Original Article
Pulmonary Aspergillosis in the Acquired Immunodeficiency Syndrome
N Engl J Med 1991; 324:654-662March 7, 1991
- Abstract
- Abstract
Background and Methods.
Symptomatic pulmonary aspergillosis has rarely been reported in patients with the acquired immunodeficiency syndrome (AIDS). We describe the predisposing factors, the clinical and radiologic features, and the therapeutic outcomes in 13 patients with pulmonary aspergillosis, all of whom had human immunodeficiency virus (HIV) infection and 12 of whom had AIDS.
Results.
Pulmonary aspergillosis was detected a median of 25 months after the diagnosis of AIDS, usually following corticosteroid use, neutropenia, pneumonia due to other pathogens, marijuana smoking, or the use of broad-spectrum antibiotics. Two major patterns of disease were observed: invasive aspergillosis (in 10 patients) and obstructing bronchial aspergillosis (in 3). Cough and fever, the most common symptoms, tended to be insidious in onset in patients with invasive disease (median duration, 1.3 months before diagnosis). Breathlessness, cough, and chest pain predominated in the three patients with obstructing bronchial aspergillosis, who coughed up fungal casts. radiologic patterns included upper-lobe cavitary disease (sometimes mistaken for tuberculosis), nodules, pleural-based lesions, and diffuse infiltrates, usually of the lower lobe. Transbronchial biopsies were usually negative, but positive cultures were obtained from bronchoalveolar-lavage fluid or percutaneous aspirates. Dissemination to other organs occurred in at least two patients, and direct invasion of extrapulmonary sites was seen in two others. The results of treatment with amphotericin B, itraconazole, or both were variable. Ten of the patients died a median of 3 months after the diagnosis (range, 0 to 12 months).
Conclusions.
Pulmonary aspergillosis is a possible late complication of AIDS; if diagnosed early, it may be treated successfully. (N Engl J Med 1991; 324:654–62.)
Media in This Article
Figure 1
Detail of Chest Radiograph of Patient 8, with Probable Invasive Aspergillosis.Figure 2
Chest Radiograph of Patient 11, Who Had Obstructing Bronchial Aspergillosis on Admission to the Hospital.Article Activity
- Article
REMARKABLY, aspergillosis is unusual in patients with the acquired immunodeficiency syndrome (AIDS). Only 3 cases were included among the first 1762 cases of AIDS in the United States reported to the Centers for Disease Control.1 Of 1067 patients with AIDS and pulmonary complications, only 6 had fungal pneumonia, none due to aspergillus.2 These figures contrast with the relatively high frequency of aspergillosis in most other seriously immunocompromised patients. For example, up to 70 percent of patients with leukemia have pulmonary aspergillosis after 30 days of neutropenia.3 Of 400 patients recently receiving heart transplants at Stanford, 55 (14 percent) had aspergillosis.4 Many other risk groups have been identified, particularly recipients of bone marrow, renal, and liver transplants, other patients with neutropenia or those receiving corticosteroids, and those with chronic granulomatous disease, diabetes, and burns. A few nonimmunocompromised patients with invasive aspergillosis have also been described.5 It is therefore surprising, perhaps, that patients with AIDS seem to be at such apparently low risk for aspergillosis. However, patients with AIDS have major functional deficits of T cells, with less marked defects of neutrophils or macrophages, and the latter are the important defects that may allow the development of invasive aspergillosis.6
In the past year, we have treated 13 patients with human immunodeficiency virus (HIV) infection who had pulmonary aspergillosis. We describe several different clinical and radiologic presentations of this condition, together with the outcomes after treatment. We also examine the possible underlying factors that led to aspergillosis.
Methods
In this report we describe all patients known to us who had a diagnosis of pulmonary aspergillosis in the context of HIV disease. Because various patterns of disease were observed, we use the following operational definitions for purposes of clarity and classification. "Confirmed invasive aspergillosis" describes all patients who had histologically proved disease, either ante mortem or at autopsy (three patients), and those who had a positive culture for aspergillus species obtained by percutaneous aspiration of lung (three patients) or bone (one patient). "Probable invasive aspergillosis" describes all patients who had the development of a new cavity in previously normal lung and a positive bronchoscopic culture for aspergillus species (two patients) or who had noncavitary new pulmonary infiltrates with a positive bronchoscopic culture for aspergillus species without the identification of other pathogens (one patient). "Obstructing bronchial aspergillosis" describes three patients with major respiratory symptoms, including dyspnea and fever, together with the production of fungal casts or balls found in sputum (two patients) or detected on bronchoscopy (one patient) without evidence of invasion of tissue at the time of diagnosis.
Patients who were treated with itraconazolc received their medication under one of two protocols (one from the National Institute for Allergy and Infectious Diseases Mycoses Study Group) approved by the institutional review board of the Santa Clara Valley Medical Center. Serum itraconazole concentrations were determined by bioassay as described elsewhere.7 , 8 Susceptibility testing (to determine minimal inhibitory and minimal fungicidal concentrations) was performed with macrodilution broth tests as described elsewhere.9
Results
Predisposing Factors
All 13 patients were men. Aspergillosis developed late in the course of AIDS in all patients except one, who had asymptomatic HIV infection. Among the 11 patients with AIDS for whom we have data, the median interval between the diagnosis of AIDS and the diagnosis of aspergillosis was 25 months (mean, 24; range, 10 to 36). At the present time, the median life expectancy of patients with AIDS is about 14 months.10 The mean delay between the onset of symptoms and the diagnosis of pulmonary aspergillosis in the 11 symptomatic patients was 1.3 months (range, 3 days to 3 months).
Possible predisposing factors for the development of aspergillosis are given in Table 1Table 1
Underlying Disease, Possible Predisposing Factors, Clinical and radiographic Presentation, and Mode of Diagnosis of Pulmonary Aspergillosis in 13 Patients.*. All but one of the patients had AIDS, and the patients had usually had many other complications of AIDS before the development of aspergillosis. Helper T-cell counts were usually extremely low (<0.03×109 per liter) in patients with AIDS in whom the count was made at the time of the diagnosis of aspergillosis. Neutropenia (defined as a neutrophil count <500×106 per liter) was a likely contributing factor in 6 of 11 patients, and it was as likely to be related to zidovudine as to ganciclovir. Corticosteroid use was possibly predisposing in four patients (two of whom also had neutropenia). Four patients were known to have smoked marijuana, three of them regularly, but data were not available for seven patients. Marijuana has previously been associated with invasive aspergillosis.11 , 12 Four patients had had cytomegalovirus disease previously (ocular in three and colonie in one). In two of these, neutropenia and aspergillosis developed within a short time. Cytomegalovirus pneumonia has previously been associated with increased pulmonary infections in transplant recipients,13 , 14 but it is not clear that there is any such association in AIDS. Among the 10 patients with AIDS for whom data are available, all had previous Pneumocystis carinii pneumonia. The majority were given prophylaxis with aerosolized pentamidine, but at least one received oral trimethoprim–sulfamethoxazole.Invasive Pulmonary Aspergillosis
The symptoms reported on presentation are shown in Table 1. Only one patient was asymptomatic. Fever and cough were the most frequent symptoms. The cough was more frequently nonproductive than productive. Dyspnea was infrequent (40 percent of the patients), as was hemoptysis (10 percent), although Patient 1 died of hemoptysis. Chest pain, usually pleuritic in nature, was often poorly localized. Two patients had extrapulmonary disease of a nondisseminated form. Patient 7, who was HIV-positive only, had chest-wall disease in a pattern seen most frequently in children with chronic granulomatous disease.15 Patient 4 presented with symptoms of brachial neuritis due to locally invasive aspergillosis.
