July 1999
Aspergillosis was included as an AIDS-defining opportunistic infection in the initial case definition of AIDS developed by the Centers for Disease Control in 1982 (CDC 1982, Jaffe and Selik, 1984). However, it was subsequently dropped from the CDC case definition due to lack of evidence that either CD4 lymphopenia was a predisposing factor or that there was any significant increase in the incidence of invasive aspergillosis among HIV-infected patients (Schaffner 1984). That subsequent immunologic studies have indicated defects in macrophage/monocyte function in HIV-infected patients (Roilides et al., 1993, Bender et al., 1988), and that a significant proportion of reported cases have not been associated with recognized risk factors for invasive aspergillosis (Minamoto et al., 1992, Lortholary and Dupont, 1997) suggest that it should be reinstated as an AIDS-defining condition, at least for those cases not associated with neutropenia or corticosteroids.
Aspergillosis was rarely reported in HIV patients prior to 1990; since then there has been a surge of reports predominantly from North America and Europe (Denning et al., 1991, Minamoto et al., 1992, Lortholary et al., 1993, Januszewska et al., 1993, Kemper et al., 1993, Keating et al., 1994, Miller et al., 1994, Staples et al., 1995, Kronish et al., 1996, Addrizzo-Harris et al., 1997, Woitas et al., 1998). The paucity of reported cases during the early years of the HIV epidemic may have been partly accounted for by the short median survival time of two years from the development of the first AIDS-defining illness. As median survival improved in associated with the introduction of antiretrovirals and prophylactic therapies, the duration of susceptibility to aspergillosis also increased. Furthermore, certain medical advances in AIDS care were often associated with neutropenia (e.g. zidovudine, ganciclovir and cytotoxic chemotherapy for Kaposi's sarcoma) or involved the use of corticosteroids (e.g. in moderate to severe PCP), both recognized risk factors for invasive aspergillosis.
Determination of the true incidence of aspergillosis among HIV-infected patients has been hampered by the difficulty in establishing an antemortem diagnosis which was possible in only 71 % of patients (Khoo and Denning, 1994). However among five autopsy series, antemortem diagnosis was established in only 9 (22 %) of the 41 reported cases (Khoo and Denning, 1994). Among retrospective reviews of clinically diagnosed disease, the incidence ranged from 0.9 % to 8.6 %, compared to twelve autopsy series where the prevalence ranged from 0-12 % (mean 4 %) (Khoo and Denning, 1994).
Pediatric studies have indicated that compared to normal controls, macrophages from HIV-infected children exhibit reduced phagocytic activity and impaired inhibition of germination of intracellular A. fumigatus (Roilides et al., 1993, Roilides et al., 1993A). Corticosteroid therapy and neutropenia (less than 500 x 106/L) were previously reported in 39 %, and 6-50 % of evaluable patients, respectively (Khoo and Denning, 1994). Severe CD4 lymphopenia appears to be a risk factor for aspergillosis in HIV-infected patients. Almost all cases are diagnosed in late stage HIV disease, at a median of 10-26 months following the first AIDS defining disease (Khoo and Denning, 1994), at a time when the CD4 count is typically less than 50/mm3. Only occasional cases have been reported with CD4 counts greater than 200/mm3. As for HIV negative patients, previous lung damage resulting in cystic or cavitary lesions may be predispose to aspergilloma (Addrizzo-Harris et al., 1997).
A small case-control study of HIV-related invasive aspergillosis was recently reported, including ten cases and ten HIV-infected controls, matched with respect to age, HIV risk factor, gender and duration of HIV-infection (Woitas et al., 1998). The aspergillosis patients had more AIDS-defining events (median 3.5 versus 2, p<0.05), longer median survival time since the first AIDS-defining illness (median survival 31.5 months versus 20.5 months, p<0.005), and lower CD4 counts (median 7/mm3 versus 27/mm3, p<0.05) compared to controls. There was a trend to more of the aspergillosis patients having severe neutropenia (defined as less than 700 neutrophils 106/litre) compared to controls. In another case-control study, an increased incidence of neutropenia (defined as < 1,000/mm3) was observed among 11 HIV-positive patients with IPA compared with 20 historical controls (Tumbarello et al., 1993). However, a more convincing definition of neutropenia is < 500/mm3.
