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Low-Dose Amphotericin B Therapy for Acute Pulmonary Histoplasmosis

1977; Elsevier BV; Volume: 71; Issue: 3 Linguagem: Inglês

10.1378/chest.71.3.404

1931-3543

B A Naylor,

Lymphatic Disorders and Treatments

A patient with acute epidemic pulmonary histoplasmosis was treated with 500 mg of amphotericin B. Traditionally, such patients have not been treated, since the illness is usually self-limited; however, fatalities have been reported, and some authorities have recommended therapy with small doses of amphotericin B. Patients with acute pulmonary histoplasmosis who are acutely ill should be considered for low-dose treatment with amphotericin B, inasmuch as they are likely candidates for early dissemination. Cures have been reported with as little as 105 mg of amphotericin B administered intravenously. A patient with acute epidemic pulmonary histoplasmosis was treated with 500 mg of amphotericin B. Traditionally, such patients have not been treated, since the illness is usually self-limited; however, fatalities have been reported, and some authorities have recommended therapy with small doses of amphotericin B. Patients with acute pulmonary histoplasmosis who are acutely ill should be considered for low-dose treatment with amphotericin B, inasmuch as they are likely candidates for early dissemination. Cures have been reported with as little as 105 mg of amphotericin B administered intravenously. Following its introduction in 1956, amphotericin B has become the mainstay of medical therapy for histoplasmosis. Its efficacy in the treatment of both the disseminated and the chronic pulmonary forms of the disease has been well documented, and standardized dosage schedules have been recommended in the literature.1Sutliff WD Histoplasmosis cooperative study: Amphotericin B dosage for chronic pulmonary histoplasmosis.Am Rev Respir Dis. 1972; 105: 60-67PubMed Google Scholar, 2Parker JD Sarosi GA Doto IL et al.Treatment of chronic pulmonary histoplasmosis.N Engl J Med. 1970; 283: 225-229Crossref PubMed Scopus (43) Google Scholar, 3Sarosi GA Voth DW Dahl BA et al.Disseminated histoplasmosis: Results of long-term follow-up.Ann Intern Med. 1971; 75: 511-516Crossref PubMed Scopus (116) Google Scholar Acute pulmonary histoplasmosis is usually a self-limited disease, and specific drug therapy is not commonly required; however, an occasional patient appears seriously ill during the primary infection, and drug therapy may seem to be indicated even in the absence of documented dissemination of the disease. Wynne and Olsen4Wynne JW Olsen GN Acute histoplasmosis presenting as the adult respiratory distress syndrome.Chest. 1974; 66: 158-161Crossref PubMed Scopus (36) Google Scholar reported the successful treatment of a patient critically ill with acute pulmonary histoplasmosis presenting as adult respiratory distress syndrome, in which they used only 150 mg of amphotericin B in addition to numerous other modes of therapy. Low-dose therapy with amphotericin B is alluded to in several texts on pulmonary disease,5Hinshaw HC Diseases of the Chest. 3rd ed. WB Saunders Co, Philadelphia1969: 713Google Scholar, 6Hinshaw HC Buechner HA Management of Fungus Diseases of the Lungs. Charles C Thomas, Springfield, Ill1971: 150Google Scholar but examples are not frequently reported in the literature. This case history is presented to document the therapy of acute pulmonary histoplasmosis with amphotericin B in a dosage schedule far below that usually recommended for patients with disseminated or chronic pulmonary histoplasmosis. In May 1974, a 25-year-old white man spent three weeks in Mexico on a bat research project and was exposed to large quantities of guano. One week prior to his admission, the patient developed lethargy and myalgia, followed by fever, headache, nonproductive cough, and increasing dyspnea. The remainder of his history was entirely unremarkable. On admission the patient had an oral temperature of 39.4°C (102.9°F), a blood pressure of 98/58 mm Hg, a pulse of 80 beats per minute, and a respiration rate of 29/minute. The findings from funduscopic and cardiac examination were normal. Dry rales were heard throughout both pulmonary fields. The results of cardiac