key: cord-0690235-iknkjl4w authors: Lai, Chih-Cheng; Yu, Weng-Liang title: COVID-19 associated with pulmonary aspergillosis: A literature review date: 2020-09-24 journal: J Microbiol Immunol Infect DOI: 10.1016/j.jmii.2020.09.004 sha: 32bdf04b40864c4efab7eee27f0c4055cd4f7950 doc_id: 690235 cord_uid: iknkjl4w Bacterial or virus co-infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported in many studies, however, the knowledge on Aspergillus co-infection among patients with coronavirus disease 2019 (COVID-19) was limited. This literature review aims to explore and describe the updated information about COVID-19 associated with pulmonary aspergillosis. We found that Aspergillus spp. can cause co-infections in patients with COVID-19, especially in severe/critical illness. The incidence of IPA in COVID-19 ranged from 19.6% to 33.3%. Acute respiratory distress syndrome requiring mechanical ventilation was the common complications, and the overall mortality was high, which could be up to 64.7% (n =22) in the pooled analysis of 34 reported cases. The conventional risk factors of invasive aspergillosis were not common among these specific populations. Fungus culture and galactomannan test, especially from respiratory specimens could help early diagnosis. A. fumigatus was the most common species causing co-infection in COVID-19 patients, followed by A. flavus. Although voriconazole is the recommended anti-Aspergillus agent and also the most commonly used antifungal agent, aspergillosis caused by azole-resistant Aspergillus is also possible. Additionally, voriconazole should be used carefully in the concern of complicated drug-drug interaction and enhancing cardiovascular toxicity on anti-SARS-CoV-2 agents. Finally, this review suggests that clinicians should keep alerting the possible occurrence of pulmonary aspergillosis in severe/critical COVID-19 patients, and aggressively microbiologic study in addition to SARS-CoV-2 via respiratory specimens should be indicated. In addition, coinfection between SARS-CoV-2 and other respiratory pathogens have become another serious concern in the treatment of patients with COVID-19. [4] [5] [6] [7] [8] [9] Many bacteria, such as Streptococcus pneumoniae, Interleukin (IL)-10 has a key function in the regulation of cellular immune responses and is involved in various inflammatory diseases. 22 Highly elevated level of sera IL-6 and IL-10 in pandemic influenza (H1N1) patients may lead to disease progression. 23 A rat model of aspergillosis was significantly associated with increased production of IL-10, which mediate the influx of phagocytic cells and might limit the extent of local tissue destruction of Aspergillus infection. 24 However, greater Th2 responses (involving an increase of IL-10) or lesser Th1 responses, might be related to down-regulation of macrophage responses, and increase the host susceptibility to lethal Aspergillus infection. 25, 26 Collectively, post respiratory viral Th-2 immune response of increasing IL-10 followed by temporary Th1 immune depression predisposes to invasive aspergillosis. Proinflammatory cytokines and chemokines, such as TNFα, IL-6, IL-10, interleukin-1β, and monocyte chemoattractant protein-1 were significantly elevated in severe COVID-19 patients. 27, 28 The elevated cytokine levels may also contribute to the lethal complications of COVID-19. In severe COVID-19 patients with elevated inflammatory cytokines, postmortem pathology has revealed tissue necrosis and interstitial infiltrations with macrophage and J o u r n a l P r e -p r o o f monocyte in the lung, heart and gastrointestinal mucosa. Among the excessive cytokines releasing syndrome (CRS), IL-6 is one of the key cytokines. IL-6 is a multi-functional cytokine and can play an important role in protective immunity against Aspergillus and there is a significant increase in the IL-6 after Aspergillus fumigatus infection. 29, 30 The patients with IPA may exhibit reduced responsiveness of T cells to IL-6. 31 However, excessive IL-6 signaling in COVID-19 patients with CRS leads to several biological effects such as increasing vessel permeability, acute respiratory distress syndrome (ARDS), cardiac arrhythmia and reducing myocardium contractility. Moreover, the nonimmunocompromised patients with ARDS may become vulnerable to IPA, which prevalence can reach up to 15% of patients. 15 The immunomodulators may be a beneficial addition to antiviral therapy. IL-6 blockade targeting the host immune system that may be effective for (60/243) COVID-19 patients had co-infection with Aspergillus. Moreover, they found that pulmonary aspergillus could develop in patients with asymptomatic, mild, moderate, severe and critical COVID-19. However, no detailed clinical manifestations were described in this report. 