INTRODUCTION
Histoplasma capsulatum is a pathogenic fungus known to cause a spectrum of clinical diseases including acute pulmonary infiltration with or without adenopathy, chronic cavitary lung disease, rheumatologic symptoms including arthralgia and arthritis, pericarditis, fibrosing mediastinitis, granulomatous mediastinitis, and widespread disseminated infection including involvement of the skin, liver, spleen, adrenal, and occasionally the central nervous system22. The fungus was first identified by Darling in 19066. A chronic cavitary form of pulmonary histoplasmosis was first identified on autopsy in 194115 and in a living patient in 19484,13.
Shortly after its discovery, researchers evaluated chronic pulmonary histoplasmosis to determine the relevant demographics, natural history, and response to treatment. Most of these early studies were largely based on inpatient populations, usually from Mycobacteria tuberculosis (TB) sanatoriums1,8,9,12,14,16,18 or from patients in respiratory and United States Department of Veterans Affairs (VA) hospitals initially suspected of having TB11,12. Some of the other early studies of treatment of chronic histoplasmosis did not detail the inclusion criteria, making it difficult to determine if the results apply to current definitions of chronic pulmonary histoplasmosis3,20. In the small number of community hospital studies, patients were largely included based on the presence of cavitary lung disease2,7,22. These studies serve as the foundation for much of the current clinical perspective on the spectrum of chronic pulmonary histoplasmosis, namely that it predominantly represents a chronic, progressive cavitary lung disease in white, middle-aged, smoking males21. In contrast, investigations that define chronic pulmonary histoplasmosis based on the duration of symptoms rather than radiologic findings are generally lacking. In addition, there are far fewer data from community patients, especially outpatients. In 1 small study of 14 general hospital inpatients, there is a suggestion that the presence of cavitary disease may be lower than initially reported and patients may have a lower incidence of chronic obstructive pulmonary disease (COPD)19. Accordingly, we postulated that the current clinical impression of chronic pulmonary histoplasmosis may not fully describe the complete spectrum of disease. Therefore, we conducted the current study to define further the full spectrum of chronic pulmonary histoplasmosis, based on duration of symptoms in a large tertiary referral practice, encompassing both outpatient and inpatient settings.
PATIENTS AND METHODS
Patient Identification
This investigation was reviewed and approved by the Mayo Clinic Institutional Review Board (Mayo Clinic, Rochester, MN). We searched the medical record database for patients seen at the Mayo Clinic Rochester from January 1, 1976, through December 31, 2000, with the diagnoses of "pulmonary histoplasmosis" or "chronic pulmonary histoplasmosis." We reviewed the 228 charts identified for inclusion criteria. Patients were included if they had symptoms compatible with pulmonary histoplasmosis for 6 weeks or greater and had either cultures positive for H. capsulatum (from any source, including sputum, bronchoalveolar lavage [BAL], gastric lavage, or biopsy cultures) or significantly reactive histoplasma serum antibodies (complement fixation titers for yeast or mycelia at 1:32 or greater). High titer serology was used based on a previous analysis that a titer of 1:32 brought the specificity of yeast and mycelial complement fixation tests to nearly 100%4. Patients younger than 18 years old at the time of diagnosis or who declined research participation were also excluded. Patients with blood or bone marrow cultures positive for histoplasmosis suggesting extensive disseminated disease were excluded from the study. Patients with clinical features or diagnosis of fibrosing mediastinitis were similarly excluded. Using these criteria, 46 patients were identified for further analysis.
Clinical Data Collection
We reviewed medical records to determine the age at diagnosis, smoking status and exposure history, medical comorbidities, time from symptom onset to diagnosis, symptoms, related procedures, chest radiograph (CXR) and computed tomography (CT) findings, treatment and duration of treatment, pulmonary function, and recurrences. The symptoms and treatment of recurrences were abstracted. The time of diagnosis was defined as the date of the first reactive serology or positive culture. Smoking history was recorded as the number of pack years (PY), found by taking the reported number of years of smoking multiplied by the reported average number of packs smoked per day.
Exposure history was taken from clinical records specifically noting exposure to birds, bats, or demolition/construction sites. Symptoms were recorded from onset to last clinical encounter or to clinical resolution of disease. Radiograph findings were obtained from the interpretation by Mayo Clinic thoracic radiologists recorded in the clinical record.
Outside radiographs were included only if there was an independent interpretation by a Mayo Clinic radiologist. The duration of treatment was up to the last clinical encounter recorded at the institution.