examination were normal. The liver and spleen were not detectably enlarged. The patient had no lymphadenopathy. On admission the findings from a hemogram, serial platelet counts, blood cultures, and plasma cortisol values were negative or within normal limits. A liver scan revealed mild hepatomegaly, and splenomegaly could be appreciated on the scan. A chest x-ray film showed diffuse disease with patchy air-space consolidation and a primary acinar pattern throughout both pulmonary fields (Fig 1). A small quantity of pleural fluid was documented bilaterally by a lateral decubitus chest x-ray film. A spirogram revealed mild restriction of vital capacity, with no obstruction to air flow. Arterial blood gas measurements with the patient breathing room air revealed the arterial oxygen pressure to be 74 mm Hg, the arterial carbon dioxide tension to be 29 mm Hg, and the pH to be 7.50. The titer on the initial histoplasmin latex agglutination test was 1:64, and a follow-up titer obtained 15 days after the initial value was 1:32. Fungal cultures of bronchial washings grew Histoplasma capsulatum. During the first two days of hospitalization, the patient continued to have spiking temperatures in the range of 40°C (104°F) and complained of severe headache, myalgia, and recurring shaking chills. No evidence of dissemination was found, but bone marrow aspiration was not performed. Examination with the fiberoptic bronchoscope revealed only diffuse findings of mild bronchitis. A histoplasmin skin test applied at the time of admission revealed no induration after three days. The patient's therapy with amphotericin B was begun on the fourth day of hospitalization. He began to improve shortly after the initiation of amphotericin B therapy and was afebrile after a dosage of 250 mg had been administered. Treatment was continued until a total dose of 500 mg was achieved. The patient was discharged from the hospital asymptomatic on the 18th day of hospitalization, without significant radiologic improvement at that time. Eighteen months after treatment, pulmonary function tests revealed normal spirometric valves, lung volumes, and single-breath diffusing capacity. A chest x-ray film showed virtually complete clearing of the infiltrate. The patient remains asymptomatic with respect to pulmonary symptoms. Acute pulmonary histoplasmosis is generally believed to be an asymptomatic infection, since as many as 80 percent of persons in an endemic area may manifest reactivity to histoplasmin skin tests. Frequently, an infection may be manifested only as a flu-like illness. On the other hand, exposure to exceedingly large numbers of organisms may result in an overwhelming illness and eventual death from what is sometimes referred to as “epidemic” histoplasmosis.7Del Valle J Pedroza S Alcantara R et al.Pulmonary histoplasmosis in Mexico.Rev Mex Tuberc. 1957; 18: 521-532Google Scholar, 8Hosty TS Ajello L Wallace GD et al.A small outbreak of histoplasmosis.Am Rev Tuberc. 1958; 78: 576-582PubMed Google Scholar It is not clear whether such cases represent acute dissemination or merely toxicity from overwhelming pulmonary infection. Some studies9Baker RD Histoplasmosis in routine autopsies.Am J Clin Pathol. 1964; 41: 457-470Crossref PubMed Scopus (8) Google Scholar indicate that fewer than 30 percent of primary infections heal without leaving traceable scars in the spleen or the liver. Thus, self-limited hematologic dissemination may be presumed to occur in a majority of those infected. The finding of pleural effusion in this case is thought to be unusual,10Murray JF Howard D Laboratory acquired histoplasmosis.Am Rev Respir Dis. 1964; 89: 631-640PubMed Google Scholar even though pleuritic pain has been reported to be a common complaint with the disease.11Byrd RB Leavey R Trunk G The Chanute histoplasmosis epidemic: New variations of urban histoplasmosis.Chest. 1975; 68: 791-795Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar The patient in question surely was exposed to a very large inoculum of organisms. His illness could be classified as an “epidemic” form of acute pulmonary histoplasmosis. Because of the acute, debilitating nature of the illness, which had continued for ten days, it was believed that therapy with amphotericin B was indicated. This decision could be debated; Byrd et al11Byrd RB Leavey R Trunk G The Chanute histoplasmosis epidemic: New variations of urban histoplasmosis.Chest. 