9 Additionally, two studies reported the incidence of co-IPA among COVID-19 patients requiring ICU admission was 20.6% (7/34) 35 in Belgium and 19.6% (6/31) in Netherland, 36 respectively. In France, Alanio et al 34 showed the incidence of COVID-19 associated with IPA was 33.3% (9/27) among mechanically ventilated patients. Another study in China between January and March 2020 by Wang et al identified 8 (7.7%) of 104 COVID-19 patients who had IPA at the same time.33 The mean age of these 8 patients was 73 + 13 years and all were male. Seven (87.5%) patients had various underlying diseases, including hypertension (n = 7), diabetes mellitus (n = 2), chronic obstructive pulmonary disease (COPD) (n = 2), chronic kidney disease (n = 2) and heart disease (n = 1). Six patients received corticosteroid treatment but none of them had immunodeficiency or cancer. Additionally, several case series [34] [35] [36] [37] or case reports 38-43 including a total of 34 cases provided the detailed clinical characteristics of COVID-19 patients with aspergillosis (table 1) . They were widely reported from France (n = 11), Germany (n = 7), the Netherland (n = 7), Belgium (n = 7), Italy (n = 1) and Austria (n =1). Their mean age was 66.1 ± 12.3 years and 20 (58.8%) patients were ≥ 65 years. Man compromised 82.4% (n = 28) cases. Hypertension (n = 15), diabetes mellitus (n = 9), obesity (n = 7), COPD (n = 5), hypercholesterolemia (n = 5), and ischemia heart disease (n = 3) were common underlying diseases, but 5 (14.7%) patients did not have any comorbidity. At least one-third of patients had received systemic steroids. Several studies 33, 34, 37, 38, 41 reported the radiographic findings of COVID-19 associated pulmonary aspergillosis. Wang et al 33 showed that typical IPA presentation including nodules with cavities and dendritic signs could present in the early stage. Additionally, several radiographic findings, such as peripheral nodule, air crescent, reverse halo sign, nodular consolidation, ground-glass opacities, crazy paving pattern, pleural effusion, and pulmonary cysts were reported among patients with COVID-19-associated pulmonary aspergillosis by other reports. 34, 37, 38, 41 Several mycological studies, including fungus culture, PCR, galactomannan tests, β-D-glucan test and rarely lateral-flow device were applied to detect the presence of Aspergillus spp among these patients. In the review of 34 cases, among 29 patients who had culture-confirmed aspergillosis, Aspergillus fumigatus was the most common pathogens (89.7%, n = 26), followed by Aspergillus flavus (6.9%, n = 2). In addition, one case of azole-resistant A. J o u r n a l P r e -p r o o f fumigatus was reported by Meijer et al. 43 Furthermore, the levels of galactomannan in bronchoalveolar lavage (BAL) fluid were always higher than those in serum. Among the 34 reported cases, the lopinavir-ritonavir combination was the most common anti-SARS-CoV-2 agents, followed by azithromycin and hydroxychloroquine. Voriconazole was the most commonly used antifungal agents, followed by caspofungin, isavuconazole and liposomal amphotericin B, however, 8 patients (23.5%) did not receive any antifungal agent. In the report by Wang et al, 33 all IPA cases caused by A. fumigatus developed in patients with severe/critical COVID-19 after tested negative for SARS-CoV-2. ARDS was the most common complication (50%, n = 4), followed by liver damage (12.5%, n = 1) and acute kidney injury (12.5%, n = 1). All deaths and the overall case fatality rate was 64.7% among these 34 cases. Overall, the findings of this review provide several important information. First, in addition to common bacteria and viruses, Aspergillus spp. can cause co-infections in patients with COVID-19, especially in severe/critical illness. Most importantly, the outcome of these patients was poor. ARDS requiring MV support was the common complications, and the overall mortality was high. 453.3 ± 37.0 ms, p = 0.004). Seven patients (3.5%) required discontinuation of these medications due to QTc prolongation. 46 Patients with pre-existing heart disease are especially susceptible to drug-induced arrhythmias. 45 This is J o u r n a l P r e -p r o o f important because up to one-third of patients with COVID-19 have cardiac injury or cardiomyopathy, which can further increase the risk of cardiac arrhythmias. 47 Clinical protocols to manage COVID-19 and avoid cardiac adverse effects are recommended. If baseline electrocardiographic testing reveals a moderately prolonged QTc (QTc ≥ 480ms for female, ≥ 470ms for male, but < 500ms), optimization of medications and electrolytes may permit therapy. If the QTc is markedly prolonged (QTc ≥ 500ms or increased by ≥ 60ms), the above-mentioned drugs that might further prolong QTc should be avoided. 48 Voriconazole is a standard first-line treatment for IPA but intravenous therapy can prolong the QT interval and the potential for drug-drug interactions. 49, 50 For COVID-19 patients treated with voriconazole for IPA, another concern would be increased the risk for QTc prolongation for these patients, especially in the presence of baseline QTc ≥ 450ms. 51 During this COVID-19 pandemic, aspergillus can cause co-infection with SARS-CoV-2 despite these patients who did not have a traditional risk factor of aspergillus infection. Respiratory specimens for mycologic studies, such as culture, galactomannan tests, and PCR can help early diagnosis. 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