Aspergillosis in AIDS

Contents:

• Introduction
• Epidemiology
• Clinical syndromes
  • Pulmonary aspergilloma
  • Chronic pulmonary aspergillosis
  • Allergic bronchopulmonary aspergillosis
  • Invasive pulmonary aspergillosis
  • Pseudomembranous or ulcerative tracheobrinchitis
  • Aspergillus rhinosinusitis
  • Invasive external otitis (otomastoiditis)
  • Central nervous system (CNS) aspergillosis
  • Aspergillosis of the genitourinary tract
  • Cutaneous aspergillosis
  • Cardiac aspergillosis
  • IRIS
• Prophylaxis
• Management

 

Introduction

Invasive aspergillosis (IA) is a life-threating opportunistic infection which usually occurs in the advanced stage of human immunodeficiency virus (HIV) infection (CD4 cell count less than 100 cells/µL). It is, however, uncommon in AIDS compared to other types of immunosuppression, with a stable incidence over the past 20 years despite the advent of highly active antiretroviral therapy (HAART) (Denis, 2015). However, IA remains being an important worldwide threat, with numerous HIV-patients untreated, especially in developing countries, and a three-month mortality rate of 30% reported in the last decades; with some improvement in survival related to HAART and voriconazole (Denis, 2015).

IA was removed from the Centres for Disease Control and Prevention’s list of AIDS-defining opportunistic infections in 1984 due to its rarity and the lack of a clear relationship between HIV-induced immunosuppression and aspergillosis (Schaffner, 1984; Selik, 1987). In 2008 the European Organisation for Research and Treatment of Cancer/National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG; hereafter “EORTC”) proposed new criteria for hematologic-oncologic settings, based on host factors and clinical and mycological features (Upton, 2007; De Pauw, 2008). HIV infection was not included in the main host factors. In a study evaluating the use of EORTC criteria for the diagnosis of IA in 242 HVI-infected patients in a French cohort, only 124 (51%) fulfilled EORTC criteria for IA (Denis, 2015). This highlights the need of a better risk-assessment and diagnostic criteria for HIV-infected patients.

Some studies showed that even with normal levels, neutrophils and peripheral blood macrophages from HIV-infected individuals exhibit impaired activity against Aspergillus fumigatus in vitro (Roilides, 1993; Pitrack, 1993). Furthermore, although a decline in peripheral blood CD4 T-cell count has historically been a significant predictor of risk for opportunistic fungal infection in HIV, there is increasing recognition that complex effects of HIV infection in both myeloid and lymphocytoid lineages contribute to increased susceptibility to invasive fungal infections (IFI) at earlier stages of CD4 decline (Okoye, 2013).

HIV infection leads to rapid destruction of memory CD4 T cell clones and ultimately the failure of infection-specific effector populations. Impaired CD4 T cell responses are strongly associated with a failure to produce interferon-gamma (IFN- Ƴ) or tumour necrosis factor-alfa (TNF-alfa), which has been related to worse outcome in invasive aspergillosis (Ok, 2011; Wojtowicz, 2015). Similarly, HIV displays tropism for both monocytes and macrophages inducing multiple direct and indirect effects on innate immune function, in the immune recognition of pathogens, cytokine signalling and phagocytosis. As a consequence, phagocytosis of Aspergillus in airways is impaired and mannose receptor expression is reduced (Collini, 2010).

Epidemiology

IA is generally considered a rare opportunistic infection in patients with AIDS. In a study of 35,252 HIV-infected patients in a national database, the incidence of aspergillosis was 3.5 cases per 1000 person-year (Holding, 2000). From another database of 38 million hospital discharge diagnoses nationwide, aspergillosis was diagnosed in 0.43% of HIV-infected patients (Tong, 2009). However, it is important to note that some studies in AIDS patients have demonstrated that IFIs are underdiagnosed in life and their incidence is higher than reported (Holding, 2000; Khoo and Denning, 2004; Sodqi, 2011). A retrospective autopsies study from 1984 to 2002 which included 1630 patients with AIDS with proven-IFIs showed that invasive aspergillosis was the second most frequently identified mycosis. Indeed, it should be highlighted that its prevalence did not significantly change over time, despite the introduction of HAART (Antinori, 2009).