All the patients had abnormal chest films, but the radiographic appearances were extremely heterogeneous (Table 1). Unilateral disease was seen as frequently as bilateral disease. Upper-lobe disease was slightly more frequent than lower-lobe disease, but two patients had both upper- and lower-lobe disease. Cavitary disease was seen only in the upper lobes. Two patients had pleural-based parenchymal disease. Cavitary disease was the only pattern seen in the five patients in whom it occurred, and it was initially mistaken for tuberculosis in at least two patients (Patients 5 and 8) (Fig. 1Figure 1
Detail of Chest Radiograph of Patient 8, with Probable Invasive Aspergillosis.).No laboratory or imaging procedures yielded specific information that was helpful for an etiologic diagnosis. In the patients with dyspnea, arterial-blood gas levels were abnormal to differing degrees, with no particular pattern. Peripheral-blood cell counts, electrolyte levels, and the results of liver-function and other biochemical tests were often abnormal, but the abnormalities were not specific. Bronchoscopic examination of the airways was normal in all five patients with definitely or probably invasive aspergillosis who underwent the procedure. However, bronchoalveolar-lavage specimens yielded useful information on culture in all patients. We have no data about the specificity of a positive culture for aspergillus species from bronchoalveolar-lavage fluid in this context, although aspergillus species may be cultured from the sputum of patients with AIDS who do not have invasive aspergillosis.16 Transbronchial biopsy in patients with definitely or probably invasive aspergillosis was negative in all three at the time of diagnosis, although one (Patient 3) had extensive disease confirmed at autopsy. Patient 5 had a second bronchoscopy when his condition was deteriorating, and transbronchial biopsy showed the presence of hyphae in pulmonary parenchyma that were not seen in the original biopsy.
The most useful diagnostic procedure for invasive disease, which entailed no complications in the four patients who underwent it, was transthoracic aspiration of a pleural-based lesion or a cavity (Table 1). Both cytologie preparations to detect the presence of hyphae and cultures were positive in all four patients (in tests performed at four different institutions).
The response to treatment varied (Table 2Table 2
Treatment and Outcome in 13 Patients with Pulmonary Aspergillosis in AIDS.*). Two patients were not treated, and one received less than seven days of therapy with amphotericin B before dying (Patient 3). Another patient had severe rigors, fevers, and hypotension with two doses of amphotericin B. Three patients were treated with amphotericin B for more than seven days, and all three responded to treatment. One (Patient 4) received less than 30 mg daily for three weeks (total dose, 560 mg), with symptomatic improvement but no radiologic changes. He later had a relapse. Patient 9 received 1600 mg of amphotericin B over a three-week period, with slow improvement but continuing respiratory distress and positive sputum cultures for A. fumigatus. He continued to receive amphotericin B as an outpatient but had cytomegalovirus cholangitis and Pseudomonas aeruginosa bacteremia. Patient 9 died three months after the diagnosis of aspergillosis with progressive pulmonary infiltrates that were not further characterized, having stopped taking amphotericin B for the last month of his life. The third patient (Patient 1) received amphotericin B for one month after treatment with itraconazole was unsuccessful, and he responded clinically but not radiologically, later dying of massive hemoptysis, a well-recognized complication of invasive pulmonary aspergillosis.4 Six patients were treated with itraconazole, and four responded to treatment (Table 2). In the two patients who did not clearly respond, low serum concentrations of itraconazole were either documented (0.32 μmol per liter in Patient 1) or suspected (Patient 6 was taking rifampin concurrently after seven days of itraconazole therapy). Of the four patients who responded to itraconazole treatment, one (Patient 5) had a clinical and radiologic response, but there was later a recrudescence of his disease at a time when his serum itraconazole concentration was approximately 7 μmol per liter. The second patient to respond (Patient 4) did not respond initially and had an undetectable serum itraconazole concentration while taking rifampin concurrently. When rifampin was stopped and the dose of itraconazole increased, the serum itraconazole concentration reached an acceptable range, and a complete clinical response followed. There was no radiologic change, however, although cultures obtained by a repeated transthoracic aspiration were negative. The third patient who responded to itraconazole (Patient 10) was improving after two months of therapy. The fourth (Patient 7) had clinical and radiologic improvement over a period of two months before ceasing to comply with the treatment.
