Advances in *Aspergillus* and Aspergillosis

#### **Chapter 1**

## Allergic Bronchopulmonary Aspergillosis/Mycosis: An Underdiagnosed Disease

*Solange Oliveira Rodrigues Valle, Augusto Sarquis Serpa and Faradiba Sarquis Serpa*

#### **Abstract**

Allergic bronchopulmonary aspergillosis (ABPA) is an immune-allergic disease of the lung due to a hypersensitivity reaction to antigens of *Aspergillus fumigatus* after colonization into the airways. Predominantly, it affects patients with bronchial asthma and those having cystic fibrosis (CF). Despite being recognized as a distinct entity nearly 70 years ago, this disease remains underdiagnosed. This may be due to the diagnostic methods employed, lack of standardized tests, and diagnostic criteria. The mainstay treatment for ABPA is systemic steroid. Azole antifungal agents represent an alternative for the treatment of exacerbations and are preferential strategy for corticosteroids sparing. Biologic drugs are expected to play an important role in the treatment of ABPA based on their mechanism in inhibition of type 2 inflammation, regulation of eosinophils and IgE levels, and modulation of inflammatory cytokines. Therefore, other studies are necessary for a better understanding of this disease so that an early detection can be done as well as a correct management.

**Keywords:** allergic bronchopulmonary aspergillosis, *Aspergillus fumigatus*, asthma, cystic fibrosis, diagnostic criteria, bronchiectasis, eosinophilia

#### **1. Introduction**

Allergic bronchopulmonary aspergillosis (ABPA) was first identified in 1952 by Dr. K. F.W. Hinson who described eight cases with typical clinical characteristics, including bronchitis/asthma, eosinophilia, bronchiectasis and/or mucus plugs, and isolation of *Aspergillus fumigatus* in lung tissue [1]. In 1968, ABPA was first reported in the United States [2] and 6 years later, in Brazil by our department at Federal University of Rio de Janeiro but remains underdiagnosed to this day, both in Brazil and worldwide [3].

ABPA is a complex pulmonary disorder characterized by an exaggerated hypersensitivity reaction to *Aspergillus* generally *fumigatus* specie, resulting in airway inflammation, mucus plugging, and bronchiectasis [4]. People most at risk of developing ABPA are patients with asthma or cystic fibrosis (CF). Given the propensity of the disease to cause irreversible complications, it is essential to formulate screening protocols for ABPA in these patients. Early detection of the disease is crucial for a better prognosis.

#### **2. Epidemiology**

The prevalence of ABPA remains uncertain and is likely to differ across geographical locations. ABPA affects 2.5–15% of patients with asthma and 7–9% of patients with CF, subject to variations within the studied population [5, 6]. In a recent systematic literature review, the pooled prevalence of ABPA in adults with asthma was 11.3%, and in adults, asthmatics sensitized to *A. fumigatus* (*Af*) was 37% [7]. For children, the pooled prevalence of ABPA in subjects with asthma was 9.9% [8]. Studies conducted in our center demonstrated 19% of ABPA prevalence among asthmatics sensitized to *Af* [9] and 12,5% of ABPA prevalence in children diagnosed with CF [10]. Worldwide, more than 4 million people are affected by ABPA [6, 11].

Additionally, genetic predisposition, such as specific HLA-DR alleles, may contribute to the development of ABPA in susceptible individuals [12]. There is no particular age or gender predilection for the occurrence of ABPA, although ABPA is uncommon in patients without asthma or CF [13].

The real prevalence of ABPA is difficult to determine due to the diagnostic methods employed, lack of standardized tests, diagnostic criteria, and the populations studied.

#### **3. Pathogenesis**

The pathogenesis of ABPA is complex, involving genetic factors, host–pathogen interactions, hypersensitivity reactions, eosinophilic inflammation, and cytokine dysregulation.

Genetic factors may contribute to the susceptibility to ABPA. Human leukocyte antigen (HLA) genotyping studies have identified specific HLA-DR alleles, such as HLA-DR2 and HLA-DR5, to be associated with an increased risk of developing ABPA in asthmatic and CF patients, respectively [12]. On the other hand, HLA-DQ2 contributes to resistance [14].

*Aspergillus* is an airborne ubiquitous saprophytic fungus that is found in soil and grows on decaying vegetation [15]. Spores are small (2–3 mm), facilitating their deposition throughout the airways. Inhalation of *Aspergillus* spores can lead to colonization and germination in the airways of susceptible individuals, such as those with asthma or CF [16]. *Aspergillus* spores persist in lower airways and develop the ability to germinate into mycelial filaments. This results in the secretion of metabolites that drive the activation of mucosal innate immune response and exposition of *Aspergillus* to the immune system. The impaired mucociliary clearance and local immune response in these individuals facilitate the persistence of *Aspergillus* hyphae in the airways, triggering an exaggerated immune response [17].

ABPA is characterized by a combination of type I (immediate) and type III (immune complex-mediated) hypersensitivity reactions [16]. In type I hypersensitivity, *Aspergillus* antigens bind to immunoglobulin E (IgE) on the surface of mast cells and basophils, leading to the release of inflammatory mediators such as histamine, leukotrienes, and prostaglandins, causing bronchoconstriction, increased vascular permeability, and mucus production [18]. In type III hypersensitivity, immune complexes composed of *Aspergillus* antigens and immunoglobulins (IgG) deposit in the

*Allergic Bronchopulmonary Aspergillosis/Mycosis: An Underdiagnosed Disease DOI: http://dx.doi.org/10.5772/intechopen.112166*

lung tissue, activating complement and attracting inflammatory cells, leading to tissue damage and eosinophilic inflammation [19].

Eosinophils play a central role in the pathogenesis of ABPA, contributing to airway inflammation, mucus production, and bronchial hyperresponsiveness [16].

There is a strong type-2 (T2) inflammation in ABPA combining a massive infiltration of airways by eosinophils and a high level of polyclonal IgE. Cytokines, such as interleukin IL-4, IL-5, and IL-13, produced by Th2 cells, stimulate eosinophil recruitment, activation, and survival [20]. Additionally, IL-4 and IL-13 promote the production of IgE by B cells and induce goblet cell hyperplasia, increasing mucus secretion. Airway inflammation leads to production of dense eosinophil mucus containing Charcot–Leyden crystals that obstructs airways. Mutation in CF transmembrane conductance regulator (CFTR) may play a role in ABPA even in the absence of CF, although this is still not clear [21].

#### **4. Clinical manifestation**

The clinical presentation of ABPA is heterogeneous, ranging from mild to severe respiratory symptoms. The primary clinical manifestations of ABPA are respiratory symptoms, which are often similar to those of asthma or CF, making the differentiation between these conditions difficult [22]. Common respiratory symptoms of ABPA include paroxysmal episodes of coughing, wheezing, dyspnea, and chest tightness [23]. Patients with ABPA may also experience recurrent episodes of pulmonary exacerbations, characterized by worsening respiratory symptoms and increased sputum production [4].

A characteristic feature of ABPA is the expectoration of brownish-black mucus plugs, which contain fungal hyphae and eosinophilic material [23]. These mucus plugs can lead to airway obstruction and impaired mucociliary clearance, contributing to the development of bronchiectasis and recurrent infections [22].

Systemic symptoms, such as fever, malaise and weight loss, may occur in ABPA, particularly during exacerbations [23]. These symptoms are thought to be related to the release of inflammatory mediators and the immune response to *Aspergillus* antigens [4].

Evolution is marked by the occurrence of ABPA exacerbations characterized by the onset, or an increase in, the clinical manifestations of ABPA often associated with radiological abnormalities and elevation of eosinophils and total IgE.

#### **5. Diagnostic criteria**

ABPA occurs mainly in patients diagnosed with asthma or CF. The diagnosis is based on a combination of clinical manifestations, radiological, and immunological features [24]. A thorough examination of the existing literature highlights the importance of early recognition and appropriate management of ABPA to prevent disease progression and associated complications. Over the years, the diagnostic criteria and approaches for ABPA have evolved significantly (**Table 1**).

The first diagnostic criteria described for ABPA were primarily based on clinical features, blood eosinophilia, and radiological findings [1]. In the 1970s, after the description of the IgE antibody isotype, serology came to occupy a central role in diagnosing ABPA. Rosenberg and Patterson proposed two groups of criteria to improve diagnostics. These criteria (seven primary, three secondary) have since been the most used in the diagnosis of ABPA [25].


**Table 1.**

*Diagnostic criteria for ABPA.*

#### *Allergic Bronchopulmonary Aspergillosis/Mycosis: An Underdiagnosed Disease DOI: http://dx.doi.org/10.5772/intechopen.112166*

However, these criteria lacked sensitivity and specificity, leading to underdiagnosis or misdiagnosis. In 2013, the ABPA Working Group of the International Society for Human and Animal Mycology (ABPA-ISHAM) proposed new diagnostic criteria to provide standardized guidelines for ABPA diagnosis [26]. New evidence then came to light about the "sensibility and specificity" of the ISHAM criteria. This evidence emerged through a study that used a latent class analysis to explore the performance of various existing and novel diagnostic criteria [27]. It has been demonstrated that IgE-specific tests are more responsive than skin tests to identify sensitization to *Aspergillus* and that the sensitivity and specificity of these criteria increased using a threshold for total IgE at 500 kIU/l [27]. In addition, a *cut-off* for specific IgG to *Aspergillus* was proposed. This evidence led the ISHAM to modify the diagnostic criteria. These modifications offered improved diagnostic performance and were published in 2021 [27]. The criteria proposed by ISHAM were validated but revealed that the sensitivity was poor for cases with non-*Aspergillus* Allergic Bronchopulmonary Mycosis (ABPM). Asano et al. proposed and validated new diagnostic criteria that showed improved sensitivity and specificity compared to Rosenberg-Paterson and ISHAM's previous criteria, even in atypical cases without asthma or non-*Aspergillus* ABPM (**Table 1**) [27].

The diagnostic of ABPA often follows an algorithm that integrates multiple pieces of clinical, immunological, and radiological information. The starting point is a clinical assessment, looking for key symptoms and risk factors, especially asthma or CF and then elevated specific IgE to *Af*. Total serum IgE levels are also evaluated, which typically exceed 500 IU/mL, while peripheral eosinophils >500 cels/μL and specific IgG-*Af* > 27 mgA/l provide further evidence of a patient's immunological response to the fungus [27]. Chest high-resolution computed tomography (HRCT) is another essential component of the algorithm because it provides a classification of ABPA based on the features observed (**Figure 1**).

