S60
Disseminated Histoplasmosis in Patients Infected with Human Immunodeficiency Virus George A. Sarosi and Philip C. Johnson
From the Department of Medicine, University of Arizona College of Medicine, and the Department of Internal Medicine, Maricopa Medical Center, Phoenix, Arizona; and the Division of General Medicine, University of Texas Health Science Center, Houston, Texas
Progressive disseminated histoplasmosis (PDH) is an uncommon manifestation of the infection caused by the thermal dimorphic fungus Histoplasma capsulatum. In two large communitywide outbreaks of histoplasmosis, the incidence of PDH was 0.12/1,000 in Mason City, Iowa [1], and 0.46/ 1,000 in the huge outbreak in Indianapolis [2]. The higher figure in the more recent outbreak is most likely due to the extremely large numbers of immunocompromised individuals who became infected. In fact, with the advent of aggressive regimens with multiple cytotoxic drugs and the widespread use of glucocorticoid therapy for nonmalignant disease, immunosuppression emerged as the single most common risk factor for the development of PDH, far exceeding the extremes of age and male sex, the two main risk factors of old [3, 4]. It is therefore not surprising that infection with the human immunodeficiency virus (HIV), leading to the development of AIDS, should predispose the patient to the development of PDH. In spite of being noted in one of the earliest reports of opportunistic infections in AIDS [5], PDH was not included among the opportunistic infections that could meet the case definition of AIDS until 1987 [6]. Even though PDH was not officially recognized as one of the AIDS-defining illnesses until recently, beginning in 1983 [7], an ever-increasing number of patients with this combination of illnesses have been reported in the English-language literature.
With the publication by Wheat et al. [8] in late 1990 of a report of 72 patients, the total number of such patients has exceeded 230. The purpose of this review is then to collate the accumulated information. The emphasis will be on the clinical manifestations and an outline of a rational approach to diagnosis and treatment. Materials and Methods
Patients with PDH and AIDS were identified on the basis of three sets of findings: 1) from our clinical experience in Houston, at the University of Texas (UT) Medical School, 2) from the article by Wheat et al. [8], and 3) from a search of the English-language literature with use of COLLEAGUE software (BRS/Saunders, Latham, NY). Patients were accepted for review if they met the case definition for AIDS as defined by the Centers for Disease Control (Atlanta) [6]. The diagnosis of PDH was accepted if the fungus was recovered from culture or seen in histopathologic examination of extrapulmonary material. Occasional patients were accepted as having PDH on the authors' say-so, even though full documentation was not published. Thus, this review will deal with 64 patients from Houston, 72 patients from Indiana, and 97 patients selected from the review of the medical literature. As always with reviews of this type, completeness was sought, but most probably not achieved.
Reprints and correspondence: Dr. George A. Sarosi, Department of Medicine, Maricopa Medical Center, P.O. Box 5099, Phoenix, Arizona 85010.
Findings
Clinical Infectious Diseases 1992;14(Suppl 1):S60-7 © 1992 by The University of Chicago. All rights reserved. 1058-4838/92/1403-0008802.00
To avoid repetition, we will refer to the three main groups as 1) UT series, 2) Indiana series, and 3) medical literature.
Downloaded from http://cid.oxfordjournals.org/ at Emory University on August 16, 2015
Progressive disseminated histoplasmosis (PDH) is a common opportunistic infection complicating the course of infection with human immunodeficiency virus (HIV). PDH has been noted in areas nonendemic for histoplasmosis and occurs more frequently in areas heavily endemic for the fungus. PDH is frequently the AIDS-defining illness and presents as a febrile and wasting disease. The respiratory component may be overshadowed by the severity of the systemic illness. Chest roentgenograms show diffuse reticulonodular infiltrates. Frequently, the initial chest roentgenogram may show no abnormalities. Timely diagnosis requires a high index of diagnostic suspicion. Blood cultures, with use of the lysis-centrifugation system, are highly useful, as is the examination of the bone marrow, the peripheral blood smear, and the respiratory secretions. An experimental serological test that detects histoplasma polysaccharide antigen appears to be the simplest diagnostic test. Amphotericin B is the drug of choice for initial therapy, followed by further administration of amphotericin B for suppression. Early results with itraconazole are encouraging for long-term suppression.
CID 1992;14 (Suppl I)
S61
Histoplasmosis in Patients with AIDS
Table 1. Summary of symptoms and signs of progressive dissemi-
Table 2. Summary of results of initial chest roentgenogram in
nated histoplasmosis in patients with AIDS.
patients with progressive disseminated histoplasmosis.