Although antibacterial use is common in advanced HIV disease, this is unlikely to represent a risk factor for aspergillosis given that the portal of entry for most cases is by inhalation of air-borne conidia, and that there is no competing microbial flora at the point of initial contact in the lower respiratory tract (Schaffner 1991). However, the significance of other suspected risk factors remains unclear including marijuana use, alcohol, injection drug use, and recent or concomitant pneumonia due to Pneumocystis carinii, cytomegalovirus or various bacteria.
In a previous review, A. fumigatus accounted for 84 % of cases where the organism was recovered in culture and identified to the species level; A flavus (8 %), A. niger (5 %), and A. terreus (3 %) accounted for the remaining cases (Khoo and Denning, 1994).
HIV-related aspergillosis may present with a wide variety of clinical syndromes, although disease involving one or another portion of the respiratory tract was present in 85 % of previously reported cases (Khoo and Denning, 1994). Non-respiratory tract sites of involvement were reported in 25 % of cases and 2 or more organs were involved in 16 % (Khoo and Denning, 1994).
Lower respiratory tract infections due to Aspergillus spp. may present with one of five clinical syndromes including: i) invasive pulmonary aspergillosis; ii) obstructing bronchial aspergillosis; iii) ulcerative or pseudomembranous tracheobronchitis; iv) aspergilloma; v) and rarely empyema (Denning et al., 1991, Khoo and Denning, 1994, Lortholary et al., 1993, Miller et al., 1994, Woods and Goldsmith, 1990, Keating et al., 1994, Addrizzo-Harris et al.,1997).
IPA accounted for 71 % of all cases of aspergillosis in AIDS in a previous review (Khoo and Denning, 1994). The most frequent presenting symptoms among 93 definite cases included fever (86 %), cough (70 %), dyspnoea (66 %), pleuritic chest pain (27 %), malaise/anorexia/weight loss (13 %), neurologic symptoms 11 %, and hemoptysis (5 %) (Mylonakis et al., 1998). Hemoptysis was reported more often as a complication of cavitary disease compared to other forms of respiratory tract aspergillosis (Miller et al., 1994).
Various radiologic patterns were observed including localized or diffuse pulmonary infiltrates, nodules, or cavities (Denning et al., 1991, Khoo and Denning, 1994, Gallant, 1996). The cavities are usually located in the upper lung zones, and although both thick and thin walls have been reported, radiologic-pathologic correlation suggests that they are typically thick-walled (Staples et al., 1995). Invasive pulmonary aspergillosis in HIV-negative patients is seldom associated with diffuse pulmonary infiltrates, although this presentation has been reported in occasional HIV positive adults (Denning et al., 1991, Lortholary et al., 1993) and children (Shetty et al., 1997). Some patients with diffuse infiltrates on chest radiograph who did not undergo lung biopsy or post-mortem examination may have had unrecognized co-infections with organisms more frequently associated with diffuse infiltrates such, as Pneumocystis carinii or CMV. The chest radiology of 44 definite cases of IPA included the following findings, either alone or in combination: consolidation(s)/infiltrate(s) 73 %; cavity(ies) (34 %); nodule(s) (14 %); adenopathy (11 %); pleural effusion(s) (7 %); and cardiomegaly (5 %) (Mylonakis 1998). The differential diagnosis of cavitary pulmonary lesions in HIV positive individuals is wide and may include various bacterial, fungal, and mycobacterial organisms, in addition to neoplasia and vasculitis (Gallant, 1996). However in patients with advanced HIV disease and severe CD4 lymphopenia (e.g. less than 50 cells/mm3) tuberculosis is unlikely to result in cavitary disease, a presentation usually associated with a more intact immune response in patients with earlier HIV disease.
