Work

Practice Guidelines for the Management of Patients with Histoplasmosis

Year: 2000

Type: article

Abstract: Objective. The objective of this guideline is to provide recommendations for treating patients with the more common forms of histoplasmosis. Participants and consensus process. A working group of 8 experts in this field was convened to develop this guideline. The working group developed and refined the guideline through a series of conference calls. Outcomes. The goal of treatment is to eradicate the infection when possible, although chronic suppression may be adequate for patients with AIDS and other serious immunosuppressive disorders. Other important outcomes are resolution of clinical abnormalities and prevention of relapse. Evidence. The published literature on the management of histoplasmosis was reviewed. Controlled trials have been conducted that address the treatment of chronic pulmonary and disseminated histoplasmosis, but clinical experience and descriptive studies provide the basis for recommendations for other forms of histoplasmosis. Value. Value was assigned on the basis of the strength of the evidence supporting treatment recommendations, with the highest value assigned to controlled trials, according to conventions established for developing practice guidelines. Benefits and costs. Certain forms of histoplasmosis cause life-threatening illnesses and result in considerable morbidity, whereas other manifestations cause no symptoms or minor self-limited illnesses. The nonprogressive forms of histoplasmosis, however, may reduce functional capacity, affecting work capacity and quality of life for several months. Treatment is clearly beneficial and cost-effective for patients with progressive forms of histoplasmosis, such as chronic pulmonary or disseminated infection. It remains unknown whether treatment improves the outcome for patients with the self-limited manifestations, since this patient population has not been studied. Other chronic progressive forms of histoplasmosis are not responsive to pharmacologic treatment. Treatment options. Options for therapy for histoplasmosis include ketoconazole, itraconazole, fluconazole, amphotericin B (Fungizone; Bristol-Meyer Squibb, Princeton, NJ), liposomal amphotericin B (AmBisome; Fujisawa, Deerfield, IL), amphotericin B colloidal suspension (ABCD, or Amphotec; Seques, Menlo Park, CA), and amphotericin B lipid complex (ABLC, or Abelcet; Liposome, Princeton, NJ). Histoplasma capsulatum is endemic in certain areas of North and Latin America, but cases have also been reported from Europe and Asia. In the United States, most cases have occurred within the Ohio and Mississippi River valleys. Precise reasons for this endemic distribution pattern are unknown but are thought to include moderate climate, humidity, and soil characteristics. Bird and bat excrement enhances the growth of the organism in soil by accelerating sporulation. These unique growth requirements explain, in part, the localization of histoplasmosis into so-called microfoci. Activities that disturb such sites are associated with exposure to H. capsulatum. Air currents carry the spores for miles, exposing individuals who were unaware of contact with the contaminated site. Furthermore, environmental sites that are not visibly contaminated with droppings may harbor the organism, making it difficult to suspect histoplasmosis in most cases. Severity of illness after inhalation exposure to H. capsulatum varies, depending on the intensity of exposure and the immunity of the host. Asymptomatic infection or mild pulmonary disease follows low-intensity exposures in healthy individuals, whereas heavy exposure may cause severe diffuse pulmonary infection. Hematogenous dissemination from the lungs to other tissues probably occurs in all infected individuals during the first 2 weeks of infection before specific immunity has developed, but is nonprogressive in the majority of cases, which leads to the development of calcified granulomas in the liver and/or spleen. Progressive dissemination occurs primarily in those with underlying immunosuppressive disorders or those at the extremes of age. Progressive pulmonary infection is common in patients with underlying centrilobular emphysema. A variety of acute and chronic manifestations of histoplasmosis appear to result from unusual inflammatory or fibrotic responses to the infection, including rheumatologic syndromes and pericarditis during the first year after exposure, and chronic mediastinal inflammation or fibrosis, broncholithiasis, and enlarging parenchymal granulomas occurring later. A variety of treatment options are available, but first the decision must be made to treat or to observe, since most patients with histoplasmosis recover without therapy (table 1). Specific treatment recommendations for the more common types of histoplasmosis are