Radiological and spirometric changes in relation to drugs used in post COVID pulmonary fibrosis in a cohort of COVID-19 survivors

Background It has been proposed that prolonged use of anti‑inflammatory and anti‑fibrotic drugs dimin‑ ish the probability of development of lung fibrosis. Prolonged low‑dose corticosteroid may prevent remodeling of the lung in survivors. Pirfenidone and colchicine may exhibit anti‑fibrotic and anti‑inflammatory properties as well. Methods This retrospective observational study was conducted at post COVID‑19 clinic, Mansoura University Hospi‑ tals, during the period between October 2020 and March 2022. This study included 104 patients who had COVID‑19 pneumonia confirmed either by RT‑PCR or radiologically by CT scan and divided into 3 groups; group A (corticos‑ teroids only) included 33 (31.7%) patients, group B (corticosteroids and colchicine) included 56 (53.8%) patients, and group C (corticosteroids, colchicine, and pirfenidone) included 15 (14.4%) patients. All patients were assessed during follow‑up visits in post COVID‑19 clinic 1 and 3 months after discharge by evaluation of resting SpO2, spirom‑ etry, and radiological assessment. Patients’ data during hospitalization was collected from hospital electronic systems. Results There was non‑statistically significant improvement in FEV1 in group A while there was statistically sig‑ nificant improvement in FEV1 in groups B and C ( P value = 0.002 and 0.041, respectively) 1 month and 3 months after discharge. Group B exhibited more statistically significant improvement in FVC as well compared to group C ( P value = 0.003 and 0.025, respectively) while group A showed non‑statistically significant improvement in FVC. There was a statistically significant decrease in CT severity score in all the groups during follow‑up with P value < 0.001 in groups A and B and to less extent less statistically significant decrease in group C comparing the 3 groups to each other. Conclusion


Background
The COVID-19 pandemic Caused by the SARS-CoV-2 virus, has raised significant concerns because to its high fatality rate and the absence of targeted and efficient treatment options [1].Post-acute COVID-19 could be defined as persistent symptoms and/or delayed or long-term complications of COVID-19 infection beyond 4 weeks from the onset of symptoms.It is further divided into two categories: subacute or ongoing symptomatic COVID-19, which includes symptoms and abnormalities present from 4 to 12 weeks beyond acute COVID-19, and chronic or post COVID-19 syndrome refers to symptoms and abnormalities that persist or are present beyond 12 weeks after the onset of acute COVID-19 and cannot be attributed to any other diagnosis [2].
It has been proposed that prolonged use of anti-inflammatory and anti-fibrotic drugs diminish the probability of development of lung fibrosis.Prolonged low-dose corticosteroid may prevent remodeling of the lung in survivors.Also, anti-fibrotic drugs, such as pirfenidone and nintedanib, have anti-inflammatory effects as well and thus they may be used even in the acute phase of COVID-19 pneumonia.Pirfenidone exerts anti-fibrotic, anti-oxidative, and anti-inflammatory effects.Pirfenidone could attenuate ARDS-induced lung injury as it reduces lipopolysaccharide (LPS)-induced acute lung injury and subsequent fibrosis [1].
Colchicine can decrease the expression of the TNF-α receptor in macrophages and reduce cytokines IL-1β, IFN γ, IL-18, and IL-6.Over the years, many studies have shown its therapeutic potential for various inflammatory conditions.The colchicine has anti-fibrotic effects as a microtubule-destabilizing agent.Myofibroblast differentiation plays a critical role in wound healing and the pathogenesis of fibrosis [3].