UT series N = 64 Symptoms Fever Weight loss Respiratory Signs Hepatomegaly Splenomegaly Skin and mucosal lesions
Indiana series N= 72
Medical literature N = 97
50 33 24
NA NA 38
51 35 51
10 19 7
19 9 2
23 28 6
Clinical Presentation In the UT series, 52 patients had sufficient information for dating the diagnosis of both PDH and AIDS. In 26 patients PDH was the AIDS-defining illness. For 75 of the 97 patients from the medical literature there was sufficient information; in 27, PDH was the AIDS-defining illness (or diagnosis was made within 60 days of when the diagnosis of AIDS was made). In the Indiana series, 43 patients presented with PDH as the AIDS-defining illness or simultaneously with another opportunistic infection. Thus, it appears that PDH usually occurs relatively early during the course of the HIV infection and, in at least one-half of the cases, is the AIDS-defining illness. A summary of the clinical symptoms and signs of the three groups is shown in table 1. The picture that emerges is that of a febrile and wasting illness, for which fewer than half of the patients do not have any respiratory symptoms. In addition, a number of other symptoms have been listed, including diarrhea. Results of physical examination were less helpful, since for many of the patients, results of examination were completely normal, except for evidence of recent weight loss. The presence of hepatosplenomegaly was the most common finding, followed by skin or mucous membrane lesions in a few patients. Palpable lymph nodes were also seen. Neurological findings were uncommon, and usually not focal, but showed evidence of encephalopathy. Occasional patients showed involvement of the gastrointestinal tract. A number of patients were critically ill, and in these cases manifestations and the tempo of the illness were similar to those of septic shock [9]. Results of laboratory evaluation were usually not helpful. Many patients had anemia, leukopenia, and thrombocytopenia and occasionally showed evidence of a coagulopathy. Many patients who presented with the septic shock—like picture also had evidence of disseminated coagulopathy, frequently accompanied by multiple-organ failure leading to
Normal Diffuse disease Local disease Calcified granulomas
UT series N= 59
Indiana series N = 72
Medical literature N = 83
16 34 5 2
31 32 8 2
23 39 7 2
rapid death. Laboratory evaluation of these patients showed the expected perturbations. Results of the initial chest roentgenogram taken at the time of admission are listed in table 2. Diffuse pulmonary involvement was the most common abnormality, present in about half of the patients. The diffuse abnormality was usually described as either interstitial or reticulonodular. In our experience most chest roentgenograms showed clear-cut interstitial involvement, with many small, 1-2-mm nodules interspersed. Fewer than 10% of the chest roentgenograms showed focal lesions that included pleural effusions. An occasional patient had single or multiple calcified granulomas. For about one-third of the patients, results of chest roentgenogram on admission were completely normal. Many of our patients (UT series) with initially unremarkable chest roentgenograms then proceeded to develop diffuse reticulonodular infiltrates during their hospital stay. Similar information was not available for other patients. Diagnosis
The diagnosis of PDH in the vast majority of patients was made on the basis of either recovery of the fungus in culture or visualization of the organism in histopathologic material. Table 3 lists the sites of positive identification for H. capsulatum. As determined by culture and examination, the bone
Table 3.
Sites of positive identification of H. capsulatum.
Site Bone marrow Blood Respiratory secretions Lymph node Biopsy of other tissues (li v er, skin lesions, etc.) CNS (CSF, brain) Detection of histoplasma polysaccharide antigen
UT series
Indiana series
Medical literature
33 20 21 6
37 44 25 9
42 49 28 8
14 5
1 3
15 1
ND
7
ND
.
NOTE.
ND = not determined.
Downloaded from http://cid.oxfordjournals.org/ at Emory University on August 16, 2015
NOTE. NA = data not available.
Radiologic findings
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CID 1992;14 (Suppl 1)
Sarosi and Johnson
Treatment
Patients in neither the UT nor the medical literature series were treated by any recognizable protocol; treatment was largely determined by the preference of the individual physician. Thus, comparisons are difficult to make. Although there appears to be greater uniformity of treatment in the Indiana series, these patients were not part of a prospective protocol either until later during the study. Both ketoconazole and amphotericin B were used as initial therapy. Ketoconazole presumably was used in relatively
Table 4. Results of initial ketoconazole treatment in patients
with progressive disseminated histoplasmosis. UT series Result Improved Failed
N=7
it
6
Indiana series N = 5*
Medical literature N=3
0 5
0 3
* Ketoconazole was used in therapy for two other patients who did not have progressive disseminated histoplasmosis when they were initially treated. t Lost to follow-up care after 2 months.
healthy patients, although this was difficult to ascertain. Clearly, in the UT series ketoconazole was used in patients who were less critically ill [17]. Results of initial ketoconazole treatment of PDH and AIDS are shown in table 4. Generally, the drug was ineffective, with the vast majority of patients experiencing progressive disease while receiving therapy. Symptoms for only one patient were described as improving; he was lost to follow-up care after only 2 months. It does appear that initial therapy with ketoconazole is not effective therapy. In all three series amphotericin B was the initial drug of choice for most patients. Most attending physicians infused high doses of amphotericin B rapidly during the early treatment period. Once the patients' conditions stabilized, either they were given ketoconazole for long-term suppression or therapy with amphotericin B was continued at a reduced dosage. A substantial number of patients did not receive suppressive therapy after the initial course of amphotericin B. In early experiences, this method was prevalent, before the need for suppression was appreciated. Although comparable data do not exist among the three series, certain observations may be made. Amphotericin B used in the initial treatment course is highly effective. Although there are clear-cut treatment failures, most patients who have received at least 500 mg of amphotericin B did well [8, 17]. Wheat et al. [8] calculated that 57 of 65 patients who were started on therapy with amphotericin B responded, whereas the remaining patients died before receiving at least 500 mg. It is also clear that lifelong suppressive therapy is needed for prevention of relapse of PDH in AIDS. Early during our experience, many patients were treated successfully with large initial doses of amphotericin B but were not given suppressive therapy after completion of the initial treatment course [18]. Fourteen of our 40 patients experienced a relapse, for an unacceptably high relapse rate of 35% [17]. The Indiana experience was even more striking, where four (80%) of five of the patients experienced a relapse [8]. The small experience from Dallas shows PDH relapsed in one out of four patients who were treated with amphotericin B and who did not receive suppressive therapy [13].
