Allergic Bronchopulmonary Aspergillosis
ABPA is a lung inflammation characterized by pulmonary infiltrates and bronchiectasis [
6], that is mainly observed in patients with asthma or cystic fibrosis (CF). In those patients, inhaled
A. fumigatus may invade the lung ,evading the innate immune system and triggering a lymphocyte response, with activation of the inflammatory cytokines cascade resulting in sensitization [
7]. The high IgE levels in serum for
A. fumigatus antigens are the result of an immediate hypersensitivity to
Aspergillus.
Symptoms of ABPA are often non-specific and reported in more common lung diseases [
8], and the most common symptom is a chronic productive cough that could be associated with wheezing, hemoptysis, weight loss, and fever.
Generally, patients with controlled asthma may be asymptomatic for ABPA, and diagnosis is mainly based on routine testing; ABPA should be promptly suspected in patients with poorly controlled asthma or in patients affected by CF [
9]. Screening tests are performed using the
Aspergillus skin prick test or the
A. fumigatus-specific IgE blood test which shows higher sensitivity [
10]. If the screening is positive in the diagnostic tests for ABPA, IgE levels should be obtained in these patients. Then, ABPA is diagnosed based on these international criteria established in 2013 [
6]:
1.
Presence of 1 of the following predisposing condition: asthma or CF.
2.
Main criteria:
Positive Aspergillus skin test or elevated IgE against A. fumigatus.
Total serum IgE > 1000 IU/mL.
3.
Adjunctive criteria (2 out of 3):
Serum precipitins or IgG against Aspergillus fumigatus;
radiological features suggestive for ABPA;
a blood eosinophil count > 500 cells/L in corticosteroid-naive patients.
Of interest, in 2013, Baxter and coworkers proposed three distinct classes of aspergillosis in CF using serologic, RT-PCR, and galactomannan (GM) data. This classification could improve phenotyping, studies on pathogenesis, and management of patients with CF and pulmonary aspergillosis [
11]. The rationale of this specific classification is that patients with CF demonstrated a wide range of hypersensitivity responses to
Aspergillus infection, beyond ABPA, which requires a different classification.
Few definitive data are available about the therapeutic approach. Therapy is mainly based on the use of glucocorticoids and antifungals [
12]. In patients with acute ABPA, steroids are used alone, at an initial dose of 0.5 mg/kg for a total duration of 3–5 months [
13]. Of interest, in a randomized trial, different dosages of prednisolone were compared: a medium-dose versus high-dose regimen in asthmatic patients with ABPA. Data reported an efficacy of both regimens with significantly fewer side effects in patients treated with a medium-dose regimen [
14].
In patients with asthma and the development of ABPA plus bronchiectasis, in the absence of improvement after steroid treatment, antifungal therapy may be considered as an adjunctive therapy [
15]. Itraconazole is mainly used as a second-line or adjunctive therapy (with or without steroids) to essentially maintain the disease’s remission for a longer period [
16]. Of interest, the use of itraconazole was compared to prednisolone in a recent trial on patients with acute ABPA and asthma not previously treated. The authors reported, in patients of the prednisolone-group, after 6 weeks of therapy, a higher rate of efficacy compared to the itraconazole-group (100% vs. 88%;
p = 0.007). However, the reduction of serum IgE levels and the rates of exacerbation/year and time to first exacerbation were similar in both groups [
17]. Therefore, in selected cases, the combination therapy itraconazole-prednisolone could be considered, but definitive data on efficacy are necessary.
The assessment of therapy response is mainly based on a 25% decline in the total IgE level associated with a clinical and radiological improvement. In contrast, exacerbation is defined as at least a doubling in the baseline total IgE level plus clinical and/or radiological deterioration. Finally, remission is defined as the absence of exacerbations for at least 6 months after steroid therapy [
18].
The overall prognosis of patients with ABPA is not well characterized [
19]. However, early detection with prompt initiation of therapy generally leads to a good prognosis [
20].
Chronic Pulmonary Aspergillosis
CPA involves a spectrum of diseases that affect immunocompetent patients with pre-existing structural pulmonary alteration [
21]. These patients can show a clinical presentation from weight loss to the appearance of chronic productive cough, hemoptysis, and comparison of nodules and cavities at chest imaging. These clinical and radiological features should be present for at least 3 months at the time of diagnosis [
4].
The most important progress of CPA is to chronic fibrosing pulmonary aspergillosis; aspergilloma represents a less severe form of CPA, consisting of
Aspergillus hyphae with fibrin contained in a previously formed lung cavity [
22,
23]. Its development is subsequent to colonization of the cavity by
Aspergillus species: tubercular and nontubercular mycobacterial infections are the primary underlying lung conditions predisposing to the formation of aspergilloma [
24]. Other less common predisposing conditions are ABPA, chronic obstructive pulmonary disease (COPD), lung transplantation, recurrent low respiratory tract infections, and sarcoidosis. Cough is the most common symptom, while life-threatening hemoptysis is reported in a high percentage of patients [
25‐
27].