Obstructing Bronchial Aspergillosis
The clinical presentation of the three patients with obstructing bronchial aspergillosis differed from that of the patients with invasive aspergillosis. The onset of cough was progressive, with the spontaneous production in two patients of fungal casts of the airways. Chest pain, dyspnea, hemoptysis, and fever were each seen in two patients. There was no wheezing. Two patients required supplemental oxygen because of dyspnea. One had a high alveolar—arterial gradient with a partial pressure of carbon dioxide of 7.3 kPa while breathing room air. No patient had eosinophilia. Chest radiographs showed bilateral lower-lobe infiltrates in all three patients and also upper-lobe infiltrates in Patient 12 (Fig. 2Figure 2
Chest Radiograph of Patient 11, Who Had Obstructing Bronchial Aspergillosis on Admission to the Hospital. and 3Figure 3
Chest Radiograph of Patient 12, with Obstructing Bronchial Aspergillosis.). A gallium scan was normal in one patient. Microscopical examination and culture of sputum casts (expectorated in two patients) was diagnostic in all three. Bronchoscopy was normal in Patient 12 (except for cultures that grew copious amounts of aspergillus species), revealed multiple fungal casts in Patient 11, and showed the formation of a pseudomembrane in Patient 13 about two weeks before death. All three patients were treated with itraconazole. In one (Patient 11), bronchoscopic lavage removed a large aspergilloma and other debris from the left lower lobe, with rapid and substantial improvement subsequently. In Patient 12, who had acute renal failure (the creatinine level rose from 140 to >700 μmol per liter) requiring hemodialysis after three doses of amphotericin B (1.8 mg per kilogram of body weight; total dose, 135 mg), itraconazole was given for one month, with gradual improvement in clinical and radiologic status. Sputum cultures reverted to negative status for A. fumigatus. Patient 13 presented with cough and hemoptysis and expectorated fungal casts. No antifungal therapy was given for two months, and the patient went on to have first aspergillus sinusitis and later pseudomembranous tracheobronchitis, with hyphae seen in the mucosa and bronchial submucosa in transbronchial-biopsy specimens. He underwent Caldwell—Luc surgery for the sinusitis and received amphotericin B intravenously, but cerebral aspergillosis developed later and the patient died after having received only two doses of itraconazole.Eventual Outcome
Ten of the 13 patients studied have died. One of the others (Patient 7) was lost to follow-up. Another is alive and improving after two months of itraconazole therapy. Aspergillosis was in remission in the third patient four months after therapy. In the patients who died, survival after the development of aspergillosis was usually short. The mean interval from the onset of symptoms to death (in 10 patients) or the end of observation (in 3) was 5 months (range, 1 to 12; median, 4). The mean interval from the diagnosis of aspergillosis to death (or the end of observation) was 4 months (range, 0 to 12; median, 3). These short periods of survival may reflect the generally advanced state of AIDS in most of the patients or the intrinsic severity of aspergillosis in these patients. Three patients died of aspergillosis — the pulmonary type in Patient 1, and the disseminated type in Patients 3 and 13. In five patients aspergillosis was not a primary or major contributing cause of death; two patients died with pulmonary aspergillosis (Patients 4 and 5), two died with untreated aspergillosis (Patients 2 and 8), and one (Patient 11) had obstructing bronchial aspergillosis that was in remission. In one patient (Patient 9), the activity of aspergillosis was in doubt, but the patient died with extensive pulmonary infiltrates a month after discontinuing amphotericin B. One patient (Patient 6) had a slight response to therapy before he died of an intracranial event (possibly caused by cerebral aspergillosis).
Case Histories
Patient 4
This 40-year-old man had P. carinii pneumonia in May 1987, with two subsequent episodes, disseminated infection with Mycobacterium avium–intracellulare, and cytomegalovirus retinitis complicated by a retinal detachment in the left eye in January 1988 that left him almost blind in that eye. He received increasing doses of ganciclovir over the subsequent months but had progressive visual loss in the right eye. He had profound neutropenia (70×106 neutrophils per liter) and two episodes of probable sepsis in April and December 1988. He received two long courses of antibacterial therapy plus clofazimine, ethambutol, and rifampin for his mycobacterial disease, beginning in January 1989.
In January 1989, the patient had radicular symptoms involving pain and numbness in his right scapula and shoulder. Pain and numbness advanced down the right arm to the elbow. A mass in the right apical area was seen on a chest film and confirmed on a CT scan. Needle aspiration in February yielded a small amount of fluid that showed hyphae on smear and grew A. fumigatus in culture. Initially the patient was treated with 560 mg of amphotericin B over a period of three weeks. Despite resolution of his symptoms, the mass remained unchanged radiographically. The patient tolerated the amphotericin B poorly and refused further therapy. On funduscopic examination choroidal lesions were seen that were inconsistent with cytomegalovirus infection; they appeared to resolve with the amphotericin B therapy.
After the patient discontinued antifungal therapy, his retinitis was treated with foscarnet and then in May 1989 with ganciclovir. In mid-June, approximately 3 1/2 months after the completion of the abbreviated course of amphotericin B, the radicular symptoms recurred, and a specimen obtained on repeated percutaneous aspiration of the lung again grew A. fumigatus. The minimal inhibitory and fungicidal concentrations of itraconazole for the organism were 2.2 μmol per liter. Itraconazole was started (200 mg twice daily). The patient had some subjective improvement. However, the symptoms then worsened, and serum itraconazole concentrations were undetectable. Rifampin was discontinued, and the dose of itraconazole was increased to 200 mg three times a day. At this time, the patient's T4 cell count was 0.002×109 per liter in blood. He received the increased dose of itraconazole for six weeks, and his radicular symptoms improved markedly. The lesion remained stable radiographically. A repeated percutaneous aspiration of the cavitary area in the right apex after four weeks of the higher dose showed necrotic material with some hyphae. The culture was sterile. A repeated measurement of the serum itraconazole showed a concentration of 15.4 μmol per liter. The patient's course was complicated further by adrenal insufficiency documented in August 1989 and cytomegalovirus infection in blood, urine, and bone marrow in October. He remained blind, could not tolerate dideoxyinosine, and decided to discontinue all medication on December 27, 1989. He died on January 3, 1990.
Patient 11
The patient was a 37-year-old man in whom P. carinii pneumonia developed in August 1987, followed by esophageal candidiasis and upper gastrointestinal bleeding in September. Chronic perineal herpes led to the formation of a rectourethral fistula and multiple episodes of urosepsis, for which he was given long-term ciprofloxacin therapy to suppress bacterial colonization of the bladder. He discontinued heavy alcohol use in September 1987 and smoked marijuana occasionally.
On April 23, 1989, the patient was admitted to the hospital with a two-month history of increasing dry cough with shortness of breath. He reported transient fever (temperature to 41°C). He was admitted with leukopenia, with his neutrophil count falling to 16 × 106 per liter on the second hospital day. A chest film showed bilateral fluffy lower-lobe infiltrates (Fig. 2). Zidovudine was discontinued. The patient had a rapidly downhill course despite intravenous treatment with trimethoprim–sulfamethoxazole. A bronchoscopy on the sixth hospital day revealed what appeared to be a foreign body in the left lower-lobe bronchus. It was removed, together with much necrotic, mucoid debris. On microscopical examination, the "foreign body" was necrotic, containing large numbers of hyphae and conidia in a manner typical of an aspergilloma or fungal cast. The culture grew A. fumigatus.
Clinical and radiologic improvement followed bronchoscopy, and itraconazole therapy was begun because of the concern about invasive aspergillosis in the setting of marked neutropenia. The patient tolerated the medication well at a dose of 200 mg twice daily, and the chest film became normal over the subsequent six weeks, after which itraconazole was discontinued. A sputum specimen cultured for fungus four weeks after the start of therapy was negative. After the initial improvement with itraconazole, the patient had recurrent urosepsis, associated with dehydration and marked confusion. Nine weeks after the discontinuation of itraconazole, he died of progressive dementia complicated by recurrent pneumonia and sepsis. There was no postmortem examination.