Downloaded from http://cid.oxfordjournals.org/ at Emory University on August 16, 2015
marrow was a productive site. PDH is a disease of the reticuloendothelial system [10]. The simplest and safest means of sampling the reticuloendothelial system is by bone marrow examination [11], and during our early experience we examined the bone marrow first. Blood culture is a simple and effective way to recover the organism. While standard blood cultures may recover the fungus, utilization of the lysis-centrifugation system (DuPont ISOLATOR, Wilmington, DE) increased the success rate [12]. Most of the patients in the UT series were seen before widespread use of the system. Fully one-third of the positive blood cultures for patients from the medical literature were from a single, recent series. In this series, specimens for blood cultures were obtained during clinical illness as well as monthly during follow-up care of asymptomatic HIV-infected patients (surveillance cultures) [13]. Patients in the Wheat series represent a mixed group—high frequency of isolation from blood culture at Indiana University Hospitals, and a much lower rate of isolation at the other Indiana hospitals. The former institutions used the lysis-centrifugation system; the latter did not. Respiratory secretions are also a productive site for the recovery of the organism. Material obtained by bronchial washings or brushings or by biopsy, as well as material from bronchoalveolar lavage, is useful [14]. Results of biopsy of lymph nodes, skin, or mucous membrane ulcers were frequently positive [15]. Detection of H. capsulatum polysaccharide antigen (HPA) was done only in Indianapolis and appears to be an excellent method of diagnosis [8, 16]. Standard serodiagnostic studies were not done routinely in Houston (UT series) nor were results of these studies evaluable by reviewing the Englishlanguage medical literature. The data for the Indiana series were better but were by no means complete. Immunodiffusion (ID) testing for M-precipitin bands was surprisingly effective, while testing for the H-precipitin band was positive on only one occasion. The standard CF serological test was also useful, results being positive in 71% of the patients so tested in Indiana. At Indiana University when the ID and CF tests were both done, >80% of the patients had a positive serological test result [8].
CID 1992;14 (Suppl I )
Histoplasmosis in Patients with AIDS
Table 5. Results of maintenance therapy with amphotericin B in
patients with progressive disseminated histoplasmosis.
Outcome Survival Death from other causes Relapse of PDH
McKinsey et al. [19] (N = 16)
Wheat et al. [8] (N = 21)
Nightingale et al. [13] (N = 4)
13 2 1
17 NS 4
3 0 1
NOTE. NS = not stated.
Discussion
That PDH should emerge as a significant opportunistic infection among HIV-infected patients should not come as a surprise. Indeed, as early as 1981, PDH was noted to complicate the course of AIDS [5]. What was somewhat surprising was that PDH was not considered an AIDS-defining infection until 1987 [6]. This delayed recognition was most likely due to the fact that early during the course of the HIV epidemic most patients were reported from both the East and
West coasts of the United States, where H. capsulatum is not endemic and is seldom thought of. Beginning in 1983 a number of isolated case reports describing PDH in AIDS started appearing in the literature [7]. As the HIV outbreak started to move to the Midwest, a number of small series were reported, a fact indicating that in areas endemic for H. capsulatum PDH would become a significant problem. In 1984 and 1985 Wheat et al. [9, 21] reported an astonishingly high incidence of PDH complicating HIV infection, where six (67%) of nine of their patients with AIDS also had PDH. Bonner et al. [22], also in 1985, reported three of four patients with AIDS from Alabama who also had PDH. Even in areas of less endemicity, PDH was clearly emerging as a major complication of AIDS. In 1988 we reported a 5% incidence among patients infected with HIV from Houston [18]. It is of interest that many patients with PDH were reported from New York City [14, 23, 24]—a city not normally considered to be endemic for H. capsulatum. Whether these patients represent reactivation of previously dormant histoplasmosis in HIV-infected individuals or whether the infection was recently acquired in an area nonendemic for H. capsulaturn is still unclear. Probably both mechanisms are operative [7]. It is clear that when HIV-infected patients become infected with the fungus, most will develop PDH. The extremely high incidence of H. capsulatum infection among HIV-infected patients from Indianapolis is most likely due to an ongoing epidemic of histoplasmosis that began during the fall of 1988. During that time, of 239 patients with AIDS from Indianapolis, 64 (27%) developed PDH. At the same time, 341 HIV-infected patients were known in the rest of Indiana, with only seven patients (2%) developing PDH. This extremely high incidence of PDH among patients with AIDS in Indianapolis is most compatible with the hypothesis that the illness represents widespread dissemination of the primary infection in T cell immunocompromised patients [8]. On the other hand, evidence exists that immunocompromised patients residing in areas nonendemic for H. capsulaturn may also develop PDH. In 1978 we reported a small series of patients with PDH who resided in Minneapolis, an area of nonendemicity. All of these patients had previously lived in areas known to be endemic for Histoplasma and were recently prescribed therapy with glucocorticoids and cytotoxic agents. This observation was most compatible with the reactivation hypothesis [4]. Similarly, most patients with PDH and AIDS who were reported from New York City lived for variable periods of time in or near areas endemic for H. capsulatum, such as the Caribbean and Puerto Rico [14, 23, 24]. The clinical manifestations of PDH in HIV-infected patients indicated a febrile and wasting disease with marked
