for the treatment of histoplasmosis is summarized in Table Clinical Manifestations and Therapy of Histoplasmosis.
  • Asymptomatic or mildly ill patients and patients with sarcoid-like disease generally do not benefit from antifungal therapy. Therapy may be helpful in symptomatic patients whose conditions have not improved during the first month of infection.
  • Patients with mild, self-limited disease, chronic disseminated disease, or chronic pulmonary histoplasmosis who have no underlying immunosuppression can usually be treated with either oral ketoconazole or intravenous amphotericin B.
  • In AIDS patients, intensive 12-week primary (induction and consolidation therapy) antifungal therapy is followed by lifelong suppressive (maintenance) therapy with itraconazole.
  • In AIDS patients, amphotericin B should be administered in patients who require hospitalization. Itraconazole 200 mg twice daily may be used to complete a 12-week course.
  • Response to therapy should be measured by resolution of radiologic, serologic, and microbiologic parameters and improvement in signs and symptoms of infection.
  • Once the initial course of therapy for histoplasmosis is completed, lifelong suppressive therapy with oral azoles or amphotericin B (1 to 1.5 mg/kg weekly or biweekly) is recommended, because of the frequent recurrence of infection.
  • Relapse rates in AIDS patients not receiving preventive maintenance are 50% to 90%.

Blastomycosis

  • North American blastomycosis is a systemic fungal infection caused by Blastomyces dermatitidis.
  • Pulmonary disease probably occurs by inhalation conidia, which convert to the yeast forms in the lungs. It may be acute or chronic and can mimic infection with tuberculosis, pyogenic bacteria, other fungi, or malignancy.
  • Blastomycosis can disseminate to virtually every other body organ including skin, bones and joints, or the genitourinary tract without any evidence of pulmonary disease.

Blastomycosis

Clinical Presentation

  • Acute pulmonary blastomycosis is generally an asymptomatic or self-limited disease characterized by fever, shaking chills, and a productive, purulent cough.
  • Pulmonary blastomycosis may present as a more chronic or subacute disease, with low-grade fever, night sweats, weight loss, and a productive cough resembling that of tuberculosis rather than bacterial pneumonia.
  • Chronic pulmonary blastomycosis is characterized by fever, malaise, weight loss, night sweats, and cough.

Diagnosis

  • The simplest and most successful method of diagnosing blastomycosis is by direct microscopic visualization of the large, multinucleated yeast with single, broad-based buds in sputum or other respiratory specimens, following digestion of cells and debris with 10% potassium hydroxide.
  • Histopathologic examination of tissue biopsies and culture of secretions should be used to identify B. dermatitidis.

Treatment

  • In patients with mild pulmonary blastomycosis, the clinical presentation of the patient, the immune competence of the patient, and the toxicity of the antifungal agents are the main determinants of whether or not to administer antifungal therapy. All immunocompromised patients and patients with progressive disease or with extrapulmonary disease should be treated (Table Therapy of Blastomycosis).
  • Some authors recommend ketoconazole therapy for the treatment of self-limited pulmonary disease, with the hope of preventing late extrapulmonary disease.
  • Itraconazole, 200 to 400 mg/day, is an effective as a first-line agent in the treatment of non-life-threatening non-central nervous system blastomycosis.
  • All patients with disseminated blastomycosis and those with extrapulmonary disease require therapy (ketoconazole, 400 mg/day orally for 6 months). Central nervous system disease should be treated with amphotericin B for a total cumulative dose greater than 1 g.
  • Patients who fail or are unable to tolerate itraconazole therapy, or who develop central nervous system disease, should be treated with amphotericin B for a total cumulative dose of 1.5 to 2.5 g.
  • HIV-infected patients should receive induction therapy with amphotericin B and chronic suppressive therapy with an oral azole antifungal. Itraconazole is the drug of choice for non-life-threatening histoplasmosis.

Coccidioidomycosis

Coccidioidomycosis is caused by infection with Coccidioides immitis. The endemic regions encompass the semi-arid regions of the southwestern United States from California to Texas, known as the Lower Sonoran Zone.