Of importance, immunocompromised patients could develop a locally destructive CPA that tends to progress more rapidly, from 1 to 3 months. This subacute invasive aspergillosis is another subgroup of CPA that shows characteristics very similar to IPA.
CPA diagnosis is based on the presence of characteristic symptoms and radiologic features, present for at least 3 months, with microbiologic evidence of
Aspergillus strains to confirm the diagnosis [
4]. Symptomatic patients with cavities, aspergilloma, or nodular infiltrates at CT scan should be tested for the presence of serum
A. fumigatus IgG; the presence of aspergilloma is associated with positivity of
A. fumigatus IgG in serum. Alternatively, the when antibodies are negative, the positive
Aspergillus cultures from the lower respiratory tract may support the diagnosis [
28]. GM in bronchoalveolar lavage (BAL) showed a good diagnostic performance if compared to serum GM, and appears to be a valuable diagnostic assay [
29]. Of interest, the combination of serum GM plus 1,3-beta-
d glucan (BDG) could be help physicians to confirm or exclude
Aspergillus infection, but their diagnostic values have not been well characterized [
30,
31]. Finally, a biopsy from cavities showing the presence of
Aspergillus hyphae is crucial to differentiate tissue invasion typical of subacute invasive aspergillosis from other forms of CPA, but the risks associated with the biopsy procedures should be carefully assessed in each patient [
32].
The goal of CPA treatment is to prevent life-threatening hemoptysis and to improve symptoms and the patient’s quality of life. Oral itraconazole, at a dose of 200 mg twice daily, is considered the first-line therapy [
22]. Voriconazole and posaconazole are second-line oral therapies [
33,
34], and in selected cases the use of short-term courses of intravenous amphotericin B and echinocandins have also been successfully used, especially in patients with rapid progression of the infection, failure of therapy, or azole resistance of
Aspergillus strains [
35]. Of importance, therapeutic drug monitoring (TDM)-guided dosing has been shown to be clinically beneficial for voriconazole, especially in ICU patients. In critically ill patients treated with voriconazole, TDM should always be performed to assess adequate serum levels [
36].
A 6-month duration of therapy is recommended, and asymptomatic patients can be reassessed every 3–6 months [
37].
Finally, there is a strong recommendation to perform a surgical resection of a simple aspergilloma in symptomatic patients with low surgical risk, if important symptoms are reported and hemoptysis is persistent. Of importance, surgery should also be considered in patients with
Aspergillus-localized CPA unresponsive to antifungal therapy [
4].
Invasive Pulmonary Aspergillosis
IPA has been traditionally considered in the differential diagnosis of infection mainly occurring in patients with specific risk factors: neutropenia and hematologic malignancies, allogeneic bone marrow transplantation, SOT, neoplasm, or HIV patients [
4]. Of importance, in recent years, an increasing number of studies have also reported the role
Aspergillus spp. in non-neutropenic patients, including those with end-stage COPD requiring chronic high-dose steroid therapy, Child–Pugh C liver cirrhosis, and patients receiving immunosuppressive therapies (i.e., monoclonal agents) [
38]. Moreover, patients admitted to the intensive care units (ICU) may also be susceptible to IPA, and recent important observations demonstrate the association between influenza, especially H1N1 virus, and IPA or other predisposing risk factors such as acute respiratory distress syndrome [
3,
39‐
41]. Of interest, a state of immunoparalysis is described in these categories of patients predisposing to the development of IPA [
42‐
44]. Moreover, recent data showed a possible association between COVID-19 caused by SARS-CoV-2 and the development of IPA in critically ill patients with moderate to severe ARDS [
45]. Finally, environmental factors, including climatic variables, airborne mold concentration, geographic area, remodeling or construction work, and environmental quality of the air, may predispose to IPA [
31].
Of importance, non-neutropenic patients show a non-specific symptomatology that makes clinical manifestations of IPA indistinguishable from other bacterial bronchopneumonia [
46]. In this setting, the clinical diagnosis of IPA is a challenge, because diagnostic definitions [
4,
47,
48] have been validated only for neutropenic patients and cannot also be used for those non-neutropenic.
Blot and coworkers proposed a clinical diagnostic algorithm aiming to discriminate colonization from probable IPA in ICU patients with
Aspergillus-positive in bronchial cultures [
49]. Fungal culture- and non-culture-based methods should be performed in all patients with relevant risk factors for IPA, and the development of pneumonia or the presence of a persistent pulmonary infection, despite broad-spectrum antibiotics, should drive physicians to further diagnostic exams to exclude or confirm IPA [
50].