While recent updates to diagnostic criteria have led to some advances, ABPA remains a challenging condition to diagnose in clinical practice. It is important to note that the diagnostic algorithm may vary slightly based on specific guidelines and updates in diagnostic technology, for example, the determination of specific IgE levels indicative of ABPA is subject to debate. Patterson et al. in 1983 had already described that the levels of specific IgE and IgG for *Af* were twice as high in patients with ABPA as compared to patients with Af-sensitive asthma [29]. Employing a cutoff of 0.35 kUA/L for *Af*-IgE could potentially result in overdiagnosis of ABPA [30]. Furthermore, the cutoff to IgG-Af proposed in ISHMA criteria was determined in Asian population using the ImmunoCAP® method and is much lower than values reported by other European studies in ABPA patients [31].

Recently, the application of molecular allergology has been proposed. These tests evaluate IgE-directed against alergens components of *Af* (r*Asp*) to improve diagnosis taking into account that *Af*-specific IgE cannot distinguish sensitization from allergy to *Af* [32]. It is well established that specific proteins of *Af* could play a significant role in ABPA, and these can be detected through this approach. The presence of either r*Asp* f1 or r*Asp* f3 demonstrated high sensitivity and r*Asp* f4 or r*Asp* f6 showed high specificity in diagnosing ABPA in patients with asthma and CF [33]. Based on the proposal of a diagnostic algorithm that includes r*Asp* to improve the accuracy of diagnosis [32], the EAACI ABPA Task Force proposed changes to the algorithm and reinforced the need to adequate recommendations for countries with limited resources (**Figure 2**)[30].

#### **Figure 1.**

*Algorithm to diagnosis and radiographic classification of ABPA. Af:* Aspergillus *fumigatus; HCTR: Highresolution computed tomography; ABPA-S: Serologic ABPA; ABPA-B: ABPA with bronchiectasis; ABPA-HAM: ABPA with high-attenuation mucus; ABPA-CPF: ABPA with chronic pleuropulmonary fibrosis.*

#### **Figure 2.**

*Laboratorial investigation of recombinant* Aspergillus *antigen-based algorithm for diagnosing ABPA. \*chronic obstructive pulmonary disease, altered bronchopulmonary structure; \*\*consider the establishment of locally validated cut-offs; \*\*\*consider the ratio of sIgE to molecular allergens vs. Af sIgE.*

#### *Allergic Bronchopulmonary Aspergillosis/Mycosis: An Underdiagnosed Disease DOI: http://dx.doi.org/10.5772/intechopen.112166*

Chest radiographic imaging plays a vital role in the diagnosis and management of ABPA and may exhibit features, ranging from normal to manifestations of pulmonary fibrosis (**Table 2**) [34]. This spectrum of presentations reflects the potential progression of the disease and the variability of the individual's response to *Aspergillus*. Several studies have investigated these radiographic features [34–36]. HRCT was demonstrated to be the gold standard for detecting bronchiectasis distribution and in identifying subtle radiographic changes, such as tree-in-bud opacities, which may indicate small airway involvement in ABPA [36, 37].

In the acute stage of ABPA, transient pulmonary infiltrates may be observed, typically manifesting as patchy opacities or consolidation [26, 34–36]. These infiltrates may resolve spontaneously or with treatment.

As ABPA progresses, more prominent, persistent changes can be detected in HRCT. These include central bronchiectasis, predominantly in the upper lobes [35]. High-attenuation mucus (HAM) within bronchi, often associated with bronchial dilations resembling a "finger-in-glove" sign, is another critical feature [26]. HAM is said to be present when the density of mucus is visibly greater than that of the paraspinal muscle, and that it may be related to the presence of calcium salts and metal ions (manganese or iron) [38] or desiccated mucus [39]. Chronic stage indicators also encompass bronchial wall thickening and parenchymal scarring, reflective of longstanding inflammation and damage [34–36]. Centrilobular nodules with a "tree-inbud" pattern, indicative of small airway inflammation, often associated with chronic inflammation, are commonly identified in ABPA [37]. The end stage of the disease is fibrotic and can be identified by the presence of fibrosis and architectural distortion, predominantly involving upper lobes. Pulmonary fibrosis can manifest as traction bronchiectasis, honeycombing, and volume loss on HRCT [34, 37].


**Table 2.**

*Radiographics features described in ABPA.*

#### **Figure 3.**

*(a) A 64-year-old female. Radiograph with consolidation in the right lower lobe (black arrow), in addition to some bilateral bronchiectasis with parietal thickening (white arrows). (b) Chest CT of the same patient demonstrates multiple central bronchiectasis in the left lower lobe with thickening and interspersed hyperdense content, a finding highly specific for ABPA (allergic bronchopulmonary aspergillosis). (c) a 16-year-old female. Radiograph shows consolidations in the peripheral region of the left lung (red arrow) and in the right lower lobe (blue arrow), in addition to bronchiectasis with thickened walls, the tram-track sign (white arrows).*

The nuanced insights that HRCT offers into the extent and characteristics of ABPA make it a key tool in the image-based classification of this disease [26, 35].

Using HRCT, ABPA can be classified into four types or phenotypes. Patients showing no abnormalities on chest scan are classified as having serologic ABPA (ABPA-S) [26, 40]. In contrast, those with evidence of central bronchiectasis are labeled as having ABPA Central Bronchiectasis (ABPA-CB) [26, 40]. The presence of HAM leads to the categorization of the disease as ABPA-High Attenuation Mucus (ABPA-HAM) [36, 40]. Lastly, if at least two radiological features suggestive of fibrosis (fibrocavitary lesions, pulmonary fibrosis, and pleural thickening) are observed in the absence of mucoid impaction (or HAM), the disease is classified as ABPA-Chronic Pleuropulmonary Fibrosis (ABPA-CPF) (**Figures 1**, **3**, and **4**) [36, 40].

Timely recognition and appropriate monitoring of radiographic changes are essential for optimizing patient care and outcomes in ABPA.

#### **6. Staging of ABPA**

Staging of ABPA is an important aspect of its diagnosis, management, and understanding of the disease's progression. These stages were initially proposed by

#### **Figure 4.**

*CT imaging of patients diagnosed with ABPA: (a) multiple bilateral bronchiectasis with parietal thickening and mucoid impactation; (b) mucoid impactation in mediastinal window of the same patient (white arrow); (c) central bronchiectasis in a corticosteroid-dependent patient who has experienced multiple exacerbations.*

*Allergic Bronchopulmonary Aspergillosis/Mycosis: An Underdiagnosed Disease DOI: http://dx.doi.org/10.5772/intechopen.112166*


#### **Table 3.**

*Staging of ABPA.*

Rosenberg et al. and have been widely used [25]. The staging has been revisited and revised by Agarwal et al., who proposed a more detailed, six-stage system, which also subdivides some stages based on radiological findings (**Table 3**) [26, 40].

#### **7. Differential diagnosis**

The differential diagnosis of ABPA includes several pulmonary disorders that share clinical and radiological features with ABPA, such as asthma with *Af* sensitization, idiopathic chronic eosinophilic pneumonia, tuberculosis, nontuberculous mycobacterial infections, eosinophilic granulomatosis with polyangiitis (GEPA) [4]. Distinguishing ABPA from these conditions requires a thorough clinical assessment, including the identification of predisposing factors, and appropriate tests to confirm or exclude these conditions.

#### **8. Treatment**

ABPA is recognized as a treatable trait in patients with bronchiectasis and the expected benefits of treatment are the prevention of lung damage, improved outcome and quality of life [41]. To achieve these goals, the management of ABPA varies depending on the stage of the disease and involves a combination use of systemic corticosteroid, antifungal therapy, immunobiological agents, and airway clearance techniques tailored to individual patient needs (**Table 4**).


*\*First-line treatment. For treating the first exacerbation, corticosteroids could be used alone and combined with azoles for subsequent exacerbation.*

*† Itraconazol could be used alone in those with contraindications to corticosteroids. The associated use with prednisolone may reduce the chance of exacerbations.*

*# Randomized Clinical Trials evaluating immunobiologicals are necessary to clarify the role of these agents in treatment of ABPA. § Nebulized amphotericin B may be considered when prolonged use of systemic corticosteroids and/or azoles are necessary.*

#### **Table 4.**

*Drugs used in the management of ABPA.*

#### **8.1 Corticosteroids**

Oral corticosteroids are the first-line treatment for ABPA [42]. However, the ideal dosage and duration of treatment remain undefined, and there are several treatment regimens, each featuring varying dosages and durations of use [40]. The most common regimen begins with a daily administration of 0.5 mg/kg of prednisolone over a period of 14 days, followed by 0.5 mg/kg/day on alternate days for 8 weeks, then taper by 5 mg every 2 weeks to complete a total steroid duration of 3–5 months [23].

Although disease remission can be achieved in most cases treated with medium- to high-dose systemic corticosteroids, relapse occurs in a substantial proportion of patients (13.5–45%) and can become corticosteroid-dependent [42, 43].

Intravenous pulse dose of corticosteroids can be used as a substitute for oral administration. Methylprednisolone, 15 mg/day (note exceeding 1 g), has been used in children to minimize the side effects of daily corticosteroid therapy [44] and in cases of refractory ABPA exacerbations [45].

#### **8.2 Antifungal therapy**

Antifungal agents decrease the fungal burden in the airways, antigenic stimulus, inflammatory response, and can contribute to reducing exposure to systemic corticosteroids. The use of azole agents alone or in combination with corticosteroid is an option in the treatment of ABPA [46]. Azoles, such as itraconazole, is generally prescribed at a dose of 200 mg twice daily for 16 weeks [40]. The combined use of itraconazole and prednisolone resulted in a greater reduction in the one-year exacerbation rate when compared to the use of these drugs individually [46].

However, drug interactions, hepatotoxicity, and variable bioavailability may limit the use [4]. Other azoles, such as voriconazole and posaconazole, have also been effective in treating ABPA, especially in cases of itraconazole intolerance or resistance [47].

The efficacy of nebulized amphotericin B in the management of ABPA exacerbations seems to be limited. However, they may be considered when other alternative options have been exhausted [24].

#### **8.3 Immunobiological drugs**

Posttreatment recurrences of ABPA are commonly seen, whether using oral corticosteroids, antifungal therapy or a combination of both, and prolonged treatment can result in adverse effects. Therefore, the necessity for new, safe, and effective treatment strategies is clear. Given the pathogenesis of ABPA, biologics designed to target type 2 inflammation, initially developed for severe asthma management, are expected to potentially serve as effective treatment alternatives for ABPA [48]. Although limited by the scarcity of randomized controlled trials, recent case reports and case series have demonstrated the benefits of target type 2 inflammation in the treatment of ABPA [48–51].