Statistical Analysis
Differences between patient groups were assessed using the Wilcoxon rank sum for continuous variables or the chi-square or Fisher exact test for categorical variables employing the JMP 6.0 Statistical Package (SAS Inc., Cary, NC). In all cases p values less than 0.05 were considered significant.
RESULTS
Demographics
Forty-six patients were identified as having clinical symptoms for 6 weeks or greater and either a reactive H. capsulatum serology or culture-documented histoplasmosis, as defined under the methods. This cohort included 24 male and 22 female patients with a median age of 56 years (range, 20-85 yr) (Table 1).
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TABLE 1: Characteristics of Included Patients
The smoking history included 28% current cigarette smokers and 1 (2%) pipe smoker, 41% former smokers, and 26% never smokers (1 patient had no information recorded). The median number of cigarette exposure was 20 PY (range, 0-90 PY) for the entire cohort and 30 PY (range, 1.5-90 PY) for the group of current and former smokers.
Patients reported a probable environmental exposure to a likely histoplasmosis source in 37% of cases. This was most commonly bird or bat droppings, demolition or construction sites, farm environments, or a combination of these potential sources. Comorbid medical conditions included COPD (20%), alcoholism (15%), gastroesophageal reflux disease (GERD)/peptic ulcer disease (22%), known malignancy before diagnosis (13%), diabetes mellitus (7%), asthma (9%), and TB (2%). Only 1 patient required chronic oxygen therapy before diagnosis.
Twenty-eight of the 46 patients (61%) were managed exclusively as outpatients. Five of the remaining patients were admitted only for surgical biopsy, and 1 other patient was admitted for atrial fibrillation.
Presenting Symptoms
Clinical symptoms reported were cough or upper respiratory infection symptoms (85%), weight loss/decreased appetite (76%), fevers/chills/night sweats (76%), dyspnea (48%), arthralgia/malaise/myalgia (43%), fatigue (33%), chest pain (26%), headache (13%), and hemoptysis (11%). The median time from symptom onset to diagnosis was 5 months (range, <1 mo-240 mo). The overall duration of symptoms was a median of 9 months (range, 2-84 mo), with the limitation that some of the patients had on-going symptoms at the last recorded clinical encounter.
Diagnostic Studies
Of the 44 patients tested, 42 had significantly reactive serologies to Histoplasma. The median yeast titer was 1:128, and the median mycelial titer was 1:8. Although we did not use the immunodiffusion serologic test as an inclusion criterion, data were available on most patients. Of the 44 patients with immunodiffusion testing, 16 exhibited an M band alone, 13 patients were found to have both an H and an M band, and 1 patient was found to have an H band alone.
Thirty-eight patients had at least 1 specimen submitted to culture. Of those patients who had cultures performed, 13 patients exhibited at least 1 positive culture. Data for culture-positive cases and serology-positive cases are compared in Table 2. Ten of 32 patients had at least 1 positive sputum culture for H. capsulatum. Six of 26 patients had at least 1 positive BAL culture for the fungus. Six patients had gastric washes performed, with 2 gastric wash cultures revealing H. capsulatum.
TABLE 2: Comparison of Culture-Positive and Serology-Positive Patients
A total of 31 patients underwent bronchoscopic examination. Of the 6 bronchoscopies performed outside of our institution, the available clinical records described 1 patient with bronchitis and 1 having some compression of the right and left mainstem bronchi. Of the 25 patients who underwent bronchoscopy at Mayo Medical Center, 14 examinations were described as normal and 11 revealed endobronchial abnormalities. Abnormalities included mucopurulent secretions, erythema, bronchitis, as well as nodular mucosa, narrowing, atrophy, friability, and ulceration of the bronchi.
Fourteen patients underwent thoracic surgical procedures to obtain biopsy materials. Six video-assisted thoracoscopic procedures (1 converted to open), 5 open thoracotomies, 1 Chamberlain procedure, 4 mediastinoscopies/mediastinotomies, and 3 transthoracic needle biopsies were performed on these 14 patients. Of all 24 patients with biopsies obtained by bronchoscopy, transthoracic needle aspiration, or surgically, only 6 biopsies cultures were positive.
Radiographic Features
Standard CXRs were performed in all patients. We note that cavitations were detected in only 28% of these patients (plus 1 other by outside radiology report). The most common findings on standard CXR were nodules (74%), infiltrates (61%), and lymphadenopathy (41%). Other CXR findings included fibrosis (37%), thickened pleura (35%), volume loss (24%), hyperinflation/emphysema (15%), atelectasis (11%), and bronchiectasis (7%).
