TITLE: Post-infectious bronchiolitis obliterans in children after the end of the COVID-19 pandemic.To the Editor,Bronchiolitis obliterans (BO) is a rare disease in which the main characteristic is chronic obstruction of the small airways. Post-infectious is the most common cause in children, mainly due to adenovirus (ADV), followed by other viruses such as respiratory syncytial virus (RSV), influenza or parainfluenza. Histologically, inflammation and fibrosis of the terminal bronchioles occurs, with total or partial obliteration of their lumen. The diagnosis of post-infectious bronchiolitis obliterans (PIBO) relies on a compatible clinical history of previous respiratory infection, usually severe, followed by chronic symptoms such as cough, tachypnea, intercostal retractions, hypoxemia and/or pathological auscultation with bilateral or unilateral fine crackles. Computed tomography (CT) of the lungs shows signs of mosaic perfusion pattern, with or without bronchiectasis, and pulmonary function tests with fixed airflow obstruction1. Treatment consists of a combination of anti-inflammatory drugs, oxygen therapy, bronchodilators, respiratory physiotherapy and antibiotics in case of acute infections2.Different authors have described their PIBO cases, highlighting ADV as the main microorganism involved. The highest incidence and prevalence are found in different South American countries with an Amerindian population, such as Argentina, probably related to the presence in these individuals of a characteristic HLA haplotype (DR8-DQB1*0302). The prevalence of PIBO reported in patients developing the disease with severe pneumonia was 30.3% in the province of Jilin, China, after an epidemic outbreak of ADV that occurred in the period from 2018 to 20203. To date, the increase in the number of PIBO cases after the end of the COVID-19 pandemic and the lockdown measures imposed to stop its spread remains unpublished for any geographic area.The epidemiological, etiological, clinical, diagnostic and evolutionary characteristics of 18 pediatric cases with PIBO over a period of 15 years in our center (January 2008 to January 2023) are described. Using the Shapiro-Wilk test, we described quantitative variables as mean and standard deviation (SD) when having a normal distribution, and median and interquartile range (IQR) if they corresponded to non-parametric variables.Of 18 patients diagnosed with PIBO, most are male (67%) and Caucasians (90%). Regarding the causal infection, it occurred at a median age of 1.76 years (IQR 0.96-3.02), with the time interval between October 2022 and January 2023 having the highest number of cases (10 cases) (Figure 1). The most frequent symptoms were cough (100%), fever (94%) and respiratory distress (94%); 100% were diagnosed with bronchitis and 71% with bronchitis and pneumonia. In 11 cases (61%) ADV was isolated as a causal agent, and in the remaining 7 cases ADV could not be confirmed (not analyzed in 5 and unknown in 2). The most frequent findings on chest radiography were pulmonary hyperinflation with unilateral (47%) or bilateral (33%) infiltrate. Hospital admission was required in 94%, out of which 11% were serious infections admitted to the Intensive Care Unit (ICU). Hospitalization time was 9 days (IQR 6.3-14.8 days). Treatment of acute infection was with short-acting beta2-agonist (SABA) nebulization (100%), systemic corticosteroids (SCS) (79%), antibiotics (93%) and oxygen therapy (93%). Two patients required non-invasive mechanical ventilation and 1 endotracheal intubation with invasive mechanical ventilation (IMV).The characteristic clinical history (persistent obstructive respiratory symptoms after a severe infectious condition) and typical radiological findings (mosaic perfusion pattern on CT of the lungs) is the basis for diagnosis. The median age at diagnosis was 3.10 years (IQR 1.89-6.34), with a median time between the causal infection and diagnosis in the entire sample of 1.21 years (IQR 0.65-3.38) and of those infected in 2022-23 of 0.65 years (IQR 0.48-0.78). The most frequent clinical finding after the acute infection was persistent pathological lung auscultation (89%) and recurrent bronchitis (61%). All cases showed a mosaic perfusion pattern on CT of the lungs, 83% bilateral and 17% unilateral (Swyer-James syndrome). A valid forced spirometry test was possible in 56%, all of them showing an obstructive airflow pattern defined by a Z-Score lower than –1.64 (lower limit of normality) of the forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) (FEV1/FVC ratio). The mean Z score (±SD) values of forced spirometry are FVC -1.75 (±1.59); FEV1 -3.25 (±1.22); FEV1/FVC -2.66 (±0.59); and the forced expiratory flow at 25-75% (FEF25-75%) is -3.34 (±0.68). The maintenance treatments they received are inhaled corticosteroids (ICS) (28%); ICS with long-acting bronchodilators (LABA) (56%), oral azithromycin (56%); leukotriene-receptor antagonist (78%); SABA rescue inhalers (100%) and 11% do not receive any maintenance treatment. The median course of the disease is 1.30 years (IQR 1.21-8.18).In summary, most cases with PIBO diagnosed in our center had the causal infection with less than 2 years of age, with ADV being the main virus involved, isolated or in coinfection with other viruses such as RSV. Seventeen patients required hospital admission and the most common diagnosis was bronchitis with bilateral pneumonia. Two patients required admission to the ICU due to severe respiratory failure, one of them requiring orotracheal intubation. The basis of the diagnosis is persistent symptoms after the initial infectious condition, supported by the involvement of ADV and an obstructive pattern in spirometry. CT of the lungs with mosaic perfusion pattern served as diagnostic confirmation in all patients. No lung biopsy was required in any of them. The time from the initial injury to the diagnosis of PIBO in our series is approximately 1 year with a disease progression time of 1.3 years. The treatments used, the most in the chronic phase, are ICS with or without LABA, montelukast and oral azithromycin. Only one patient currently requires home oxygen therapy (Table 1).The authors would like to highlight the significant increase in the number of pediatric cases of PIBO in our geographical area, the Autonomous Community of Aragón (Spain), during the months of October 2022 to January 2023 after the end of health restrictions for the recent COVID-19 pandemic. This phenomenon to our knowledge in not published or documented by other authors. Of the 18 cases, 7 had the initial infection related to ADV during this period, and in 2 patients the involvement of ADV is unknown. We are unable to demonstrate in our center an increase in the incidence of serious ADV infections after the COVID-19 pandemic. Regardless, we believe that, as has happened with other microorganisms such as Streptococcus pyogenes group A4 or RSV5, the end of COVID-19 restrictions has led to the appearance of more aggressive infections, in atypical epidemic seasons, a phenomenon known as “immunity debt”6. A recent hypothesis is that children born during the COVID-19 pandemic, where there was a clear decrease in the circulation of viruses, lowered physiological development of immunity due to minimal contact with these infectious agents. After returning to “normality”, the usual infections have appeared in greater numbers and aggressiveness. Analyzing the subgroup of patients infected after the pandemic, all of them were born during the lockdown periods (2020-2022), the disease began at an age of 1.35 years, and the time until diagnosis was shorter than in the total number of patients, 0.65 years. Another interesting fact extracted from our series is that, unlike what other authors describe, most of our patients did not require oxygen therapy for more than 60 days, so we believe that this criterion is not essential for the diagnosis, relying more on other variables such as persistent pathological lung auscultation and subsequent severe bronchitis.