Coccidioidomycosis

Clinical Presentation

  • Most of those infected are asymptomatic or have nonspecific symptoms that are often indistinguishable from those of ordinary upper respiratory infections, including fever, cough, headache, sore throat, myalgias, and fatigue. A fine, diffuse rash may be appear during the first few days of illness.
  • «Valley fever» is a syndrome characterized by erythema nodosum and erythema multiforme of the upper trunk and extremities in association with diffuse joint aches or fever. Valley fever occurs in approximately 25% of infected persons, although, more commonly, a diffuse mild erythroderma or maculopapular rash is observed.
  • Pulmonary coccidioidomycosis can also present as acute pneumonia or develop into a chronic, persistent pneumonia complicated by hemoptysis, pulmonary scarring, and the formation of cavities of bronchopleural fistulas.
TABLE. Therapy of Blastomycosis
Type of Disease Preferred Treatment Comments
Pulmonarya
Life-threatening Amphotericin Bb intravenous 0.7-1 mg/kg/day intravenous (total dose 1.5-2.5 g) Patients may be initiated on amphotericin B and changed to oral itraconazole 200-400 mg orally daily once patient is clinically stabilized and a minimum dose of 500 mg of amphotericin B has been administered
Mild to moderate Itraconazole 200 mg orally twice daily x ≥6 monthsc Alternative therapy: Ketoconazole 400-800 mg orally daily x≥6 months or fluconazole 400-800 mg orally daily x≥6 monthsd

In patients intolerant of azoles or in whom disease progresses during azole therapy: Amphotericin B 0.5-0.7 mg/kg/day intravenous (total dose 1.5-2.5 g)

Disseminated or Extrapulmonary
CNSe Amphotericin B 0.7-1 mg/kg/day intravenous (total dose 1.5-2.5 g) For patients unable to tolerate a full course of amphotericin B, consider lipid formulations of amphotericin B or fluconazole ≥ 800 mg orally daily
Non-central nervous system
Life-threatening Amphotericin B 0.7-1 mg/kg/day intravenous (total dose 1.5-2.5 g) Patients may be initiated on amphotericin B andchanged to oral itraconazole 200-400 mg orally daily once stabilized
Mild to moderate Itraconazole 200-400 mg orally daily x≥6 months Ketoconazole 400-800 mg orally daily or fluconazole 400-800 mg orally daily x≥6 months

In patients intolerant of azoles or in whom disease progresses during azole therapy: Amphotericin B 0.5-0.7 mg/kg/day intravenous (total dose 1.5-2.5 g)

Bone disease: Therapy with azoles should be continued for 12 months

Immunocompromised Host (Including Patients with AIDS, Transplants, or Receiving Chronic Glucocorticoid Therapy)
Acute disease Amphotericin B 0.7-1 mg/kg/day intravenous (total dose 1.5-2.5 g) Patients without central nervous system infection may be switched to itraconazole once clinically stabilized and a minimum dose of 1 g of amphotericin B has been administered; long-term suppressive therapy with an azole is advised
Suppressive therapy Itraconazole 200-400 mg orally daily For patients with central nervous system disease or those intolerant of itraconazole, consider fluconazole 800 mg orally daily
aSome patients with acute pulmonary infection may have a spontaneous cure. Patients with progressive pulmonary disease should be treated.

bDesoxycholate amphotericin B.

cIn patients not responding to 400 mg, dosage should be increased by 200 mg increments every 4 wk to a maximum of 800 mg daily.

dTherapy with ketoconazole is associated with relapses, and fluconazole therapy achieves a lower response rate than itraconazole.

eCentral nervous system.

  • Disseminated infection occurs in less than 1% of infected patients. Dissemination may occur to the skin, lymph nodes, bone, meninges, spleen, liver, kidney, and adrenal gland.

Diagnosis

  • Most patients develop a positive skin test within 3 weeks of the onset of symptoms.
  • Infection is characterized by the development of IgM to C. immitis, which peaks within 2 to 3 weeks of infection and then declines rapidly, and immunoglobulin G, which peaks in 4 to 12 weeks and declines over months to years.
  • Recovery of C. immitis from infected tissues or secretions for direct examination and culture provides an accurate and rapid method of diagnosis.