A definitive diagnosis of invasive aspergillosis is based upon histologically proven disease in addition to cases where percutaneous needle aspirates of lung yielded positive cultures for Aspergillus species. Probable cases include those with a new pulmonary infiltrate or cavitary lesion associated with recovery of Aspergillus species from bronchoalveolar lavage fluid culture, in the absence of other respiratory tract pathogens (Lortholary et al., 1993, Denning et al., 1991). Sputum culture is neither sensitive nor specific for the diagnosis, and Aspergillus may be a commensal in the respiratory tract of at least 4 % of AIDS patients (Pursell et al., 1992, Khoo and Denning 1994). Among 972 AIDS patients followed at one center, 45 had Aspergillus recovered from the respiratory tract (sputum 31, bronchoscopy 14); 5 (11 %) were documented to have invasive aspergillosis, and the other 40 (89 %) were considered to be colonized (Pursell 1992). In contrast, Aspergillus recovered from the respiratory tract in a pediatric HIV population was highly predictive of invasive disease (Shetty et al., 1997). However in other immunocompromised patient populations, particularly neutropenic patients, recovery of Aspergillus in sputum cultures in the setting of a compatible clinical presentation is highly predictive of invasive disease and should be considered to be present until proven otherwise (Yu 1986). Similarly in HIV-infected patients with lower respiratory tract disease, demonstration of Aspergillus in the sputum should prompt further investigations in order to establish or exclude a diagnosis. Due to the generally slower tempo of disease in many AIDS cases compared to those with hematologic malignancy, empiric antifungal therapy may not be considered necessary while investigating patients with Aspergillus in sputum, or other suggestive findings.
Diagnostic procedures to be considered in patients with compatible presentations include: CT scan, preferably high resolution computed tomography (HRCT) (Pompili et al., 1998); bronchoscopy with bronchoalveolar lavage; and possibly percutaneous transthoracic needle aspiration (Khoo and Denning 1994, Pervez et al., 1985). HRCT appears to be a sensitive and non-invasive method for demonstrating lesions suggestive of IPA, such as nodules associated with the halo sign or cavitation (Pompili et al., 1998). However disease involving the airways shows no characteristic radiologic pattern (Pompili et al., 1998). Transbronchial biopsy and bronchial brushings should not be routinely performed and may only add expense and risk of complications (Lewin et al., 1995).
Serodiagnostic methods remain investigational and none are widely accepted; similarly, PCR-based assays for Aspergillus have yet to improve upon conventional diagnostic methods (Muller et al., 1999).
Obstructing bronchial aspergillosis (Denning et al., 1991, Januszewska et al., 1993, Le Gros and Stern, 1988) has rarely been described in HIV-infected patients, and presenting symptoms may include cough, dyspnoea, wheeze, fever and hemoptysis. The chest radiograph may show areas of atelectasis in the lower lung zones. A characteristic feature is the expectoration of large mucoid casts containing Aspergillus organisms. The diagnosis is established by bronchoscopy with bronchoalveolar lavage (BAL), where the same casts may be demonstrated and the organism recovered in BAL fluid. Although this is considered to be a non-invasive form of aspergillosis with little bronchial inflammation in the early stages, there may be progressive disease and tissue invasion resulting in pseudomembranous or ulcerative tracheobronchitis.
Pseudomembranous or ulcerative tracheobronchitis due to Aspergillus is also rare, and patients may present with dyspnoea, wheeze, cough, hemoptysis and fever. Chest radiograph and CT scan are generally unhelpful unless there is associated invasive disease involving lung parenchyma (Pompili et al., 1998, Lortholary et al., 1993, Pervez et al., 1985, Kemper et al., 1993). The diagnosis is established by bronchoscopy and BAL fluid culture. Involvement of adjacent lung parenchyma may be seen in 50 %, and extra pulmonary dissemination in 25 % of cases (Khoo and Denning, 1994). A few cases of invasive tracheobronchial aspergillosis have also been described in HIV-negative patients with hematologic malignancy (Sancho et al., 1997).