Downloaded from http://cid.oxfordjournals.org/ at Emory University on August 16, 2015
Once it became obvious that suppressive therapy was needed, many of our patients (UT series) [17], as well as other patients reported in the literature, received ketoconazole. Unfortunately, no prospective study was done for evaluation of this method. Retrospective evaluation, putting together fragmentary data from the series reported by Wheat et al. [8], shows that of 48 patients, 21 experienced a relapse. Even though this form of suppression was better than no suppression at all, it was clearly not good enough [8]. Here, too, the Dallas experience was better with three of four patients maintaining remission on suppressive therapy with ketoconazole—but the numbers are small [13]. More recently, continued suppressive therapy with amphotericin B emerged as the best method for maintaining patients in a disease-free state. McKinsey et al. [19] published their series of patients who received continuing suppressive therapy with amphotericin B, and Wheat et al. [8] used this method toward the end of their study as well. Table 5 shows the results of continuing suppressive therapy with amphotericin B. Briefly, this method calls for a period of intensive treatment with amphotericin B, totaling 1-2 g, followed by infusion of 50-80 mg of amphotericin B each week or every other week. With inclusion of the Dallas experience [13], a total of 41 patients received this form of treatment, and only six patients experienced a relapse during the period of observation (up to 23 months). More recently, the new triazole, itraconazole, has been used for suppressive therapy. A recent abstract presentation [20] reported 42 patients enrolled in the study: 35 were observed for at least 6 months and suffered no relapses over the period of observation.
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CID 1992;14 (Suppl 1)
Figure 1. Magnetic resonance image of a deep-seated lesion on the right side of the basal ganglia in an HIV-infected patient who
had a febrile illness. Cultures of the blood and CSF fluid were positive for H. capsulatum.
weight loss. Respiratory complaints were frequently overshadowed by the generalized nature of the disease state. Skin and mucous-membrane lesions occur, which may help in early diagnosis. Similarly, the presence of lymphadenopathy is helpful, since biopsy of these lesions can also hasten the diagnosis. CNS involvement is uncommon (only three of our 64 patients had CNS involvement), but histoplasmosis should be considered in the differential diagnosis of altered mental status in AIDS [25] (figure 1). Gastrointestinal manifestations are also uncommon, but may be dramatic—perforation of the small intestine or presence of large colonic polyps have been reported (figure 2). The remainder of findings of the initial physical evaluation are seldom helpful, except when hepatosplenomegaly is noted. Except for the rather uncommon abdominal B-cell lymphoma, splenomegaly is uncommon in HIV-infected patients. Thus, the presence of palpable splenomegaly should signal PDH [ 1 7]. It is apparent that PDH in patients with AIDS is not significantly different from the disease observed in non-HIV-infected patients. Nevertheless, the disease is frequently much more severe in patients with AIDS. Wheat et al. [9] were the first to draw attention to a syndrome resembling septic shock in these patients, characterized by hypotension, multiple-organ failure, and disseminated coagulopathy. We also observed this clinical picture in Houston [18]. The nature of
Figure 2. Resected omentum showing multiple large lymph nodes containing H. capsulatum in a patient who presented with a perforated small bowel during the course of PDH.
Downloaded from http://cid.oxfordjournals.org/ at Emory University on August 16, 2015
inflammatory mediators responsible for this syndrome is still unclear, but it is most likely related to the overwhelming nature of this infection. The initial chest roentgenogram may provide evidence for the diagnosis. The diffuse reticulonodular infiltrate is suggestive of PDH (figure 3). Up to one-third of the patients present with normal findings on chest roentgenogram, although eventually all patients develop abnormalities evidenced on chest roentgenograms. The cornerstone of effective treatment is rapid diagnosis. Measurement of HPA is highly specific and sensitive, but it is available only in Wheat's laboratory [8, 16]. Standard ID and CF serological tests are ultimately positive in —80% of the patients [8], but the slow turnaround time and the relatively low sensitivity make reliance on these tests problematic. Both biopsy and culture of bone marrow specimens are rapid, sensitive, and specific tests [4, 8, I 1 ]. Aspirated material can be stained with both periodic acid–Schiff and silver stain on the same day, and sections are available in 24 hours [17]. Frequently the fungus can be seen in circulating phago-
CID 1992;14 (Suppl 1)
Histoplasmosis in Patients with AIDS
S65