reviewed below and in table 2. Fever, chills, headache, myalgia, anorexia, cough, and chest pain characterize this form of histoplasmosis and are seen in 85%–100% of cases. Patients may experience pleuritic pain. The findings on examination are usually unremarkable, except for fever, but may include rales or pleural friction rubs. The course after low-level exposure is benign in immunocompetent patients. Symptoms usually abate within a few weeks of onset [1]. Therapy may be helpful in symptomatic patients whose conditions have not improved during the first month of infection. Fever persisting for >3 weeks in acute histoplasmosis may indicate that the patient is developing progressive disseminated disease, which may be aborted by therapy. Whether antifungal therapy hastens recovery or prevents complications is unknown, since it has never been studied in prospective trials. Patients with diffuse radiographic involvement following more intense exposure often experience more severe disease. They may become hypoxemic and even require ventilatory support. Without treatment, recovery is usually slow and the outcome may be fatal. Localized pulmonary histoplasmosis. Treatment is not indicated in the typical patient with acute pulmonary histoplasmosis because the illness is self-limited and associated with minimal morbidity (EIII; see article by Sobel [2] for definitions of categories reflecting the strength of each recommendation for or against its use and grades reflecting the quality of evidence on which recommendations are based). Treatment with itraconazole, 200 mg once daily for 6–12 weeks, should be considered for patients who have shown no clinical improvement after 1 month of observation (BIII). Blood concentrations of itraconazole obtained 2–4 h after administration of a dose could be monitored in selected situations: suspected treatment failure, concern about compliance or absorption, use of medications that may reduce the solubility of itraconazole or accelerate its metabolism, and desire to reduce the dose from 200 mg twice daily to 200 mg once daily. Although the “therapeutic” concentration has not been defined, the MIC90 of itraconazole for H. capsulatum is .02 µg/mL, which suggests that serum concentrations of 1 µg/mL measured by bioassay should be therapeutic. Among AIDS patients, the median plasma concentration was about 6 µg/mL for patients receiving a dosage of 200 mg twice daily and ∼3 µg/mL for those receiving 200 mg once daily [3]. Diffuse pulmonary histoplasmosis in an immunocompetent host. Amphotericin B, 0.7 mg/kg/d (or 1 of the lipid preparations at a dose of 3 mg/kg/d for patients with renal impairment) should be used initially in those patients with more severe manifestations who require ventilatory supportive therapy (AIII). If amphotericin B is used exclusively because the patient cannot be treated with oral medications, a total course of ≤35 mg/kg is recommended, but this situation is expected to be rare (AIII). The inflammatory response may contribute to the pathogenesis of the respiratory compromise; thus, corticosteroids may be helpful, and prednisone could be administered at a dosage of 60 mg daily for 2 weeks [4] (CIII). The role of corticosteroids for treating extensive pulmonary histoplasmosis in the immunocompromised host is less clear. Patients with AIDS and concurrent disseminated histoplasmosis and Pneumocystis carinii pneumonia who received corticosteroids in conjunction with treatment for both microbial pathogens did not appear to do more poorly than other patients treated with antifungal therapy only. After discharge from the hospital, itraconazole, 200 mg once or twice daily, should be used to complete a 12-week course (BIII). Itraconazole alone, 200 mg once or twice daily for 6–12 weeks, could be used for patients who are not sufficiently ill to require hospitalization (BIII). Patients with underlying lung disease may develop chronic pulmonary infection after exposure to H. capsulatum. The clinical and radiographic findings resemble those seen in reactivation tuberculosis [5]. Without treatment, the illness is progressive, causing loss of pulmonary function in most patients and death in up to half [5, 6]. In 1 study, although only 30% of cases progressed after 1 year, 79% progressed with longer observation [5]. Although some patients improve spontaneously, they remain at risk for recrudescence. Treatment is indicated in all patients with chronic pulmonary histoplasmosis. Studies have shown amphotericin B to be effective in 59%–100% of cases [6–14] (table 3). Ketoconazole and itraconazole are effective in 75%–85% of case patients, but their use is also complicated by high relapse rates [11–13]. Fluconazole, 200–400 mg daily, appears to be less effective (64% response) than ketoconazole or itraconazole [14]. Itraconazole, 200 mg once or twice daily for 12–24 months, is the treatment