key: cord-0282184-g3t3x3b3
authors: Garg, A.; Nagpal, P.; Goyal, S.; Comellas, A. P.
title: Small Airway Disease as long-term Sequela of COVID-19: Use of Expiratory CT despite Improvement in Pulmonary Function test
date: 2021-10-22
journal: nan
DOI: 10.1101/2021.10.19.21265028
sha: 7fb2d450d35a2e2b0752399d4cfbc6f084d87882
doc_id: 282184
cord_uid: g3t3x3b3

Background- It is important to understand the spectrum of pulmonary diseases that patients are presenting after recovery from initial SARS-CoV-2 infection. We aim to study small airway disease and changes in Computed Tomography (CT) and pulmonary function tests (PFTs) with time. Methods: This is retrospective observation study including adult patients with confirmed SARS-CoV-2 infection with at-least two CT scans either during acute (defined as < 1 month) or subacute (1-3 months) or chronic (>3months) phase after positive test. Radiological features and follow up PFTs were obtained. Results: 22 patients met the inclusion criteria with mean age 57.6 years (range 36-83). Out of these,18 (81.81%) were hospitalized. Mean duration of diagnosis to CT and PFT was 192.68 (112-385) days and 161.54 (31-259) days respectively. On PFTs, restrictive pulmonary physiology was predominant finding during subacute 56.25% (9/16) and chronic phases 47% (7/15). PFTs improved significantly with time {FEV1((p=0.0361), FVC (p=0.0341), FEF 25%-75% (p=0.0259) and DLCO (p=0.0019)}, but there was persistent air trapping in the expiratory chronic phase CT. There was resolution of ground glass opacity, consolidation, and bronchiectasis however air trapping increased with time in 41.61% (10/21) of subacute CTs compared to 81.25% (13/16) in chronic CTs. Conclusion - Our study shows evidence of airway as well as parenchymal disease as relatively long-term sequel of SARS-CoV-2 infection. It also highlights the natural course and spontaneous recovery of some radiological and pulmonary function test abnormalities over time with evidence of persistent small airway disease (air trapping) on expiratory CT imaging months after infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than 2 196 million people and has resulted in more than 4 million deaths worldwide. 1 Patients 3 who have survived the acute illness are increasing and they are now presenting with 4 persistent respiratory complains like dyspnea and cough, months after acute illness. 2 Now 5 known as Post-Acute Sequalae of SARS-CoV-2 (PASC) or long COVID, it is important to 6 understand the spectrum of underlying respiratory diseases during this phase. 3 Acute 7 pulmonary complications of this respiratory virus include viral pneumonia, acute 8 respiratory distress syndrome (ARDS), pulmonary embolism whereas long term 9

complications include but not limited to persistent interstitial abnormalities, bronchiectasis 10 and pulmonary fibrosis. [4] [5] [6] [7] [8] Follow-up data from other studies report persistent 11 physiological and parenchymal abnormalities, especially in hospitalized patients with 12

severe initial SARS-CoV-2 infection. [9] [10] [11] However, there are only limited number of studies 13

reporting evidence of functional small airway disease (fSAD) after SARS-CoV- 2 14 infection. 12,13 15 Small airways are non-cartilaginous (less than 2 mm in diameter), start from generation 16 8th of lung branching and are often defined as 'quiet zones' of the lungs. 13, 14 Being small 17 is diameter, they are susceptible to occlusion by small, inhaled toxins or pathogens (also 18 known as post infectious bronchiolitis) or by local or systemic inflammatory damage with 19 underlying conditions like connective tissue disease, post lung or bone marrow transplant 20 and environmental or inhalational exposure (e.g. smoking). 13, 15 The diagnosis is difficult 21 to establish as traditional lung function tests remain normal until late in disease course 22

and direct assessment of small airways is beyond resolution of routine Computed 23 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 22, 2021. ; https://doi.org/10.1101/2021. 10.19.21265028 doi: medRxiv preprint Tomography (CT) scanners. 14 However, small airways are indirectly evaluated on CT by 1 subjective and quantitative measures of air trapping (or gas trapping) and mosaic 2 attenuation especially in expiratory scans which suggests heterogenous distribution of 3 airway disease. 13, 14, 16 4 The aim of this study was to understand the natural course of radiological and pulmonary 5 function tests, in a cohort of patients who presented to post-Covid-19 clinic and underwent 6 longitudinal follow up with expiratory and inspiratory pulmonary imaging and pulmonary 7 function test (PFT). The greater aim was to find the proportion of patients who had 8 evidence of small airway disease based on imaging and pulmonary function tests. 9