Most cases reported in the last 15 years have occurred in untreated patients with AIDS and those with advanced immunosuppression (CD4 cell counts <50 cells/uL), noncompliant patients or patients whose multiple antiretroviral regimens have failed. It has also been reported in HIV patients with identified risk factors for the development of invasive disease, such as corticosteroid use or neutropenia (Libanore, 2002; Martinez, 2009; Baddley, 2011; Armstrong-James, 2014). Neutropenia in HIV-patients is frequently secondary to medications that can cause bone-marrow suppression, such as ganciclovir, trimethroprim-sulfamethoxazole or antineoplastic agents. It can also occur in the setting of advanced AIDS due to myelodysplasia. These two risk factors have been identified in almost half of cases of IA in HIV-infected patients (Holding, 2000). Other clinical risk factors include administration of broad-spectrum antibiotics, alcohol or marijuana use, intravenous drug-use, underlying lung disease, a prior history of one or more opportunistic infections (e.g. Pneumocystis jirovecii or cytomegalovirus infection), and leukopenia (Denning, 1991; Pursell, 1992; Miller, 1994; Wallace, 1998; Mylonakis, 1998; Holding, 2000; Libanore, 2002).

Clinical Syndromes

Lung involvement accounts for more than 80% of cases of Aspergillus infection in HIV-infected patients (Mylonakis, 1998, Libanore 2008). Disseminated infection can involve multiple organs, including lungs, central nervous system, heart, kidney and sinuses.  

1. Pulmonary aspergilloma

When Aspergillus colonises a pre-existing lung cavity, a fungus ball formed by masses of hyphae, biofilm matrix and cellular debris, called an ‘aspergilloma’, may appear. This typically affects the apex in residual cavities following tuberculosis (TB) or Pneumocystis pneumonia (PCP) in AIDS (Addrizzo-Harris, 1997). Aspergilloma may be seen in chronic pulmonary aspergillosis (CPA).

Diagnosis is established radiologically by CT and confirmed by culture or histological identification of Aspergillus hyphae in sputum, BAL or trans-thoracic needle aspirates or by serological demonstration of Aspergillus precipitins or antibodies. Treatment with antifungals should be given if the patient is significantly immunocompromised or there is evidence of progression or multiple symptoms (e.g. haemoptysis, significant weight loss or fatigue). Long term suppressive treatment is likely to be required, especially in certain immunosuppressed patients (Walsh, 2008). In a prospective study comparing HIV positive and negative patients with aspergilloma, 50% of HIV-infected patients at advanced stage of disease showed progression despite treatment (Yoganathan, 2009). Surgical treatment should be evaluated to minimize fatal haemoptysis, which can occur up to 25%.

 

2. Chronic pulmonary aspergillosis (CPA)

CPA is a severe, progressive respiratory infection characterized by multiple pulmonary cavities and increased levels of antibodies to Aspergillus species (Denning, 2016). It is estimated to affect ~1.2 million people in the world as a sequel of TB (Denning, 2011). In AIDS patients, it is often seen after a pulmonary insult as TB or PCP. In recently completed study in Uganda, CPA was seen as frequently in HIV-TB coinfection as in non-HIV infected patients (Page, 2016), with less pleural thickening and cavitation visible in HIV patients. Additional studies are required.

 

3. Allergic bronchopulmonary aspergillosis (ABPA)

ABPA is a lung disease, usually complicating asthma, marked by hypersensitivity response to inhaled Aspergillus species, most commonly A. fumigatus. ABPA typically presents with periods of exacerbations and others of remission. Airways colonisation by Aspergillus exacerbates underlying airway injury, leading to chronic inflammation and fibrosis with destruction of bronchial elements, bronchiectasis and scarring. Poorly controlled asthma, peripheral eosinophilia, immediate skin test reactivity to Aspergillus (IgE), elevated serum IgE and pulmonary infiltrates mark the syndrome for ABPA (Patterson, 2010). ABPA has been rarely reported in HIV-infected patients (Lain, 2000) although antibodies to fungal antigens in serum may be more common in HIV-infected individuals (Bhatnagar, 1996). Therapy is aimed at reducing inflammation and immunological activity. Therefore, management includes the use of corticosteroids during exacerbations as well as antifungal drugs.