of choice for chronic pulmonary histoplasmosis (AII). Amphotericin B, 50 mg daily, or about 0.7 mg/kg/d, is recommended for patients who are judged to require hospitalization because of ventilatory insufficiency or general debilitation, inability to take itraconazole because of drug interactions or allergies, inability to absorb itraconazole, inability to achieve detectable concentrations of itraconazole in the blood, or failure to improve clinically after at least 12 weeks of itraconazole therapy (AII). Some patients may not be able to tolerate that dosage of amphotericin B, which justifies reducing the dosage to 0.5–0.6 mg/kg/d or to use of 1 of the lipid formulations. If amphotericin B is administered for the full course of therapy, at least 35 mg/kg should be given at doses of 50 mg 3 times weekly, if tolerated. In most patients, however, treatment can be changed to itraconazole, 200 mg once or twice daily. Fluconazole, 200–400 mg daily, is less effective than amphotericin B or itraconazole and yielded a response rate of 64% in 1 study [14]. Fluconazole could be used in patients who cannot receive itraconazole or are unable to achieve detectable blood concentrations with itraconazole, but the dose should be increased to 400–800 mg daily (BII). In a study of patients with AIDS who had disseminated histoplasmosis, 800 mg daily was used for histoplasmosis [15]. Ketoconazole (200 mg, 400 mg, or 800 mg daily) is reasonably effective but less well-tolerated than itraconazole or fluconazole [12, 13]. Toxicity is more common in patients receiving the 800 mg daily dosage, which is discouraged. Underlying immunosuppressive conditions and extremes of age are risk factors for dissemination, and illness is more severe in immunocompromised individuals. Fever and weight loss are the most common symptoms, and hepatomegaly or splenomegaly are common physical findings of disseminated histoplasmosis. Other frequent sites of dissemination include the oropharyngeal or gastrointestinal mucosa, the skin, and the adrenal glands. Shock, respiratory distress, hepatic and renal failure, and coagulopathy may complicate severe cases [16]. CNS involvement occurs in 5%–20% of cases, presenting as chronic meningitis or focal brain lesions. Histoplasma rarely infects the spinal cord. The mortality without treatment is 80% but can be reduced to <25% with antifungal therapy [6, 11–22] (table 4). Treatment is indicated for all patients with progressive disseminated histoplasmosis. In studies that mostly included immunocompetent hosts and specifically excluded those with AIDS, amphotericin B was effective in 68%–92% of patients [6, 17, 18], itraconazole (200–400 mg daily) in 100% (only 10 patients studied) [11], ketoconazole (200–400 mg daily) in 56%–70% [12, 13], and fluconazole (200–400 mg daily) in 86% [14] (table 4). Among patients with AIDS, therapy with amphotericin B was effective in 74%–88% of patients [19, 20], itraconazole (400 mg daily for 12 weeks) in 85% [21], ketoconazole (200–400 mg daily) in 9% (only 11 cases) [16], and fluconazole (800 mg daily for 12 weeks) in 74% [15] (table 4). Of note, patients with severe or moderately severe clinical manifestations were excluded from the prospective studies that used itraconazole [21] and fluconazole [15] but not from the retrospective reviews of patients treated with amphotericin B. Of patients with severe disease, nearly half died despite treatment with amphotericin B, whereas 98% of those with less severe illness responded to therapy [20]. There are no published reports about the use of the newer lipid preparations of amphotericin B for treating histoplasmosis [16]. Most patients respond to therapy rapidly, with resolution of fever in 1–2 weeks. Therapy is not curative for patients with AIDS. Lifelong maintenance therapy is needed to prevent relapse in patients with AIDS and disseminated histoplasmosis. Amphotericin B, 50 mg given weekly or twice weekly, is highly effective (81%–97%) but inconvenient and not well-tolerated [16, 23]. Itraconazole, 200–400 mg daily, was effective in at least 90% of cases [22]. Fluconazole, 100–400 mg daily was effective maintenance therapy in 88% of patients with AIDS who received amphotericin B induction therapy [24]. However, in a prospective study, relapse occurred in nearly one-third of patients who received fluconazole, 400 mg daily, after successful induction therapy with fluconazole, 800 mg a day [15]. In vitro resistance to fluconazole developed in isolates from about half of those patients who relapsed [15]. Immunocompetent hosts and immunocompromised hosts without AIDS. Amphotericin B, 0.7–1.0 mg/kg/d is recommended for patients who are sufficiently ill to require hospitalization (table 2) (AII). Experience using the lipid formulations of amphotericin B for treating histo-plasmosis has not been reported. Most patients respond quickly to