The anti-IgE monoclonal antibody, omalizumab, has shown potential in reducing corticosteroid use, improving lung function, and preventing relapses [50]. Omalizumabe is administered subcutaneously every 2–4 weeks, with the dosage determined based on the patient's weight and baseline serum total IgE levels [50]. However, the doses used might be suboptimal due to the high levels of IgE observed in ABPA.

The two groups of biologics target IL-5/eosinophil pathway: monoclonal antibodies that target IL-5, like mepolizumab and reslizumab, and those against the IL-5 receptor-alpha chain (IL-5Rα), such as benralizumab, have demonstrated efficacy in managing resistant eosinophilic pulmonary disorders, including ABPA. These anti-IL-5/IL-5Rα mAbs have been successful in reducing exacerbation frequency, dosage of oral corticosteroids, and enhancing pulmonary function in patients with asthma-complicated ABPA, even those unresponsive to omalizumab [48].

Dupilumab, anti-IL-4Rα monoclonal antibody, have been shown therapeutic effects on the symptoms and pulmonary function [49, 52]. Some patients with ABPA refractory to treatment with omalizumab or mepolizumab responded to dupilumab treatment [49, 53].

Tezepelumab a human IgG2 monoclonal antibody that binds specifically to thymic stromal lymphopoietin (TSLP) was demonstrated to improve the control of severe asthma by normalizing broad inflammatory pathways [54]. A recently published case report on a patient using mepolizumab, showed benefits in control of symptoms and reduction of the mucus plugs and pulmonary opacities [51].

Airway clearance techniques, such as chest physiotherapy and positive expiratory pressure devices, may be beneficial in patients with ABPA, particularly those with coexisting CF [4]. These techniques can help remove mucus plugs, improve lung function, and reduce the risk of recurrent infections.

The treatment of ABPA in CF is not very different from that of ABPA in asthma. As patients with CF often have coexisting malabsorption, treatment is more complex as oral medications, especially itraconazole capsules may be poorly absorbed [4].

#### **8.4 Monitoring of treatment**

The response to treatment should be monitored with clinical parameters, chest radiograph, and measurements of the serum total IgE concentration every 8 weeks. There should be a resolution of radiographic opacities and a 25% minimum reduction in serum total IgE levels and it is necessary to establish the "new" baseline level [4]. Clinical and/or radiological worsening along with 50% increase in IgE levels suggests an exacerbation [4].

#### **9. Conclusion**

ABPA is an immune-allergic disease of airways occurring in genetically predisposed patients as asthma and CF. The exact prevalence is not yet well known, and range is quite extensive as there is no single clinical, radiological, or serological parameter to make the diagnosis, leading to the use of various diagnostic criteria. Due to the absence of a consensus, ABPA may be easily underdiagnosed. Therapeutic management is based on few controlled studies conducted in asthma and extrapolated to ABPA. The first line of treatment of exacerbations remains on use of oral corticosteroids. Azole antifungal agents represent an alternative for the treatment of exacerbations and are preferential strategy for corticosteroids sparing. Asthma biologics may be a potential pharmacological management in the future. Therefore, more studies are needed regarding the diagnostic and therapeutic criteria for a better management of these patients.

*Allergic Bronchopulmonary Aspergillosis/Mycosis: An Underdiagnosed Disease DOI: http://dx.doi.org/10.5772/intechopen.112166*

#### **Conflict of interest**

The authors declare that they have no conflict of interest regarding this work.

#### **Author details**

Solange Oliveira Rodrigues Valle<sup>1</sup> \*, Augusto Sarquis Serpa2 and Faradiba Sarquis Serpa<sup>3</sup>

1 Department of Internal Medicine, Immunology Service, Clementino Fraga Filho University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

2 Federal University of São Paulo, Diagnostic Imaging Department, São Paulo, Brazil

3 Santa Casa de Misericórdia de Vitória School of Sciences, Asthma Reference Center, Espírito Santo, Brazil

\*Address all correspondence to: solangervalle@gmail.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 2**

### Post-Viral Aspergillosis

*Mohammadreza Salehi, Fariba Zamani and Sadegh Khodavaisy*

#### **Abstract**

Post-viral aspergillosis (PVA) is a clinical form of *Aspergillus* infection that occurs after some viral infections. *Aspergillus* is the most common respiratory fungal co-pathogen in patients with viral infections. Most cases of PVA have been reported as invasive pulmonary aspergillosis (IPA) after influenza, COVID-19, and the cytomegalovirus infection. PVA is more commonly reported in critically ill patients with viral pneumonia. Suggested risk factors for PVA include cellular immune deficiency, ARDS, pulmonary tracts and parenchyma damage, and corticosteroid therapy. New pulmonary nodules such as dense, well-circumscribed lesions with or without a halo sign, air crescent sign, or cavity, or wedge-shaped and segmental or lobar consolidation on the chest CT scan can suggest PVA. As in the treatment of invasive aspergillosis in other settings, triazoles, such as voriconazole or isavuconazole, have been suggested as the first-line treatment for PVA. It seems that the presence of PVA has significantly decreased the survival rate in patients with viral infections.

**Keywords:** aspergillosis, influenza, COVID-19, cytomegalovirus, viral infection

#### **1. Introduction**

Invasive pulmonary aspergillosis (IPA) is the most severe clinical form of *Aspergillus* infections and is typically seen in severely immunocompromised hosts, particularly those with hematologic malignancies undergoing chemotherapy and recipients of hematopoietic stem cell or solid organ transplantations [1, 2]. Due to the growing use of immunosuppressive agents in the treatment of many diseases and in advanced intensive care, the number of patients at risk of IPA is increasing [3]. *Aspergillus* is the most common respiratory fungal co-pathogen in patients with viral infections [4–6]. Although IPA after viral infections mainly occur in immunocompromised hosts, it has also been reported in apparently immunocompetent patients [3, 7, 8].

Viral types of pneumonia are serious health threats in the world and can occur on a seasonal, sporadic, epidemic, or even pandemic scale [9]. During the past decade, we have been faced with increasing reports of IPA in critically ill patients with viral pneumonia [10]. Viruses, such as cytomegalovirus (CMV), severe acute respiratory syndrome (SARS) virus, influenza virus, respiratory syncytial virus (RSV), parainfluenza 3 virus, and, more recently, severe respiratory syndrome coronavirus 2 (SARS-CoV-2), are among the most important causes of severe pneumonia that can cause respiratory failure and send patients to the intensive care unit (ICU) [7, 9, 11–14]. Although there are reports of the association of IPA with all severe viral pneumonia, IPA is more commonly reported in critically ill patients with influenza and COVID-19 pneumonia [14].

#### **2. Influenza-associated pulmonary aspergillosis (IAPA)**

Influenza viruses have an RNA-based genome, which lacks proofreading mechanisms, and therefore undergo constant mutations [15]. Despite medical development, Influenza is still an important virus causing serious respiratory and epidemic infections in humans and animals [16]. Influenza infections place a significant strain on health systems each year and are responsible for a large number of deaths worldwide [17]. It seems that the transmission of the influenza virus through person-to-person respiratory droplets is one of the important ways of spreading the virus and causing the disease epidemic [18]. Secondary bacterial pulmonary infections are common complications of influenza associated with a high mortality rate [19, 20]. Common bacterial pathogens causing secondary pneumonia in patients with influenza include Haemophilus influenzae, Streptococcus pyogenes, Staphylococcus aureus, and Streptococcus pneumoniae [19]. Secondary bacterial infections have been well described as complications of influenza. Pulmonary involvement with different species of *Aspergillus* also seems to be a potential complication of influenza; however, more studies are still needed to understand its different aspects [21].

The first case of IAPI was reported by JD Abbott et al. in 1952 [22]. The development of invasive fungal infections after influenza was a rare influenza complication before 2009, but the number of reported cases has been increasing since the 2009 H1N1/swine flu/influenza virus pandemic [7, 23, 24]. Almost all influenza patients with aspergillosis have had pulmonary fungal infection, but cases of tracheobronchitis and even cerebral involvement have also been reported [21].

The influenza virus infection has recently been considered as a risk factor for the development of aspergillosis in various studies [4, 5, 8]. In various studies on critically ill patients with influenza, the rate of the aspergillosis has been reported from less than 2% to more than 20% [4, 25–28]. Interestingly, to date, most reported cases of IAPA have been associated with the influenza A H1N1 subtype, but limited cases of influenza B with aspergillosis have also been presented [5, 29, 30]. The pathogenesis of IAPA is still not fully understood, but several risk factors have been mentioned [10]. Understanding the pathogenesis of IAPA requires understanding the pathogenesis of the influenza virus infection and aspergillosis and the conditions of the human host [5]. The influenza virus has been reported to cause cellular immune deficiency, alveolar epithelial damage, disruption of normal ciliary clearance in the respiratory tract, and leukopenia [31, 32]. Only few patients with the influenza infection have been reported to require hospitalization, and less than 30% of hospitalized patients have developed progressive pneumonia, but these few cases have been accompanied by a profound inflammatory response and the most severe form of acute lung injury called acute respiratory distress syndrome (ARDS) [33]. Radiological findings of the lung usually include diffuse alveolar infiltration and bilateral ground glass opacities [34]. Histopathological examination of lung parenchymal tissue in severe and fatal cases of influenza H1N1 has shown different degrees of diffuse alveolar damage with hyaline membranes and necrotizing bronchiolitis [35]. Patients with ARDS have shown the higher plasma levels of pro-inflammatory markers, such as interleukin-6, interleukin-10, and interleukin-15. than patients with the less severe disease [36]. Despite the controversial role of corticosteroids in the

#### *Post-Viral Aspergillosis DOI: http://dx.doi.org/10.5772/intechopen.111875*

treatment of ARDS, it has been reported that a significant percentage of patients with ARDS secondary to the influenza infection receive corticosteroids [37, 38]. In a report of hospitalized patients with 2009 H1N1 influenza, not only patients with ARDS but also most patients without this complication received corticosteroids [34]. Classic risk factors for IPA in patients without influenza include cellular immune deficiency, chronic obstructive pulmonary disease (COPD), ICU stay, and corticosteroid therapy [39–41]. However, several reports show that critically ill patients often develop IPA even in the absence of classic risk factors [41–43]. It seems that pulmonary tracts and parenchyma damage, ARDS, immune system dysregulation, male sex, need for the prolonged ICU stay, and broad-spectrum antibiotics, and corticosteroids therapy are probably the most important risk factors for IAPA (**Figure 1**) [4, 8, 18, 44]. In a report, treatment with neuraminidase inhibitors, such as oseltamivir, was also mentioned as a possible risk factor for IAPA [45].