Computerized tomography scans of the chest were available from 30 patients (Figure 1). The most common findings were nodules (93%), lymphadenopathy (67%), and infiltrate (63%). Cavitary disease was present in 30%. Other findings on these thoracic CT scans included bronchopleural fistula (3%), bronchiectasis (10%), and emphysema (23%).
FIGURE 1: (A-C) Computerized tomography scans of the chest.
Treatment
Patients were treated over a spectrum of 25 years, during which time triazoles were introduced as an antifungal agent. The year of diagnosis and treatments given are delineated in Table 3. Of the 24 patients treated with itraconazole, the median therapeutic course was 6 months. Nine patients received ketoconazole, with a median treatment duration of 9 months. Ten patients received amphotericin B, typically in conjunction with an azole. Five patients received fluconazole therapy (median, 0.5 mo). Six patients had intolerance to 1 of the triazoles, requiring discontinuation of therapy or change to an alternate regimen. Thirteen patients did not receive any treatment.
TABLE 3: Treatment Received by Year of Diagnosis
Outcomes
Most patients exhibited good response to therapy. Of the 33 patients who received antifungal therapies in the current series, 23 patients had a good response with resolution of infection. Of the remainder, there were 5 recurrences, 2 failures to clear the radiographic abnormalities, and 3 patients with a prolonged course. Of the 13 patients who did not receive initial therapy, 2 patients had progressive disease and 1 had persistent infiltrate on CXR. No deaths due to histoplasmosis were recorded. Due to the limited number and nonrandomized approach to therapy, and with amphotericin B being reserved for patients with more severe or progressive disease, we did not attempt to attribute superior treatment responses to any given therapeutic regimen. Response monitoring with serology, culture, or histoplasmosis urine antigen was not done routinely. Furthermore, at recurrence serologies were less than or equal to the serology at presentation. Practitioners did follow radiographs and patient symptoms to assess for disease progression or response to treatment.
Female Patients
Because most prior investigations describing chronic histoplasmosis have focused on male populations, we separately analyzed the clinical features of female patients with this infection (Table 4). Twenty-two women met criteria for the study. The median age of these women at diagnosis was 50 years (range, 20-78 yr). There was no statistically significant difference in time from symptom onset to diagnosis in female (median, 5 mo; range, 2-84 mo) versus male patients (median, 4.5 mo; range, 0-240 mo). There was also no difference in the duration of symptoms (female patients: median, 8 mo; range, 2-40 mo; males: median, 9.5 mo; range, 2-84 mo). Eight of the female patients reported an exposure history before symptom onset. Fewer female patients were smokers than male patients. Three were smokers, 11 former smokers, and 8 were never smokers. The median number of PY was also less for women compared with men at 10 versus 40 PY (p = 0.002) (see Table 4).
TABLE 4: Comparison of Male and Female Patients
Comorbidities in these female patients with chronic histoplasmosis included 4 patients with asthma, 2 patients with cancer diagnosis before histoplasmosis diagnosis, 7 with GERD or peptic ulcer disease, and 1 each with diabetes mellitus, previous aspergillus, bronchiectasis, and chronic bronchitis. In contrast to the males, none of the female patients was clinically diagnosed with COPD.
Parallel to the male patients, the most common symptoms in female patients with chronic histoplasmosis were cough/upper respiratory infection symptoms (86%), fever (68%), and arthralgia (55%). Other symptoms included weight loss (10%), chest pain (32%), dyspnea (27%), fatigue (32%), and wheeze in nonasthmatic patients (18%). Two patients reported headache, and 1 reported hemoptysis.
Strikingly, culture positivity was uncommon in these female patients with chronic histoplasmosis and was significantly less than that in males (p = 0.005) (see Table 4). One out of 12 patients had a positive sputum culture. One out of 14 patients had a positive biopsy culture.
No patient had a positive gastric culture (out of 1 obtained), and none had a positive BAL culture (out of 12 obtained). Twelve female patients underwent bronchoscopy at Mayo, with 7 being normal. Four patients underwent bronchoscopy before referral to our center. Other procedures included 5 video-assisted thoracoscopic procedures, 3 open thoracotomies, 3 mediastinoscopies/mediasternotomies, 1 Chamberlain procedure, and 2 transthoracic needle aspiration. The female patients appeared to be subjected to invasive procedures more often than males during the course of their clinical evaluation. Overall, 19 of 22 female patients underwent bronchoscopy, surgical biopsy, or transthoracic needle aspiration.