amphotericin B and can then be treated with itraconazole. The transition from amphotericin B to itraconazole therapy could occur after the patient becomes afebrile, no longer requires blood pressure or ventilatory support or iv fluids or nutrition, and is able to take oral If amphotericin B is to be used for the full the total dosage should be 35 mg/kg given 2–4 months. Itraconazole, 200 mg once or twice daily for months, is the treatment of choice for patients with mild or only moderately severe symptoms who do not require and for of therapy in those whose has improved in response to amphotericin B (AII). Fluconazole should be used only in patients who cannot take itraconazole (BII). The fluconazole dosage should be at least 400 mg daily in individuals and 800 mg daily in those with severe immunosuppressive H. capsulatum may develop resistance to fluconazole during therapy, to relapse and including of H. capsulatum concentration in blood and (BIII). 200 mg once or twice daily, is also reasonably effective response but less well-tolerated than itraconazole or fluconazole [12, 13]. Ketoconazole could be used in some itraconazole is (BII). may be for therapy in patients with disseminated histoplasmosis. Most of the on the use of the for therapy are from studies of patients with AIDS. concentrations with therapy [16, and with relapse Some that treatment should be concentrations to or at least of If treatment is before concentrations in and serum to patients should be for and should be monitored they become (BIII). Patients with AIDS as the cause of Therapy is into an 12-week to a in the clinical illness and then by a chronic maintenance to prevent relapse. A may be in other patients without AIDS who have relapsed after of therapy. induction therapy, amphotericin B is recommended for patients who are sufficiently ill to require hospitalization (table 2) (AII). Amphotericin B can be with itraconazole, 200 mg twice daily the patient no longer requires hospitalization or iv to complete a 12-week total course of induction therapy. Itraconazole, 200 mg 3 times daily for 3 and then twice daily for 12 weeks is the treatment of choice for patients who have mild or moderately severe symptoms who do not require hospitalization (AII). Fluconazole, 800 mg daily, is an for patients who cannot take itraconazole (BII). Patients who are receiving fluconazole should be clinically for and concentrations in and blood should be monitored and at the of suspected relapse (BIII). maintenance therapy, the treatment of choice is itraconazole 200 mg once or twice daily for life (AII). concentrations in serum and should be monitored to provide evidence that maintenance therapy is to the of infection (BIII). Amphotericin B, 50 mg iv once weekly, is an but is not as well-tolerated or by patients and should be for patients who cannot take itraconazole (BII). Fluconazole, 400–800 mg daily, could be used for patients who cannot tolerate or do not absorb itraconazole and not to be treated with amphotericin B, but fluconazole therapy is because of its reduced as chronic maintenance therapy for histoplasmosis Patients receiving fluconazole should be clinically for and concentrations in and blood should be monitored and at the of suspected relapse. in immunocompromised itraconazole is A itraconazole, 200 mg daily, in patients with a in the of histoplasmosis in the itraconazole with the group during a median of 1 year In high rates of histoplasmosis with itraconazole is recommended (200 mg once daily) Fluconazole is not an because of its against H. and for treatment of histoplasmosis [15]. include focal brain or spinal by involvement or and diffuse Symptoms usually have been for to before Fever, headache, or focal may be abnormalities include and in patients with or may be seen by or in the brain or spinal of those with parenchymal involvement The course of the disease is progressive and if not although the of clinical is highly The response to therapy is to that in other types of of patients with meningitis to the infection, despite treatment with amphotericin B, and up to half of relapse after therapy is The treatment for Histoplasma meningitis is unknown, but an is recommended because of the Amphotericin B, mg/kg/d to complete a 35 mg/kg total dose has been used most often (BIII). Fluconazole, 800 mg daily, be for after of amphotericin B, to reduce the risk for relapse (BIII). amphotericin B mg/kg/d or other day given a month be considered for patients who have therapy with amphotericin B by fluconazole (CIII). In liposomal amphotericin B concentrations in the blood and brain than did amphotericin B or the other lipid formulations which a basis for its use in However, the lipid amphotericin B achieve detectable concentrations in and have been in cases of Histoplasma fluconazole maintenance therapy, 800 mg daily, should be considered for patients who