The European Organization for Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) has released criteria for diagnosing invasive aspergillosis in critically ill patients. The criteria include definitions for proven and probable cases although most reported patients are compatible with the definition of probable cases [21–23, 46]. Suggested criteria to define probable cases of IAPA in the ICU setting are (1) cytology, direct microscopy, and/or culture showing the presence of *Aspergillus* species in a sample of the lower respiratory tract; (2) galactomannan (GM) antigen >0.5 in plasma/serum and/or galactomannan antigen >0.8 in the bronchoalveolar lavage (BAL) specimen [46]. The diagnostic approach in most studies focuses on the BAL culture and detection of GM in serum and BAL (probable IPA) [8]. However, *Aspergillus* spp. isolated from BAL examinations in ICU patients with influenza may be overlooked as a contamination despite their potential to cause an invasive disease [3]. Although most patients under mechanical ventilation undergo bronchoscopy, the absence of a positive fungal culture does not rule out the diagnosis of IPA [41]. Although the usual radiological findings of IPA, including cavitary lesions, halo sign, or air crescent sign, have been seen only in a small number of critically ill patients, performing chest CT scan may

**Figure 1.** *Post-Viral Aspergillosis Risk Factors.*

be helpful in diagnosis [21, 47]. (1-3)-β-d-glucan (BDG) is of limited value in the diagnosis of IPA; however, the combination with GM or the polymerase chain reaction (PCR) method may give this noninvasive test a more diagnostic role [48].

The mean time between the diagnosis of influenza and aspergillosis has been reported to be 6 days (range 0–32) [21]. In patients with influenza, especially in critical cases with clinical, mycological, or radiological suspicion of IPA, it is recommended to start antifungal agents (voriconazole as the treatment of choice) as soon as possible [21, 49]. In the absence of an appropriate response to treatment, therapeutic drug monitoring (TDM), evaluating resistance to azoles, and then a tissue biopsy of the suspicious lesions should be considered [50]. Complete mycological evaluations, including identification of *Aspergillus* species, are mandatory because some species are intrinsically azole resistant. Preferably, the antifungal susceptibility pattern should be performed for *Aspergillus* isolates [48].

The overall mortality rate of patients with H1N1 has been reported to be less than 0.5% [18]. It seems that IPA in critically ill patients with influenza can be associated with a poorer outcome [4]. Early reports considered the mortality rate of the IAPA at nearly 100%, but the rate has been reported between 33 and 67% in later studies, although this mortality may be higher in patients with a history of immunodeficiency [5, 8, 21, 30, 47, 51, 52]. Mortality rate in critically ill patients without influenza in ICU has been 80% and in patients with COPD has been about 95% [40, 41].

#### **3. COVID-19 associated pulmonary aspergillosis (CAPA)**

In December 2019, the first cases of pneumonia with an unknown origin were reported from Wuhan, the capital city of China's Hubei province [53]. The isolated pathogen causing this infection was identified as a novel enveloped RNA betacoronavirus, currently named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is phylogenetically similar to SARS-CoV [54]. Since most of the first reported patients had contact with a southern Chinese seafood market in Wuhan, it is widely believed that COVID-19 originated from wild animals such as bats [55]. Finally, the World Health Organization (WHO) declared the 2019 coronavirus disease (COVID-19) as a public health emergency of high international concern [56]. The common transmission routes for previous coronaviruses and influenza, that is, respiratory droplets and direct contacts, are also the main ways for SARS-COV-2 transmission [57]. SARS-CoV-2 is contagious and transmissible during the incubation period and can cause numerous clusters [58].

The COVID-19 pandemic caused by SARS-CoV-2 has affected the health and life of all people in all continents and has caused a high rate of morbidity and mortality in human societies [59]. This pandemic has continued for over 3 years and is still a global threat [60]. The extensive and continuous evolution of SARS-CoV-2 has caused the emergence and spread of several variants of concern (VOCs), such as alpha (B.1.1.7), beta (B.1.351), gamma (P.1), delta (B.1.617.2), and omicron (B.1.1.529) around the world [61].

The incubation period of this infection is between 1 day and 2 weeks [62]. This viral disease usually begins with flu-like symptoms such as myalgia, fever, stuffy nose, and cough [63]. From the beginning, it was evident that ARDS is the final cause of death in many COVID-19 patients [62]. The common risk factors for the progression of the disease toward ARDS are male gender, old age, pregnant women, and the presence of underlying diseases, especially hypertension, diabetes mellitus,

#### *Post-Viral Aspergillosis DOI: http://dx.doi.org/10.5772/intechopen.111875*

and cardiovascular diseases [64, 65]. The most common laboratory changes in patients with COVID-19 are lymphocytopenia, increased C-reactive protein (CRP), increased lactate dehydrogenase (LDH), and leukocytopenia [66, 67]. Several antiviral drugs and anti-inflammatory agents were examined for the treatment of COVID-19 patients, but they were unsuccessful [68–70]. At the beginning of the pandemic, corticosteroids were prescribed by many clinical teams to treat hospitalized COVID-19 patients, but after the publication of the successful results of recovery trials, the administration of dexamethasone was introduced to most therapeutic protocols to save hospitalized patients [71, 72]. Finally, in many critical patients with COVID-19, the high doses of corticosteroids (pulse therapy) were prescribed [73, 74].

Not much time had passed since the beginning of the pandemic when the possibility of invasive fungal infections such as aspergillosis, candidiasis, mucormycosis, and pneumocystosis in COVID-19 patients was raised [75]. In subsequent studies, the risk of bacterial and fungal co-infections with COVID-19 was strongly considered [76, 77]. Not only the incidence of COVID-19 co-infections reported from different medical centers is varied but also the rate of bacterial secondary infections is lower in COVID-19 patients than in patients with severe influenza [77]. The reason for the difference in the reported incidence rate of CAPA is probably the diagnostic challenges of CAPA in patients with severe COVID-19 [78]. In the absence of a comprehensive definition for CAPA, classification criteria are modified and vary widely between the studies and are often based on the mycological evidence, such as direct microscopic examination and culture or even GM testing in serum or tracheal aspirates [79, 80]. Considering the same criteria, a median prevalence of more than 20% (1.5–38%) was reported for CAPA in critical patients with COVID-19 who required invasive mechanical ventilation [80, 81]. The most common risk factors for CAPA include the history of immunosuppressive agent use, especially the combination of dexamethasone and tocilizumab, aggressive mechanical ventilation, and old age **(Figure 1)** [82].

The pathogenesis of CAPA is complex and requires the understanding of the biological and immunological processes caused by SARS-CoV-2 in the host. Similar to previous coronaviruses, SARS-CoV-2 targets and destroys epithelial cells and pneumocytes through viral protein binding to angiotensin-converting enzyme 2 (ACE2) receptors [83, 84]. Two possible mechanisms for the development of CAPA in COVID-19 patients with ARDS have been described: The first mechanism involves the release of danger-associated molecular patterns (DAMPs) by damaged cells, which act as signals intensifying the immune and inflammatory response leading to lung damage. DAMPs also develop advanced glycation end products, which integrate with Toll-like receptors (TLRs) to generate and amplify the inflammatory response in aspergillosis. Ultimately stimulation of inflammatory signals appears to increase the risk of CAPA [84]. The second mechanism can be severe lymphocytopenia, which is one of the known factors in the development of IPA in patients with hematological malignancies; however, severe lymphopenia and lymphocyte dysfunction are usually observed in patients with severe COVID-19 and probably contribute to the development of CAPA [85, 86].

The clinical features and radiological findings of CAPA are very similar to those of severe cases of COVID-19, especially cases with ARDS [78, 84]. CAPA is diagnosed in an average of 8 days (range 0–31 days) after the transfer of critically ill patients with COVID-19 to the ICU [82]. Although the radiological evidence of severe COVID-19 can be similar to that of IPA, it is recommended that a thorough work-up should be done with the observation of multiple new pulmonary nodules or lung cavities to diagnose probable CAPA as these cases are less common with COVID-19. Although some radiological features like the halo sign are typical for IPA, it is not sufficient to diagnose CAPA without mycological evidence as the halo sign is indicative of local infarction and is an intrinsic part of imaging observations of severe COVID-19 [87].

Due to the clearance of GM from the systemic blood circulation by neutrophils in non-neutropenic patients, the serum GM test might not have the necessary


*CAPA: COVID-19 associated pulmonary aspergillosis, NBL: non-bronchoscopic lavage, Allo-HSCT: allogeneic hematopoietic stem cell transplant, SOT: solid organ transplant, GVHD: Graft-versus-host disease, LFA: lateral flow assay.*

#### **Table 1.**

*Case definitions for patients with possible, probable, and proven CAPA.*

#### *Post-Viral Aspergillosis DOI: http://dx.doi.org/10.5772/intechopen.111875*

diagnostic sensitivity for CAPA [88, 89]. Early bronchoscopy and BAL in COVID-19 patients with suspected CAPA may lead to a faster diagnosis and better management; however, bronchoscopy is rarely performed in these patients due to concerns about SARS-COV2 transmission [90]. Finally, in 2020, the diagnostic criteria for CAPA were released by the European Confederation of Medical Mycology/the International Society for Human and Animal Mycology (ECMM/ISHAM), and the definitions were described as possible, probable, and proven (**Table 1**) [87]. The implementation of noninvasive diagnostic criteria with an emphasis on the GM test, culture, PCR, and non-bronchoscopic lavage for diagnosing possible CAPA has significantly reduced the diagnosed cases of CAPA and the prevalence of CAPA to about 10% among critically ill patients with COVID-19 [82, 90, 91]. As in the treatment of invasive aspergillosis in other settings, triazoles, such as voriconazole or avuconazole, have been suggested as the first-line treatment for CAPA, and in suspected cases of resistance to azoles, liposomal amphotericin B is the main alternative [87].

It seems that the presence of CAPA has significantly decreased the survival rate in COVID-19 patients, in studies on patients with CAPA, the mortality rate has been reported to be more than 40% [78]. In a large multicenter study from French ICUs conducted on the COVID-19 patients under respiratory support with mechanical ventilation, CAPA was an independent risk factor for death, with a hazard ratio of 1.45 compared with those without the infection. In this study, the administration of triazoles, such as voriconazole and other antifungal agents, did not change the patients' outcomes [92].