 

4. Invasive pulmonary aspergillosis (IPA)

IPA usually affects patients with advance AIDS. Major risk factors for IPA in HIV patients include CD4 count <50 cells/uL, neutropenia (from myelodysplasia or medications) and corticosteroid use (Mylonakis, 1998; Wallace, 1998). Moreover, opportunistic infections, especially those involving the lungs such as PCP and CMV infection may predispose patients to IPA by impairing pulmonary macrophage function (Mylonakis, 1998). The most frequent presenting symptoms at diagnosis among 54 AIDS patients with proven IPA included fever (76 %), cough (46 %), chest pain (30%), dyspnoea (31%) and hemoptysis (7%) (Libanore, 2002).

Chest radiographic findings in HIV-infected patients with aspergillosis are similar to those seen in HIV-negative immunocompromised hosts, with the exception of the classic “halo” or “air crescent” signs, which are more frequently seen among neutropenic patients with hematologic malignancies. An explanation for this has been speculated to be that this sign is associated with rapid recovery from severe immunosuppression, a highly unusual phenomenon when HIV infection is involved (Caillot, 2001; Miller, 1994). Non-specific infiltrates are the most common radiographic findings followed by lung cavities (predominantly in upper lobes) and areas of consolidation (Khoo and Denning, 1994; Moreno, 2000; Libanore, 2002). Other radiological findings such as nodules, an interstitial pattern or pleural effusion are also found (Mylonakis, 2000). Conventional chest radiography is the first line imaging modality when pulmonary complications are apparent (Zaspel, 2004). CT has a higher sensitivity for pulmonary complications in AIDS patients.

When pulmonary aspergillosis is suspected, bronchoalveolar lavage (BAL) or percutaneous aspiration/biopsy should be performed, depending on the accessibility of the lesion, oxygenation and any bleeding tendency. Culture for Aspergillus is positive in BAL in 60% of IPA cases in HIV (Lortholary, 1999; Libanore, 2002). Trans-bronchial biopsy with BAL increases diagnostic sensitivity. The predictive value of BAL fluid culture or repeated positive sputum cultures in severely immunosuppressed HIV-infected patients who develop suggestive symptoms and/or radiographic findings has been reported previously (Denning, 1991; Lortholary, 1993; Khoo, 1994; Bouza, 2005). However, in a study in 2002, BAL cultures were negative in 11% of patients with pulmonary aspergillosis subsequently confirmed post-mortem (Libanore, 2002).

AIDS patients who develop a new cavity or infiltrate in a previously normal lung and whose bronchoscopy cultures test positive for Aspergillus, warrant antifungal treatment pending definitive diagnosis (Singh, 1991; Mylonakis, 1999; Libanore 2002).

Detection of Aspergillus specific antibodies were found in 25.8% by ELISA and 32.3% by ultrasensitive luminescent immunoassay (LIA) of HIV-positive multi-transfused (MT) thalassaemic children compared to 2% of HIV-negative MT children. One patient with positive antibodies developed AIDS with fatal outcome. Therefore, this technique was suggested for screening of IA in HIV patients although the sensitivity of this test is relatively limited (Sharma, 1997). Antigen detection methods such as galactomannan (GM) and beta-D-glucan have not been thoroughly studied in HIV patients with Aspergillus infection; therefore, the role of these molecular diagnostic assays is uncertain in this patient population. However, detection of GM in BAL samples has been shown to be more sensitive than detection in serum samples, although BAL samples are not always available (Horvath, 1996).

Isolation of Aspergillus spp in airways was found in up to 67% of advanced HIV-patients, presumably, in most cases, due to airway colonization (Staib, 1989). Some studies have estimated that around 4% of patients with advanced HIV disease and symptomatic respiratory disease had Aspergillus colonization (Pursell 1992; Daleine, 1993). This was later confirmed by a study where Aspergillus was cultured from the sputum of 45 patients with advanced HIV disease and 5 (11%) had invasive disease (Denning, 1994). Another case-control study reported an incidence of 1.6% in HIV patients in all stages of HIV infection (Wallace, 1998). This data suggests a lack of specificity in this group of patients. However, detection of Aspergillus DNA in BAL samples showed high sensitivity for the diagnosis of IA in patients without haematological cancer (Guinea J, 2013). On the other hand, isolation of Aspergillus species in blood cultures is rare, representing only 0.5-2% of all fungemias (Duthie, 1995). Laboratory contamination has become less common with the introduction of closed blood culture collection systems.