The clinical significance of
Aspergillus from cultures of the lower respiratory tract remains a challenge for physicians, considering that
Aspergillus spp. (especially in some specific populations like COPD patients) could be considered only a simple colonization [
51]. The detection of fungus should be applied to the clinical characteristics of the patients. However, in a recent revision and update of the consensus definitions of invasive fungal disease, important aspects in the diagnosis of probable invasive pulmonary mold disease have been introduced, such as the use of
Aspergillus PCR in diagnosis, as reported in Table
2 [
48]. In recent years, the diagnosis of IPA has been improved using new markers based on the detection of fungal cell wall components or fungal DNA in blood or lung specimens; moreover, these markers showed the characteristic to differentiate colonization from infection. The detection of GM is currently the gold standard to early identification of IPA. Studies have reported that, in the BAL, a cutoff value of GM > 0.5 shows a sensitivity up to 100% and a specificity over 75% [
52,
53]. The role of GM in hematological patients has been assessed, and the test may be used to obtain an early diagnosis and to monitor the treatment response. However, the efforts are now directed to also definitively assess the routine use of GM in non-neutropenic patients [
54,
55].
Table 2
Criteria for diagnosis of probable IPA, which requires the presence of at least 1 host factor + a clinical feature + mycological evidence
Recent history of neutropenia (< 500 neutrophils/mm3) for > 10 days or recognized hematologic malignancy | The presence of one of the following on CT scan: Dense, well-circumscribed lesions with or without a halo sign Air crescent sign Cavity Wedge-shaped and segmental or lobar consolidation | Aspergillus spp. detected in sputum, BAL, bronchial brush, or aspirate |
Receipt of an allogeneic stem cell transplant or a solid organ transplant or acute graft-versus-host disease grade III or IV involving the gut, lungs, or liver that is refractory to first-line treatment with steroids | Tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar seen on bronchoscopic analysis | Galactomannan antigen detected in plasma, serum, or BAL, any one of the following: Single serum or plasma: ≥ 1.0 BAL fluid: ≥ 1.0 Single serum or plasma: ≥ 0.7 and BAL fluid ≥ 0.8 |
Prolonged use of corticosteroids for ≥ 3 weeks in the past 60 days or treatment with T-cell or B-cell immunosuppressants during the past 90 days | ICU admission | Aspergillus PCR, any one of the following: Plasma, serum, or whole blood, 2 or more consecutive PCR tests positive BAL fluid, 2 or more duplicate PCR tests positive At least 1 PCR test positive in plasma, serum, or whole blood, and 1 PCR test positive in BAL fluid |
Inherited severe immunodeficiency | Prolonged stay in the ICU (> 21 days) | 1-3-β-d-glucan value |
At least one of the following conditions: End-stage COPD requiring chronic high-dose steroid therapy Child–Pugh C liver cirrhosis Influenza (H1N1) | Presence of a persistent pulmonary infection despite broad-spectrum antibiotic therapy | New tests under development: Aspergillus species genes amplification Lateral flow device Detection of volatile organic compounds Gliotoxin and bis(methylthio)gliotoxin |
Conversely, the 1-3-
β-
d-glucan assay is another important test that, in patients with hematological disease, showed a high sensitivity with a very low specificity for the diagnosis of fungal infection [
56‐
58]. In contrast, its negative predictive value of 80–90% could make 1-3-
β-
d-glucan potentially useful to rule out the diagnosis of IPA rather than to confirm it. However, the role of this marker in the diagnosis of IPA is still unknown, and future studies are necessary to definitively assess its use in clinical practice [
59]. Few studies have evaluated the role of 1-3-
β-
d-glucan in BAL, also indicating a low specificity for IPA in immunocompromised patients [
60].