cytes (figure 4). In experienced hands, examination of the buffy coat may be the fastest way to make the definitive diagnosis. In the Dallas experience, 12 of 26 peripheral smears examined were positive for H. capsulatum. In 10 of these 12 instances, the peripheral smear was the first positive test [13]. With the lysis-centrifugation blood culture system (DuPont ISOLATOR), an excellent method was made available for rapidly establishing the diagnosis. The Indiana University experience is noteworthy: 91% of the patients had a positive lysis-centrifugation blood culture, whereas in other Indiana hospitals, only 57% of blood cultures were positive when standard techniques were used [8]. Although the results of the Dallas experience are not quite as outstanding (77% positive), investigators there are now using the technique during the monthly follow-up examinations of HIVinfected patients in whom the CD4 count is
Disseminated Histoplasmosis in Patients Infected with Human Immunodeficiency Virus George A. Sarosi and Philip C. Johnson
From the Department of Medicine, University of Arizona College of Medicine, and the Department of Internal Medicine, Maricopa Medical Center, Phoenix, Arizona; and the Division of General Medicine, University of Texas Health Science Center, Houston, Texas
Progressive disseminated histoplasmosis (PDH) is an uncommon manifestation of the infection caused by the thermal dimorphic fungus Histoplasma capsulatum. In two large communitywide outbreaks of histoplasmosis, the incidence of PDH was 0.12/1,000 in Mason City, Iowa [1], and 0.46/ 1,000 in the huge outbreak in Indianapolis [2]. The higher figure in the more recent outbreak is most likely due to the extremely large numbers of immunocompromised individuals who became infected. In fact, with the advent of aggressive regimens with multiple cytotoxic drugs and the widespread use of glucocorticoid therapy for nonmalignant disease, immunosuppression emerged as the single most common risk factor for the development of PDH, far exceeding the extremes of age and male sex, the two main risk factors of old [3, 4]. It is therefore not surprising that infection with the human immunodeficiency virus (HIV), leading to the development of AIDS, should predispose the patient to the development of PDH. In spite of being noted in one of the earliest reports of opportunistic infections in AIDS [5], PDH was not included among the opportunistic infections that could meet the case definition of AIDS until 1987 [6]. Even though PDH was not officially recognized as one of the AIDS-defining illnesses until recently, beginning in 1983 [7], an ever-increasing number of patients with this combination of illnesses have been reported in the English-language literature.
With the publication by Wheat et al. [8] in late 1990 of a report of 72 patients, the total number of such patients has exceeded 230. The purpose of this review is then to collate the accumulated information. The emphasis will be on the clinical manifestations and an outline of a rational approach to diagnosis and treatment. Materials and Methods
Patients with PDH and AIDS were identified on the basis of three sets of findings: 1) from our clinical experience in Houston, at the University of Texas (UT) Medical School, 2) from the article by Wheat et al. [8], and 3) from a search of the English-language literature with use of COLLEAGUE software (BRS/Saunders, Latham, NY). Patients were accepted for review if they met the case definition for AIDS as defined by the Centers for Disease Control (Atlanta) [6]. The diagnosis of PDH was accepted if the fungus was recovered from culture or seen in histopathologic examination of extrapulmonary material. Occasional patients were accepted as having PDH on the authors' say-so, even though full documentation was not published. Thus, this review will deal with 64 patients from Houston, 72 patients from Indiana, and 97 patients selected from the review of the medical literature. As always with reviews of this type, completeness was sought, but most probably not achieved.
Reprints and correspondence: Dr. George A. Sarosi, Department of Medicine, Maricopa Medical Center, P.O. Box 5099, Phoenix, Arizona 85010.
Findings
Clinical Infectious Diseases 1992;14(Suppl 1):S60-7 © 1992 by The University of Chicago. All rights reserved. 1058-4838/92/1403-0008802.00
To avoid repetition, we will refer to the three main groups as 1) UT series, 2) Indiana series, and 3) medical literature.
Downloaded from http://cid.oxfordjournals.org/ at Emory University on August 16, 2015
Progressive disseminated histoplasmosis (PDH) is a common opportunistic infection complicating the course of infection with human immunodeficiency virus (HIV). PDH has been noted in areas nonendemic for histoplasmosis and occurs more frequently in areas heavily endemic for the fungus. PDH is frequently the AIDS-defining illness and presents as a febrile and wasting disease. The respiratory component may be overshadowed by the severity of the systemic illness. Chest roentgenograms show diffuse reticulonodular infiltrates. Frequently, the initial chest roentgenogram may show no abnormalities. Timely diagnosis requires a high index of diagnostic suspicion. Blood cultures, with use of the lysis-centrifugation system, are highly useful, as is the examination of the bone marrow, the peripheral blood smear, and the respiratory secretions. An experimental serological test that detects histoplasma polysaccharide antigen appears to be the simplest diagnostic test. Amphotericin B is the drug of choice for initial therapy, followed by further administration of amphotericin B for suppression. Early results with itraconazole are encouraging for long-term suppression.
CID 1992;14 (Suppl I)
S61
Histoplasmosis in Patients with AIDS
Table 1. Summary of symptoms and signs of progressive dissemi-
Table 2. Summary of results of initial chest roentgenogram in
nated histoplasmosis in patients with AIDS.
patients with progressive disseminated histoplasmosis.
