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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.
Research Center for Antibiotic Stewardship and Anti-microbial Resistance, Department of Infectious Diseases, Tehran University of Medical Sciences, Tehran, Iran
Fariba Zamani
Research Center for Antibiotic Stewardship and Anti-microbial Resistance, Tehran University of Medical Sciences, Tehran, Iran
Sadegh Khodavaisy
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
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, 5, 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, 12, 13, 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].
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, 26, 27, 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 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, 40, 41]. However, several reports show that critically ill patients often develop IPA even in the absence of classic risk factors [41, 42, 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].
Figure 1.
Post-Viral Aspergillosis Risk Factors.
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, 22, 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 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].
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, 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, 69, 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 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].
CAPA definition
Host factors
Clinical features
Laboratory evidence
Possible
Need to intensive care; glucocorticoid therapy [equivalent to prednisone, 20 mg/day]; dexamethasone plus tocilizumab; history of hematological malignancy or All-HSCT or SOT or GVHD
New pulmonary infiltrate or cavity lesion on the chest CT scan that has no other causes
Presence of at least one of the following: microscopic detection of mold elements in NBL; positive NBL culture for mold; single NBL galactomannan>4.5; NBL galactomannan >1.2 twice or more; NBL galactomannan >1.2 plus another NBL mycology test positive (PCR or LFA)
Probable
Need to intensive care; glucocorticoid therapy [equivalent to prednisone, 20 mg/day]; dexamethasone plus tocilizumab; history of hematological malignancy or All-HSCT or SOT or GVHD
New pulmonary infiltrate on the chest CT scan that has no other causes as follows: dense, well-circumscribed lesions with or without a halo sign, air crescent sign, cavity, or wedge-shaped and segmental or lobar consolidation
Presence of at least one of the following: microscopic detection of fungal elements in sputum, bronchoalveolar lavage, bronchial brush, or aspirate indicating a mold; Aspergillus recovered by culture of bronchoalveolar lavage or bronchial brush; single serum or plasma galactomannan ≥1.0, bronchoalveolar lavage fluid galactomannan ≥1.0, single serum or plasma galactomannan ≥0.7 and bronchoalveolar lavage fluid galactomannan ≥0.8; or two or more positive Aspergillus PCR on plasma, serum, or whole blood; or on bronchoalveolar lavage fluid
proven
Need to intensive care; glucocorticoid therapy [equivalent to prednisone, 20 mg/day]; dexamethasone plus tocilizumab; history of hematological malignancy or All-HSCT or SOT or GVHD
New pulmonary infiltrate on the chest CT scan that has no other causes as follows: dense, well-circumscribed lesions with or without a halo sign, air crescent sign, cavity, or wedge-shaped and segmental or lobar consolidation
Presence of at least one of the following: histopathological detection of fungal hyphae showing invasive growth with associated tissue damage; Aspergillus recovered by culture or microscopy; or histology or PCR obtained by a sterile aspiration or biopsy from a pulmonary site
Table 1.
Case definitions for patients with possible, probable, and proven CAPA.
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].
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, 104, 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, 120, 121, 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].
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 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), ganciclovir-induced 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.
We would like to thank the staff of research center for antibiotic stewardship and antimicrobial resistance of Tehran University of Medical Sciences, Tehran, Iran.
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Written By
Mohammadreza Salehi, Fariba Zamani and Sadegh Khodavaisy
Submitted: 02 May 2023Reviewed: 16 May 2023Published: 02 August 2023
Open access peer-reviewed chapter