despite full of therapy, as (CIII). Itraconazole, although more than fluconazole against H. not the which it a choice for treatment of meningitis and its use for this Of note, however, the role of concentrations of antifungal in the outcome of treatment of meningitis is Patients who relapse despite chronic maintenance therapy are for administration of amphotericin B into the or Experience using or therapy, however, has not been this to therapy is except for patients for all other to therapy have involvement of the brain or spinal in the of meningitis may be more responsive to antifungal therapy. Of 6 such cases in without AIDS, all responded to amphotericin B therapy, but 2 relapsed Amphotericin B is recommended for the therapy (BIII). of the may not be for successful therapy of parenchymal itraconazole, 200 mg 2 or 3 times daily, may be after the conditions have improved with amphotericin B (CIII). rarely require Symptoms that include chest cough, and may be by of the or pulmonary in patients with These syndromes inflammation of the mediastinal than fibrotic to infection. Although symptoms are often mild and a few months, they may be more severe and therapy has been helpful in some cases treatment with corticosteroids to have been beneficial in 1 patient who had of is that has been helpful for patients with Amphotericin B, 0.7–1.0 mg/kg/d, should be considered as therapy for patients with severe complications of mediastinal histoplasmosis (BIII). Therapy could be changed to itraconazole, 200 mg once or twice daily, after improvement is for treatment. Itraconazole, 200 mg once or twice daily for 6–12 months, is recommended for patients with manifestations that for month (table (BIII). mg daily for 2 weeks, could be considered in those with (CIII). of the mediastinal should be for patients who remain symptomatic and to of mediastinal despite a of antifungal therapy (BIII). is a of histoplasmosis from and and of the and Patients often symptoms of several at the of The course is progressive and often Although most that antifungal treatment the outcome of have reported improvement after antifungal therapy is on which to treatment The progressive course of this however, it difficult to antifungal therapy. If the clinical findings are with a more acute inflammatory than a chronic fibrotic if and the rate are treatment may be A 12-week of itraconazole, 200 mg once or twice daily, is if clinical findings do not from (CIII). Patients who have are not expected to respond to antifungal therapy. The only basis to therapy 12 weeks be radiographic of of in which case therapy could be for 1 therapy has not been helpful when and is should be with in patients with severe complications of and only in those who are expected to from the without in the management of should be (CIII). of has been helpful in some patients with pulmonary or pulmonary and be in patients with severe manifestations (CIII). occurs in of patients with acute histoplasmosis and appears to be by the inflammatory response to the infection than the infection These manifestations rarely may be a of disseminated histoplasmosis Patients with pericarditis respond to without antifungal therapy, but those with often require or of the outcome is with only rare to pericarditis therapy is not recommended Therapy with is recommended for weeks, on the basis of clinical resolution of the symptoms and physical findings of pericarditis (BIII). be for 1–2 weeks in patients with by treatment with the clinical findings and radiographic evidence of (CIII). itraconazole, 200 mg once or twice daily for 12 weeks, could be given with to reduce the concern that corticosteroids of the infection (CIII). or is recommended for patients with more severe findings of or with moderately severe evidence of that not respond to corticosteroids (AIII). There is no evidence that or therapy prevents pericarditis The is and in half of cases and of the and with half of patients with rheumatologic manifestations and/or The symptoms usually in response to treatment with therapy is not recommended Therapy with is recommended for weeks, on the basis of resolution of the symptoms and physical findings of and (BIII). may occur after therapy is for weeks. with histoplasmosis should not be treated with antifungal because of the of this of to cause Amphotericin B, however, is during and is the treatment of choice for such cases. The of the lipid preparations of amphotericin B during is There is no evidence that histoplasmosis is more severe during or that dissemination occurs to the for antifungal treatment in patients with histoplasmosis. of treatment recommendations for treatment of patients with histoplasmosis. of antifungal therapy for patients with chronic pulmonary histoplasmosis. of antifungal therapy for patients with disseminated histoplasmosis.

Source: Clinical Infectious Diseases

DOI: 10.1086/313752