The overall mortality of IPA is extremely high with a case fatality rate reported to be up to 85.7% in HIV-patients in 2001 (Lin, 2001). In a recently large national observational study has been described a 3-month mortality rate of 30% in the most recent decade (Denis, 2015).

 

5. Pseudomembranous or ulcerative tracheobronchitis

Tracheobronchitis with Aspergillus is an uncommon manifestation of infection due to Aspergillus species, occurring in less than 7% of cases of pulmonary aspergillosis (Mylonakis, 1998). Fever and respiratory complaints (cough, dyspnoea, stridor or wheezing) are the most frequent symptoms (Fernandez-Ruiz, 2012). Some patients develop extensive pseudomembranes, which can completely occlude the lumen of large airways.

Bronchoscopy with pathology and culture of bronchial specimens plays a key role in diagnosis. It could be manifested with some degree of diffuse tracheobronchitis, multiple ulcerative or ‘plaque-like’ inflammatory lesions, and occasionally nodules involving the main stem and segmental bronchi (Kemper, 1993; Arizcorreta, 1995; Denning, 1995).Histopathologic demonstration of Aspergillus-like hyphae invading the bronchial mucosa is diagnostic. In a series of four patients reported by Kemper et al., chest radiograph was abnormal in two patients showing patchy multinodular or interstitial infiltrates (Kemper, 1993) but they are usually non-specific. Since the introduction of HAART there are only two cases reported, one of them with Influenza A coinfection (Antinori 2011; Lee, 2014). Due to the limited number of reports, the assessment of the prognosis and optimal therapeutic strategy is not easy. Treatment includes mold-active triazole agent or intravenous lipid formulations of Amphotericin B. It is also recommended bronchoscopy clearance of pseudomembranes and/or mucous plugs (Patterson, 2016).

 

6. Aspergillus rhinosinusitis

Invasive Aspergillus sinusitis is poorly responsive to treatment, with a survival rate after diagnosis frequently less than six months. It is usually seen in HIV-patients with CD4-cell counts under 100/uL. Concomitant corticosteroid therapy and neutropenia are probably contributing factors (Hunt, 2000; Mylonakis, 1997).

Diagnosis is based on both clinical and laboratory findings. CT scan of the sinuses provides data about the severity and extent of disease. Magnetic resonance is used to evaluate intraorbital and intracranial involvement. Nevertheless, fungal cultures of sinus aspirates and especially histologic examination of surgical specimens are needed for definitive diagnosis. Treatment requires aggressive surgical debridement and voriconazole or amphotericin B (Patteron, 2016); although patients often have poor overall outcome despite these measures (Keller, 1997; /article_database/sphenoid-sinusitis-aids-0). Furthermore, outcome in HIV-infected patients seems to be worse than in HIV-negative patients despite therapy, for unclear reasons (Ho, 2010).

 

7. Invasive external otitis (otomastoiditis)

Mastoid is usually affected as a consequence of local involvement (e.g. nasopharynx or nasal sinus). Aspergillus fumigatus is the most frequent species involved in this infection. The clinical presentation of invasive external otitis due to Aspergillus includes otalgia and is usually associated with reduced hearing followed by development of facial nerve palsy. CT scan is the preferred imaging method for demonstration of bone destruction, whereas MR has better sensitivity for inflammatory changes in the 7th and 8th cranial nerves (Muñoz et al., 1998).  It is hard to diagnose as the symptoms and signs progress very slowly with consequent delay in late diagnosis and terrible outcome. Hence, as it has an invasive and fulminating behaviour (which could lead to CNS involvement), it must be aggressively treated with surgery and systemic antifungals (Rodrigues-Carenzi, 2009).

 

8. Central nervous system (CNS) aspergillosis

The brain is the second most frequent affected organ in post-mortem studies of AIDS patients with fungal infections (Khoo and Denning, 1994). However, the results of treatment for CNS aspergillosis are usually discouraging and short-term outcome is usually fatal despite treatment, with mortality rate >90% (Walsh, 2008; Lin, 2001). This is especially true for CNS aspergillosis in the setting of HIV (Gasch, 2009), although most cases predate the introduction of voriconazole.

