key: cord-1028500-srj2n3dt
authors: Yamaoka, Mai; Banshodani, Masataka; Muraoka, Shiro; Tanaka, Kenta; Kimura, Ayaka; Tani, Hiroki; Hashimoto, Shinji; Shiraki, Nobuaki; Shintaku, Sadanori; Moriishi, Misaki; Tsuchiya, Shinichiro; Masaki, Takao; Kawanishi, Hideki
title: COVID-19-associated pulmonary aspergillosis in hemodialysis patients
date: 2022-01-29
journal: Clin Kidney J
DOI: 10.1093/ckj/sfac027
sha: d1bec4bf5f62fd72b2e26db703d5a06073b1f02b
doc_id: 1028500
cord_uid: srj2n3dt

BACKGROUND: Coronavirus Disease 2019-associated pulmonary aspergillosis (CAPA) is a fatal complication in the general population. However, there are few reports on CAPA in patients undergoing hemodialysis (HD). METHODS: This retrospective observational cohort study was conducted at a single center between December 2020 and June 2021. We enrolled 21 HD patients with Coronavirus Disease 2019 (COVID-19) undergoing treatment and divided them into two groups: CAPA and non-CAPA (COVID-19 with and without pulmonary aspergillosis); we evaluated their characteristics, clinical outcomes, and comorbidities. RESULTS: The log-rank test revealed that the 90-day survival rate after the initiation of treatment for COVID-19 was significantly lower in the CAPA (n = 6) than in the non-CAPA group (n = 15) (P = 0.0002), and the 90-day mortality rates were 66.6% and 0% in the CAPA and non-CAPA groups, respectively. In the CAPA group, four patients died due to respiratory failure (on days 6 and 20), gastrointestinal bleeding (day 8), and sepsis (day 33); the RT-PCR for SARS-CoV-2 remained positive when they died. The remaining two patients survived, and the negative conversion of RT-PCR for SARS-CoV-2 was confirmed on days 10 and 15. The negative conversion of serum (1, 3)-β-D-glucan (BDG) was confirmed on day 15 in one patient; the BDG remained positive on day 64 in the other. CONCLUSIONS: CAPA is a fatal complication in HD patients and the general population. Therefore, clinicians should consider the possibility of testing for CAPA in patients undergoing hemodialysis. Mycological workups may be helpful for the early detection of CAPA.

The coronavirus disease that appeared in 2019 , which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in Wuhan, China, and it rapidly spread throughout the world (1) . Chronic kidney disease (CKD) is reported to be an independent factor affecting mortality and is associated with poor outcomes in patients diagnosed with COVID-19 (2) . Moreover, mortality due to COVID-19 is higher in dialysis than in non-dialysis patients (3) . Recently, reports of COVID-19 associated with pulmonary aspergillosis (CAPA) have been increasing in the general population (4, 5) . Therefore, it is possible that the number of dialysis patients with CAPA has also increased. However, few studies have reported on CAPA in patients undergoing HD (6) (7) (8) .

Although the mechanism underlying the development of CAPA remains controversial, COVID-19 is suspected to cause lymphopenia, inflammatory cytokine responses, and extensive damage to the respiratory epithelium, making affected patients prone to secondary infections (6, 9) . In addition, immunosuppressive therapies are considered one of the causes of secondary fungal infections (10). Several studies have reported on CAPA in the general population; however, the factors adversely affecting outcomes and mortality have not been fully clarified (11) (12) (13) . We conducted a retrospective observational cohort study to compare patient characteristics, clinical outcomes, and differences in complications between HD patients with and without CAPA (COVID-19 with and without pulmonary aspergillosis). 

The present study was a retrospective observational cohort study conducted at Tsuchiya

General Hospital between December 1, 2020, and June 30, 2021 . We enrolled 21 HD patients who were diagnosed with COVID-19 in the study and treated them in a dialysis intensive care unit (ICU), which was treated as a quarantine ward where depressurized rooms with high-efficiency particulate air filters were included. Of the 21 patients, three (14.3%) were transferred from other hospitals due to exacerbation of their symptoms, and nine (42.9%) were treated in an inpatient setting. The present study was performed in accordance with the principles of the Declaration of Helsinki and approved by the Tsuchiya General Hospital Institutional Review Board for Human Investigation (approval number: E210719-6). The requirement for written informed consent was waived because of the retrospective observational nature of the study and the strict maintenance of patient anonymity.

The following clinical baseline (admission or transfer to the ICU due to positive reverse (14) . 

Moderately and severely affected patients received oxygen inhalation, while percutaneous oxygen saturation was monitored in real-time. Critically affected patients received oxygen inhalation, orotracheal intubation with a virus removal filter, and invasive mechanical ventilation with a pressure-regulated, volume-controlled mode under deep sedation (Richmond Agitation-Sedation Scale [RASS] (17): score -4) while undergoing real-time monitoring for percutaneous oxygen saturation and end-tidal carbon dioxide in the AIIRs. When a patient could not be withdrawn from mechanical ventilation two weeks after initiation, a tracheostomy was performed.