#### **4. Cytomegalovirus-associated aspergillosis (CAA)**

Cytomegalovirus (CMV) is a member of the Herpesviridae family and, like the other viruses of this family, develops a persistent state after the initial acute infection, which serves as a reservoir for reactivation and subsequent infection, particularly in immunocompromised hosts [93]. CMV is transmitted through salivary secretions, sexual contact, placenta, breastfeeding, blood transfusion, and solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT) [94]. CMV infects many people in the world, and its primary infection is usually asymptomatic [95]. In some immunocompetent hosts, CMV can lead to a mononucleosis-like syndrome with pharyngitis, fever, myalgia, and lymphadenopathy [93]. The global prevalence of seropositive individuals for CMV has been reported to be over 80% in the general population, with the highest seroprevalence observed in the Eastern Mediterranean region of the World Health Organization (WHO) and the lowest in the European WHO region [96]. The broad cellular tropism of CMV probably contributes to the development of a diverse number of pathologies associated with the infection in different organs [97].

CMV is one of the most important pathogens that cause serious diseases in immunocompromised hosts [98]. Before the treatment of HIV/AIDS patients with antiretroviral therapy (ART), approximately 40% of people living with HIV developed diseases caused by CMV [99]. CMV is one of the most important opportunistic viruses in solid organ transplantation (SOT), causing infections and diseases, which can have adverse consequences for allograft and recipient survival, increase the patient cost, and affect the quality of life [100]. Despite the progress made in the prevention of CMV, it remains one of the main causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) [101]. The evidence shows that critically ill patients are at risk of developing CMV viremia or infection, with an average infection rate of 25% reported among these patients [102].

CMV seems to have immunosuppressive effects, and its infection is an independent risk factor for developing other systemic infections in SOT recipients [103–105]. Studies have shown that CMV infection aggravates the immunosuppression status including leukopenia in transplant recipients and increases not only the risk of bacterial infections but also the possibility of invasive fungal infections in these patients [106, 107]. The CMV infection has been reported to be an important risk factor for posttransplant *Pneumocystis jirovsi* pneumonia (PJP) [108, 109]. Studies have shown that neutropenia, Graft-versus-host disease (GVHD), corticosteroid therapy, lymphopenia, and CMV infection are risk factors for posttransplant aspergillosis [110, 111].

The CMV infection and IPA have been found to be important infectious diseases in transplant recipients [112]. The incidence of posttransplant IPA varies by transplant type and reporting transplant centers [113, 114]. Early IPA occurs within the first 90 days after transplantation and is more related to the hemodialysis or critical conditions of transplant recipients, while late IPA, after 90 days of transplantation, is more related to conditions of immunosuppression and the allograft rejection [115, 116]. Interestingly, in a study on lung transplant recipients with CAA, a respiratory CMV infection was seen, and the virus was previously detected in their BAL secretions [117]. CMV in transplant recipients can significantly increase the chance of CAA regardless of the transplantation type, although this may not include asymptomatic CMV viremia [112, 118]. The proposed risk factors for the development of CAA include intensified immunosuppression, higher CMV viral load, graft rejection, host genetics (polymorphisms in the toll-like receptor-4), ganciclovir-induced neutropenia, and leukopenia **(Figure 1)** [107, 119–122].

Two important points in preventing CAA in transplant patients are paying attention to the protocols for CMV prevention after transplantation and starting aspergillosis prophylaxis in the transplant recipients infected with CMV [112, 117, 123].

Timely diagnosis of CAA, treatment of both infections, attention to possible drug interactions, and reducing as much as possible the level of the patient's immunodeficiency level may reduce the risk of death [112, 117].

#### **5. Conclusions**

Post-viral aspergillosis (PVA) is a clinical form of *Aspergillus* infection that happens after some viral infections. *Aspergillus* is the most common respiratory fungal co-pathogen in patients with viral infections. Most cases of PVA have been reported as invasive pulmonary aspergillosis after influenza, COVID-19, and cytomegalovirus.

Influenza-associated pulmonary aspergillosis (IAPA): The first case of IAPI was reported in 1952. The development of an invasive fungal infections after influenza was a rare influenza complication before 2009, but the number of reported cases has been increasing since the 2009 H1N1 influenza pandemic. Almost all influenza patients with aspergillosis have had pulmonary fungal infection. The rate of IAPI has been reported from less than 2% to more than 20%. It seems that IPA in critically ill patients with influenza can be associated with a poorer outcome.

COVID-19-associated pulmonary aspergillosis (CAPA): Not much time had passed since the beginning of the pandemic when the possibility of invasive fungal infections such as aspergillosis in COVID-19 patients was raised. The clinical features and radiological findings of CAPA are very similar to those of severe cases of COVID-19, especially cases with ARDS. CAPA is diagnosed in an average of 8 days after the transfer of critically ill patients with COVID-19 to the ICU. Although the radiological evidence of *Post-Viral Aspergillosis DOI: http://dx.doi.org/10.5772/intechopen.111875*

severe COVID-19 can be similar to CAPA, it is recommended that a thorough work-up should be done with the observation of multiple new pulmonary nodules or lung cavities to diagnose probable CAPA as these cases are less common with COVID-19. It seems that the presence of CAPA has significantly decreased the survival rate in COVID-19 patients.

Cytomegalovirus-associated aspergillosis (CAA): CMV seems to have immunosuppressive effects, and its infection is an independent risk factor for developing other systemic infections such as fungal infections. CMV in transplant recipients can significantly increase the chance of CAA regardless of the transplantation type, although this may not include asymptomatic CMV viremia. The proposed risk factors for the development of CAA include intensified immunosuppression, higher CMV viral load, graft rejection, host genetics (polymorphisms in the toll-like receptor-4), ganciclovirinduced neutropenia, and leukopenia. Timely diagnosis of CAA, treatment of both infections, attention to possible drug interactions, and reducing as much as possible the level of the patient's immunodeficiency level may reduce the risk of death.

#### **Acknowledgements**

We would like to thank the staff of research center for antibiotic stewardship and antimicrobial resistance of Tehran University of Medical Sciences, Tehran, Iran.

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Mohammadreza Salehi1 \*, Fariba Zamani2 and Sadegh Khodavaisy3

1 Research Center for Antibiotic Stewardship and Anti-microbial Resistance, Department of Infectious Diseases, Tehran University of Medical Sciences, Tehran, Iran

2 Research Center for Antibiotic Stewardship and Anti-microbial Resistance, Tehran University of Medical Sciences, Tehran, Iran

3 Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

\*Address all correspondence to: salehi.mohamad3@gmail.com; mr-salehi@sina.tums.ac.ir

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 3**

### *Aspergillus* and Aspergillosis in People with Chronic Diseases

*Bismark Dabuo, Nunekpeku Xorlali, Ndego Timothy Amoliga, Zyaara Kono Atibodu, Precious Mavis Newman, Alhassan Mohammed, Raymond Adongsakiya Ali and Abubakari Abudu*

#### **Abstract**

Numerous human diseases are caused by *Aspergillus* species. Mold infections can be more severe in people with weakened immune systems and chronic illnesses. People with underlying chronic conditions are more likely to contract an *Aspergillus* infection than immunocompromised patients, who are more likely to develop an invasive infection with these opportunistic molds. These disorders include *Aspergillus* bronchitis, allergic bronchopulmonary aspergillosis, diabetes, cystic fibrosis, severe asthma with fungal sensitivity, and other inflammatory and allergic conditions. The impact of *Aspergillus* infections in patients with selected chronic infections and the treatment of these infections are discussed in this review along with the most recent research on these topics.

**Keywords:** cystic fibrosis, chronic disease, immunocompromised, *Aspergillus*, hypersensitive syndrome

#### **1. Introduction**

According to Merad et al. [1], *Aspergillus* is a form of fungi that is frequently found in a variety of environmental niches, including soil, decaying plant matter, and indoor air. *Aspergillus* recolonizes indoor areas with high humidity levels, such as air conditioning units and wet carpets [2]. Even though the genus *Aspergillus* contains more than 300 species, *Aspergillus fumigatus*, *Aspergillus flavus*, *Aspergillus niger*, and *Aspergillus terreus* have a disproportionate amount of pathogenicity. The most well-known and often found pathogenic species is *Aspergillus fumigatus*, followed by *A. flavus*; however, *A. niger* and *A. terreus* also exhibit virulence. As a saprophyte organism, *Aspergillus* is capable of colonizing the mucus masses and residual cavities of individuals with chronic obstructive pulmonary disease (COPD) [3].

Although *Aspergillus* infection often does not harm healthy people, people with chronic conditions are more likely to contract the infection, which could have serious negative effects on their health. Chronic conditions including asthma, chronic

obstructive pulmonary disease (COPD), cystic fibrosis, and diabetes impair the immune system and make a person more susceptible to infections. *Aspergillus* bronchitis, *Aspergillus* pneumonia, and allergic bronchopulmonary aspergillosis (ABPA) are only a few of the respiratory conditions that can develop after inhaling *Aspergillus* spores [4]. An important consequence of *Aspergillus* infection in people with chronic medical problems is an increased incidence of morbidity and mortality. These people with chronic illnesses who contract an *Aspergillus* infection are more likely to endure worsened symptoms, extended hospital stays, and complications such as the potentially fatal invasive aspergillosis. Additionally, *Aspergillus* infection may worsen preexisting chronic disorders, creating new difficulties in treating them [5]. *Aspergillus* colonization of the airways is linked to an increased incidence of disease exacerbations and a reduction in lung function, making *Aspergillus* infection a serious hazard to people with cystic fibrosis. *Aspergillus* infection can sporadically result in deadly invasive pulmonary aspergillosis (IPA) in cystic fibrosis (CF) patients. *Aspergillus* infections can harm a person's health if they already have a chronic illness [6]. To reduce their risk of infection, people with chronic illnesses must take certain precautions. These precautions include avoiding settings with a lot of mold and fungi, practicing excellent hygiene, and seeking immediate medical attention if they feel symptoms of an infection. The clinical progression of chronic disorders can be significantly influenced by *Aspergillus* and aspergillosis. People who already have respiratory conditions like asthma, COPD, or cystic fibrosis run the risk of having their symptoms worsened by *Aspergillus*, which could result in progressive lung damage. Long-term *Aspergillus* exposure, especially in susceptible people, may be a factor in the emergence of chronic lung diseases. The therapy of *Aspergillus* infection is also significantly complicated by the increased risk of severe forms of aspergillosis in immunocompromised persons [7]. In this body of research, we will look at how *Aspergillus* infections affect patients with chronic conditions as well as how to avoid and treat them.