Of importance, these tests, especially GM, could be affected by the high frequency of false-positive results based on the use of
β-lactam antibiotics, human blood components, and hemodialysis [
61]. New tests are actually under development and validation but not yet universally standardized [
62,
63], and cannot be, to date, included as a criterion in the EORTC/MSG guidelines [
4,
47]. The most important are: (1)
Aspergillus species gene amplification in which the detection of genetic sequences, mainly represented by 18S rDNA, 28SrDNA, 5.8 SrDNA, and mithocondrial DNA, is obtained directly from fungal cultures and/or in direct clinical samples;
Aspergillus PCR is processed in a few hours and, when these results are combined with other fungal biomarker (like GM or BDG) in serum or in BAL (mainly GM), the diagnostic sensitivity up to 100% further supports the introduction of this process in the new definitions of invasive fungal infection by the EORTC/MSG; (2) a lateral flow device (LFD) that detects a glycoprotein antigen in the serum and BAL of patients with IPA: this technique has been proposed as a new point-of care diagnostic approach for an early detection of IPA in non-neutropenic patients, but also in SOT or critically-ill patients in ICU; in a multicenter study evaluating the use of LFD devices in BAL of ICU patients showed a sensitivity of 80%, a specificity of 81%, positive and negative predictive values of 96% and 44%, respectively; however, further and larger studies are crucial to assess the use of LFD in clinical practice, despite these first promising results; (3) innovative technologies have recently been tested in the breath of patients infected with IPA: these technologies detect volatile organic compounds exhaled with a sensitivity ranging from 94 to 100% and a specificity from 83 to 93%; and (4) gliotoxin and bis(methylthio)gliotoxin have been applied in the diagnosis of IPA with significant and promising results [
64‐
68]. However, the diagnosis of IPA remains challenging considering that none of the available diagnostic tests, actually introduced in clinical practice, show high sensitivity and specificity if used alone. The rationale could be the use of diagnostic strategies, including cultures, surrogate biomarkers, and molecular tools in a simultaneous performance to achieve the best possible approach to patients with suspected IPA.
Despite the introduction in clinical practice of new antifungals and the use of supportive measures, the mortality in patients with IPA remains very high. In the IDSA guidelines, prophylaxis during prolonged neutropenia and immunosuppression is recommended [
19]. Moreover, strong recommendations have been reported about the use of voriconazole or posaconazole for prophylaxis in large randomized clinical trials [
69]. As second-line therapies also reported for prophylaxis are itraconazole, micafungin, and caspofungin, which may also be effective [
70,
71]. Of interest, studies highlight the important role of non-pharmacologic prophylaxis measures to reduce exposure to fungal conidia. These strategies are based on placing severely immunocompromised patients in “protected environments”, with high-efficiency particulate air filtration and positive pressure, to avoid some activities that are associated with high exposure to
Aspergillus spores, like moldy hay handling and construction, using personal protective equipment.
To date, despite the possibility of using many therapeutic options, the mortality rate of IPA remains high [
72], and is reported to be higher in non-neutropenic patients than that reported in the neutropenic population. Probably, non-neutropenic patients at high risk of IPA for predisposing conditions like COPD, prolonged use of steroids and immunosuppressive therapy, Child–Pugh C liver cirrhosis, and ICU-related immunoparalysis should receive adequate antifungal therapy upon suspicion of the
Aspergillus infection. The goal of IPA management is to obtain, as soon as possible, a CT scan, fungal cultures, and a combination of serological biomarkers represented by GM (especially in BAL),
Aspergillus PCR, and 1-3-
β-
d-glucan assay. The antifungal treatment should be re-discussed and eventually discontinued if the diagnosis of IPA is not confirmed.
The antifungal agents approved as the first-line for the treatment of IPA are voriconazole, isavuconazole, and amphotericin B with its lipid formulation [
19]. The selection of the best drug for the treatment of IPA is mainly based on different steps: the assessment of severity of the infection, clinical features, the presence of renal or hepatic insufficiency, possible drug–drug interactions (especially in patients undergoing particular treatments for underlying diseases), the need for therapeutic drug monitoring, and, no less important, the costs of antifungal drugs.
Of these, isavuconazole is a new drug of the triazole class that can be given once daily, and it shows a wider spectrum of antifungal activity compared to voriconazole. Isavuconazole activity also includes
Mucorales infections and (as opposed to voriconazole) its intravenous formulation does not include cyclodextrin, which is a nephrotoxic and hepatotoxic compound typical of intravenous formulations of other triazoles, used to increase solubility. Also, compared to voriconazole, isavuconazole has fewer CYP enzyme-mediated drug interactions and shows linear and predictable pharmacokinetics, for which therapeutic drug monitoring is not necessary [
73]. In an important randomized, double-blind trial, the non-inferiority of isavuconazole versus voriconazole has been demonstrated in terms of mortality. Isavuconazole has been used as a primary treatment for IPA or other filamentous fungi infections, also showing a superior safety profile [
74]. Finally, all echinocandins have shown in vitro and in vivo activity against
Aspergillus spp., but only caspofungin is licensed for the treatment of IPA, as second-line therapy. In specific cases or in refractory disease, the use of a combination therapy with echinocandin plus voriconazole or liposomal amphotericin B may be considered.
Adequate duration of antifungal therapy for IPA is an unresolved issue. IDSA guidelines recommend that the treatment of IPA should be continued for at least 6–12 weeks, considering the clinical condition of the patient and their response to therapy; moreover, serum biomarkers and radiological follow-up with a CT scan should be considered to monitor the therapeutic response to IPA.