Among HIV-infected persons, CNS aspergillosis usually occurs in patients with a CD4-T cell count of <50 cells/mm3 and commonly as a consequence of haematogenous dissemination from a pulmonary focus or as a direct extension of paranasal sinus or orbital infection (Mylonakis, 2000). It is usually manifest as one or more brain abscesses or haemorrhagic or mycotic aneurysms (Denning, 1998), with subsequent neurologic symptoms including focal neurologic deficits, altered mental status and headache. In rare cases, the spinal cord may be affected (Tendolkar, 2005; Murtagh, 2008; Roosouw, 2011).

Brain CT scan usually shows low density lesions with little or no mass effect and minimal or no enhancement, and the brain MRI shows intermediate signal intensity surrounded by high signal on T2 images. Most patients require both microscopic analysis of tissue and identification of organism by culture for definitive diagnosis, which is usually made by biopsy or post-mortem (Walsh, 2008).

Recent reports suggest that treatment of CNS aspergillosis, even among HIV-infected patients, should be based on voriconazole. This recommendation is supported by the favourable CNS penetration of this agent and its pharmacokinetic properties (Tattevin, 2006; Elter, 2006; Balasubramaniam, 2007; Walsh, 2008; Reus-Banuls, 2012, Patterson, 2016). Combination therapy initially may be necessary if there is any doubt about adequate concentrations or azole resistance (Swchartz, 2005; Hal, 2005; Hidron, 2009; Gasch, 2009). If the patient stabilises on therapy, many months of therapy is typical, depending on host immune status and imaging improvement. Whenever feasible, combined with systemic antifungals, surgery resection of lesions should be done; it has shown better survival rates and allows management of complications such as elevated intracranial pressure or haemorrhage (Hidron, 2009). In a cohort study published in 2005, 81 patients with definitive or probable CNS aspergillosis were treated with voriconazole. Complete and partial responses were recorded in 35% of patients, and after 390 days a 31% survival rate was still maintained. Multifactorial analysis revealed that neurosurgery was also associated with improved survival in this cohort (Schwartz, 2005).

 

9. Aspergillosis of the genitourinary tract

Aspergillus involvement of the genitourinary tract is a very rare complication that usually occurs at an advanced stage of AIDS disease (Blanco, 2001; Kimmerle, 1998), although it has also been described in well-controlled HIV-patients (Meya D, 2005; Oosten, 2008). Most patients have renal involvement and a few had prostatitis or epididymitis (Hood, 1998; Cervero, 1999). Prognosis was worse before HAART era; recently, with advances in antifungal therapy and surgical management survival has improved.

Renal aspergillosis may develop as single or multiple parenchymal abscesses, usually as a result of haematogenous dissemination or, less commonly, secondary to a surgical procedure or as fungal balls in the pelvis of the kidney. Clinical manifestations generally include constitutional symptoms, flank pain, haematuria or ureteral obstruction. Diagnosis of renal aspergillosis requires imaging techniques, histopathology and microbiological examinations. At ultrasonography, renal abscesses appear as hypoechoic or anechoic lesions. Differential diagnosis with neoplastic lesions should be made (Fung, 1997). Renal CT shows one or more hypodense and well-defined lesions with ring enhancement (Kimmerle, 1998). Guided needle aspiration biopsy of the lesion is the gold standard diagnostic approach which allows histopathological evidence of tissue invasion by fungal hyphae and identification of the organism by direct microscopy and cultures (Metta, 2010). Urine cultures are usually negative, unless a fungus ball is present in the collecting system (Hood, 1998). A. fumigatus is the most frequently species isolated, followed by A. flavus.

Reports of management are limited to individual cases. Treatment of renal abscesses includes percutaneous drainage and the administration of systemic antifungal drugs being voriconazole the preferred agent, although amphotericin B could be used as well. All available antifungal agents with activity against Aspergillus spp penetrate renal parenchyma; however, because none of these agents is excreted into the pelvis of the kidney or urine, management of pelvicalyceal and ureteral infection may require nephrostomy with instillation of amphotericin B (dose may be 0.75-1mg/Kg/day, total dose 2-4g) (Walsh, 2008; Patterson, 2016). Most authors recommend long-term antifungal oral suppressive treatment (Oosten, 2008). If antifungal therapy fails, nephrectomy followed by antifungal systemic therapy is required, if disease is unilateral (Metta, 2009; Bisi, 2003).