#### **2. Clinical manifestations, diagnosis, and epidemiology of the spectrum of** *Aspergillus* **diseases**

Lung infections brought on by *Ammophilus fumigatus* are produced by airborne conidia, which are present in both indoor and outdoor settings at concentrations ranging between 1 and 100 conidia per m<sup>3</sup> , but which can reach up to 108 conidia per m<sup>3</sup> in some circumstances [8]. Because of this, *Aspergillus* spp. are regularly found in the respiratory tract cultures of asymptomatic patients who do not exhibit any symptoms of an invasive or allergic illness [9], and *Aspergillus* DNA has been found in 37% of lung biopsy samples from healthy persons. Additionally, *Aspergillus* colonization in up to 30% of people with chronic obstructive pulmonary disease (COPD) has been confirmed by culture [10]. Inadequate expression of the transcriptional factor ZNF77 in bronchial epithelia leads to defective epithelial cell integrity and upregulation of extracellular matrix (ECM) proteins that support conidial adhesion, which is the genetic basis of *Aspergillus* colonization, according to recent research [8]. Although *Aspergillus* colonization does not always result in infection, it increases the risk of invasive infection in several immunocompromised individuals. However, because invasive pulmonary aspergillosis arises from breathing *Aspergillus conidia*, environmental exposures affect the epidemiology of the disease. There have been several nosocomial clusters of invasive pulmonary aspergillosis (IPA) reported over the past

#### **Figure 1.**

*Syndromes related to aspergillosis patients with various immune statuses.*

three decades, which are typically associated with issues with hospital architecture and air-handling equipment [11].

*Aspergillus* species are responsible for a wide range of human ailments. Based on the underlying immunological status of the host, *Aspergillus* illnesses can be roughly categorized into three classes [8]. These three categories have various pathogenetic routes, clinical manifestations, and overlapping traits. These three groups are depicted in **Figure 1** based on their respective clinical importance. The sections that follow will discuss a few chronic illnesses and their connections to the *Aspergillus* species.

Among the syndromes related to aspergillosis patients with various immune statuses are allergy-related bronchial pulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis (CPA), invasive pulmonary aspergillosis (IPA), and invasive bronchial aspergillosis (IBA) as shown in **Figure 1** [8].

#### **3. Effect of** *Aspergillus* **infections on people with lung chronic disease**

#### **3.1 Asthma**

The increased incidence and prevalence of asthma in the industrialized world have generated significant concerns and coordinated research efforts. Numerous theories to explain this significant change in public health have emerged as a result of the lack of clarity surrounding the etiopathogenesis of asthma. One of the most well-liked theories, the hygiene hypothesis, makes use of the fascinating interaction between the innate and acquired immune systems. According to this theory, the developed world's increased hygiene is a direct cause of the growth in asthma [12]. Even while this advancement has all but eliminated many infectious diseases like cholera, the lack of pathogen exposure in early children seems to cause allergies and asthma later in life.

The hygiene hypothesis states that any bacterium that triggers a sizable type 1 cytokine response may prevent the onset of asthma later in life even if no established list of illnesses that are "protective" has been created [13]. The emergence of Th1-type autoimmune illnesses and the anti-allergic benefits of robust Th2-cytokine-mediated parasite infections cannot exclusively be attributed to insufficient environmental pathogen exposure. The same cannot be stated for the growth of allergies and asthma. Many studies are currently devoted to figuring out how genetics affects allergies and asthma [14].

Inhalant allergens have a key role in triggering the airway inflammation seen in patients with allergic asthma. It is becoming increasingly clear that fungi are important inhalant allergens [13]. Numerous studies have linked asthma to the vast genus of spore-forming fungus known as *Aspergillus*. The "aspergillum" brush used to dispense holy water is referenced in the name of this fungus. All people inhale its spores, although a healthy, normal person is rarely affected by them [15]. However, the fungus spores get stuck in the thick, viscous secretions that are frequently present in the airways of asthmatics. To maintain this state, which commonly develops in atopic people and produces asthma, *Aspergillus* antigens are continuously breathed [3].

It is significant to mention that allergic broncho-pulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA) can confuse asthmatic patients'symptoms [16]. The primary cause of allergic bronchopulmonary aspergillosis, which is primarily linked to *Aspergillus fumigatus*, is hypersensitivity illness. The threatening type of aspergillosis is usually present in people with allergic bronchopulmonary aspergillosis [8]. Asthma sufferers are prone to respiratory infections brought on by the common mold genus *Aspergillus*. According to Seyedmousavi et al. [17], exposure to *Aspergillus* can cause allergic reactions in people with asthma, resulting in airway inflammation and constriction and making it harder to breathe.

The effects of *Aspergillus* infections on people with asthma can vary depending on the infection's intensity and the person's general health. *Aspergillus* infections may sporadically result in the development of allergic bronchopulmonary aspergillosis (ABPA), a chronic respiratory illness marked by symptoms like coughing, wheezing, and dyspnea, according to Chotirmall et al. [7]. When *Aspergillus* infections are severe, they can result in invasive aspergillosis, a condition that can be fatal and seriously harm the lungs. Kosmidis and Denning [18] claim that those with weakened immune systems, such as those undergoing chemotherapy or organ transplantation, are more likely to contract this condition.

Epithelial cells or alveolar macrophages cause inflammation as part of innate immunity's protective mechanisms. Toll-like receptors (TLRs), C-type lectin receptors (CLRs), and nucleic-binding oligomerization domain (NOD)-like receptors (NLRs) are examples of pattern recognition receptors that are used by innate immunity to identify fungi. *Aspergillus* stimulates these receptors, which activates cytokines and results in cellular and humoral immune responses. *Aspergillus* is protected and eliminated by T-helper cell type 1, while T-helper cell type 2 reacts by preventing its elimination. The severe inflammation seen in allergic bronchopulmonary aspergillosis, which results in eosinophilia, increased mucus formation, and IgE antibody production is caused by an excessive T-helper cell type 2 response. This inflammation leads to airway hypersensitivity, which aggravates asthma by causing bronchial obstruction [19, 20]. The clinical spectrum of *Aspergillus*-associated hypersensitivity respiratory diseases includes *Aspergillus*-induced asthma, allergic bronchopulmonary aspergillosis (ABPA), and allergy *Aspergillus* sinusitis (AAS). Hypersensitivity pneumonitis can also be brought on by *Aspergillus*, albeit this is often only seen in non-atopic persons.

*Aspergillus*-caused asthma has not yet received the attention it merits. Given the association between the mold *Aspergillus* and asthma, it is imperative to understand the frequency of *Aspergillus* sensitivity in asthmatic participants in each geographical area [21].

#### **3.2 Arthritis**

Gamaletsou et al. [22] found that *Aspergillus* infection can elevate inflammatory levels in the body, which can aggravate arthritic symptoms. Infections with *Aspergillus* can affect the respiratory system and result in symptoms, including coughing, wheezing, and shortness of breath. This may be particularly difficult for people with arthritis who already experience breathing issues due to joint pain and stiffness [23]. Furthermore, those with impaired immune systems who have arthritis are more likely to develop *Aspergillus* infections. For those who take immunosuppressive medicines to address their arthritic symptoms, this may be very challenging. Furthermore, *Aspergillus* infections can increase pain, stiffness, and mobility issues in those who already have arthritis by damaging their joints [22]. Due to the infection's potential to hinder the body's capacity to absorb medication, *Aspergillus* infections can also undermine the efficacy of arthritis treatments [24].

#### **3.3 Cystic fibrosis**

Cystic fibrosis (CF), the most common fatal genetically inherited disease that is caused by a mutation in a gene that encodes the CFTR protein, affects one in every 2400 live births in Caucasian cultures [25]. Two thousand different CFTR variations have so far been identified, with the most frequent being F508del, a single amino acid loss that accounts for about 70% of disorders [26]. Infants born today are expected to live into their fifth decade with CF, which has improved throughout a generation from a condition that often killed infants in their early years to one with a median lifespan of 28 years.

Ion fluxes and intracellular calcium homeostasis are compromised when the CFTR protein is absent from the cell membrane, where it acts as an ATP-driven chloride channel. Through a cycle of infection and exaggerated inflammation, thickened mucus forms in the airway epithelial cells, impeding the mucociliary clearance of inhaled pathogens and ultimately leading to respiratory failure [27, 28]. Continual lung infections and airway inflammation are the primary causes of mortality and morbidity in CF patients. To end this destructive cycle, the prevention and treatment of airway infection have been the cornerstones of clinical management; yet, respiratory failure brought on by chronic or recurrent infection still accounts for over 90% of fatalities [29]. The pathogenesis of respiratory decline has typically been studied through the role of bacterial pathogens like *Staphylococcus aureus*, *Pseudomonas aeruginosa*, *Haemophilus influenzae*, and the *Burkholderia cepacia* complex. The significance of *Aspergillus* species and other filamentous fungi in the pathogenesis of non-ABPA (allergic bronchopulmonary aspergillosis) respiratory illness in CF has received little attention, despite their frequent isolation in respiratory samples. However, it has become clearer that *Aspergillus fumigatus* may also be crucial for the CF lung [30]. People with CF are susceptible to respiratory infections brought on by the fungus *Aspergillus* [31].

*Aspergillus* infections can have a variety of impacts on CF patients, depending on the infection's severity and overall health. The following are a few of the implications of *Aspergillus* infections in people with CF: *Aspergillus* infections can cause a variety of respiratory symptoms, including coughing, wheezing, shortness of breath, chest pain, and fever. These symptoms can be extremely severe in CF patients because the underlying illness of CF already damages a person's lungs [18]. Again, *Aspergillus* infections can damage the lungs and impede their ability to function, leading to greater breathing issues and a worsening of CF symptoms. Lung damage caused by *Aspergillus* infections can occasionally be permanent [32]. Furthermore, *Aspergillus* infections can reduce the quality of life of CF patients by limiting their ability to perform routine tasks, attend school or work, and participate in social activities [33]. Infections with *Aspergillus* can also weaken immunity, raising the possibility of further respiratory infections in CF patients [34]. Additionally, treating *Aspergillus* infections in CF patients can be difficult and typically requires lengthy courses of antifungal medication. The infection may occasionally come back even after treatment [35].