Discussion
This report details two distinct forms of pulmonary aspergillosis in 12 patients with AIDS: invasive and obstructing bronchial aspergillosis. It also describes invasive aspergillosis in one HIV-positive patient. Both patterns of disease were observed in patients who had AIDS for a median of two years. Other predisposing factors may include neutropenia (due to the disease, to drugs toxic to bone marrow, or both), corticosteroid therapy, marijuana use, previous P. carinii pneumonia and cytomegalovirus disease, and broad-spectrum antibiotics, including those used in prophylaxis for P. carinii pneumonia. Qualitatively abnormal leukocyte function in HIV-infected patients17 may be a predisposing factor. long-standing T-cell defects in AIDS may be involved, mediated by dysfunction of neutrophils and macrophages; both these effector cells can normally be activated by T cells to have antifungal activity.18 In view of this, patients with AIDS, especially those who have neutropenia or are receiving corticosteroids, should probably avoid exposure to aspergillus, such as is involved in smoking marijuana.
Twelve cases of invasive pulmonary aspergillosis in AIDS are described in the literature,19 20 21 22 23 24 as well as an aspergilloma in a patient with AIDS-related complex.25 The underlying factors in these cases, in addition to HIV disease, were corticosteroid therapy,22 23 24 alcoholism,20 neutropenia,22 , 23 and possibly emphysema.23 Aspergillosis was diagnosed ante mortem in all our patients; in the literature, six were diagnosed ante mortem21 , 22 , 24 and six post mortem.19 , 20 , 22 , 23 One of the patients described in the literature was clinically asymptomatic,21 as was one of our patients. Cough and fever with an insidious development were the most prominent clinical symptoms in our patients with invasive disease, as they were in five of the patients described elsewhere.22 Cavitary lung disease or diffuse infiltrates have been noted previously in patients with invasive pulmonary aspergillosis in AIDS,21 , 22 and these were the most frequent radiologic findings in our patients. We also noted pleural-based lesions and solitary nodules.
The therapeutic outcomes in our patients with invasive disease and those described elsewhere have been generally poor. Although six of our seven patients who were treated for more than seven days had some response to itraconazole or amphotericin B, two of the three patients who responded to treatment with amphotericin B relapsed, the third died of hemoptysis, and one of the four patients who responded to itraconazole had a recrudescence of aspergillosis while receiving therapy. Poor results were observed previously. Ketoconazole, which has little activity against aspergillus species,4 failed in one patient.19 Amphotericin B was successful in one patient who later relapsed,20 and was unsuccessful in two.21 , 24 Itraconazole represents an attractive therapeutic alternative for these patients, because it is active after oral administration. Previous work has shown that itraconazole has efficacy in the treatment of invasive aspergillosis in other immunocompromised patients, with response rates of approximately 80 percent in pulmonary aspergillosis,4 , 26 and in patients with AIDS and cryptococcal meningitis.27 However, as compared with patients without AIDS, serum itraconazole concentrations were lower in patients with AIDS (mean steady-state concentration, 5 μmol per liter). Published and unpublished data indicate that adequate serum itraconazole concentrations are probably important for efficacy; steady-state concentrations below 7 μmol per liter were associated with failure26 in 26 patients with invasive aspergillosis. There is no satisfactory explanation of the marked variability among patients or of the lower concentrations in patients with AIDS. In addition, low and often extremely low serum concentrations of itraconazole are seen when concurrent therapy with rifampin, phenytoin, or carbamazepine is given,28 to the extent that the use of these drugs precludes the concurrent or immediately subsequent use of itraconazole in life-threatening situations. This interaction of itraconazole with rifampin was further documented in our series (Patient 4).
Dissemination of aspergillus to several organs was seen at autopsy in two of our patients (and presumed in two others), and it has been reported in several other patients with AIDS.20 21 22 , 24 In fact, most of the cases of invasive aspergillosis described in patients with AIDS are cases of cerebral aspergillosis in neuropathological autopsy series. Seventeen such cases of cerebral aspergillosis have been reported.22 , 29 30 31 32 Involvement of the heart,20 , 22 , 24 sinus,33 skin,34 mediastinal lymph nodes,22 and thyroid22 has also been reported in patients with AIDS. One patient had renal aspergillosis that was diagnosed ante mortem,22 but he probably had an addiction to intravenous drugs, which is a risk factor in its own right.
Our three patients with obstructing bronchial aspergillosis became more acutely ill than those with invasive aspergillosis, because they had hypoxemia, bilateral infiltrates (predominantly in the lower lobe and presumed to be due to local atelectasis), and chest pain. Two of the three patients coughed up fungal casts. One HIV-positive patient who had mucus plugging the airways has been described elsewhere.35 It is interesting to contrast the cases of obstructing bronchial aspergillosis that we have observed with previous reports of allergic bronchopulmonary aspergillosis and mucoid impaction of the bronchi. Allergic bronchopulmonary aspergillosis is an unusual allergic disease that occurs in patients with asthma or cystic fibrosis. It is characterized by wheezing; patchy, variable pulmonary infiltrates; central bronchiectasis; eosinophilia; and various allergic manifestations (e.g., elevated serum IgE levels and aspergillus-specific antibodies).36 Some patients describe coughing up brown plugs or casts of their bronchi. Few serologic assays pertinent to the diagnosis of allergic bronchopulmonary aspergillosis were performed in our three patients, but they did not have asthma, wheezing, or eosinophilia, suggesting different pathogenetic mechanisms. Mucoid impaction of the bronchi most closely approximates what was observed in our patients, except that there is thought to be complete overlap between allergic bronchopulmonary aspergillosis and mucoid impaction of the bronchi when aspergillus is implicated as the cause of the latter.37 Mucoid impaction of the bronchi is typically seen in patients with asthma or bronchitis, and the patients usually have some combination of productive cough, upper respiratory infections, fever, chest pain, and hemoptysis.38 Pathologically, mucoid impaction of the bronchi is characterized, presumably in its most chronic form, by dilated bronchi with thinned walls, focal areas of atrophie cartilage, and rough mucosal surfaces. These pathologic features were not seen in our patients, although the patients had many of the clinical features described. Usually infection or colonization with aspergillus is not present. If it is, the patients almost always have allergic bronchopulmonary aspergillosis. Although endobronchial colonization with aspergilli occurs in a variety of conditions associated with anatomical abnormalities of the bronchi, our patients did not have this predisposing factor. We therefore believe that our three patients represent a new clinical entity that is related to the presence of large quantities of aspergillus species in the airways and is possibly peculiar to patients with AIDS. It may represent a stage before recognizable invasive disease, at least in some patients. We believe the term "obstructing bronchial aspergillosis" best describes this entity, because it is a functional description of an entity with no bronchial inflammation in its early stages.