Patients and methods
This retrospective observational study was conducted at post COVID-19 clinic, Mansoura University Hospitals, Dakahlia, Egypt, during the period between October 2020 and March 2022.Study protocol was approved by Institutional Research Board, Faculty of Medicine, Mansoura University, with the proposal code: MD.21.09.526.R1.Also, this study was registered at ClinicalTrials.gov with title "Anti-inflammatory and Anti-Fibrotic Drugs in Post COVID-19 Pulmonary Fibrosis" with ID NCT05648734.
The study population included 104 patients and they were divided into 3 groups according to received treatment as shown in Fig. 1.
Adult patients who had COVID-19 pneumonia confirmed either by RT-PCR or radiologically by CT scan were included in our study and according to WHO severity classification are classified to moderate, severe, or critical disease and had received either: Fig. 1 Flowchart of patients included and excluded in the study Group A: Corticosteroids alone (≥ 20 mg prednisolone or its equivalent with gradual tapering for ≥ 1 month after hospital discharge) Group B: Corticosteroids (≥ 20 mg prednisolone or its equivalent with gradual tapering for ≥ 1 month after hospital discharge) in combination with colchicine (1 mg/day for ≥ 1 month) Group C: Corticosteroids (≥ 20 mg prednisolone or its equivalent with gradual tapering for ≥ 1 month after hospital discharge) in combination with colchicine (1 mg/day for ≥ 1 month) and pirfenidone (≥ 267 mg TID for ≥ 1 month) These patients attended at post COVID-19 clinic, Mansoura University Hospitals, for assessment of resting SpO2, spirometry, and radiological changes after 1 and 3 months of discharge from hospital.
Patients with any of the following had been excluded from our study: Non-COVID-19 pneumonia, mild cases of COVID-19, patients with previous pulmonary disease that could affect their spirometry results, patients receiving antifibrotic or anti-inflammatory drugs due to other chronic disease, patients who received anti-fibrotic and/or antiinflammatory drugs for duration and/or doses less than presumed or those who reported non-compliance to treatment, patients who develop severe intolerable side effects or derangement of liver enzymes more than 5 folds or clinical signs and symptoms of drug-induced liver injury, pregnant ladies with COVID-19 infection, and patients who could not complete follow-up visits at post COVID-19 clinic as scheduled or had missing data.

Radiological scoring
High-resolution computed tomography (HRCT) chest scan had been performed for the patients 1 and 3 months after discharge.
Both CT scans performed during the two clinic visits together with the baseline CT scan performed during hospitalization have been reviewed by an expert radiologist, retrospectively and independently evaluated all CT scans on the picture archiving and communication system (PACS) workstation, and have been subjected to the following scoring.

Chest CT-severity scoring (Chest CT-SS) for assessing the severity of pulmonary involvement
The score depends on the degree of lung opacification, which serves as an indicator of the spread of the disease within the lungs.The anatomical structure of the lungs consists of 18 segments, which are further divided into 20 regions.The apico-posterior segment of the left upper lobe is subdivided into apical and posterior segmental regions, while the anteromedial basal segment of the left lower lobe is subdivided into anterior and basal segmental regions.
The chest CT images are used to subjectively evaluate the lung opacities in all 20 lung regions.A scoring system is employed, giving scores of 0, 1, and 2 based on the extent of parenchymal opacification in each region: 0% involvement, < 50% involvement, or ≥ 50% involvement, respectively.The CT-SS is calculated by adding together the scores of each of the 20 lung segment regions, with a possible range of 0 to 40 points [4].

Total fibrosis score for quantifying pulmonary fibrosis (5)
The total fibrosis score (TFS) is a convenient and simple approach for measuring lung fibrosis in patients with IPF.For analysis, 6 specific axial sections of the chest HRCT were chosen based on anatomical landmarks.The initial segment was defined by the aortic arch; the subsequent segment was positioned 1 cm below the carina; the following segment was demarcated by the confluence of the pulmonary veins, and the fourth section was midway between the third and fifth sections.The fifth section was positioned 2 cm superior to the right hemidiaphragm, whereas the sixth section was situated 1 cm inferior to the right hemidiaphragm.
All spirometry data was collected and tabulated and classification of physiological impairment of PFTS was defined based on ERS/ATS technical standard on interpretive strategies for routine lung function tests where an obstructive ventilatory impairment is defined by FEV1/ FVC below the LLN, which is defined as the 5th percentile of a normal population [6].The presence of a restrictive impairment may be suspected from spirometry when FVC is reduced and FEV1/FVC is normal or increased.

Statistical analysis
Data analysis was performed by SPSS software, version 25 (SPSS Inc., PASW statistics for Windows version 25.Chicago: SPSS Inc.).Chi-square and Monte Carlo tests were used to compare qualitative data between groups as appropriate.Mann-Whitney U and Kruskal-Wallis tests were used to compare between 2 studied groups and more than 2 studied groups, respectively, for nonnormally distributed data.Wilcoxon signed rank test was used to compare between more than 2 studied periods.Student t-test was used to compare 2 independent groups for normally distributed data.Paired t-test was used to compare 2 paired readings for normally distributed data.One-way ANOVA test was used to compare more than 2 independent groups with post hoc Tukey test to detect pair-wise comparison.