Treatment

  • Only 5% of infected persons require therapy. Candidates for therapy include those with severe primary pulmonary infection or concurrent risk factors (e.g., HIV infection, organ transplant, or high doses of glucocorticoids), particularly patients with high complement fixation antibody titers in whom dissemination is likely.
  • Specific antifungals (and their usual dosages) for the treatment of coccidioidomycosis include amphotericin B intravenous (0.5 to 0.7 mg/kg/day), ketoconazole (400 mg orally daily), intravenous or oral fluconazole (usually 400 to 800 mg daily, although dosages as high as 1200 mg/day have been utilized without complications), and itraconazole (200 to 300 mg orally twice daily as either capsules or solution). If itraconazole is used, measurement of serum concentrations may be helpful to ascertain whether oral bioavailability is adequate. Amphotericin B is generally preferred as initial therapy in patients with rapidly progressive disease, whereas azoles are generally preferred in patients with subacute or chronic presentations. Treatments for primary respiratory disease (mainly symptomatic patients) are 3- to 6-month courses of therapy.

Cryptococcosis

Cryptococcosis is a noncontagious, systemic mycotic infection caused by the ubiquitous encapsulated soil yeast Cryptococcus neoformans.

Cryptococcosis

Clinical Presentation

  • Primary cryptococcosis in humans almost always occurs in the lungs. Symptomatic infections are usually manifested by cough, rales, and shortness of breath that generally resolve spontaneously.
  • Disease may remain localized in the lungs or disseminate to other tissues, particularly the central nervous system, although the skin can also be affected.
  • In the non-AIDS patient, the symptoms of cryptococcal meningitis are nonspecific. Headache, fever, nausea, vomiting, mental status changes, and neck stiffness are generally observed.
  • In AIDS patients, fever and headache are common, but meningismus and photophobia are much less common than in non-AIDS patients.

Diagnosis

  • Examination of cerebrospinal fluid in patients with cryptococcal meningitis generally reveals an elevated opening pressure, cerebrospinal fluid pleocytosis (usually lymphocytes), leukocytosis, a decreased cerebrospinal fluid glucose, an elevated cerebrospinal fluid protein, and a positive cryptococcal antigen.
  • Antigens to C. neoformans can be detected by latex agglutination.
  • C. neoformans can be detected in approximately 60% of patients by India ink smear of cerebrospinal fluid and cultured in more than 96% of patients.

Treatment

  • Treatment of cryptococcosis is detailed in Table Therapy of Cryptococcocosis.
  • For asymptomatic, immunocompetent persons with isolated pulmonary disease and no evidence of central nervous system disease, careful observation may be warranted. With symptomatic infection, fluconazole or amphotericin B is warranted.
TABLE. Therapy of Cryptococcocosisa,b
Type of Disease and Common Clinical Manifestations Therapy/Comments
Nonimmunocompromised Host Comparative trials for amphotericin Bc versus azoles not available
Isolated pulmonary disease (without evidence of central nervous system infection) Asymptomatic disease: Durg therapy generally not required; observe carefully or fluconazole 400 mg orally daily x 3-6 months

Mild to moderate symptoms: Fluconazole 200-400 mg orally daily x 3-6 months; Severe disease or inability to take azoles: Amphotericin B 0.4-0.7 mg/kg/day (total dose of 1-2 g)

Cryptococcemia with positive serum antigen titer (>1:8), cutaneous infection, a positive urine culture, or prostatic disease Clinician must decide whether to follow the pulmonary therapeutic regimen or the central nervous system (disseminated) regimen
Recurrent or progressive disease not responsive to amphotericin B Amphotericin Bd intravenous 0.5-0.75 mg/kg/day В± IT amphotericin B 0.5 mg 2-3 times weekly
Isolated pulmonary disease (without evidence of central nervous system infection) Mild to moderate symptoms or asymptomatic with a positive pulmonary specimen: Fluconazole 200-400 mg orally daily x lifelong

or

Itraconazole 200-400 mg orally daily x lifelong

or

Fluconazole 400 mg orally daily + flucytosine 100-150 mg/kg/day orally x 10 wk

Severe disease: Amphotericin B until symptoms are controlled, followed by fluconazole