The condition of one of our patients with obstructing bronchial aspergillosis progressed, without treatment, to include a patchy but extensive exudate in the tracheobronchial tree, with invasion of the bronchial mucosa and submucosa by hyphae; we termed this pseudomembranous bronchial aspergillosis. Two patients with bronchial aspergillosis in AIDS have been described elsewhere,33 , 39 each with extensive membranes covering the bronchial mucosa. Local invasion of peribronchial tissue was seen in both patients, with invasion of local blood vessels but without invasion of the pulmonary parenchyma in either case. This pattern could allow dissemination to distant organs without apparent pulmonary involvement. Dissemination was seen in one patient who had focal blood-vessel invasion of the muscularis of the esophagus33 and in our patient with obstructing bronchial aspergillosis and later pseudomembranous bronchial aspergillosis who died with cerebral aspergillosis. This patient received antifungal therapy late in his course, unlike our other two patients with obstructing bronchial aspergillosis, who were treated with a combination of bronchoscopic lavage and itraconazole and in whom no invasive disease developed. This suggests that antifungal treatment is indicated for these patients, to prevent the development of invasive aspergillosis. Both patients received a short course (four to six weeks) of itraconazole, and invasive aspergillosis did not occur. Of course, in the absence of controlled data, we do not know for certain that invasive aspergillosis would have developed in these patients.
As patients with AIDS survive longer, different patterns of disease may emerge. The later development of other functional immunologic abnormalities related to HIV infection or its treatment may allow the appearance of opportunistic infections different from those now well known. We believe that pulmonary aspergillosis is one such example. With earlier recognition and better therapy, the poor results of therapy we have observed in pulmonary aspergillosis in AIDS should improve.
Presented in part at the Sixth International Conference on AIDS, San Francisco, June 20–24, 1990.
We are indebted to the following physicians for data on their patients taking itraconazole: David Gilbert, in Portland, Oreg.; William Marshall, in Boston; David Parenti, in Washington, D.C.; and John Bartlett, in Durham, N.C.; and to Maureen Cervelli for assistance in the preparation of the manuscript.
Source Information
From the Divisions of Infectious Diseases and Clinical Microbiology, Departments of Medicine and Pathology, Santa Clara Valley Medical Center, and the California Institute for Medical Research, both in San Jose, Calif. (D.W.D., D.A.S.); the Division of Infectious Diseases, Department of Medicine, Stanford University Medical School, Stanford, Calif. (D.W.D., D.A.S.); the Infectious Diseases Associates Medical Group, San Francisco (S.E.F.); St. Vincent Medical Center, Los Angeles (M.S.); Community Hospital, Indianapolis (S.N.); the Veterans Affairs Hospital, Martinez, Calif. (H.E.).; and the National Institute for Allergy and Infectious Diseases Mycoses Study Group, Bethesda, Md. (D.W.D., D. A.S.). Address reprint requests to Dr. Stevens at the Santa Clara Valley Medical Center, 751 S. Bascom Ave., San Jose, CA 95128.
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Urschel
CrossRef | Medline39
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- Citing Articles (97)
Citing Articles
1
Tatjana A. Pejčić, Ivana Stanković, Ivanka Djordjević, Dušica Pavlović, Tatjana Radjenović Petković, Tatjana Jeftović Stoimenov, Desa Nastasijević Borovac. (2011) Necrotizing pulmonary aspergillosis caused by anorexic syndrome — a case report. Central European Journal of Medicine
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R. S. Karthikeyan, S. M. Leal, N. V. Prajna, K. Dharmalingam, D. M. Geiser, E. Pearlman, P. Lalitha. (2011) Expression of Innate and Adaptive Immune Mediators in Human Corneal Tissue Infected With Aspergillus or Fusarium. Journal of Infectious Diseases 204:6, 942-950
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John W. Baddley. (2011) Clinical risk factors for invasive aspergillosis. Medical Mycology 49:S1, S7-S12
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Cristina Cunha, Fernando Rodrigues, Teresa Zelante, Franco Aversa, Luigina Romani, Agostinho Carvalho. (2011) Genetic susceptibility to aspergillosis in allogeneic stem-cell transplantation. Medical Mycology 49:S1, S137-S143
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Marie Charles, Chantal Le Guellec, Damien Richard, Frédéric Libert. (2011) Niveau de preuve du suivi thérapeutique pharmacologique de l’itraconazole. Thérapie 66:2, 103-108
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Avinash K. Shetty, Yvonne A. Maldonado. 2011. Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome in the Infant. , 622-660.
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David A. Stevens, George L. Melikian. (2011) Aspergillosis in the ‘Nonimmunocompromised’ Host. Immunological Investigations 40:7-8, 751-766
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Bryan Corrin, Andrew G. Nicholson. 2011. Infectious diseases. , 155-262.
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Elly Scheermeyer, Igor E. Agranovski. (2009) Design and evaluation of a new device for fungal spore aerosolization for laboratory applications. Journal of Aerosol Science 40:10, 879-889
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Thomas E. Cleveland, Jiujiang Yu, Natalie Fedorova, Deepak Bhatnagar, Gary A. Payne, William C. Nierman, Joan W. Bennett. (2009) Potential of Aspergillus flavus genomics for applications in biotechnology. Trends in Biotechnology 27:3, 151-157
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Teresa Zelante, Silvia Bozza, Antonella De Luca, Carmen D'angelo, Pierluigi Bonifazi, Silvia Moretti, Gloria Giovannini, Francesco Bistoni, Luigina Romani. (2009) Th17 cells in the setting of Aspergillus infection and pathology. Medical Mycology 47:s1, S162-S169
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Mariska M. Leeflang, Yvette J Debets-Ossenkopp, Caroline E Visser, Rob JPM Scholten, Lotty Hooft, Henk A Bijlmer, Johannes B Reitsma, Patrick MM Bossuyt, Christina M Vandenbroucke-Grauls, Mariska M. Leeflang. 2008. Galactomannan detection for invasive aspergillosis in immunocompromized patients. .
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Jiujiang Yu†, Gary A. Payne†, William C. Nierman†, Masayuki Machida, Joan W. Bennett, Bruce C. Campbell, Jane F. Robens, Deepak Bhatnagar, Ralph A. Dean, Thomas E. Cleveland. (2008) Aspergillus flavus genomics as a tool for studying the mechanism of aflatoxin formation. Food Additives & Contaminants: Part A 25:9, 1152-1157
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Daniel Podzamczer. (2008) Tratamiento de las infecciones oportunistas en pacientes adultos y adolescentes infectados por el virus de la inmunodeficiencia humana en la era del tratamiento antirretroviral de gran actividad. Enfermedades Infecciosas y Microbiología Clínica 26:6, 356-379
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Su W. HII, Jeff D. C. TAM, Bruce R. THOMPSON, Matthew T. NAUGHTON. (2008) Bullous lung disease due to marijuana. Respirology 13:1, 122-127
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John G. Bartlett. 2008. Other HIV-related Pneumonias. , 323-332.