UT series N = 64 Symptoms Fever Weight loss Respiratory Signs Hepatomegaly Splenomegaly Skin and mucosal lesions
Indiana series N= 72
Medical literature N = 97
50 33 24
NA NA 38
51 35 51
10 19 7
19 9 2
23 28 6
Clinical Presentation In the UT series, 52 patients had sufficient information for dating the diagnosis of both PDH and AIDS. In 26 patients PDH was the AIDS-defining illness. For 75 of the 97 patients from the medical literature there was sufficient information; in 27, PDH was the AIDS-defining illness (or diagnosis was made within 60 days of when the diagnosis of AIDS was made). In the Indiana series, 43 patients presented with PDH as the AIDS-defining illness or simultaneously with another opportunistic infection. Thus, it appears that PDH usually occurs relatively early during the course of the HIV infection and, in at least one-half of the cases, is the AIDS-defining illness. A summary of the clinical symptoms and signs of the three groups is shown in table 1. The picture that emerges is that of a febrile and wasting illness, for which fewer than half of the patients do not have any respiratory symptoms. In addition, a number of other symptoms have been listed, including diarrhea. Results of physical examination were less helpful, since for many of the patients, results of examination were completely normal, except for evidence of recent weight loss. The presence of hepatosplenomegaly was the most common finding, followed by skin or mucous membrane lesions in a few patients. Palpable lymph nodes were also seen. Neurological findings were uncommon, and usually not focal, but showed evidence of encephalopathy. Occasional patients showed involvement of the gastrointestinal tract. A number of patients were critically ill, and in these cases manifestations and the tempo of the illness were similar to those of septic shock [9]. Results of laboratory evaluation were usually not helpful. Many patients had anemia, leukopenia, and thrombocytopenia and occasionally showed evidence of a coagulopathy. Many patients who presented with the septic shock—like picture also had evidence of disseminated coagulopathy, frequently accompanied by multiple-organ failure leading to
Normal Diffuse disease Local disease Calcified granulomas
UT series N= 59
Indiana series N = 72
Medical literature N = 83
16 34 5 2
31 32 8 2
23 39 7 2
rapid death. Laboratory evaluation of these patients showed the expected perturbations. Results of the initial chest roentgenogram taken at the time of admission are listed in table 2. Diffuse pulmonary involvement was the most common abnormality, present in about half of the patients. The diffuse abnormality was usually described as either interstitial or reticulonodular. In our experience most chest roentgenograms showed clear-cut interstitial involvement, with many small, 1-2-mm nodules interspersed. Fewer than 10% of the chest roentgenograms showed focal lesions that included pleural effusions. An occasional patient had single or multiple calcified granulomas. For about one-third of the patients, results of chest roentgenogram on admission were completely normal. Many of our patients (UT series) with initially unremarkable chest roentgenograms then proceeded to develop diffuse reticulonodular infiltrates during their hospital stay. Similar information was not available for other patients. Diagnosis
The diagnosis of PDH in the vast majority of patients was made on the basis of either recovery of the fungus in culture or visualization of the organism in histopathologic material. Table 3 lists the sites of positive identification for H. capsulatum. As determined by culture and examination, the bone
Table 3.
Sites of positive identification of H. capsulatum.
Site Bone marrow Blood Respiratory secretions Lymph node Biopsy of other tissues (li v er, skin lesions, etc.) CNS (CSF, brain) Detection of histoplasma polysaccharide antigen
UT series
Indiana series
Medical literature
33 20 21 6
37 44 25 9
42 49 28 8
14 5
1 3
15 1
ND
7
ND
.
NOTE.
ND = not determined.
Downloaded from http://cid.oxfordjournals.org/ at Emory University on August 16, 2015
NOTE. NA = data not available.
Radiologic findings
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Sarosi and Johnson
Treatment
Patients in neither the UT nor the medical literature series were treated by any recognizable protocol; treatment was largely determined by the preference of the individual physician. Thus, comparisons are difficult to make. Although there appears to be greater uniformity of treatment in the Indiana series, these patients were not part of a prospective protocol either until later during the study. Both ketoconazole and amphotericin B were used as initial therapy. Ketoconazole presumably was used in relatively
Table 4. Results of initial ketoconazole treatment in patients
with progressive disseminated histoplasmosis. UT series Result Improved Failed
N=7
it
6
Indiana series N = 5*
Medical literature N=3
0 5
0 3
* Ketoconazole was used in therapy for two other patients who did not have progressive disseminated histoplasmosis when they were initially treated. t Lost to follow-up care after 2 months.
healthy patients, although this was difficult to ascertain. Clearly, in the UT series ketoconazole was used in patients who were less critically ill [17]. Results of initial ketoconazole treatment of PDH and AIDS are shown in table 4. Generally, the drug was ineffective, with the vast majority of patients experiencing progressive disease while receiving therapy. Symptoms for only one patient were described as improving; he was lost to follow-up care after only 2 months. It does appear that initial therapy with ketoconazole is not effective therapy. In all three series amphotericin B was the initial drug of choice for most patients. Most attending physicians infused high doses of amphotericin B rapidly during the early treatment period. Once the patients' conditions stabilized, either they were given ketoconazole for long-term suppression or therapy with amphotericin B was continued at a reduced dosage. A substantial number of patients did not receive suppressive therapy after the initial course of amphotericin B. In early experiences, this method was prevalent, before the need for suppression was appreciated. Although comparable data do not exist among the three series, certain observations may be made. Amphotericin B used in the initial treatment course is highly effective. Although there are clear-cut treatment failures, most patients who have received at least 500 mg of amphotericin B did well [8, 17]. Wheat et al. [8] calculated that 57 of 65 patients who were started on therapy with amphotericin B responded, whereas the remaining patients died before receiving at least 500 mg. It is also clear that lifelong suppressive therapy is needed for prevention of relapse of PDH in AIDS. Early during our experience, many patients were treated successfully with large initial doses of amphotericin B but were not given suppressive therapy after completion of the initial treatment course [18]. Fourteen of our 40 patients experienced a relapse, for an unacceptably high relapse rate of 35% [17]. The Indiana experience was even more striking, where four (80%) of five of the patients experienced a relapse [8]. The small experience from Dallas shows PDH relapsed in one out of four patients who were treated with amphotericin B and who did not receive suppressive therapy [13].
