key: cord-0878815-y0uvgyfj authors: Imoto, Waki; Himura, Hoshi; Matsuo, Kenji; Kawata, Sae; Kiritoshi, Ayako; Deguchi, Ryo; Miyashita, Masahiro; Kaga, Shinichiro; Noda, Tomohiro; Yamamoto, Katsumi; Yamada, Koichi; Uchida, Kenichiro; Nishimura, Tetsuro; Yamamoto, Hiromasa; Mizobata, Yasumitsu; Kakeya, Hiroshi title: COVID-19-associated pulmonary aspergillosis in a Japanese man: A case report date: 2021-02-25 journal: J Infect Chemother DOI: 10.1016/j.jiac.2021.02.026 sha: ab51cf018eedd7d2ef39ed18e4721ebd038448f2 doc_id: 878815 cord_uid: y0uvgyfj CAPA (COVID-19 associated pulmonary aspergillosis) is an important complication of COVID-19. It has been reported that the incidence of CAPA is as high as 19%–33 % worldwide. However, its onset has not been reported in Japan. A 72-year-old Japanese man was diagnosed with COVID-19 and was transferred to our hospital due to deterioration of respiratory condition. Treatment with remdesivir, dexamethasone (DEXA), and antibiotics was performed under mechanical ventilation. Although the condition improved temporarily, a new shadow appeared in the lung, and Aspergillus fumigatus was cultured from sputum. The patient was clinically diagnosed with CAPA and treated with voriconazole. However, his progress deteriorated and he died. High-risk COVID-19 patients should be tested for Aspergillus to ensure early diagnosis of CAPA. performed as a confirmatory test, was also positive, and the patient was diagnosed with COVID-19. He had a history of hypertension, atrial fibrillation, and chronic obstructive pulmonary disease (COPD) in addition the stroke, and was taking anticoagulants, antiplatelet drugs, an inhaled long-acting β2-agonist, and a long-acting muscarinic antagonist. He was 175 cm tall, weighed 61 kg, and had been a smoker until about a year before hospitalization with a cigarette consumption of about 50 packs/year. Antiplatelet drug infusion was started for cerebral infarction and DEXA was started for COVID-19. Ceftriaxone (2g/day) and azithromycin (AZM: 500mg/day, the total dose of AZM was 1500mg) were administered empirically for possible bacterial infection. However, his respiratory condition deteriorated from day 6, and he was transferred to our hospital on CT scan showed that the collection of nodular shadows in the right lower lobe had grown and become a massive shadow. Additional nodules had appeared in other parts of the right lower lobe and he had developed consolidation in both lower lobes ( Figure 1c ). As his β-D glucan level was high (30.4 pg/mL, cut-off index ≤20 pg/mL) and Aspergillus fumigatus was detected in sputum culture collected on day 14 using a tracheal intubation tube submitted on day 14, he was diagnosed with probable invasive pulmonary aspergillosis (IPA) or CAPA [11, 12] . The antimicrobial sensitivity profile is shown in J o u r n a l P r e -p r o o f fumigatus was confirmed [14] . Aspergillus fumigatus was also cultured from sputum samples submitted on days 17 and 20, and an Aspergillus serum galactomannan test was positive (0.6, cut-off index ≤0.50). His respiratory condition continued to worsen ( Figure 2 ), and he developed frequent episodes of paroxysmal supraventricular tachycardia. On day 23 his tachycardia could not be controlled with medication and his blood pressure dropped and did not respond to catecholamine administration. The patient's family was informed of the treatment options, and after obtaining consent, he was moved to palliative care and died on day 26. The total dose of DEXA until death was about 100 mg (treatment was skipped a few days at the hospital where the patient was hospitalized before being transferred). Although no autopsy could be performed, perhaps the patient's death was associated with CAPA, as his respiratory condition deteriorated sharply after CAPA onset. Invasive pulmonary aspergillosis (IPA) has been identified as a complication of immunosuppression [15] [16] [17] , but may occur in patients who are not immunosuppressed. Risk factors include short-or long-term steroid use; use of broad-spectrum antibiotics; organ failure; underlying chronic or acute pulmonary disease, including COPD; severe influenza; and ARDS [18] . CAPA is an important complication of COVID-19 [5-10]. The risk factors for CAPA in patients with COVID-19 have not been determined, but a previous report identified immunomodulatory drugs and treatment in facilities that do not meet standards for appropriate room ventilation or air changes as possible risk factors [10] . Dellière et al. [19] reported that administration of a cumulative dose of azithromycin (AZM) ≥1500mg was associated with CAPA. They attributed this to decreased serum interleukin-6 and delays in the downregulation of the neutrophil oxidative