This study was a retrospective observational descriptive study conducted at University of 12

Iowa hospitals & clinics. The study was approved by Institutional board review (IRB# 13 2020055421). The study included patients from inception of post covid clinic from June 14 1,2020 to July 15 th ,2021. Written informed consent was obtained from all the patients 15 included in the study. 16

All adult patients who presented to outpatient post-COVID-19 clinic for follow up, had 17 either a positive SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) 18 or positive SARS-CoV-2 antibody test and had at least two temporal CT scans since the 19 diagnosis and a PFT were included in the study. CT imaging was classified as acute CT 20 (defined as CT < 1 month since COVID-19 diagnosis), subacute CT (1-3 months since 21 COVID-19 diagnosis) or a chronic CT (> 3 months since COVID-19 diagnosis). The CT 22

imaging protocol consisted of acquisition of lung imaging at inspiration (coached to total 23 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted October 22, 2021. ; https://doi.org/10.1101/2021.10.19.21265028 doi: medRxiv preprint lung capacity) and expiration (coached to residual volume). The details of the CT imaging 1 protocol used for the COVID-19 clinic patients is detailed elsewhere. 16 All the patients 2 who had prior documented history of lung fibrosis or interstitial lung disease (ILD) were 3 excluded from the study. 4

We collected demographics (age, sex, race, ethnicity, BMI, smoking history), past medical were reviewed by an experienced pulmonologist and further characterized as subacute 12

(1-3 months after COVID-19 diagnosis) or chronic (>3 months after COVID-19 diagnosis). 13

CT images were interpreted using standardized imaging nomenclature (such as ground-14 glass opacity [GGO], consolidation, air-trapping). 17 All PFTs were obtained and 15 interpreted using Standardized American Thoracic Society criteria. 18 The PFTs were 16 timed with either subacute or chronic CT scans. The following parameters were PFT variables with values less than 80% were considered abnormal. Resting pulmonary 22

hyperinflation was defined as RV/TLC ratio of more than or equal to 40%. 23 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 22, 2021. ; https://doi.org/10.1101/2021.10.19.21265028 doi: medRxiv preprint

Primary outcomes were the clinical characteristics and abnormalities in the initial imaging 2 and the follow up pulmonary imaging. Results were expressed using proportions, 3 percentages, means and standard deviation or minimum and maximum values, as 4 appropriate. Paired t-test was used to measure changes in FEV1, FVC and DLCO. A p-5 value less than 0.05 was considered statistically significant. Table  16 1. 17

The mean duration of follow up pulmonary function test from positive SARS-CoV-2 test 19 was 161.54 (range 31-259) days. Spirometry was obtained during the subacute phase in 20 72.72% (16/22) patients. From these patients, 56.25% (9/16) had restrictive lung 21 physiology and only 12.5% had obstructive lung physiology (2/16). In subacute phase, 22 DLCO was measured in 50% (11/22) of the patients, out of which 72.72% (8/11) had 23 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) In addition, a group of 7 patients out of 22 patients had both spirometry measured during 5 the subacute and chronic phases. As shown in Figure 1 , FEV1((p=0.0361), FVC 6 (p=0.0341) and FEF 25%-75% (p=0.0259) improved significantly with time. Four patients 7

in this group had also DLCO measured during these time points, with significant 8 change(p=0.0019). These results demonstrate improvement in lung function without any 9 therapeutic intervention (including steroids). 10

The quality of all CT images was evaluated by Radiologist and only images with excellent 12 quality with no motion or good quality with mild motion were included in the study. The 

In this study we report that PFT changes including FEV1, FVC, FEF25-75%, DLCO, and 18 lung parenchymal changes, such as GGO, bronchiectasis, architectural distortion, and 19 even parenchymal scarring can improve over time. However, the proportion of patients 20 with air trapping increased from the acute phase (23.52%) to the chronic phase (81.25%). 21