Pulmonary aspergilloma in AIDS has been reported now in 15 patients (Lombardo 1987, Hohler et al., 1995, Torrents et al., 1991, Keating et al., 1994, Miller et al., 1994, Addrizzo-Harris et al., 1997). Prior associated lung disease which appeared to predispose to development of aspergilloma by way of cavity formation or cystic lesions included not only tuberculosis but also PCP (Addrizzo-Harris et al., 1997). Two of these cases were reported to have died of massive hemoptysis (Lombardo 1987, Addrizzo-Harris et al., 1997). Among 7 cases with aspergilloma who received either intracavitary or systemic antifungal therapy, radiologic improvement was noted only in one (Torrents 1991). In a series of 25 cases of aspergilloma (10 HIV-infected and 15 HIV-negative) disease progression occurred in 4 of the 8 (50 %) HIV-positive individuals compared to 1 of 13 (8 %) of those who were HIV-negative, where follow-up evaluation was available (Addrizzo-Harris 1997). The same proportions of patients in the two groups died during the period of follow-up. All of those with disease progression had CD4 counts below 100 cells/mm3, although 2 of the 10 HIV-infected patients in this series had CD4 counts above 500/mm3. Severe hemoptysis, defined as greater than 150 ml/day was observed in 33 % and 10 % of the HIV-negative and HIV-positive groups, respectively.
Aspergillus sinusitis has been reported in 29 HIV-infected patients (Teh et al., 1995, Kronish et al., 1995; Lee et al., 1995, Johnson et al., 1999). A. fumigatus accounted for all but one of 25 cases where the species was indicated. Evidence of progressive disease with intracranial, orbital, or mastoid (or other bone) involvement was documented in 15, 10, and 7 of the 29 cases, respectively. Among the 27 cases diagnosed antemortem, 22 received amphotericin B or a lipid formulation of amphotericin B. Itraconazole therapy was given either initially or following amphotericin B therapy in 10 of 27 patients. Topical therapy was given to 6 of 27 patients, only one of whom did not also receive systemic antifungal therapy. Twenty of the 27 patients diagnosed antemortem were also treated surgically with a variety of procedures directed to the sinuses and/or the adjacent orbital cavity, as well as debulking procedures for areas of intracranial extension. Among the 29 cases, 23 died, all but one attributed to progressive aspergillosis. Only 2 of the 27 treated patients were considered to have responded to therapy; one had middle ear disease treated topically with clotrimazole, and the other had ethmoid sinusitis extending into the orbit treated surgically in addition to both intravenous and local amphotericin. The longest survivors in one series were 2 patients who also received highly active antiretroviral therapy (see Management ) (Johnson et al., 1999).
Otomastoiditis, which originates from the external auditory canal is a slowly progressive condition involving osteomyelitis of the base of the skull, particularly the temporal bone. It occurs almost exclusively in diabetic patients with the causative organism being Pseudomonas aeruginosa. Rarely, other organisms may be responsible and Aspergillus has been described in patients with other immunodeficiency states such as neutropenia (Phillips, 1990). Ten cases have been described in HIV-infected patients (Lortholary et al., 1993, Reiss et al., 1991, Strauss and Fine, 1991, Lyos et al., 1993, Hall and Farrior, 1993, Yates et al., 1997, Diop et al., 1998, Muñoz and Martinez-Chamorro, 1998). All but one of these cases had advanced HIV disease (Strauss and Fine 1991). This latter case was less well documented. Eight of the ten cases died, three due to progressive aspergillosis involving central nervous system extension (survival up to 10 months), and five died of other causes (survival ranging from 2 weeks to 8 months). One patient with advanced HIV disease was still alive at 7 months following mastoidectomy in combination with amphotericin B initially, followed by itraconazole and topical 1 % povidone iodine. Seven of the ten patients received systemic antifungal therapy with amphotericin B and/or itraconazole and five patients underwent mastoidectomy. Four of the nine severely immunocompromised patients were considered to have had a clinical response to therapy (Reiss 1991, Lyos 1993, Yates 1997). All four of these patients received systemic antifungal therapy, and three of the four underwent mastoidectomy.