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C.J. Scott, J.S. Lambert, C.B. Taylor, M.B. Poulton. (2007) Invasive Aspergillus fumigatus associated with liver and bone involvement in a patient with AIDS. International Journal of Infectious Diseases 11:6, 550-553
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Khurshid Ahmad Dar, Naveed N. Shah, Rakesh Bhargava, Zuber Ahmed, Deepak K. Pandey, Nisar H. Dar, Arshad A. Bachh, Md S. Akhtar, Faiz Ahmed, Veena Maheshwari. (2007) Endobronchial Aspergilloma in a 30-year-old Man. Journal of Bronchology 14:3, 207-209
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Renaud Gueret, Gourang P. Patel, David Simon, Robert A. Balk. (2007) Invasive Aspergillosis. Clinical Pulmonary Medicine 14:4, 197-205
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S. Perkhofer, G. Blum, C. Speth, A. Mayr, M. P. Dierich, C. Lass-Flörl. (2007) Influence of amphotericin B and amphotericin B colloidal dispersion on the functions of human phagocytes in defence against Aspergillus species. European Journal of Clinical Microbiology & Infectious Diseases 26:6, 413-417
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Valério R. Aquino, Luciano Z. Goldani, Alesssandro C. Pasqualotto. (2007) Update on the contribution of galactomannan for the diagnosis of invasive aspergillosis. Mycopathologia 163:4, 191-202
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John C.M. Brust. 2007. Cannabis. , 273-314.
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Yvonne A. Maldonado. 2006. Acquired Immunodeficiency Syndrome in the Infant. , 667-692.
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Teresa Zelante, Claudia Montagnoli, Silvia Bozza, Silvia Bellocchio, Pierluigi Bonifazi, Antonella De Luca, Giovanni Bistoni, Paolo Mosci, Luigina Romani. (2006) Manipulating immunity against Aspergillus fumigatus. Medical Mycology 44:s1, 237-243
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Christopher P. Johnson, Charles E. Edmiston, Yong-Ran Zhu, Mark B. Adams, Allan M. Roza, Viswanath Kurup. (2005) A Murine Model of Invasive Aspergillosis: Variable Benefit of Interferon-Gamma Administration under In Vitro and In Vivo Conditions. Surgical Infections 6:4, 397-407
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Vladimir Sabayev, Richard H. Savel, Angela Schiteanu, Deborah Asnis, Alice Veloudios. (2005) Invasive Aspergillosis-Associated Pulmonary Artery Pseudoaneurysm: A Rare Cause of Hemoptysis in an HIV-Infected Patient. Clinical Pulmonary Medicine 12:5, 297-300
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H. Sambatakou, D. W. Denning. (2005) Invasive pulmonary aspergillosis transformed into fatal mucous impaction by immune reconstitution in an AIDS patient. European Journal of Clinical Microbiology & Infectious Diseases 24:9, 628-633
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Gulru POLAT, Gulcan URPEK, Ufuk YILMAZ, Melih BUYUKSIRIN, Serpil KARADAG POLAT, Servet ULUER, Gultekin TIBET. (2005) Successful treatment of invasive pulmonary aspergillosis in an immunocompetent host. Respirology 10:3, 393-395
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Fernanda Silveira, David L Paterson. (2005) Pulmonary fungal infections. Current Opinion in Pulmonary Medicine 11:3, 242-246
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Cornelia Lass-Florl, E. Gunsilius, G. Gastl, M. Freund, M. P. Dierich, A. Petzer. (2005) Clinical evaluation of Aspergillus-PCR for detection of invasive aspergillosis in immunosuppressed patients. Klinische Bewertung der Aspergillus-PCR zum Nachweis der invasiven Aspergillose bei immunsupprimierten Patienten. Mycoses 48:s1, 12-17
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S. Bellocchio, S. Bozza, C. Montagnoli, K. Perruccio, R. Gaziano, L. Pitzurra, L. Romani. (2005) Immunity to Aspergillus fumigatus : the basis for immunotherapy and vaccination. Medical Mycology 43:s1, 181-188
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Eva Castañer, Xavier Gallardo, Josep Maria Mata, Lola Esteba. (2004) Radiologic approach to the diagnosis of infectious pulmonary diseases in patients infected with the human immunodeficiency virus. European Journal of Radiology 51:2, 114-129
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David A. Stevens. (2004) Vaccinate Against Aspergillosis! A Call to Arms of the Immune System. Clinical Infectious Diseases 38:8, 1131-1136
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Michelle D. Furler, Thomas R. Einarson, Margaret Millson, Sharon Walmsley, Reina Bendayan. (2004) Medicinal and Recreational Marijuana Use by Patients Infected with HIV. AIDS Patient Care and STDs 18:4, 215-228
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D. Buchheidt, A. Weiss, S. Reiter, G. Hartung, R. Hehlmann. (2003) Pseudomembranous tracheobronchial aspergillosis: a rare manifestation of invasive aspergillosis in a non-neutropenic patient with Hodgkin's disease. Fallbericht. Pseudomembranose tracheobronchiale Aspergillose: Seltene Manifestation einer Aspergillus-Infektion bei einer nicht-neutropenischen Patientin mit Morbus Hodgkin. Mycoses 46:1-2, 51-55
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Kieren A Marr, Thomas Patterson, David Denning. (2002) Aspergillosis. Infectious Disease Clinics of North America 16:4, 875-894
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M. Cornet, L. Fleury, C. Maslo, J.-F. Bernard, G. Brücker. (2002) Epidemiology of invasive aspergillosis in France: a six-year multicentric survey in the Greater Paris area. Journal of Hospital Infection 51:4, 288-296
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Cornelia Lass-Florl, M. Nagl, E. Gunsilius, C. Speth, H. Ulmer, R. Wurzner. (2002) In vitro studies on the activity of amphotericin B and lipid-based amphotericin B formulations against Aspergillus conidia and hyphae . In vitro-Empfindlichkeit von Aspergillus-Konidien und -Hyphen gegenuber Amphotericin B und Amphotericin B-Lipidpraparationen. Mycoses 45:5-6, 166-169
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Jeanne M. Wallace. (2001) The Role of Bronchoscopy in Pulmonary Mycoses. Journal of Bronchology 8:3, 213-221
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Donald P. Tashkin. (2001) Effects of Smoked Marijuana on the Lung and Its Immune Defenses. Journal of Cannabis Therapeutics 1:3-4, 87-102
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Javier Afeltra, Jacques F. G. M. Meis, Johan W. Mouton, Paul E. Verweij. (2001) Prevention of invasive aspergillosis in AIDS by sulfamethoxazole. AIDS 15:8, 1067-1068
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Cornelia Lass-Florl, Johannes Aigner, Eberhard Gunsilius, Andreas Petzer, David Nachbaur, Gunther Gastl, Hermann Einsele, Jurgen Loffler, Manfred P. Dierich, Reinhard Wurzner. (2001) Screening for Aspergillus spp. using polymerase chain reaction of whole blood samples from patients with haematological malignancies. British Journal of Haematology 113:1, 180-184