Prostatic aspergillosis may be diagnosed by trans-rectal ultrasonography demonstrating an enlarged prostate with areas of echogenicity or CT of the pelvis which usually reveals a large, non-homogeneous mass contiguous with the prostate gland. Isolated prostate aspergillosis has been controlled with transurethral resection alone (Hood, 1998); however, multifocal disease requires systemic antifungal therapy (Kaplan-Pavlovcic, 1999). As in renal aspergillosis, antifungal therapy is required, and voriconazole is preferred. Surgical treatment is commonly needed (transurethral resection or open prostatectomy) followed by a short-course of antifungals (Hemal AK, 1999). Prostatic aspergillosis mandates a total assessment of the patient with imaging of the chest and genitourinary system.

 

10. Cutaneous aspergillosis

Primary cutaneous aspergillosis is rare and usually due to A. fumigatus. Aspergillus spp. cause primary cutaneous aspergillosis by direct post-trauma inoculation (e.g. intravenous catheters) (Camus M, 2010), or secondary skin lesions that result from invasive disease with haematogenous dissemination, usually seen in immunocompromised individuals and which carry worse outcome.

Its manifestations include rashes, verrucuous plaques and pustules, hemorrhagic ulcers, ulcerated nodules and thickened areas of overlying erythema (Arikan, 1998; Stanford, 2000; Gedela, 2012;). The lesions are usually found on the extremities or head, sparing the chest, apart from infection directly related to Hickman lines (Girmenia, 1995; Romero, 1995). Skin biopsy is necessary for diagnosis which may show histopathologic evidence of tissue invasion by fungal hyphae and identification of the microorganism by direct microscopy and culture.Biopsies should be taken from the centre of the lesion and reach the subcutaneous fat to visualize hyphae invading blood vessels of the dermis and subcutaneous tissues.

Lesions of primary cutaneous aspergillosis may require both surgery and systemic antifungal therapy. Voriconazole is preferred or another azole; if drug interactions are problematic amphotericin B has been used. Itraconazole reaches a high concentration in the skin, and may be a suitable treatment for some patients with cutaneous aspergillosis (Walsh, 2008). Surgical intervention, for primary cutaneous infection, may be a useful adjunct to antifungal therapy.

Prognosis for primary cutaneous disease appears to be favourable compared other organ involvement; however, there is the potential for progression to disseminated disease (Walsh, 1998).

 

11. Cardiac aspergillosis

In AIDS patients, cardiac aspergillosis is uncommon and usually occurs if severe CD4 lymphopenia exists. The first case was reported in 1985 (Henochowicz, 1985), with a few reports since (Lortholary, 1993). The endocardium, myocardium and pericardium may be separately or collectively involved (Minamoto, 1992). One route of infection is direct injection into the bloodstream to the right heart in intravenous drug abusers. However, it may follow invasive pulmonary aspergillosis, either by haematogenous dissemination or by direct invasion. The clinical presentation may include fever, features of cardiac dysfunction or embolic phenomena. Most of the reported cases of cardiac aspergillosis were diagnosed at autopsy (Lang, 1989; Schonheyder, 1992). Aspergillus species are rarely isolated from premortem blood cultures (Duthie, 1995).

In Aspergillus endocarditis early surgery combined with antifungal therapy is recommended in attempts to prevent embolic complications and valvular decompensation. Voriconazole and lipid formulation of AmB are the systemic antifungal agents recommended. Lifelong antifungal therapy should be considered in order to prevent late recurrence as well as frequent clinical and echocardiographic assessment (Patterson, 2016). To date, the mortality among AIDS patients with cardiac aspergillosis has been 100% despite appropriate therapy.

 

12. IRIS

Since the introduction of HAART in 1996, new clinical observations of florid inflammatory responses to infectious agents have been noted, which have come to be known as immune reconstitution inflammatory syndrome (IRIS). This exacerbation of a wide variety of latent infections, with the expression of complex clinical pictures and paradoxical reactions, coincides with improvement in CD4+ lymphocyte counts and decreases in plasma viral load and is probably related to an antigen-specific T-cell response.

IRIS has also been described after IPA (Sambatakou, 2005). IRIS can complicate the management of fungal infections and requires an optimised treatment regime (Denis, 2015); however, there is an overall good prognosis for patients who continue both HAART and specific therapy for opportunist infections (DeSimone, 2000). Anti-inflammatory agents, such as non-steroidal drugs and local or systemic steroids seem to give promising results in terms of arresting the acute inflammatory damage that occurs during IRIS in HIV-positive patients. Corticosteroids should be avoided in IRIS related to aspergillosis, unless antifungal therapy is demonstrably effective.