The clinical presentation of invasive external otitis due to Aspergillus includes otalgia and is usually associated with reduced hearing followed by development of a facial nerve palsy. Other features may include fever, and progressive disease with intracranial complications such as venous sinus thrombosis and brain abscess. Combined systemic antifungal therapy with amphotericin B, or a lipid formulation of amphotericin B, or itraconazole in combination with surgical débridement appears to be the optimal approach to management. CT scan is the preferred imaging method for demonstration of bone destruction, whereas MR had better sensitivity for inflammatory changes in the 7th and 8th cranial nerves (Muñoz et al., 1998).
Central nervous system (CNS) aspergillosis is the most common extrapulmonary site of disease among HIV-infected patients (Khoo and Denning, 1994). In one series, the proportion of patients with documented CNS involvement was 32 % (Minamoto et al., 1992). Invasive pulmonary aspergillosis may spread hematogenously resulting in CNS involvement. In other instances, this complication may develop by contiguous spread from invasive sinusitis (Kronish et al., 1996, Teh et al., 1995), or progression of invasive external otitis (otomastoiditis) (Diop et al., 1998, Strauss and Fine, 1991). The response to treatment has been particularly dismal among immunocompromised patients in general with CNS aspergillosis, with no responders among 7 patients who received at least 14 days of intravenous amphotericin B (Denning, 1996). However, the majority of cases (77 %) reviewed were untreated, since the diagnosis was usually not recognized antemortem (Denning 1996). A single case of Aspergillus spinal epidural abscess has been reported in an AIDS patient (Go 1993).
Cardiac aspergillosis in AIDS has been reported to involve endocardium, myocardium, and pericardium (Minamoto et al., 1992, Lortholary et al., 1993, Henochowicz et al., 1985, Klapholz et al., 1991, Cox et al., 1990, Woods et al., 1990). The clinical presentation may include fever, features of cardiac dysfunction (e.g. congestive heart failure, arrhythmias) or embolic phenomena. Relevant investigations include electrocardiogram, echocardiogram and blood cultures, although the latter are seldom positive. Patients with cardiac involvement frequently have widespread disseminated aspergillosis, often recognized only at autopsy (Schonheyder et al., 1992). Others may have cardiac involvement secondary to direct extension of an adjacent pulmonary focus (Staples et al., 1995).
Isolated genitourinary tract Aspergillus infection is rare and the clinical presentation in HIV infected patients has usually included a combination of constitutional symptoms, flank pain, and in some instances hematuria. Urine cultures are usually negative, unless a fungus ball is present in the collecting system (Halpern 1992, Hood 1998). Twenty-five cases of aspergillosis involving the genitourinary tract have been reported in HIV-infected patients (Just-Nubling et al., 1992, Minamoto et al., 1992, Lortholary et al., 1993, Sambeat et al., 1992, Klapholz et al., 1991, Halpern et al., 1992, Cox et al., 1990, Strauss and Fine, 1991, Woods and Goldsmith, 1990, Salomon et al., 1989, Cervero et al., 1999, Fiteni et al., 1996, Guadano et al., 1994 , Hood, 1998, Kummerle and Wedler, 1998, Martinez-Jabaloyas et al., 1995, Piketty et al., 1993, Viale et al., 1994). Among the 12 reported cases where the Aspergillus species was specified, A. fumigatus and A. flavus. accounted for 10 and 2 cases, respectively.