The results of our study are in line with our previous study of 100 patients who presented 22

for follow up after SARS-CoV-2 infection, with air trapping and evidence of small airway 23 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 22, 2021. ; https://doi.org/10.1101/2021.10.19.21265028 doi: medRxiv preprint disease in 25.5% of patients in ambulatory group (not admitted to hospital), 34.5% in 1 hospitalized group and 27.2% in intensive care group regardless of severity of infection. 13 2

disease which persisted at two months follow up. 12 This was a multicenter study done in 4

China, included 108 patients, and found evidence of small airway disease in expiratory 5 and inspiratory high-resolution CT. 6

The overall contribution of small airways is minimum to airway resistance and previous 7 spirometry data suggests that spirometry abnormalities may not present until > 75% of 8 airways are obstructed. 15, 19 In our cohort, the spirometry changes and some parenchymal 9

CT findings improved with time, but some parenchymal CT findings persist, and air sequalae of SARS-CoV-2 (PASC) present with persistent respiratory complains, it will be 20 important to understand the different phenotypes and tailor therapies so that unnecessary 21 treatments with potential side-effects can be avoided. We would also emphasize that 22

follow-up with CT imaging should be done carefully as subjecting patients to repeated 23 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 22, 2021. radiological exposure and assessment of small airway is not feasible unless clinically 1 indicated. 14 While the objective evaluation of air trapping on CT is possible, qualitative 2 assessment of air-trapping is highly subjective. 13, 16 Moreover, single point interpretation 3 of air-trapping is difficult as it is a non-specific sign and can be seen with some other 4 physiological (e.g., obesity) and pathological conditions (e.g., pulmonary vascular 5 congestion). 14, 20, 21 However, temporal changes after COVID-19 as highlighted in this 6 study can provide understanding of small airway disease change in terms of progression 7 or improvement. 8

Our study highlights the natural course of the SARS-CO-V2 infection and effects on lungs. 9

Our cohort was heterogeneous and included patients with variety of clinical 10 characteristics and disease severity describing the evolution of image characteristics and 11 spirometry with time. In this study, all the CT findings were evaluated by a single 12 experienced fellowship trained radiologist, hence excluding inter-observer variability. The 13 quality of expiratory and inspiratory films was assessed, and only studies with good or 14 excellent quality CT were included. We followed the patients with inspiratory and 15 expiratory CT scans and over more than six months follow-up (and one patient with 385 16 days follow up) and found the evidence of persistent (and even increasing) air trapping 17 despite resolution (or stability) of other changes. 18

Our study had certain limitations. It is a single center, observational study which included 19 relatively small number of symptomatic patients. However, since COVID-19 is a relatively 20 new disease our aim was to include patients with comparable follow-up. Due to 21 retrospective design, not all the patients were followed at the same regular intervals. 22

Hence, there are some missing data points (not all the patients had imaging or PFT in all 23 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 22, 2021. ; https://doi.org/10.1101/2021.10.19.21265028 doi: medRxiv preprint phases [acute, subacute, and chronic]). We cannot correlate the findings with underlying 1 co-morbidities and clinical course as the sample size is small. Due to heterogeneous 2 cohort, it will be difficult to determine which patients are more prone to developing small 3 airway disease based on their clinical characteristics and illness course during acute 4

infection. More longitudinal follow up studies including large number of patients can be 5 done in future to delineate the risk factors and prevalence of fSAD in patients after SARS-6

CoV-2 infection. Also, studies are needed to understand the long-term consequences and 7 treatment modalities in patients presenting with differing clinical and radiological 8 phenotypes. 9

Our study shows evidence of airway as well as parenchymal disease months after initial . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted October 22, 2021. ; . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted October 22, 2021. ; https://doi.org/10.1101/2021.10.19.21265028 doi: medRxiv preprint Figure 3 . A woman in her 60s (Case 12) with history of hypertension and coronary artery disease admitted to medical floor with fever, cough, dyspnea for five days. She did not require oxygen during this time. She had persistent cough and dyspnea at follow up 230 days with CT inspiratory films (A, C, E) and expiratory films (B, C, D) showing bilateral air trapping at multiple areas (white arrows pointing to some areas) in expiratory films which was not present in the acute CT.

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted October 22, 2021. ; https://doi.org/10.1101/2021.10.19.21265028 doi: medRxiv preprint

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centimeter(range) Weight, mean in Kilogram(range) Body Mass Index, mean, Kg/m2(range)

n (%) Convalescent plasma, n (%) Antibiotics, n (%) Renal replacement therapy, n (%) Oxygen after hospital discharge