The primary outcome was defined as 90-day survival after the initiation of treatment for COVID-19 in our hospital. The secondary outcome was the length of stay in the ICU.

Moreover, among the patients with CAPA, the patient characteristics, antifungal agents used, complications, causes of death, and period from the initiation of treatment for

COVID-19 to the beginning of the administration of antifungal agents were examined.

The enrolled patients were followed-up with until the study's end-point was reached, which could include death, and the analysis period ended on September 30, 2021.

The data were analyzed using JMP ® 14.2.0 (SAS Institute Inc., Cary, NC, USA) and

were expressed as either the number of participants or the percentage of the study population. The remaining data are expressed as the mean ± standard deviation (SD) or median (range). The Student's t-test and Mann-Whitney U test were used for the continuous variables, and the chi-squared test was used for the categorical variables.

The Kaplan-Meier method and log-rank test were used to evaluate the survival curve after the initiation of treatment for COVID-19 in our hospital. In all analyses, P values < 0.05 were considered statistically significant.

Twenty-one HD patients with COVID-19 were treated in our hospital during the study period, and all the participants were enrolled. We divided the HD patients with COVID-19 into two groups according to the above-mentioned definition: patients with probable IPA (CAPA group, n = 6) and patients without probable IPA (non-CAPA group, n = 15).

The baseline characteristics of the patients in both groups are shown in Table 1 . The BMI (P = 0.03) and serum albumin level (P = 0.03) were lower, whereas the proportion of ischemic heart disease (IHD) (P = 0.01) and mean baseline BDG level (P < 0.001)

were higher in the CAPA than in the non-CAPA group. The proportion of patients with mild COVID-19 was lower in the CAPA group (P = 0.03).

All 21 patients received antiviral agents (18 patients received remdesivir in the CAPA and non-CAPA groups; three patients received favipiravir in the non-CAPA group), antibiotics, and antithrombotic agents. Twenty patients received dexamethasone in the CAPA and non-CAPA groups, except for one mildly affected patient in the non-CAPA group. There were no significant differences in the dosage per day, total dosage, or duration of dexamethasone between the two groups. IVIG was administered more frequently in the CAPA (n = 6, 100%) than in the non-CAPA group (n = 6, 40%; P = 0.02). Two critically ill patients in the non-CAPA group received CRRT with AN69ST membrane and PMX-DHP (supplementary data, Table S1 ).

The 90-day survival rate after the initiation of treatment for COVID-19 was significantly lower in the CAPA than in the non-CAPA group (P = 0.0002, Figure 1 ) (90-day mortality rates, 66.6% versus 0%). The complications experienced after the initiation of treatment for COVID-19 are shown in the supplementary Table S2 .

The summarized baseline characteristics of the six patients in the CAPA group are shown in Table 2 . Two patients had severe symptoms, and four patients had moderate COVID-19. All the patients received antiviral treatment with remdesivir. The serum baseline BDG levels ranged from 13.6 to 29.6 pg/mL. In the CAPA group, four patients In four patients, the administration of antifungal medication with MCFG was initiated on day 1 (initiation of treatment for COVID-19) for a fungal infection;

subsequently, the serum GM was later found to be positive, and the antifungal medication was continued.

In one patient with a high level of BDG (29.6 pg/mL), antifungal agents were not administered at the initiation of treatment for COVID-19 because the elevation of the serum BDG level was initially considered a false positive after IVIG administration. On 

In this study, we evaluated CAPA in patients undergoing HD. We investigated the prevalence and clinical outcomes of CAPA in patients undergoing HD. The log-rank test revealed that the 90-day survival rate after the initiation of treatment for COVID-19 was significantly lower in the CAPA than in the non-CAPA group, and the 90-day mortality rates were 66.6% and 0% in the CAPA and non-CAPA groups, respectively.

Mortality due to infectious diseases is the second leading cause of death (18).

Respiratory virus infection is believed to prompt the development of IPA by causing direct damage to the airway epithelium (19). Therefore, HD patients may be susceptible to aspergillosis after ICU administration because ESKD patients have immunocompromised host factors. In the general population, the prevalence of CAPA was reported range from 0 to 33% (5, 10) . Recently, a nationwide questionnaire-based study from the Japanese Respiratory Society showed that the prevalence of CAPA was 0.54% (9/1,664 patients), and the authors concluded that the low prevalence of CAPA in Japan might be due to the following reasons: 1) the low incidence of COVID-19 in Japan; 2) the fact that CAPA was not diagnosed according to specific criteria; and 3) the fact that a routine mycological workup was not performed (19). We found that the prevalence of CAPA was 28.6% (6/21 patients), which is much higher than in a Japanese study and relatively high compared to the figure reported in previous studies from other countries (5, 10, 19) . Although the true prevalence of CAPA in HD patients remains controversial, clinicians should consider the possibility of testing for CAPA in the treatment of COVID-19 in HD patients.

In the general population, the overall mortality rate of CAPA is reported to be approximately 50.0% (10, 11), and the mortality rate of patients with CAPA is reported

to be higher than that of patients without it (5, 11) . In HD patients, the overall mortality rate of COVID-19 is reported to be approximately 25.0% (20). The mortality rate of CAPA in HD patients is 66.7%, which is higher than in the general population (10, 11).

