key: cord-0759039-9dijo20k authors: Faverio, Paola; Conti, Sara; Madotto, Fabiana; Franco, Giovanni; Renzoni, Elisabetta; Mantovani, Lorenzo Giovanni; Luppi, Fabrizio title: Idiopathic pulmonary fibrosis mortality in the Italian epicenter of COVID-19 pandemic date: 2022-04-12 journal: Pulmonology DOI: 10.1016/j.pulmoe.2022.04.002 sha: 215e3552007181dfe551ca40d0bf1b2cbca30923 doc_id: 759039 cord_uid: 9dijo20k nan To the Editor, 1 Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening interstitial pneumonia 3 of unknown cause 1 , affecting elderly, frail individuals with a median age at diagnosis of 66 1 and a 4 median estimated survival of 2.5-3.5 years after diagnosis 2-3 . 5 Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) rapidly spread 6 worldwide and the absence of effective therapies or vaccines at the beginning of the pandemic led 7 Governments to enforce strict measures in their efforts to limit the virus transmission 4 . On March, 8 9 th 2020 Italy went into a full lockdown. In parallel, hospital infrastructures were redirected towards 9 maximizing intensive care resources which resulted in routine clinical practice, including IPF 10 outpatient clinics, being considerably reduced 5 . 11 The aim of our study was to assess the mortality of IPF patients included in the cohort of the 12 tertiary outpatient IPF clinic at the -San Gerardo‖ Hospital, located in Monza (Lombardy, the most 13 populated Italian region) in relation to the social and healthcare changes due to COVID-19 14 pandemic. 15 We analyzed a cohort of 212 patients recruited between May 2008 and April 2021 and alive 16 on January 1 st 2018. We recorded mortality data comparing the characteristics between patients who 17 died in January 1st, 2018 and February 28th, 2020 (pre-pandemic and pre-lockdown period) to 18 those who died between March 1st, 2020 and April 30th, 2021 (pandemic and post-lockdown 19 period) using Chi-square or Fisher's exact tests for categorical variables and Mann-Whitney U test 20 for continuous ones. Thereafter, we computed monthly average crude mortality rates for each of the 21 two periods, with related exact 95% confidence intervals (95%CIs) based on a Poisson distribution, 22 and we compared them through incidence rate ratios (IRR). Similarly, we computed trimestral-23 specific monthly average mortality rates for the biennium 2018-2019, and we compared them with 24 those of 2020. Person-time at risk (in months) was computed for each subject from January, 1 st 25 2018 or the day of IPF diagnosis, until death or the end of the period of interest. 95%CIs for IRR 26 were based on the exact distribution of the rate of two Poisson counts, as well as 2-sided p-values. 27 All analyses were performed using SAS version 9.4 (The SAS institute, Cary, NC) and R version In the pre-lockdown period, we documented 39 deaths in our IPF cohort; in contrast, in the 31 post-lockdown period, 33 IPF patients died (Figure 1a ). We observed a significantly younger 32 median age at death and a trend toward younger median age at diagnosis in the pre-lockdown 33 compared to the post-lockdown period with similar median disease duration, pulmonary function 3 tests and severity of the disease evaluated through Gender-Age-Physiology (GAP) index (Table 1) . 35 We did not detect statistically significant differences regarding gender or antifibrotic treatment. The 36 burden of comorbidities was similar between the two groups with the exception of pulmonary 37 hypertension that was more common in the post-lockdown period. 38 We estimated that monthly average mortality rates rose from 1.03 per 100 person-months 39 Figure 1b) . 45 In the lockdown periods, patients included in our IPF cohort were regularly followed-up 46 with telephone calls and continuously received antifibrotic treatment. Asking family members, we 47 were able to determine that 3 out of 33 patients (9.1%) were hospitalized and died because of a 48 confirmed diagnosis of Coronavirus disease (COVID-19) and that the great majority, 30/33 49 (90.9%), died at home or in long-term facilities without signs or symptoms suggestive of COVID-50 This study showed a significant increase in mortality in our IPF cohort during the post-52 lockdown period that, in most of the cases, did not appear directly related to COVID-19. 53 In line with our results, Marcon and colleagues showed an excess of IPF-related deaths 54 during the first wave of the COVID-19 pandemic 6 . However, the authors did not differentiate 55 between deaths directly related to COVID-19 and other etiologies. 56 In our study, we observed a marginally significant increase in mortality during post-57 lockdown period compared to pre-lockdown. We believe that the increase in mortality is mainly 58 related to the increased frailty and to limitation of access to the IPF Referral Center for a worsening 59 of the disease during the peak of the pandemic. This is corroborated by the results of the trimestral 60 analysis which shows an increase in the period of the COVID-19 second wave (October/December 61 2020), when our province (Monza-Brianza) reached the highest level of incidence of SARS-CoV-2 62 infection. 63 In our study, a number of limitations should be acknowledged. The cause of death was not 64 confirmed for the majority of the patients. Moreover, this study was performed in a single center, 65 limiting the generalizability of the results. Finally, given the small sample size, we were not able to In conclusion, we report a statistically significant increase in mortality within our IPF cohort 69 during the COVID-19 second wave. To the best of our knowledge, only in a minority of patients 70 was the cause of death directly related to SARS-CoV-2 infection. In most patients, the cause of 71 death was possibly related to the limitations to reaching the hospital and ILD-physicians of the IPF 72 referral Center in relation to the COVID-19 pandemic in case of worsening of the disease. 73 Gender-Age-Physiology 76 written informed consent was waived given the retrospective design of the study. Individual participant data referring to this article (i.e. text, tables and figures) will be made available upon reasonable request. The study protocol will be made available for researchers who provide a methodologically sound proposal. Proposals should be directed to paola.faverio@unimib.it Idiopathic pulmonary fibrosis Clinical course and prediction of survival in idiopathic pulmonary fibrosis Idiopathic pulmonary fibrosis: a disease with similarities and links to cancer biology Containing COVID-19: Implementation of Early and Moderately Stringent Social Distancing Measures Can Prevent The Need for Large-Scale Lockdowns. Ann Glob Health Implications of SARS-CoV-2 Infection and COVID-19 Crisis on Clinical Cancer Care: Report of the University Cancer Center Hamburg Mortality Associated with Idiopathic Pulmonary Fibrosis in Northeastern Italy We acknowledge that this research was partially supported by the Italian Ministry of University and Research (MIUR)-Department of Excellence project PREMIA (PREcision MedIcine Approach: bringing biomarker research to clinic). The authors have no conflicts of interest to declare. The authors have no funding to declare. FL is the guarantor of this research. PF, SC, GF, FM, LGM and FL were responsible for study concept and design. PF, SC, GF, FM and FL contributed to data acquisition. PF, SC, GF, FM, LGM and FL performed data analysis. PF, SC, GF, FM, ER, LGM and FL contributed to the drafting of this manuscript. All authors read and approved the final manuscript.