#### **3.4 Chronic obstructive pulmonary disease**

People who have *Aspergillus* spp. growing in their airways and having chronic obstructive pulmonary disease (COPD) are often regarded as contaminants. Although it is unclear how common invasive pulmonary aspergillosis (IPA) is in this community, accumulating evidence suggests that individuals with severe COPD have an increased risk of contracting the condition [10]. According to certain estimates, COPD is the underlying illness in 1% of individuals with IPA. Given that tissue samples are infrequently taken before death in COPD patients, it may be difficult to make a definitive diagnosis of IPA. To make a diagnosis, a combination of clinical traits, radiographic findings—often from thoracic computed tomography scans—microbiological results, and occasionally serological data is used [36].

Chronic obstructive pulmonary disease (COPD), a progressive lung disorder that makes breathing challenging, can be brought on by several factors, including extended exposure to irritants like cigarette smoke [37]. A reaction to *Aspergillus* called allergic bronchopulmonary aspergillosis (ABPA) can occasionally strike patients with COPD. Wheezing, coughing, and shortness of breath are some of the symptoms of ABPA, which can worsen if left untreated [38].

#### **4. Effects of** *Aspergillus* **infections on people living with other chronic infections**

#### **4.1 Hepatitis B and C viruses**

Co-infection with *Aspergillus* may increase the pathogenicity of the hepatitis B and C viruses, leading to increased hepatocellular damage in those who are infected. There has been a hepatitis outbreak in some parts of Western India, which is characterized by jaundice, rapidly developing ascites, portal hypertension, and a high fatality rate. The illness was associated with eating maize that had been heavily contaminated with *Aspergillus flavus*. According to an analysis of contaminated samples, victims may have consumed 2–6 mg of aflatoxin per day over a month. Massive cells and bile duct development were found in a liver sample obtained during a necropsy. The sickness appears to be brought on by toxicosis [39]. Infections with *Aspergillus* can worsen preexisting liver damage and cause hepatic impairment, especially in those who also have hepatitis B or C viruses [40]. The detoxification and elimination of xenobiotics,

Aspergillus *and Aspergillosis in People with Chronic Diseases DOI: http://dx.doi.org/10.5772/intechopen.111863*

such as the mycotoxins *Aspergillus* generates, depends on the liver [41]. Fungal infections like aspergillosis might worsen the immunosuppressive effects of the hepatitis B and C viruses. *Aspergillus* infection considerably raises the risk of severe or widespread infection in people with hepatitis B or C viruses, thereby exacerbating the immune impairment already present in these individuals. As a result, an *Aspergillus* coinfection may result in more severe symptoms and a longer time to recover [42]. A prominent therapeutic strategy for treating patients with hepatitis B and C viral infections is the use of antiviral medications. Antifungal medications used to treat *Aspergillus* infection may interact unfavorably or induce drug interactions in this case with some antiviral medications [43]. Furthermore, those with hepatitis B or C virus infections may have a higher chance of dying if they also have an *Aspergillus* infection. Due to a complex interplay of impaired liver function, immunosuppression, potential drug interactions, and increased disease severity, people who have concurrent hepatitis B or C virus and *Aspergillus* co-infection may have higher mortality rates than those who only have one disease [8].

#### **4.2 Cancers**

Infections account for the majority of deaths in patients with acute leukemia and lymphoma [44]. Host defenses have been breached [45]. The most prevalent condition in these patient populations is candidiasis, which is followed by *Aspergillus* spp. related fungal infections [46]. For patients using immunosuppressive medications for illnesses including collagen vascular disorders, kidney transplants, and cardiac transplants, *Aspergillus* infections, which are the primary factors in their mortality when they exist, are extremely deadly [47].

*Aspergillus* infections in cancer patients can have a variety of effects depending on the infection's intensity and the patient's overall health. One of the most common types of *Aspergillus* infections in people with cancer is invasive aspergillosis, which occurs when the fungus enters the bloodstream and spreads to other parts of the body [48]. Other signs of this kind of virus include coughing, fever, chest pain, and shortness of breath. In extreme cases, invasive aspergillosis can result in organ failure and death [5]. Infections with *Aspergillus* can also cause additional conditions in cancer patients, including sinusitis, pneumonia, and skin infections. These infections can be difficult to recognize and treat, especially in people with weakened immune systems [49]. Chemotherapy or other cancer treatments raise the incidence of *Aspergillus* infections in cancer patients. To prevent these disorders, healthcare providers may advise antifungal medications or take other precautions, such as limiting mold exposure and preserving good hygiene practices [48].

#### **4.3 HIV/AIDS**

A study of 35,252 HIV patients in a national database estimated the incidence of invasive aspergillosis in AIDS to be 3.5 cases per 1000 person-years [50]. Aspergillosis was discovered in 0.43% of HIV patients, according to the findings of another database study of 38 million hospital diagnoses [50]. People with HIV/AIDS may be more susceptible to infections, such as aspergillosis, as a result of their suppressed immune systems [50]. Symptoms after exposure to *Aspergillus* might vary depending on how serious the illness becomes. Patients with weakened immune systems, such as those with HIV/AIDS, may experience more severe infection symptoms, including fever, coughing, shortness of breath, chest discomfort, and other respiratory symptoms.

According to Wang et al. [51], it may result in high mortality or serious lung injury. Neutropenia, which can arise as a result of HIV treatment, is a recognized risk factor for invasive aspergillosis [50]. Neutropenia or corticosteroid use is associated with nearly half of aspergillosis infections in HIV patients [51]. Additional risk factors for aspergillosis infection in HIV patients include concurrent Pneumocystis jirovecii (PCP) infection and a CD4 count of less than 50–100 cells/mm<sup>3</sup> [52].

Skin infections and infections of other organs, notably the brain, can arise from exposure to *Aspergillus* in addition to lung infections [51]. It wasn't until 2017 that researchers learned that HIV-positive patients might also get CPA and that their infection patterns were similar to those of HIV-negative people. Usually, CPA makes other respiratory conditions worse. Many people who have unexplained pulmonary tuberculosis (PTB), sometimes referred to as a smear or GeneXpert negative TB, actually have CPA instead of PTB [53], yet they are mistreated, and some of them will die as a result. According to Adams et al. [54], there is a considerable clinical and radiological overlap between CPA and subacute invasive aspergillosis.

Compared to other invasive fungal infections (IFIs), less is known, especially about the incidence and prognosis of aspergillosis in patients with HIV/AIDS [50]. This is thought to be the result of the difficulty in making a clinical diagnosis, which causes many aspergillosis patients to go untreated for the bulk of their lives. After death, aspergillosis is usually discovered [55]. The overall impact of this fungus on patients with HIV/AIDS is unknown as a result [50]. Patients with HIV/AIDS should make an effort to lower their risk of acquiring *Aspergillus* and other fungus-related illnesses. This requires practicing excellent cleanliness, avoiding areas with a lot of molds, and seeking immediate medical attention if any signs of infection emerge [56].

#### **4.4 Diabetes**

Diabetes patients experience more severe illnesses, a higher risk of infection, and a higher death rate when compared to the general population [57]. *Aspergillus fumigatus* (*A. fumigatus*) is the most common opportunistic airborne fungal infection that results in fatal invasive pulmonary aspergillosis (IPA) in immunocompromised individuals [8]. According to research by Ghanaat and Tayek [58], non-immunocompromised diabetic patients are more likely to acquire invasive aspergillosis. What makes diabetics more susceptible to an *A. fumigatus* infection is still a mystery, though. According to a study, people with diabetes had a poorer prognosis for fungal pneumonia since diabetes is an independent risk factor for long-term hospitalization for the condition [59]. Research on the effects of diabetes on pulmonary *A. fumigatus* infection uses a streptozotocin-induced mice model of diabetes as an example. A study revealed a more severe course of the pulmonary *A. fumigatus* infection in diabetic mice as demonstrated by a considerably poorer survival rate and clearance of *A. fumigatus* [60], in addition to the observed increased fungal burden 24 hours postpulmonary *A. fumigatus* infection. Both the inflammatory and immunological responses are necessary for the host to be protected from pulmonary *A. fumigatus* infection. A good inflammatory response is necessary for the fungal infection to be eradicated. The overactive immune response that produces cytokines abruptly and in enormous numbers is known as hypercytokinemia, commonly referred to as a cytokine storm, and it can be even more destructive than the diseases that are invading the body [61]. When diabetic mice were infected with *A. fumigatus* in the lungs, the inflammatory response was hyperactive, as seen by notably extended and increased lung leukocyte infiltration as well as noticeably greater plasma cytokine expression.

Aspergillus *and Aspergillosis in People with Chronic Diseases DOI: http://dx.doi.org/10.5772/intechopen.111863*

The abnormal reaction was strongest in the early phases of infection. The inflammatory and immune responses, including cytokine-cytokine receptor interaction, tumor necrosis factor (TNF) signaling pathway, nucleotide-binding oligomerization domainlike (NOD-like) receptor, and toll-like receptor (TLR) signaling pathways, were the biological processes most enriched in diabetes. On the second day after infection, a transcriptome analysis of the lung tissue indicated this. Together, these results show that pulmonary *A. fumigatus* infection in diabetes results in a rapid, exaggerated inflammatory response that raises mortality. For diabetics, aspergillosis can be very problematic. Immunity can be weakened by diabetes, making it more challenging for the body to fight infections. Some diabetes medications may potentially increase the susceptibility of the immune system. Because of this, individuals with diabetes who are exposed to *Aspergillus* may get aspergillosis more frequently and with a more serious illness [60]. To lower their risk of aspergillosis and other fungal illnesses, diabetics must take precautions. This may require controlling blood sugar levels, keeping an impeccable standard of cleanliness, avoiding contact with mold and other fungi, and seeking medical attention as soon as any signs of aspergillosis or other illnesses appear. People with diabetes should work closely with their healthcare professionals to manage their condition and watch out for any complications, such as infections [62].

#### **4.5 Obesity**

*Aspergillus* infections are caused by a fungus of that name. These diseases can affect several parts of the body, including the skin, sinuses, and lungs. There is not any evidence yet that *Aspergillus* infections have a direct impact on weight. However, several studies suggest that several environmental factors, such as exposure to toxins and diseases, may have an impact on the development of obesity. For instance, exposure to endocrine-disrupting chemicals (EDCs) and other pollutants has been linked to increased adiposity in both human and animal models. *Aspergillus* infections may indirectly cause obesity by impairing the immune system and increasing susceptibility to other infections or variables in the environment that promote obesity [63]. It is critical to realize that obesity is a complex condition with a variety of underlying causes, including genetics, lifestyle, and environmental factors. Although *Aspergillus* infections may not directly contribute to obesity, they can nevertheless have major health consequences and must be treated effectively to prevent issues.