Furthermore, the 90-day survival rate after the initiation of treatment for COVID-19 was lower in the CAPA than in the non-CAPA group (P = 0.0002). The trend was similar to that of the general population (5, 11) . However, further studies are required to confirm these findings.

Several studies have reported the following CAPA risk factors in the general population: age, low serum albumin level, high frailty, chronic obstructive pulmonary disease, diabetes mellitus, the need for invasive mechanical ventilation (severity of COVID-19), and immunosuppressive treatment, including steroids and azithromycin (12, 13, 21) . In the present study, BMI (P = 0.03), serum albumin level (P = 0.03), and the proportion of patients with mild COVID-19 symptoms (P = 0.03) were lower in the CAPA group. These findings suggest that malnutrition may be associated with CAPA in HD patients as well as in the general population. Although the proportion of IHD was higher in the CAPA group, no previous reports have evaluated the association between CAPA and IHD. Moreover, we could not demonstrate any association between dexamethasone and CAPA because we used dexamethasone in most HD patients with COVID-19. However, dexamethasone may remain harmful in HD patients because it is a long-acting glucocorticoid that leads to infection, gastrointestinal bleeding, hyperglycemia, and venous thromboembolism (22). In the present study, gastrointestinal bleeding was observed in two patients, and one of the two patients died due to gastrointestinal bleeding. Therefore, clinicians may need to modify the type and amount of steroids used (23).

In the present study, the mean baseline BDG level was significantly higher in the CAPA than in the non-CAPA group, suggesting that the baseline BDG level is a useful panfungal marker for screening at the initiation of COVID-19 treatment (24). Although the insensitivity of serum biomarkers remains a clinical concern, the combination of serum BDG and GM may be useful for the diagnosis of CAPA in HD patients.

Although triazoles are the most frequently administered treatment for CAPA (8), the therapeutic strategy for it has not yet been fully established (10). In an observational study evaluating whether antifungal prophylaxis prevents CAPA in critically ill patients, 57% of patients received antifungal prophylaxis within the first 48 hours after ICU admission (25), and a significant reduction was observed in the incidence of CAPA in patients who received antifungal prophylaxis. However, the administration of intravenous VRCZ is not approved for HD patients because it carries the risk of the accumulation of sulfobutylether beta-cyclodextrin sodium (26), and an oral suspension of VRCZ is not approved. Moreover, peak plasma concentrations of oral VRCZ close to a steady state are achieved 5-7 days after multiple oral administration (27). Taken together, we recommend that oral VRCZ should be initiated as a first-line antifungal agent in HD patients when serum BDG is positive and the patients can take it internally.

We recommend the administration of intravenous AMPH-B or MCFG in cases in which HD patients are unable to take medication and it is difficult to use VRCZ owing to drugdrug interactions. When GM is confirmed, the serum BDG should be monitored, and the combination of antifungal agents can be effective in patients with elevated serum BDG levels (i.e., refractory course) (Figure 3 ).

The present study has several limitations. First, this was a retrospective study conducted at a single center, so the sample size was small. Therefore, the small number

of subjects caused the data to lack sufficient power for accurate multivariate testing for the assessment of the risk factors of CAPA and the efficacy of antifungal agents.

Second, the true incidence of CAPA was uncertain because we did not perform a necropsy. Such procedures are invasive and arouse fears surrounding aerosol generation. The proposed case definition that we used to define probable IPA in HD patients with COVID-19 can improve the early diagnosis of CAPA and help practitioners avoid underestimating the frequency of CAPA. Despite these limitations, few previous studies have reported CAPA in HD patients (6) (7) (8) . Therefore, the present study is valuable in relation to the existing information in the field.

CAPA is a fatal complication in HD patients and in the general population. A mycological workup conducted at the initiation of COVID-19 treatment is effective for the diagnosis of CAPA, and early detection may contribute to improving a patient's prognosis. Our findings can guide clinical management practices for CAPA in HD patients.

The data and materials used are available upon request.

The supplementary data are available at ckj online. care unit; Max, maximum.

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COVID-19-related mortality in kidney transplant and dialysis patients: results of the ERACODA collaboration

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Risk factors associated with COVID-19-associated pulmonary aspergillosis in ICU patients: a French multicentric retrospective cohort

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The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients

COVID-19-associated pulmonary aspergillosis

CHF, chronic heart failure; Ct, cycle threshold; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein

DKD, diabetic kidney disease

ESKD, end-stage kidney disease

GM, galactomannan; IHD, ischemic heart disease

reverse transcriptionpolymerase chain reaction

PVD, peripheral vascular disease

WBC, white blood cell

We thank all the medical, nursing, and technical staff from the dialysis intensive care unit of our hospital for their dedication to caring for hemodialysis patients during the COVID-19 pandemic.

The authors have none to declare. History of cancer, n (%) 0 (0) 1 (7) 1.0 CCI 8 (5-10) 6 (4-9) 0.4