The most common CXR findings in the female patient group were nodules (59%) and infiltrate (73%). The most common CT scan findings (of those obtained) included nodules (94%), lymphadenopathy (81%), and infiltrates (50%). Women had less cavitary disease than men (p = 0.04) (see Table 4). Cavitary disease was present on CXR in only 3 and on CT scan in only 4 female patients.
Nine of the female patients were observed without treatment. Eleven received itraconazole for a median of 5 months. Three patients received ketoconazole for a median of 9 months. One patient required amphotericin B deoxycholate treatment. Three patients received fluconazole for a median of 0.5 months. Three patients had recurrences treated with further triazole therapy. One had progressive infiltrates and 2 had persistent infiltrates which did not clear with therapy.
Patients With Cavitary Disease
Eighteen patients had cavitary disease documented on radiography, including both male and female patients (Table 5). The median age of those with cavitary disease was 59 (range, 37-75 yr). Patients with cavitary disease were more likely to be male (p = 0.04) and we found a trend toward a higher likelihood of being a smoker (p = 0.05). If fact, only 2 of these patients were never smokers and only 5 were female. Seven of these patients with cavitary disease had clinically documented COPD. The median number of cigarette PY was higher in patients with cavitary disease at 41.5 PY versus 20 PY for those without cavitary disease (p = 0.01). Nine of these patients were hospitalized (1 was hospitalized for atrial fibrillation only). Patients with cavitary disease were more likely to have a positive sputum culture (p = 0.006) with 9 (of 16) having positive sputum cultures, 2 (of 4) with positive gastric cultures, 5 (of 13) with positive BAL cultures, and 3 (of 10) with positive biopsy cultures. In total, half of the patients with cavitary disease had at least 1 positive culture. Following treatment, there were 2 recurrences, 1 patient with progression, and 3 patients that never cleared their radiographic abnormalities at the time of last follow-up.
TABLE 5: Comparison of Patients With Cavitary and Noncavitary Disease
Never Smokers
Another unique feature of our series was the inclusion of a small but significant fraction of patients who never smoked (Table 6). There were 12 never smokers, average age of 50 yr, included in the study. Four were inpatients and 3 of those were inpatient only for biopsy. Seven of these patients had no obvious comorbidity predisposing them to infection. There was no statistically significant difference between duration of symptoms or time of symptom onset to diagnosis in these patients versus smokers. There was a difference between never smokers and smokers in number of positive cultures (p = 0.02). In fact, there were no positive cultures (out of 7 patients with sputum, 6 with BAL, and 5 with biopsy cultures) in the never-smoker group. There was also a trend toward an increase in the presence of cavitary disease on radiographs of smokers compared with never smokers (p = 0.09). None of the nonsmokers had cavitary disease on CXR, but 2 had cavitary disease on CT scan of the chest. Seven patients underwent bronchoscopy and 3 underwent thoracotomy. There was 1 recurrence and 1 never smoker developed a progressive infiltrate despite therapy.
TABLE 6: Comparison of Smokers With Never Smokers
DISCUSSION
The current series of patients with chronic histoplasmosis infection demonstrates several important differences compared with many series described in the literature. Most strikingly, cavitary disease was noted in only 39% of patients in the current series. Classically, chronic pulmonary histoplasmosis has, at times, been used interchangeably with chronic cavitary histoplasmosis. Some studies used presence of a cavity on CXR as an inclusion criterion so that all patients, by definition, exhibited cavitary disease1,7,14,22. In other series, patients were identified as eligible once suspected of having TB8,11,12, and therefore the percentage of patients with cavitary disease was extremely high. In another early study, cavitary disease was reported to be as high as 87%18. However most patients in that study were drawn from the Missouri State Sanatorium and were selected based on positive cultures for H. capsulatum. One would expect that cavitary disease would be present in a high proportion of patients suspected of having TB. Prior investigations demonstrate that cavitary forms of histoplasmosis are associated with a high degree of culture positivity compared with noncavitary disease22. Choosing cases from those with positive cultures would select a high proportion of cavitary disease. Chronic cavitary histoplasmosis has been formerly described as a cavitary lung disease of middle-aged, male smokers with COPD22. In the current series, of the patients with chronic cavitary histoplasmosis infection, 72% were male and 89% were smokers with a high average number of 40 PY. However, only 39% had a clinical diagnosis of COPD. Of the patients with cavitary disease in our series, 50% had at least 1 positive culture for H. capsulatum.