Results
This study included 104 patients divided into 3 groups; group A (corticosteroids only) included 33 (31.7%) patients, group B (corticosteroids and colchicine) included 56 (53.8%) patients, and group C (corticosteroids, colchicine, and pirfenidone) included 15 (14.4%) patients.All groups were matched for age, sex, comorbidities, and disease severity at presentation as shown in Table 1.The mean age in groups A, B, and C was 57.61 ± 13.65, 59.37 ± 10.82, and 55.53 ± 8.56, respectively, with P value of 0.483.
There was statistically significant improvement in SpO2 between (baseline and 1, 3 months after discharge) and between (1 month and 3 months after discharge) in both groups A and B, while there was non-statistically significant improvement in SpO2 between (baseline and 1, 3 months after discharge) and between (1 month and 3 month after discharge) in group C as shown in Table 2.
There was non-statistically significant improvement in FEV1 in group A while there was statistically significant improvement in FEV1 in groups B and C (1 and 3 months after discharge).Group B exhibited more statistically significant improvement in FVC as well compared to group C while group A showed non-statistically significant improvement in FVC as in Table 3.
There was a statistically significant decrease in CSS in all the groups during follow-up with P value < 0.001 in groups A and B and to less extent less statistically significant decrease in group C comparing the 3 groups to each other during follow-ups as shown in Table 4. and Fig. 2. Similarly, there was statistically significant decrease in TFS in all the groups during follow-up with P value < 0.001 in groups A and B and to less extent less statistically significant decrease in group C as in Table 5 and Fig. 3.

Discussion
During COVID-19 pandemic, the SARS-CoV-2 virus can cause acute lung injury (ALI) and, in severe cases, acute respiratory distress syndrome (ARDS).However, these conditions often recover and do not result in long-term lung damage [7].Nevertheless, many cases of ARDS advance to the more severe critical phase of pulmonary fibrosis, generally referred to as post COVID-19 pulmonary fibrosis (PCPF), which necessitates immediate attention and appropriate treatment [8].PCPF occurs as a consequence of severe lung damage after COVID-19 infection in which a significant fraction of hospitalized patients with ARDS develops progressive lung fibrosis.Chest CT scans of patients with severe COVID-19 frequently reveal radiological signs of PCPF.The incidence of these persistent abnormalities ranges from 10 to 75% among patients who require hospitalization or recurring at outpatient clinics 60 days following their initial COVID-19 diagnosis.[9].
The aim of this study was to observe the long-term effects of anti-inflammatory and anti-fibrotic drugs in post COVID pulmonary fibrosis and to compare the efficacy of corticosteroids, pirfenidone, and colchicine in reducing pulmonary fibrosis in a cohort of survivors of COVID-19 regarding functional and radiological changes.
Due to ethical concerns and the acute settings of COVID-19 pandemic, it was not appropriate to perform an interventional study comparing those anti-inflammatory and anti-fibrotic drugs.Our best decision was to do this research as a retrospective observational study till there are clear recommendations or guidelines that endorse the use of anti-inflammatory and anti-fibrotic drugs in PCPF patients.
The included patients were divided into 3 groups:  Regarding oxygen saturation by pulse oximetry (SpO2%), there was no statistically significant difference in SpO2 between the different groups when compared with each other during hospitalization (baseline), 1 month, and 3 months after discharge with P value 0.191, 0.841, and 0.608, respectively.
In groups A and B, there was statistically significant improvement in SpO2 between (baseline and 1 month after discharge), between (baseline and 3 months after discharge), and between (1 month and 3 month after discharge) with P value (< 0.001 and = 0.001), (< 0.001 and = 0.001), and (= 0.001 and = 0.001), respectively.In group C, there was no statistically significant difference in SpO2 between (baseline and 1 month after discharge), between (baseline and 3 months after discharge), and between (1 month and 3 month  after discharge) with P value 0.109, 0.072, and 0.08, respectively.In Ibrahim et al. [10] study, they compared 2 groups each included 25 patients after 3 to 7 weeks of onset of acute COVID-19 infection.The first group received 20 mg/day prednisolone in combination with pirfenidone 267 mg/day tds with increasing dose and the second group received 20 mg/day prednisolone only.SpO2 median in the first visit of each group was 81.6% and 81.8%, respectively, with no statistically significant difference (P value = 0.68).SpO2 median in the second visit after 1 month increased to 86% and 84%, respectively, with no statistically significant difference (P value = 0.37).In the third visit after 3 months of treatment, SpO2 median increased to 91.9% and 87.8% with highly statistically significant improvement in the first group (P value < 0.001).This is inconsistent with the results in our study where the steroids only group (group A) showed significant improvement in SpO2% compared with combined steroids, colchicine, and pirfenidone (group C).This could be due to the different treatment received in the second group, different sample size, and different characteristics of patients.