Downloaded from http://cid.oxfordjournals.org/ at Emory University on August 16, 2015
marrow was a productive site. PDH is a disease of the reticuloendothelial system [10]. The simplest and safest means of sampling the reticuloendothelial system is by bone marrow examination [11], and during our early experience we examined the bone marrow first. Blood culture is a simple and effective way to recover the organism. While standard blood cultures may recover the fungus, utilization of the lysis-centrifugation system (DuPont ISOLATOR, Wilmington, DE) increased the success rate [12]. Most of the patients in the UT series were seen before widespread use of the system. Fully one-third of the positive blood cultures for patients from the medical literature were from a single, recent series. In this series, specimens for blood cultures were obtained during clinical illness as well as monthly during follow-up care of asymptomatic HIV-infected patients (surveillance cultures) [13]. Patients in the Wheat series represent a mixed group—high frequency of isolation from blood culture at Indiana University Hospitals, and a much lower rate of isolation at the other Indiana hospitals. The former institutions used the lysis-centrifugation system; the latter did not. Respiratory secretions are also a productive site for the recovery of the organism. Material obtained by bronchial washings or brushings or by biopsy, as well as material from bronchoalveolar lavage, is useful [14]. Results of biopsy of lymph nodes, skin, or mucous membrane ulcers were frequently positive [15]. Detection of H. capsulatum polysaccharide antigen (HPA) was done only in Indianapolis and appears to be an excellent method of diagnosis [8, 16]. Standard serodiagnostic studies were not done routinely in Houston (UT series) nor were results of these studies evaluable by reviewing the Englishlanguage medical literature. The data for the Indiana series were better but were by no means complete. Immunodiffusion (ID) testing for M-precipitin bands was surprisingly effective, while testing for the H-precipitin band was positive on only one occasion. The standard CF serological test was also useful, results being positive in 71% of the patients so tested in Indiana. At Indiana University when the ID and CF tests were both done, >80% of the patients had a positive serological test result [8].
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Histoplasmosis in Patients with AIDS
Table 5. Results of maintenance therapy with amphotericin B in
patients with progressive disseminated histoplasmosis.
Outcome Survival Death from other causes Relapse of PDH
McKinsey et al. [19] (N = 16)
Wheat et al. [8] (N = 21)
Nightingale et al. [13] (N = 4)
13 2 1
17 NS 4
3 0 1
NOTE. NS = not stated.
Discussion
That PDH should emerge as a significant opportunistic infection among HIV-infected patients should not come as a surprise. Indeed, as early as 1981, PDH was noted to complicate the course of AIDS [5]. What was somewhat surprising was that PDH was not considered an AIDS-defining infection until 1987 [6]. This delayed recognition was most likely due to the fact that early during the course of the HIV epidemic most patients were reported from both the East and
West coasts of the United States, where H. capsulatum is not endemic and is seldom thought of. Beginning in 1983 a number of isolated case reports describing PDH in AIDS started appearing in the literature [7]. As the HIV outbreak started to move to the Midwest, a number of small series were reported, a fact indicating that in areas endemic for H. capsulatum PDH would become a significant problem. In 1984 and 1985 Wheat et al. [9, 21] reported an astonishingly high incidence of PDH complicating HIV infection, where six (67%) of nine of their patients with AIDS also had PDH. Bonner et al. [22], also in 1985, reported three of four patients with AIDS from Alabama who also had PDH. Even in areas of less endemicity, PDH was clearly emerging as a major complication of AIDS. In 1988 we reported a 5% incidence among patients infected with HIV from Houston [18]. It is of interest that many patients with PDH were reported from New York City [14, 23, 24]—a city not normally considered to be endemic for H. capsulatum. Whether these patients represent reactivation of previously dormant histoplasmosis in HIV-infected individuals or whether the infection was recently acquired in an area nonendemic for H. capsulaturn is still unclear. Probably both mechanisms are operative [7]. It is clear that when HIV-infected patients become infected with the fungus, most will develop PDH. The extremely high incidence of H. capsulatum infection among HIV-infected patients from Indianapolis is most likely due to an ongoing epidemic of histoplasmosis that began during the fall of 1988. During that time, of 239 patients with AIDS from Indianapolis, 64 (27%) developed PDH. At the same time, 341 HIV-infected patients were known in the rest of Indiana, with only seven patients (2%) developing PDH. This extremely high incidence of PDH among patients with AIDS in Indianapolis is most compatible with the hypothesis that the illness represents widespread dissemination of the primary infection in T cell immunocompromised patients [8]. On the other hand, evidence exists that immunocompromised patients residing in areas nonendemic for H. capsulaturn may also develop PDH. In 1978 we reported a small series of patients with PDH who resided in Minneapolis, an area of nonendemicity. All of these patients had previously lived in areas known to be endemic for Histoplasma and were recently prescribed therapy with glucocorticoids and cytotoxic agents. This observation was most compatible with the reactivation hypothesis [4]. Similarly, most patients with PDH and AIDS who were reported from New York City lived for variable periods of time in or near areas endemic for H. capsulatum, such as the Caribbean and Puerto Rico [14, 23, 24]. The clinical manifestations of PDH in HIV-infected patients indicated a febrile and wasting disease with marked