 

Prophylaxis

Nowadays, no antifungal prophylaxis is recommended for primary prevention of Aspergillus infection in AIDS patients. However, individual patients should be evaluated on a case basis if they have significant neutropenia and/or corticosteroid therapy (Walsh, 2008). The most compelling data come from large, randomized trials showing superiority of posaconazole compared with fluconazole or itraconazole in preventing invasive aspergillosis in neutropenic patients with haematological diseases (Halpern, 2015). Other experiences suggest utility of itraconazole, micafungin and inhaled liposomal amphotericin B (Rjinders, 2008; Ruiz Camps, 2011; Huang, 2012; Lindsey, 2012; Pagano, 2014; Paola, 2014; Xia, 2015; Patterson, 2016).

Secondary prophylaxis should be considered in patients who have had an episode of IA and experience a new period of a CD4 count <100/uL or require chemotherapy.

 

Management

When invasive disease is suspected or confirmed, prompt antifungal treatment with the optimal agent is essential. Guidelines for treatment of opportunistic infections in HIV-infected adults do not mention management on Aspergillus infection due to its low incidence in this group similar management approach to that in persons with other immunodeficiency (Guidelines, 2015). Recent IDSA guidelines recommend voriconazole as the primary treatment option (Patterson, 2016). It has shown to improve IA 3-month survival rate from 58% to 71% (Herbrecht, 2002; Upton, 2007; Walsh, 2008). Furthermore, a recent study in 2015 confirmed the positive impact of voriconazole survival in HIV-infected individuals with IA with up to a 90% reduction in the risk of death (Denis, 2015). Intravenous (iv) loading with 2 doses of 6mg/kg followed by 4mg/kg iv twice a day for 7 to 10 days should be given before converting to oral therapy. The oral continuation dose is usually either 200mg or 300mg twice a day (Leather, 2006). For patients for whom voriconazole is contraindicated (notably drug interactions), or in whom it is ineffective or if an azole-resistant strain has been isolated, liposomal amphotericin B (3mg/kg/day) or an echinocandin are an alternative (Patterson, 2016; Morrisey, 2007; Cornely, 2007; Denning, 2007; Hiemenz, 2010).

The duration of treatment in HIV-positive patients has not been systematically studied, but consensus guidelines recommend prolonged treatment until the infection is resolved and CD4 count has risen to >200/µL.

Surgical excision has an important role for lesions involving accessible sites including bone, skin, soft tissues, sinuses, orbits, CNS and localized pulmonary lesions. Surgery may also be valuable when IPA fails aggressive antifungal chemotherapy, particularly when disease affects major vascular structures with a risk of major bleeding (Muller, 1999; Limper, 2011).

Potential drug-drug interactions are a major issue with the azole classes that could lead to suboptimal antifungal treatment, especially with antiretroviral protease inhibitors. Therefore, antifungal treatment drug monitoring (TDM) should be performed in all HIV-patients receiving triazoles (itraconazole, voriconazole and posaconazole) to confirm that therapeutic levels are maintained and minimize drug-related toxicity (Ashbee, 2015). Azole interactions with available antiretrovirals are shown in table 1.

 

Prognosis

Even with the improvement in survival of HIV-infected patients in the post-HAART era, IA remains being an uncommon and important menace, with a three-month mortality rate of 30% (Denis, 2015). Patients with aspergillosis and HIV infection have a lower median survival compared with patients with haematological malignancies and aspergillosis (Tumbarello 1997).

 

Table 1. Azole interactions with antiretrovirals.

* Colour legend. Green: No clinically significant interaction expected. Amber: Potential interaction which may require dosage adjustment, altered timing of administration or additional monitoring. Red: these drugs should not be co-administered.

* The symbol (Green, amber, red) used to rank the clinical significance of the drug interaction is based on www.antifungalinteractions.org.uk (Aspergillus website) and www.hiv-druginteractions.org For additional drug-drug interactions and for a more extensive range of drugs, detailed pharmacokinetic interaction data and dosage adjustment, refer to the above-mentioned website.

 

Isabel Rodriguez Goncer
National Aspergillosis Centre, Manchester
isobel.rodriguezgoncer@manchester.ac.uk

July 2016