Table 5 Total fibrosis score (TFS) changes during follow-up distribution according to treatment received among the studied cases
Kw Kruskal Wallis, test *statistically significant , p1 difference between group A & B , P2 difference between group A& C , P3 difference between group B &C , parameters described as median (min-max) Pa, % a, comparing between baseline and after 1 month after discharge , p b, %b , comparing between baseline and after 3 months after discharge , pc, %c comparing between 1& 3 months follow up Regarding spirometry, forced vital capacity (FVC) changes 1 month and 3 months after discharge, there was non-statistically significant improvement in group A (P value = 0.06) and statistically significant improvement in groups B and C (P value = 0.003 and 0.025, respectively).Forced expiratory volume in first second (FEV1) changes 1 month and 3 months after discharge showed non-statistically significant improvement in group A (P value = 0.188) and statistically significant improvement in groups B and C (P value = 0.002 and 0.041, respectively).
In both previous results, FVC and FEV1 changes were assessed based on percent predicted (% predicted) and both showed statistically significant improvement in group B than those in group C during spirometry follow-up.
In a study which included 380 individuals who had recovered from COVID-19, it was found that some participants exhibited impaired spirometry characterized by either restrictive (15% of patients) or obstructive (7% of patients) patterns [11].An observational study was conducted to examine the changes in functional and radiological characteristics of critical COVID-19 survivors between 3 and 6 months after being discharged from the hospital.The study found that there were persistent functional abnormalities, specifically impairments in total lung capacity (TLC), in 41% and 33% of the survivors at the end of the follow-up.Notable enhancements were detected solely in the FEV1 and FVC measurements, namely at the 3-and 6-month marks following discharge [12].
Fumagalli et al. [13] found that COVID-19 pneumonia can lead to significant changes in spirometry, specifically causing a restrictive pattern in almost 75% of patients after hospital discharge.After 45 days, there was an improvement in spirometry, while a certain level of restrictive pattern remained present.
In Ibrahim et al. [10] study, FVC showed statistically significant improvement after 6 months of treatment with pirfenidone in combination with prednisolone group compared to the steroid only group (P value < 0.001).This is consistent with Acat et al. [14] who retrospectively reviewed 22 patients hospitalized with COVID-19 pneumonia and spirometry was performed 2 months after treatment.They stated that patients' second-month spirometry of the methylprednisolone + pirfenidone group had much higher FEV1, FVC%, and FEV1%/FVC values than the corticosteroids group only.
In addition, Deftereos et al. [15] in their study demonstrated a substantial therapeutic advantage of colchicine over a control group that did not receive colchicine in COVID-19 patients.Nevertheless, all their cases were hospitalized COVID-19 cases.
In a systematic review and meta-analysis of randomized control trials by Yasmin et al. [16], the researchers assessed the effectiveness and safety of colchicine in patients with COVID-19.The analysis encompassed a cohort of 16,048 individuals derived from five randomized clinical trials.Out of the total, 7957 individuals were assigned randomly to get colchicine, whereas 8091 individuals received conventional treatment.The study found that colchicine had a significant effect in reducing the severity of COVID-19 (odds ratio: 0.41, 95% confidence interval [0.22, 0.76]; P = 0.005), as well as decreasing levels of inflammatory markers.Nevertheless, this meta-analysis also reviewed hospitalized patients.
Chest CT-severity scoring (CSS) changes during follow-up of COVID-19 pneumonia survivors.CSS changes when compared during hospitalization (baseline), 1, and 3 months after discharge.There was a statistically significant decrease in CSS in all the groups during follow-up with P value < 0.001 in groups A and B and to less extent less statistically significant difference in group C (P value = 0.01, 0.001, and 0.013, respectively) when assessing the changes in the 3 CT scans.
Ibrahim et al. [10] found that CSS showed statistically significant decrease between the analyzed groups after 3 months of treatment in the pirfenidone + prednisolone group compared to the steroid only group (P value < 0.001).After 1 month of treatment, pirfenidone + prednisolone group's CSS was also lower than that of the other group as well (P value = 0.01).This is in agreement with Acat et al. [14] who compared 13 patients treated with methylprednisolone + pirfenidone with 9 patients treated with methylprednisolone only.After examining the rates of change in CT scans at the time of diagnosis and after 2 months of treatment, it was discovered that the group receiving methylprednisolone + pirfenidone experienced a significant reduction in involvement rates (P < 0.001).However, the rates of CT involvement were evaluated utilizing machine learning methods instead of CSS.