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Once it became obvious that suppressive therapy was needed, many of our patients (UT series) [17], as well as other patients reported in the literature, received ketoconazole. Unfortunately, no prospective study was done for evaluation of this method. Retrospective evaluation, putting together fragmentary data from the series reported by Wheat et al. [8], shows that of 48 patients, 21 experienced a relapse. Even though this form of suppression was better than no suppression at all, it was clearly not good enough [8]. Here, too, the Dallas experience was better with three of four patients maintaining remission on suppressive therapy with ketoconazole—but the numbers are small [13]. More recently, continued suppressive therapy with amphotericin B emerged as the best method for maintaining patients in a disease-free state. McKinsey et al. [19] published their series of patients who received continuing suppressive therapy with amphotericin B, and Wheat et al. [8] used this method toward the end of their study as well. Table 5 shows the results of continuing suppressive therapy with amphotericin B. Briefly, this method calls for a period of intensive treatment with amphotericin B, totaling 1-2 g, followed by infusion of 50-80 mg of amphotericin B each week or every other week. With inclusion of the Dallas experience [13], a total of 41 patients received this form of treatment, and only six patients experienced a relapse during the period of observation (up to 23 months). More recently, the new triazole, itraconazole, has been used for suppressive therapy. A recent abstract presentation [20] reported 42 patients enrolled in the study: 35 were observed for at least 6 months and suffered no relapses over the period of observation.
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Sarosi and Johnson
CID 1992;14 (Suppl 1)
Figure 1. Magnetic resonance image of a deep-seated lesion on the right side of the basal ganglia in an HIV-infected patient who
had a febrile illness. Cultures of the blood and CSF fluid were positive for H. capsulatum.
weight loss. Respiratory complaints were frequently overshadowed by the generalized nature of the disease state. Skin and mucous-membrane lesions occur, which may help in early diagnosis. Similarly, the presence of lymphadenopathy is helpful, since biopsy of these lesions can also hasten the diagnosis. CNS involvement is uncommon (only three of our 64 patients had CNS involvement), but histoplasmosis should be considered in the differential diagnosis of altered mental status in AIDS [25] (figure 1). Gastrointestinal manifestations are also uncommon, but may be dramatic—perforation of the small intestine or presence of large colonic polyps have been reported (figure 2). The remainder of findings of the initial physical evaluation are seldom helpful, except when hepatosplenomegaly is noted. Except for the rather uncommon abdominal B-cell lymphoma, splenomegaly is uncommon in HIV-infected patients. Thus, the presence of palpable splenomegaly should signal PDH [ 1 7]. It is apparent that PDH in patients with AIDS is not significantly different from the disease observed in non-HIV-infected patients. Nevertheless, the disease is frequently much more severe in patients with AIDS. Wheat et al. [9] were the first to draw attention to a syndrome resembling septic shock in these patients, characterized by hypotension, multiple-organ failure, and disseminated coagulopathy. We also observed this clinical picture in Houston [18]. The nature of
Figure 2. Resected omentum showing multiple large lymph nodes containing H. capsulatum in a patient who presented with a perforated small bowel during the course of PDH.
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inflammatory mediators responsible for this syndrome is still unclear, but it is most likely related to the overwhelming nature of this infection. The initial chest roentgenogram may provide evidence for the diagnosis. The diffuse reticulonodular infiltrate is suggestive of PDH (figure 3). Up to one-third of the patients present with normal findings on chest roentgenogram, although eventually all patients develop abnormalities evidenced on chest roentgenograms. The cornerstone of effective treatment is rapid diagnosis. Measurement of HPA is highly specific and sensitive, but it is available only in Wheat's laboratory [8, 16]. Standard ID and CF serological tests are ultimately positive in —80% of the patients [8], but the slow turnaround time and the relatively low sensitivity make reliance on these tests problematic. Both biopsy and culture of bone marrow specimens are rapid, sensitive, and specific tests [4, 8, I 1 ]. Aspirated material can be stained with both periodic acid–Schiff and silver stain on the same day, and sections are available in 24 hours [17]. Frequently the fungus can be seen in circulating phago-
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Histoplasmosis in Patients with AIDS
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cytes (figure 4). In experienced hands, examination of the buffy coat may be the fastest way to make the definitive diagnosis. In the Dallas experience, 12 of 26 peripheral smears examined were positive for H. capsulatum. In 10 of these 12 instances, the peripheral smear was the first positive test [13]. With the lysis-centrifugation blood culture system (DuPont ISOLATOR), an excellent method was made available for rapidly establishing the diagnosis. The Indiana University experience is noteworthy: 91% of the patients had a positive lysis-centrifugation blood culture, whereas in other Indiana hospitals, only 57% of blood cultures were positive when standard techniques were used [8]. Although the results of the Dallas experience are not quite as outstanding (77% positive), investigators there are now using the technique during the monthly follow-up examinations of HIVinfected patients in whom the CD4 count is