1975; 68: 791-795Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar suggest that amphotericin B is not indicated until an “unabated illness” has existed for three weeks. The literature makes scant mention of dosage recommendations for amphotericin B when it is used in acute pulmonary histoplasmosis. Studies by Furcolow12Furcolow ML Comparison of treated and untreated severe histoplasmosis.Am Rev Respir Dis. 1972; 105: 67Google Scholar and by Rubine et al13Rubine H Lehan PH Furcolow ML Severe non-fatal histoplasmosis: Report of a typical case with comments on therapy.N Engl J Med. 1957; 257: 599-602Crossref PubMed Scopus (6) Google Scholar recommend the use of short-term low-dose therapy with amphotericin B for those patients who appear to have severe infection, and in whom the possibility of dissemination of the disease exists. These studies characterize those patients as having marked toxicity and prolonged febrile episodes, especially when accompanied by extensive pulmonary changes. Fosson and Wheeler14Fosson AR Wheeler WE Short-term amphotericin B treatment of severe childhood histoplasmosis.J Pediatr. 1975; 86: 32-36Abstract Full Text PDF PubMed Scopus (11) Google Scholar have used low-dose amphotericin B therapy with good results in children with disseminated disease. Wynne and Olsen4Wynne JW Olsen GN Acute histoplasmosis presenting as the adult respiratory distress syndrome.Chest. 1974; 66: 158-161Crossref PubMed Scopus (36) Google Scholar reported successful therapy using only 150 mg of amphotericin B. In recounting his own encounter with the fungus, Busey6Hinshaw HC Buechner HA Management of Fungus Diseases of the Lungs. Charles C Thomas, Springfield, Ill1971: 150Google Scholar described a particularly interesting example of low-dose therapy with amphotericin B and the risks entailed in its use, noting that he had complete recovery with only 105 mg of amphotericin B. The patient reported in this study received a total dose of 0.5 gm of amphotericin B, with individual doses of 1 mg/kg of body weight. This dose is in excess of that demonstrated to provide peak serum levels equal to twice the level required for in vitro inhibition of H capsulatum, which is usually less than 50 mg daily.15Drutz DJ Spickard A Rogers DE et al.Treatment of disseminated mycotic infections.Am J Med. 1968; 45: 405-418Abstract Full Text PDF PubMed Scopus (93) Google Scholar I selected this arbitrary dosage after reviewing Sutliff's1Sutliff WD Histoplasmosis cooperative study: Amphotericin B dosage for chronic pulmonary histoplasmosis.Am Rev Respir Dis. 1972; 105: 60-67PubMed Google Scholar report on the Veterans Administration-Armed Forces Fungus Disease Cooperative Study. In that study, it was observed that an 0.5-gm dose of amphotericin B given in 3.5 weeks was adequate for control of chronic pulmonary histoplasmosis in two-thirds of the patients studied but was inadequate in the remainder. It seemed reasonable, therefore, to use the 0.5-gm dose as a goal for initial therapy and to reinstitute the therapy should evidence of relapse and progression of the disease be identified. At this writing, 18 months subsequent to the initial therapy, there is no evidence of recurrence, and the patient is asymptomatic as well. His chest x-ray film (Fig 2) shows marked resolution of the acute changes described on admission. In any disease in which spontaneous remission or healing may occur, one must be cautious in ascribing response to a therapeutic manipulation. A response to amphotericin B could not be proven in this instance; however, the rapid improvement in the patient's general status following initiation of the therapy does suggest response to this agent. Patients who appear severely and progressively ill with pulmonary histoplasmosis should be considered for low-dose therapy with amphotericin B, inasmuch as the therapy may prevent dissemination and speed recovery and, thus, shorten the stay in the hospital. Continued follow-up of patients treated with this low-dose therapy is needed to determine possible exacerbation of the disease at some remote date.