burst, which is the most important immune response mechanism to aspergillosis, increased apoptosis, and changes in the lung microbiome that promote Aspergillus colonization. Our patient had underlying COPD and ARDS caused by COVID-19. In addition, he was treated with short-term steroids and a 3-day course of AZM, which may have increased his susceptibility to CAPA. Furthermore, due to the rapid increase in the incidence of COVID-19 and a shortage of intensive care unit beds in Osaka, Japan, a ward in our hospital for severe COVID-19 patients was expanded one week before the patient's admission. An inadequate air-conditioning system may increase the risk of CAPA. Furthermore, hospital construction has been reported to be associated with IPA [20, 21] . Attention to IPA is very important because COVID-19 treatment may be performed in temporary facilities or in urgently expanded wards due to a shortage of beds. Treatment at temporary facilities due to the rapid spread of COVID-19 has been linked to increased exposure to dust and construction-related materials that increase air spore counts and facilitate Aspergillus colonization [22] . Furthermore, it can cause nosocomial infection of SARS-CoV-2 due to improper air conditioning, inappropriate exhaust systems, or inadequate negative pressure devices in the room. Therefore, it is necessary to consider room design and ventilation systems for COVID-19 wards. We inspected the exhaust system and negative pressure in our facility and confirmed that there were no problems associated with room ventilation. However, the link between construction work and Aspergillus infection cannot be ruled out, although no other CAPA cases have been found in our hospital at present. There are two possible reasons why there have been no previous reports of CAPA in Japan. First, the incidence of COVID-19 in Japan is very low compared to other countries [1, 23] . Due to the relatively low incidence of COVID-19 in Japan, there are a limited number of patients with severe COVID-19, and so the incidence of CAPA is likely to be very low. Second, clinicians in Japan may not be aware of CAPA, so there may have been cases that were undiagnosed because of a lack of specific diagnostic testing, even if J o u r n a l P r e -p r o o f the patient's clinical condition and laboratory findings were suggestive of CAPA. IPA has a high mortality rate [24] ; furthermore, the mortality of patients with CAPA is considerably higher than that of COVID-19 patients without aspergillosis [25] . Although (b) Chest CT on day 13. The ground glass shadows have improved but new nodular shadows have appeared in the right lower lobe (red arrow). Chest CT on the day 20. The nodular shadows in the right lower lobe have enlarged and coalesced to resemble a tumor shadow (red arrow). In addition, new consolidation has appeared in both lower lobes (green arrow). The patient's clinical course and timing of treatment. Abbreviations: AZM, azithromycin; CFPM, cefepime; CTRX, ceftriaxone; DEXA, Ministry of Health, Labour and Welfare Acute respiratory failure in COVID-19: is it "typical Coronavirus disease with multiple infarctions COVID-19-associated pulmonary aspergillosis (CAPA) in patients admitted with severe COVID-19 pneumonia: an observational study from Pakistan Prevalence of putative invasive pulmonary aspergillosis in critically ill patients with COVID-19 COVID-19-associated pulmonary aspergillosis COVID-19 associated pulmonary aspergillosis (CAPA)-from immunology to treatment Confronting and mitigating the risk of COVID-19 associated pulmonary aspergillosis Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients Clinical breakpoints for fungi v Executive Summary of Japanese Domestic Guidelines for Management of Deep-seated Mycosis Prolonged granulocytopenia: the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia The clinical spectrum of pulmonary aspergillosis Invasive pulmonary aspergillosis in nonimmunocompromised Hosts Risk factors associated with Covid-19-associated pulmonary aspergillosis in ICU patients: a French multicentric retrospective cohort Invasive pulmonary aspergillosis in neutropenic patients during hospital construction: before and after chemoprophylaxis and institution of HEPA filters Prevention of healthcare-associated invasive aspergillosis during hospital construction/renovation works Invasive Aspergillosis as an Under-recognized Superinfection in COVID-19 World Health Organization. WHO coronavirus disease (COVID-19) dashboard Invasive aspergillosis: current strategies for diagnosis and management Epidemiology of invasive pulmonary aspergillosis among COVID-19 intubated patients: a prospective study We would like to thank Editage (www.editage.com) for assistance