#### **4.6 Alzheimer's disease**

Alzheimer's disease is a neurological ailment that typically affects the elderly and gets worse with time. The hallmarks of this disease in the brain are amyloid plaques and neurofibrillary tangles, which result in neuronal cell death, vascular dysfunction, and inflammatory processes. In a study, researchers looked at whether people with Alzheimer's disease had fungal infections. Proteomic research provides substantial evidence that brain samples from Alzheimer's disease patients contain fungus-related proteins. Additionally, PCR analysis of these samples revealed a variety of fungal species, depending on the patient and the tissue investigated. Brain tissues included a variety of fungi, according to DNA research. Together, these results show that the brains of people with Alzheimer's disease contain fungus macromolecules. To our knowledge, these findings are the first evidence that fungi can be discovered in the brain tissues of Alzheimer's disease patients [64]. The specific impact of *Aspergillus* on people with Alzheimer's disease is unknown, though. Alzheimer's disease can make people more vulnerable to infections due to a weakened immune system, although there is no conclusive evidence linking it to an increased risk of *Aspergillus* infections [7]. However, patients with Alzheimer's disease may be more prone to developing respiratory infections, including those caused by *Aspergillus*, due to their weakened immune systems and difficulties swallowing, which can result in aspirating food or liquids into the lungs. Respiratory infections, according to Tangaleela et al. [65], can aggravate Alzheimer's disease symptoms and lead to consequences like pneumonia. Caretakers of individuals with Alzheimer's disease must take steps to prevent respiratory infections, including ensuring a clean environment, watching out for infection warning signs, and seeking medical attention as soon as symptoms develop. If an *Aspergillus* infection is suspected, a healthcare practitioner can perform diagnostic testing and recommend appropriate treatment options, such as antifungal medication [66].

#### **4.7 Depression**

Although some evidence points to *Aspergillus* infections as a possible cause of depression in some individuals, the relationship between the two conditions is convoluted and poorly understood. Continual *Aspergillus* infections have been linked to depressive symptoms such as low mood, loss of interest in activities, and low energy, according to research. The physical side effects of the infection, such as fatigue, soreness, and breathing issues, are likely what are aggravating these emotions [8]. It is likely that depressive disorders raise the risk of *Aspergillus* infections because they can weaken the immune system and make patients more susceptible to infections [67]. This is so that stress and other factors associated with depression can have this effect [67].

#### **4.8 Stroke**

Multiple organs could be affected by aspergillosis that has spread throughout the body. According to Santa-Ramrez et al. [68], the most serious side effect is brain infection, which occurs in 10–15% of patients and has a fatality rate of more than 90% even while receiving guided antifungal medication. A CNS infection may be acquired through hematogenous spread (typically from a pulmonary center), contiguous dissemination from a paranasal sinus infection, or direct iatrogenic injection during cerebral invasive procedures [69]. *Aspergillus* spp. CNS infection has been linked to numerous different clinical features. Up to 65% of these patients may have focal deficits Nevertheless, just one case report and not any clinical series have been used to describe the prevalence of clinical manifestations of acute stroke [69].

One of the infections that *Aspergillus*, a type of fungus, can cause is invasive aspergillosis, a serious condition that can affect people with weakened immune systems. It is unknown how aspergillosis impacts stroke, despite research suggesting that some illnesses, such as pneumonia and urinary tract infections, can increase the risk of the condition. According to case reports and small studies, aspergillosis may cause strokes, especially in people with compromised immune systems. The risk of stroke is increased by invasive aspergillosis, which can cause brain blood vessel inflammation and damage. Additionally, aspergillosis-related blood clots have been connected to a higher risk of stroke [70]. More research is required to completely understand the relationship between aspergillosis and stroke.

#### **4.9 Osteoporosis**

A disorder called osteoporosis is characterized by a loss of bone mass and a higher risk of fractures. There is little data on how *Aspergillus* infections affect osteoporosis, but some studies have found a link between osteoporosis and persistent *Aspergillus* lung infections. This is due to the possibility of persistent inflammation brought on by *Aspergillus* infections, which can promote bone resorption and reduce bone growth [71]. Additionally, corticosteroids and other antifungal drugs used to treat *Aspergillus* infections can raise the risk of osteoporosis. By inhibiting bone production and increasing bone resorption, corticosteroids are known to reduce bone density [72]. The link between *Aspergillus* infection and osteoporosis is complicated and can change depending on the person and the severity of the infection, and it is crucial to remember.

#### **4.10 Chronic kidney disease**

*Aspergillus* infections can be extremely difficult to cure and can have serious negative effects on the health of patients with chronic kidney disease (CKD). Immunosuppressive medications, which are frequently administered to decrease inflammation and lower the risk of rejection following kidney transplantation, are frequently linked to *Aspergillus* infections in CKD patients. These drugs may lower immunological function, increasing the risk of fungal infections in patients [73]. Patients with CKD may experience severe effects from *Aspergillus*, especially if the infection is not identified and treated right once. Invasive pulmonary aspergillosis (IPA), a potentially fatal illness that can cause lung damage, sepsis, and death, is brought on by *Aspergillus* [74]. In addition to the infection's direct effects, *Aspergillus* might aggravate the patient's underlying CKD and further jeopardize their health. Mycotoxins, which the fungus generates, can harm the kidneys and cause acute renal injury or worsen underlying CKD [41]. As many antifungal drugs can be harmful to the kidneys, treating *Aspergillus* infections in CKD patients can be difficult and necessitate close monitoring of the patient's renal function. To help the immune system more effectively combat the infection, immunosuppressive medicines may also need to be changed or stopped [75]. In conclusion, *Aspergillus* infections can have serious effects on the health of CKD patients, including deteriorating renal function and potentially fatal consequences. To lessen the effect of the infection on the patient's health, early identification and fast treatment are crucial [75].

#### **4.11 Oral disease**

A particular kind of fungus called *Aspergillus* can infect the human body, including the oral cavity. Various effects on oral health may result from these infections. Oral aspergillosis is one of the most prevalent *Aspergillus* infections of the oral cavity. This can happen to persons who have compromised immune systems, such as those who have cancer, HIV/AIDS, or other immune-compromising diseases. Additionally, it might happen to patients who have undergone particular dental treatments, like tooth extractions [76]. Several symptoms, such as discomfort, swelling, and redness in the afflicted area, can be brought on by oral aspergillosis. Along with making it difficult to speak or swallow, it can also lead to the emergence of sores or ulcers [77]. *Aspergillus* infections can contribute to the development or aggravation of other oral disorders in

addition to causing direct harm to the oral cavity. For instance, *Aspergillus* infections can raise your risk of getting gum disease, periodontitis, and other oral infections [76].

#### **4.12 Heart disease**

Infections with *Aspergillus* primarily affect the respiratory system, but they can also spread to other bodily organs, such as the heart. For people with heart problems, *Aspergillus* infections can have severe negative effects. The fungus can inflame the heart muscle, which can result in cardiac failure, arrhythmias, and pain in the chest. Additionally, *Aspergillus* can infect the heart valves, which increases the risk of endocarditis and damages the heart valves [78]. *Aspergillus* infections are more likely to occur in those with compromised immune systems, such as those with HIV/AIDS or those receiving chemotherapy. But if they breathe in a lot of *Aspergillus* spores, even those with strong immune systems can have *Aspergillus* infections [8]. Antifungal medications are frequently used to treat *Aspergillus* infections in people with heart disease because they can assist to destroy the fungus and reduce inflammation. To correct heart valve damage brought on by the infection in some circumstances, surgery may be required [79]. By avoiding places where the fungus is prone to grow, such as damp or moldy locations, and by wearing protective masks when dealing with soil, compost, or other organic materials, people with heart disease should take precautions to prevent *Aspergillus* infections.

#### **5. Conclusion**

*Aspergillus* is a genus of fungi that can infect people with weakened immune systems, especially those who already have ongoing diseases. People with persistent infections may experience everything from minor symptoms to potentially fatal complications as a result of *Aspergillus* infections. Invasive pulmonary aspergillosis (IPA), which happens when the fungus penetrates the lungs and produces inflammation, is one of the most prevalent kinds of *Aspergillus* infections. This may result in symptoms including fever, coughing, pain in the chest, and shortness of breath. IPA can be particularly harmful in patients with chronic infections, since their compromised immune systems may not be able to successfully fight off the infection. Infections with *Aspergillus* can also affect the skin, nails, and sinuses in addition to other regions of the body. These infections may be more difficult to treat in patients with persistent infections and may call for more drastic measures, such as surgery or antifungal drugs. People with chronic infections may further endure psychological and emotional repercussions in addition to the physical signs and symptoms of *Aspergillus* infections. The ongoing risk of infection can be stressful and traumatic, and the necessity for repeated medical treatments can interfere with normal life. People with persistent infections may experience significant and wide-ranging impacts from *Aspergillus* infections. People with chronic infections need to take precautions to reduce their chance of contracting *Aspergillus* infections, such as maintaining excellent hygiene and avoiding mold and other environmental triggers. Additionally, it is crucial for medical professionals to keep an eye out for any indications of *Aspergillus* infections in this population and to offer fast and effective treatment when necessary. In conclusion, *Aspergillus* infections can affect patients with chronic illnesses in a variety of ways, ranging from medical symptoms to psychological distress. Healthcare professionals and patients alike should be aware of these hazards and take precautions to reduce

#### Aspergillus *and Aspergillosis in People with Chronic Diseases DOI: http://dx.doi.org/10.5772/intechopen.111863*

them. Despite the difficulties presented by *Aspergillus* infections, persons with chronic infections can lead healthy, fulfilling lives with the right treatment and management, and also more research is need in the area of *Aspergillus* and aspergillosis in people living with chronic diseases to establish more mechanisms and associations between these fungi and other infections.

### **Author details**

Bismark Dabuo, Nunekpeku Xorlali, Ndego Timothy Amoliga, Zyaara Kono Atibodu, Precious Mavis Newman, Alhassan Mohammed, Raymond Adongsakiya Ali and Abubakari Abudu\* University for Development Studies, Ghana

\*Address all correspondence to: abuduabubakari688@gmail.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section 2