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Donald P. Tashkin. (2001) Airway effects of marijuana, cocaine, and other inhaled illicit agents. Current Opinion in Pulmonary Medicine 7:2, 43-61
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K. J. Holding, M. S. Dworkin, P.-C. T. Wan, D. L. Hanson, R. M. Klevens, J. L. Jones, P. S. Sullivan, . (2000) Aspergillosis among People Infected with Human Immunodeficiency Virus: Incidence and Survival. Clinical Infectious Diseases 31:5, 1253-1257
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Gregory B Pott, Tamara K Miller, Julie A Bartlett, Jeffrey S Palas, Claude P Selitrennikoff. (2000) The Isolation of FOS-1, a Gene Encoding a Putative Two-Component Histidine Kinase from Aspergillus fumigatus. Fungal Genetics and Biology 31:1, 55-67
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C Lass-Flörl, P.-M Rath, D Niederwieser, G Kofler, R Würzner, A Krezy, M.P Dierich. (2000) Aspergillus terreus infections in haematological malignancies: molecular epidemiology suggests association with in-hospital plants. Journal of Hospital Infection 46:1, 31-35
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Eleftherios Mylonakis, Maria Paliou, Paul E Sax, Paul R Skolnik, Miriam J Baron, Josiah D Rich. (2000) Central Nervous System Aspergillosis in Patients with Human Immunodeficiency Virus Infection. Medicine 79:4, 269-280
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D. A. Stevens, V. L. Kan, M. A. Judson, V. A. Morrison, S. Dummer, D. W. Denning, J. E. Bennett, T. J. Walsh, T. F. Patterson, G. A. Pankey. (2000) Practice Guidelines for Diseases Caused by Aspergillus. Clinical Infectious Diseases 30:4, 696-709
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A. Glasmacher, C. Hahn, E. Molitor, G. Marklein, T. Sauerbruch, I. G. H. Schmidt-Wolf. (1999) Itraconazole trough concentrations in antifungal prophylaxis with six different dosing regimens using hydroxypropyl-beta-cyclodextrin oral solution or coated-pellet capsules. Mycoses 42:11-12, 591-600
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Seema Abbasi, Jerry L. Shenep, Walter T. Hughes, Patricia M. Flynn. (1999) Aspergillosis in Children with Cancer: A 34‐Year Experience. Clinical Infectious Diseases 29:5, 1210-1219
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A. Glasmacher, C. Hahn, C. Leutner, E. Molitor, E. Wardelmann, C. Losem, T. Sauerbruch, G. Marklein, I. G. H. Schmidt-Wolf. (1999) Breakthrough invasive fungal infections in neutropenic patients after prophylaxis with itraconazole. Mycoses 42:7-8, 443-451
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Adrian I. Popp, Mary H. White, Tariq Quadri, Louise Walshe, Donald Armstrong. (1999) Amphotericin B with and without itraconazole for invasive aspergillosis: A three-year retrospective study. International Journal of Infectious Diseases 3:3, 157-160
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Suhail Raoof, Mark J. Rosen, Faroque A. Khan. (1999) ROLE OF BRONCHOSCOPY IN AIDS. Clinics in Chest Medicine 20:1, 63-76
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David L. Paterson, Nina Singh. (1999) Invasive Aspergillosis in Transplant Recipients. Medicine 78:2, 123-138
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Cornelia Lass-Florl, Georg M. Salzer, Thomas Schmid, Walter Rabl, Hanno Ulmer, Manfred P. Dierichi. (1999) Pulmonary Aspergillus colonization in humans and its impact on management of critically ill patients. British Journal of Haematology 104:4, 745-747
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HETTLICH, KUPPER, WEHLE, PFITZER. (1998) Aspergillus in the Papanicolaou stain: morphology, fluorescence and diagnostic feasibility. Cytopathology 9:6, 381-388
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R.P. Woitas, J.K. Rockstroh, A. Theisen, C. Leutner, T. Sauerbruch, U. Spengler. (1998) Changing role of invasive aspergillosis in AIDS — a case control study. Journal of Infection 37:2, 116-122
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P.J. Richards, P. Armstrong, J.M. Parkin, A. Sharma. (1998) Chest imaging in AIDS. Clinical Radiology 53:8, 554-566
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Gerald Nash, Rebecca Irvine, Russell L Kerschmann, Brian Herndier. (1997) Pulmonary aspergillosis in acquired immune deficiency syndrome: Autopsy study of an emerging pulmonary complication of human immunodeficiency virus infection. Human Pathology 28:11, 1268-1275
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Brent E. Hoozen, Carroll E. Cross. (1997) Marijuana. Clinical Reviews in Allergy & Immunology 15:3, 243-269
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S. Bretagne, A. Marmorat-Khuong, M. Kuentz, J.-P. Latgé, E. Bart-Delabesse, C. Cordonnier. (1997) Serum Aspergillus galactomannan antigen testing by sandwich ELISA: Practical use in neutropenic patients. Journal of Infection 35:1, 7-15
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Eleftherios Mylonakis, Josiah Rich, Paul R. Skolnik, Douglas F. De Orchis, Timothy Flanigan. (1997) Invasive Aspergillus Sinusitis in Patients with Human Immunodeficiency Virus Infection. Medicine 76:4, 249-255
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Mitchell S. Cappell. (1997) THE PANCREAS IN AIDS. Gastroenterology Clinics of North America 26:2, 337-365
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(1997) Medicinal Marijuana?. New England Journal of Medicine 336:16, 1184-1187
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Grace Y. Minamoto, Amy S. Rosenberg. (1997) FUNGAL INFECTIONS IN PATIENTS WITH ACQUIRED IMMUNODEFICIENCY SYNDROME. Medical Clinics of North America 81:2, 381-409
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DAIVA SHETTY, NEELAM GIRI, CORINA E. GONZALEZ, PHILIP A. PIZZO, THOMAS J. WALSH. (1997) Invasive aspergillosis in human immunodeficiency virus-infected children. The Pediatric Infectious Disease Journal 16:2, 216-221
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G. L. Sharma, P. K. Bhatnagar, D. Chattopadhya, P. U. Sarma. (1997) Analysis of HIV seropositive thalassemic children for antibodies specific toAspergillus fumigatus by luminescent immunoassay. Journal of Clinical Laboratory Analysis 11:6, 343-345
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Nicholas J. Vander Els, Diane E. Stover. (1996) APPROACH TO THE PATIENT WITH PULMONARY DISEASE. Clinics in Chest Medicine 17:4, 767-785
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Scott F. Davies, George A. Sarosi. (1996) FUNGAL PULMONARY COMPLICATIONS. Clinics in Chest Medicine 17:4, 725-744