The current series demonstrates that the spectrum of chronic histoplasmosis infection is more extensive than cavitary disease. In fact, in the current investigation, 28 patients (61%) with chronic symptoms diagnosed with pulmonary histoplasmosis had noncavitary disease. The current investigation was designed to look at the spectrum of chronic histoplasmosis by focusing on patients with chronic symptoms and clear evidence of the diagnosis regardless of the radiography findings. When the patients with chronic pulmonary histoplasmosis without cavitary disease are included, the presence of COPD falls to 20% with only 67% smokers. Culture positivity was also lower (34%) across this inclusive series of patients. A second important difference in our data compared with those in the literature is that 22 (48%) of our patients were women. There was no difference by sex in duration of symptoms or time from symptom onset to diagnosis. However, there was a significantly lower incidence of cavitary disease in women (23% vs. 54% in men). None of our female patients had underlying COPD, while 38% of the men had COPD. Furthermore, the extent of smoking was lower in women. Sixty-four percent of women in this series were current or former smokers with an average of 21 PY, compared with 79% of men with an average of 44 PY (p = 0.002). In addition, most of the female patients required an invasive procedure to establish the diagnosis of H. capsulatum infection. One could postulate that this invasive approach was influenced by previous studies that have suggested this disease to be primarily in men, or it could reflect the lower culture positivity rates in women (2 of 40 cultures obtained from women vs. 22 of 49 samples obtained from men). Most patients of both sexes were exclusively managed as outpatients (64% of women and 54% of men). Of the 22 female patients treated for chronic histoplasmosis, 6 recurred, progressed, or had persistent infiltrates.
Few data have been reported on female patients with chronic pulmonary histoplasmosis. Many of the previous studies were based largely at VA hospitals consisting mostly of male populations3,9,11,12,16,20. In addition, prior studies also focused on inpatient populations1,3,8,9,11,12,14,16,18-20. In the current study, nearly two-thirds of the female patients were managed exclusively as outpatients. Thus, our series samples a broader spectrum of disease than that reported in the earlier literature.
Our series also emphasizes interesting differences when considering patients who were never smokers. It is remarkable that there were no positive cultures in patients classified as never smokers. In addition, there was a trend toward a shorter duration of symptoms for patients classified as never smokers. These differences support our contention that the current study provides a more complete clinical picture of the spectrum of chronic histoplasmosis. These findings suggest that given the broader inclusion criterion of both inpatients and outpatients, the true spectrum of chronic pulmonary histoplasmosis includes men and women, smokers and nonsmokers.
The role of bronchoscopy in diagnosing pulmonary histoplasmosis has been previously studied17. This study from our institution did not differentiate between the acute and chronic forms of the disease. The previous study also included those patients with solitary pulmonary nodules undergoing bronchoscopy, and descriptions of visual inspections were not included. Thus, the current study adds to what was previously known regarding bronchoscopy and chronic histoplasmosis.
Limitations of this study include those inherent in any retrospective review. Data were drawn from the medical records. Subjects were not contacted by investigators. It is possible that the bronchoscopy findings are underrepresented, since some of the patients underwent bronchoscopy at an outside facility, and reports were unavailable from 4 such patients. In addition, it is possible that the duration of symptoms and treatment as well as the number of recurrences may be underestimated in this report because data are drawn from the last clinical encounter.
It is difficult to comment on treatment because of the retrospective nature of the study. Patients in most cases were highly symptomatic for a long time with CXR abnormalities leading to treatment initiation. It is clear, however, that these patients seldom received the 12-24 months of itraconazole therapy currently recommended by Infectious Diseases Society of America guidelines21 (only 4 of the 46 patients did). Three other patients received greater than 12 months of triazole therapy with a different agent, and 4 received a substantial amphotericin B cumulative dose in addition to a less-than-12-month course of triazole therapy. The difference in the duration of treatment recommended compared with the duration of treatment received likely represents the difference of defining the disease in this study by duration of symptoms rather than by presence of a cavity. The fact that cavitary disease was present in 18 patients and only 4 of these received greater than 12 months of triazole therapy is difficult to reconcile. Two of the others received substantial amphotericin B therapy. However, of the patients with cavitary disease and less than 12 months of therapy, only 1 had a documented recurrence. Perhaps given the inclusion of outpatients in this study there was a lesser severity of disease, and a shorter duration of therapy was justified.
In conclusion, we present a comprehensive retrospective review of both inpatients and outpatients managed at a large tertiary referral center identifying 46 patients with evidence of chronic pulmonary histoplasmosis. The current study differs from previous studies by defining the disease based on duration of symptoms and by describing findings in female patients, in nonsmokers, and in patients with noncavitary disease. The disease spectrum of chronic histoplasmosis appears to differ depending on the demographic features of the patients.
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