Disease of one or both kidneys was most common, with only a few cases of prostatitis, or epididymo-orchitis (Hood 1998, Cervero 1999). Among the 20 cases where the extent of disease was specified, 8 had renal involvement which was widely disseminated, usually involving lung, heart and brain. None in this subgroup survived, and the renal involvement was generally recognized only at autopsy (Cox et al., 1990, Klapholz et al., 1991, Minamoto et al., 1992, Lortholary et al., 1993, Woods and Goldsmith, 1990).
Isolated renal involvement has been reported in 10 cases; 7 were unilateral (Lortholary et al., 1993, Klapholz et al., 1991, Halpern et al., 1992, Salomon et al., 1989, Guadano et al., 1994, Viale et al., 1994), and 3 were bilateral (Fiteni 1996, Kummerle 1998, Martinez-Jabaloyas 1995), with or without perinephric extension. Among patients with isolated unilateral renal aspergillosis, 5 were treated with systemic antifungal therapy (amphotericin B or itraconazole); 3 also underwent nephrectomy. Follow-up information available for 3 of these patients indicated that all 3 responded; 2 were still alive at 4 and 8 months, and one 18 months after the diagnosis. Isolated bilateral renal involvement occurred in three patients, 2 of whom died despite systemic antifungal therapy in combination with either tube or needle aspiration drainage. The third patient with bilateral renal disease responded to medical therapy alone but also received highly active antiretroviral therapy (Kummerle et al., 1998) (see Management).
Cutaneous aspergillosis occurs as either a primary infection in which the portal of entry may be a preexisting skin lesion (Diamond et al., 1992), traumatic or burn wound (Denning 1990), or related to occlusive dressings, adhesive tape or arm boards used for securing intravenous infusion sets (McCarthy et al., 1986). Secondary cutaneous infection results from dissemination of pulmonary aspergillosis (Vedder and Schorr, 1969). Both forms of disease have been described mainly in patients with underlying hematologic disease, usually acute leukemia. Cutaneous aspergillosis may present with a variety of lesions including hemorrhagic ulcers, molluscum contagiosum-like papules (Hunt et al., 1992) necrotizing plaques or erythematous induration with overlying pustules (Romero and Hunt 1995).
Seven cases have now been reported in HIV infected patients (Hui et al., 1984, Diamond et al., 1992, Hunt et al., 1992, Romero and Hunt, 1995, Girmenia et al., 1995, Smith and Wallace, 1997). All of these cases appeared to be primary cutaneous disease, with five of seven developing under occlusive dressings at central venous catheter sites. Two patients with central venous catheter site infections subsequently developed pulmonary aspergillosis, one of whom also had multiple positive blood cultures for Aspergillus collected through the central venous catheter before it was removed (Girmenia et al., 1995). A. flavus accounts for most cases of primary cutaneous aspergillosis (Harmon 1993), however among the reported HIV-positive patients, 4 of 5 where the species was determined were due to A. fumigatus and only one was A. flavus (Diamond et al., 1992). The prognosis for primary cutaneous disease appears to be favourable compared other organ involvement; however, there is the potential for progression to disseminated disease (Girmenia et al., 1995).
Management should include: i) the use of non-occlusive dressings and catheter removal, when related to vascular access devices; ii) systemic antifungal therapy with amphotericin B or itraconazole; and iii) possibly surgical excision or debridement (Romero and Hunt, 1995, Hunt et al., 1992).
Other sites of Aspergillus infection in HIV-positive patients are rare but have included muscle (Le Bras et al., 1993, Mylonakis et al., 1996, Van den Bos et al., 1998), mouth, palate, oropharynx (Manfredi et al., 1994, Khoo and Denning, 1994), esophagus, stomach, small intestine and colon (Cappell and Hassan, 1991). Other intraabdominal sites include the spleen, a liver abscess (Brunetti et al., 1989) and a peripancreatic abscess (Bhatt and Cappell, 1990). Other head and neck locations include the thyroid (Martinez-Ocana et al., 1993), epiglottis (Sriskandabalan and Roy, 1996) and larynx (Delbrouck et al., 1998, Kingdom and Lee, 1996). One case of endogenous Aspergillus endophthalmitis has been reported (Petersen et al., 1997).