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Elias K. Manavathu, George J. Alangaden, Stephen A. Lerner. (1996) A comparative study of the broth micro- and macro-dilution techniques for the determination of the in vitro susceptibility of Aspergillus fumigatus. Canadian Journal of Microbiology 42:9, 960-964
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K. Dalhoff, J. Braun, S. Gatermann, H. Djonlagic. (1996) FatalAspergillus pericarditis in acquired immunodeficiency syndrome. Intensive Care Medicine 22:8, 831-833
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K. Arastéhi, F. Staib, G. Grosse, U. Futh, M. L'Age. (1996) Cryptococcosis in HIV Infection of Man: An epidemiological and Immunological Indicator?. Zentralblatt für Bakteriologie 284:2-3, 153-163
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David W. Denning. (1996) Aspergillosis: diagnosis and treatment. International Journal of Antimicrobial Agents 6:3, 161-168
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Lawrence R. Lee, Timothy J. Sullivan. (1995) Aspergillus sphenoid sinusitis-induced orbital apex syndrome in HIV infection. Australian and New Zealand Journal of Ophthalmology 23:4, 327-331
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G. Tronchin, J. P. Bouchara, M. Ferron, G. Larcher, D. Chabasse. (1995) Cell surface properties of Aspergillus fumigatus conidia: correlation between adherence, agglutination, and rearrangements of the cell wall. Canadian Journal of Microbiology 41:8, 714-721
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A.J. Martínez, M. Sell, T. Mitrovics, G. Stoltenburg-Didinger, J.R. Iglesias-Rozas, M.A. Giraldo-Velásquez, G. Gosztonyi, V. Schneider, J. Cervós-Navarro. (1995) The Neuropathology and Epidemiology of AIDS. Pathology - Research and Practice 191:5, 427-443
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C. Girmenia, R. Gastaldi, P. Martino. (1995) Catheter-related cutaneous aspergillosis complicated by fungemia and fatal pulmonary infection in an HIV-positive patient with acute lymphocytic leukemia. European Journal of Clinical Microbiology & Infectious Diseases 14:6, 524-526
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Maria R. Gonzalez-Crespo, Juan J. Gomez-Reino. (1995) Invasive aspergillosis in systemic lupus erythematosus. Seminars in Arthritis and Rheumatism 24:5, 304-314
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S. R. Lewin, J. Hoy, S. M. Crowe, C. F. McDonald. (1995) The role of bronchoscopy in the diagnosis and treatment of pulmonary disease in HIV-infected patients. Australian and New Zealand Journal of Medicine 25:2, 133-139
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M. Birch, N. Nolard, G. S. Shankland, D. W. Denning. (1995) DNA typing of epidemiologically-related isolates of Aspergillus fumigatus*. Epidemiology and Infection 114:01, 161
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Leland S. Rickman, William R. Freeman. (1995) Medical and Virological Aspects of Ocular Human Immunodeficiency Virus Infection for the Ophthalmologist. Seminars in Ophthalmology 10:2, 91-110
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Bart -Jan Kullberg, Jan W. Wout. (1994) Cytokines in the treatment of fungal infections. Biotherapy 7:3-4, 195-210
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David W. Denning. (1994) Treatment of invasive aspergillosis. Journal of Infection 28, 25-33
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J. Beyer, Claudia Weyer, W. Siegert, G. Barzen, Gisa Risse, S. Schwartz, K. Dullenkopf. (1994) Use of amphotericin B aerosols for the prevention of pulmonary aspergillosis. Infection 22:2, 143-148
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Pierluigi Viale, Angela Di Matteo, Marzio Sisti, Franco Voltolini, Carlo Paties, Francesco Alberici. (1994) Isolated Kidney Localization of Invasive Aspergillosis in a Patient with AIDS. Scandinavian Journal of Infectious Diseases 26:6, 767-770
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Joel B. Epstein, Crispian Scully. (1993) Oral Adverse Effects of Medical Management in Patients With HIV Infection. Aids Patient Care 7:6, 304-311
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M. Wright, S. Fikrig, J. O. Haller. (1993) Aspergillosis in children with acquired immune deficiency. Pediatric Radiology 23:6, 492-494
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G. Todeschini, C. Murari, R. Bonesi, G. Pizzolo, G. Amaddi, A. Ambrosetti, S. Cerù, I. Piacentini, N. Martini, P. Montresor, G. Perona. (1993) Oral itraconazole plus nasal amphotericin B for prophylaxis of invasive aspergillosis in patients with hematological malignancies. European Journal of Clinical Microbiology & Infectious Diseases 12:8, 614-618
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S. Marie. (1993) Diseases and drug-related interventions affecting host defence. European Journal of Clinical Microbiology & Infectious Diseases 12:S1, S36-S41
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Lynn W. Kitchen, James A. Ross, Jaime E. Hernandez, Antonio L. Zarraga, Frances J. Mather. (1993) Effect of administration of diethylcarbamazine with and without fluconazole on experimental fungal infections in mice. International Journal of Antimicrobial Agents 2:4, 237-246
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A. Serrano-Gonzalez, J. M. Merino-Arribas, M. J. Ruiz-Lopez, J. Casado-Flores. (1992) Invasive pulmonary aspergillosis with pneumopericardium and pneumothorax. Pediatric Radiology 22:8, 601-602
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Lynn W. Kitchen, James A. Ross, Jaime E. Hernandez, Antonio L. Zarraga, Frances J. Mather. (1992) Effect of administration of diethylcarbamazine on experimental bacterial and fungal infections in mice. International Journal of Antimicrobial Agents 1:5-6, 259-267
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D. SMITH, V. VELDE, R. WOESTENBORGHS, B. G. GAZZARD. (1992) The pharmacokinetics of oral itraconazole in AIDS patients. Journal of Pharmacy and Pharmacology 44:7, 618-619
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HENRIK SCHØNHEYDER, STEEN HOFFMANN, HENRIK ELVANG JENSEN, BIRGIT FISCHER HANSEN, MARIA-B. FRANZMANN. (1992) Aspergillus fumigatus fungaemia and myocarditis in a patient with acquired immunodeficiency syndrome. APMIS 100:7-12, 605-608
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B. Dupont, J.R. Graybill, D. Armstrong, R. Laroche, J.E. Touzé, L.J. Wheat. (1992) Fungal infections in AIDS patients. Medical Mycology 30:s1, 19-28
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Cabot, Richard C.Scully, Robert E., Mark, Eugene J., McNeely, William F., McNeely, Betty U., Hassoun, P.M.Mark, E.J.. (1991) Case 43-1991. New England Journal of Medicine 325:17, 1228-1239
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(1991) Pulmonary Aspergillosis in AIDS. New England Journal of Medicine 325:5, 355-357
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