central nervous system disease
Acute (induction/consolidation therapy) (follow all regimens with suppressive therapy) Amphotericin Bd intravenous 0.7-1 mg/kg/day + flucytosine 100 mg/kg/day orally x≥2 weeks, then fluconazole 400 mg orally daily x≥8 wke

or

Amphotericin Bd intravenous 0.7-1 mg/kg/day + flucytosine 100 mg/kg/day orally x 6-10 wke

or

Amphotericin Bd intravenous 0.7-1 mg/kg/day x 6-10 wke

or

Fluconazole 400-800 mg orally daily x 10-12 wk

or

Itraconazole 400-800 mg orally daily x 10-12 wk

or

Fluconazole 400-800 mg orally daily + flucytosine 100-150 mg/kg/day orally x 6 wke

or

Lipid formulation of amphotericin B intravenous 3-6 mg/kg/day x 6-10 wk

Note: Induction therapy with azoles alone is discouraged.

central nervous system disease Amphotericin Bd intravenous 0.7-1 mg/kg/day + flucytosine 100 mg/kg/day orally x 2 wk, followed by fluconazole 400 mg orally daily for a minimum of 10 wk (in patients intolerant to fluconazole, substitute itraconazole 200-400 mg orally daily)

or

Amphotericin Bd intravenous 0.7-1 mg/kg/day + 5-FC 100 mg/kg/day orally x 6-10 wk

or

Amphotericin Bd intravenous 0.7-1 mg/kg/day x 10 wk

Refractory disesase: Intrathecal or intraventricular amphotericin B

Immunocompromised Patients
Non-central nervous system pulmonary and extrapulmonary disease Same as nonimmunocompromised patients with central nervous system disease
central nervous system disease Amphotericin Bd intravenous 0.7-1 mg/kg/day x 2 wk, followed by fluconazole 400-800 mg orally daily 8-10 wk, followed by fluconazole 200 mg orally daily x 6-12 months (in patients intolerant to fluconazole, substitute itraconazole 200-400 mg orally daily)

Refractory disesase: Intrathecal or intraventricular amphotericin B

HIV-Infected Patients
Suppressive/maintenance therapy Fluconazole 200-400 mg orally daily x lifelong

or

Itraconazole 200 mg orally twice daily x lifelong

or

Amphotericin B intravenous 1 mg/kg 1-3 times weekly x lifelong

aWhen more than one therapy is listed, they are listed in order of preference.

bSee text for definitions of induction, consolidation, suppressive/maintenance therapy, and prophylactic therapy.

cDeoxycholate amphotericin B; intravenous, intravenous; IT, intrathecal; central nervous system, central nervous system.

dIn patients with significant renal disease, lipid formulations of amphotericin B can be substituted for deoxycholate amphotericin B during the induction.

eOr until cerebrospinal fluid cultures are negative

  • The combination of amphotericin B with flucytosine for 6 weeks is often used for treatment of cryptococcal meningitis. An alternative is amphotericin B for 2 weeks followed by fluconazole for an additional 8 to 10 weeks.
  • The use of intrathecal amphotericin B is not recommended for the treatment of cryptococcal meningitis except in very ill patients or in those with recurrent or progressive disease despite aggressive intravenous amphotericin B therapy. The dosage of amphotericin B employed is usually 0.5 mg administered via the lumbar, cisternal, or intraventricular (via an Ommaya reservoir) route 2 or 3 times weekly.
  • Amphotericin B with flucytosine is the initial treatment of choice for acute therapy of cryptococcal meningitis in AIDS patients. Many clinicians will initiate therapy with amphotericin B, 0.7 mg/kg/ day intravenous (with flucytosine, 100 mg/kg/day). After 2 weeks, consolidation therapy with either itraconazole 400 mg/day orally or fluconazole 400 mg/day orally can be administered for 8 weeks or until cerebrospinal fluid cultures are negative. Lifelong therapy with fluconazole is then recommended.

Relapse of C. neoformans meningitis occurs in approximately 50% of AIDS patients after completion of primary therapy. Fluconazole (200 mg daily) is currently recommended for chronic suppressive therapy of cryptococcal meningitis in AIDS patients.

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