Twelve cases of aspergillosis had been reported in HIV-positive pediatric patients (Shetty et al., 1997, Wright et al., 1993, Wrzolek et al., 1995, Zahraa et al., 1996). Involvement of lung, brain, skin and myocardium was observed in eight, three, two, and one case, respectively. Shetty et al. reported 7 cases, and an aspergillosis incidence of 1.5 % for their study population. All 5 of their pulmonary cases had a fatal outcome, with only one having had the diagnosis suspected antemortem. In contrast, both patients with primary cutaneous aspergillosis responded well to systemic antifungal therapy combined with surgical debridement (Shetty et al., 1997). As for the adult cases, the pediatric reports were associated with CD4 lymphopenia.
The prognosis of invasive aspergillosis in AIDS appears to be worse than in patients with underlying hematologic malignancy (Denning, 1996, Tumbarello et al., 1997). This has largely been attributed to the incurable nature of the underlying disease, and many have died due to unrelated complications of AIDS. Advanced HIV disease, at least prior to the availability of highly active antiretroviral therapy (HAART), has been characterized by the presence of multiple opportunistic diseases and wasting. The overall crude mortality was 81 % among 115 patients with AIDS-related aspergillosis, and only slightly better at 72 % for those patients who received treatment (Denning, 1996).
The median survival reported in an earlier review was 2-4 months after the aspergillosis diagnosis (Khoo and Denning, 1994). However, occasional reports including patients treated more recently have suggested that the survival time may have improved (Wallace et al., 1994, Weinstein et al., 1996). The mean survival for a five patient series from one center with proven invasive aspergillosis treated between 1992 and 1995 was 10 months (range 3-21 months) (Weinstein 1996). A comparative analysis of prognostic factors for aspergillosis among patients with hematologic malignancies and HIV infection identified a better prognosis for individuals treated with sequential therapy with amphotericin B followed by itraconazole, but only for those with hematologic malignancies (Tombarello 1997). However, it is unclear from this study as to whether or not the survival time required in order to be categorized as having received sequential therapy resulted in a bias favouring survivors. Patients with pulmonary disease and upper lobe cavities are at particular risk of fatal hemoptysis (Miller et al., 1994).
The role of systemic antifungal agents for primary prophylaxis of AIDS-related aspergillosis has not been determined, and they are generally not recommended for this purpose (USPHS/IDSA 1997). However, it has been suggested that primary prophylaxis could be considered for selected patients with severe CD4 lymphopenia and either respiratory tract aspergillus colonization or exposure to renovation/construction (Lortholary and Dupont, 1997).
A recent placebo-controlled, randomized trial of itraconazole prophylaxis of fungal infections in advanced HIV disease demonstrated efficacy for prevention of histoplasmosis and cryptococcosis in a histoplasmosis endemic zone (McKinsey et al., 1999). This study was not specifically designed to evaluate aspergillosis prophylaxis; however, one case of aspergillosis was observed in the itraconazole group (0.7 %) and one in the placebo group (0.7 %).
Most patients with AIDS-related aspergillosis have been treated with amphotericin B or itraconazole, or both drugs sequentially (Denning, 1996, Denning 1994, Khoo and Denning, 1994, Minimoto et al., 1992, Graybill, 1993, Lortholary et al., 1993). Occasional cases have also been treated with lipid formulations of amphotericin B (Johnson et al., 1999, Hood et al., 1998). Regardless of which antifungal agent has been employed, the clinical response rates have been generally poor and the documented responses often transient. None of 29 patients treated with amphotericin B for less than 14 days responded to therapy, compared to 20 of 54 (37 %) who received at least 14 days of therapy (Denning, 1996). High dose amphotericin B (1.0-1.5 mg/kg/day) or a lipid formulation of amphotericin B (5 mg/kg/day as a starting dose) is considered to be the treatment of choice for invasive aspergillosis (Muller et al., 1999, Khoo and Denning, 1994). Patients should be considered for "step down" therapy to itraconazole 300 mg bid for three days followed by 200 mg bid. Due to the reduced bioavailability in HIV-infected patients as well as the possibility of drug interactions resulting in enhanced metabolism of itraconazole, monitoring serum levels is of particular importance in this setting (Muller et al., 1999). The recent FDA approval of intravenous itraconazole will provide an important alternative for management of patients with problems related to oral bioavailability. Treatment should be continued lifelong in most cases (Khoo and Denning, 1994).
Oral itraconazole represents an attractive alternative for initial therapy, particularly in patients whose life expectancy may be measured in months. Prolonged intravenous therapy with amphotericin B may be inappropriate in such patients. In the absence of any expectation of partial immune reconstitution related to HAART or a salvage antiretroviral regimen, patients with severe aspergillosis should be considered for a more palliative approach to care.
A number of investigational antifungal drugs have demonstrated in vitro activity against Aspergillus spp and hold promise as potential treatment options. These include the azoles, voriconazole (Murphy et al., 1997) and SCH 56592 (Loebengerg et al., 1998), and the echinocandin MK-0991 (Scott et al., 1998). The role of growth factors such as G-CSF has not been determined in the management of HIV-related aspergillosis, although it has been shown to reverse HIV-related neutropenia (Hermans et al., 1996).
Highly active antiretroviral therapy (HAART) has been associated with resolution of a variety of opportunistic infections in the setting of advanced HIV disease. This has been most compelling for opportunistic infections for which there is no satisfactory therapy, such as progressive multifocal leukoencephalopathy, microsporidiosis, and cryptosporidiosis (Jacobson and French, 1998). Most aspergillosis cases have been managed in the pre-HAART era. However, the reports of the following three patients suggest a therapeutic role of HAART in the management of AIDS-related aspergillosis. Two patients with sino-orbital aspergillosis also received combination antiretroviral therapy including protease inhibitors (Johnson et al., 1999). The first patient survived 28 months but eventually died of intracranial extension; the CD4 count had risen from 12 to 148 cell/mm3 and the viral load became undetectable (less than 400 copies/mL) with the antiretroviral regimen. The second patient had ethmoid sinusitis with recurrent orbital disease requiring exenteration of the orbit, but was still alive at the time of the report and continuing to receive a triple drug antiretroviral regimen 13 months after the aspergillosis diagnosis (Johnson et al., 1999). A third patient with bilateral renal aspergillosis responded to medical therapy alone, consisting of systemic antifungal therapy for 3 months in addition to initiation of zidovudine (AZT), lamivudine (3TC) and indinavir. The baseline CD4 count was 9 cells/mm3 and viral load was 1.1 million copies/ml. Following the addition of indinavir, the CD4 count increased to 85 cells/mm3, and the plasma viral load became undetectable. Six months after the aspergillosis diagnosis, the patient was alive and had no evidence of residual disease (Kummerle and Wedler, 1998).
When planning therapy, the patient's prognosis should be considered, both from the perspective of the aspergillosis as well as the underlying HIV disease. The aspergillus prognosis appears to be more favourable for primary cutaneous disease, obstructing bronchial aspergillosis, isolated unilateral renal disease, and limited sinus disease when diagnosed early. For patients failing to respond to antifungal therapy for invasive pulmonary aspergillosis, central nervous system or suspected disseminated disease, HAART or a salvage antiretroviral regimen may provide the only hope for a clinical response.
Surgical management is particularly relevant for lesions involving accessible sites (Muller et al., 1999) including: skin; soft tissues; sinuses; orbits; solitary central nervous system lesions; and localized pulmonary lesions, particularly cavities and aspergillomas when there is significant risk of life-threatening hemoptysis (Lombardo, 1987, Ketting, 1994, Miller et al., 1994, Minamoto et al., 1992).