While this study showed that the addition of PFN to corticosteroids and colchicine was not superior to either corticosteroids alone or corticosteroids in combination with colchicine, Ibrahim et al. [10] and Acat et al. [14] results were not matching with our findings.As mentioned before, the difference in treatment regimens received, patients' characteristics, sample size, and most importantly the timing of PFN administration.While PFN has anti-fibrotic effect, it has also anti-inflammatory effects and the early administration of PFN during the acute phase in COVID-19 pneumonia as was proposed by Esquivel et al. [17] yielded in greater survival.In this study, the administration of PFN was achieved in all the cases immediately after hospital discharge based on the treating physicians' decision and this could not be modified due to the retrospective type of the study.
Calabrese et al. [18] researched the efficacy of corticosteroids on the chest CT scan with characteristics of COVID-19 pneumonia.The lung total severity score was acquired based on the methodology developed by Chung and his colleagues [19].In addition, the proportions of the total severity score attributed to ground-glass opacities, consolidations, crazy paving, and linear bands were calculated.The chest HRCT scores were assessed both prior to and 7-10 days following the administration of methylprednisolone at a dosage of 0.5-0.8mg/kg/ day.The administration of corticosteroids resulted in a notable reduction in the overall severity score, consolidations, and crazy paving scores on HRCT scans.Additionally, there was a large rise in linear bands.However, this study assessed the corticosteroid effect on the short term within 2 weeks only.
Zhang et al. [20] stated that the inclusion of pirfenidone in the treatment did not result in any statistically significant differences in the K-BILD survey results compared to the group of patients who received standard treatment.An upward trend was noted in individuals who were administered pirfenidone for a duration of 1 month.Similarly, after 1 month of treatment, there were no noticeable changes between the two groups regarding CT imaging (P = 0.745).Nevertheless, there were certain variations in the scores, such as consolidation, the ground-glass opacity, and the reticulation between groups, which reflected the improvement of lung inflammation and interstitial alterations.
Momen et al. [21] have documented that patients with PCPF, who were treated with standard treatment after recovering from COVID-19, did not experience any improvement.As a result, the administration of an antifibrotic drug, such as pirfenidone, became necessary.This treatment led to significant enhancements in both the radiological outcomes and the patient's clinical manifestations.However, as previously mentioned, Zhang et al. [20] reported that neither the K-BILD nor the CT scores showed a statistically significant difference between the two groups.This discrepancy may be due to features, demographics, different sample sizes of the patients, and the timing of administration of PFN as they added PFN to standard treatment in hospitalized patients.
Total fibrosis score (TFS) is a readily accessible CT scoring method to quantify fibrosis in idiopathic pulmonary fibrosis (IPF) patients which was adapted by Fraser et al. [5] to quantify the amount of fibrosis in IPF patients and can aid in assessing the efficacy of anti-fibrotic therapy.This method involves using a CT scan to visually score fibrotic characteristics, including traction bronchiectasis, ground glass with traction bronchiectasis, honeycombing, and reticulation.These features are collectively referred to as TFS.It is a 6-slice visual scoring system based on chest CT scans.
Similar to CSS, TFS also changes during follow-up of COVID-19 pneumonia survivors.TFS changes when compared during hospitalization (baseline), 1, and 3 months after discharge.There was a statistically significant decrease in TFS in all the groups during follow-up with P value < 0.001 in groups A and B and to less extent less statistically significant difference in group C (P value = 0.01, 0.001, and 0.013, respectively) when assessing the changes in the 3 CT scans.These values are similar to those noted with CSS during follow-up.
It was noted in this study that TFS was elevated at the initial CT scan (baseline) done during hospitalization and this can be explained by the extensive ground-glass opacities with traction bronchiectasis that occurred in ARDS patients as many of the patients were severe and critical.Truly this was reversible bronchiectasis known as "pseudobronchiectasis" a term that have been described in various infections before and currently have been endorsed in multiple researches in COVID-19 [22,23].
Farghaly et al. [24] demonstrated the existence of ground-glass opacities (95%), honeycombing (25%), and pulmonary consolidations (9%) in individuals diagnosed with PCPF.Patients who required mechanical ventilation or were admitted to the ICU had a higher CT score.Additionally, a high CT score was linked to extended hospital stay and severe dyspnea.
Besutti et al. [25] employed a visual assessment of consecutive follow-up CT scans to classify the CT patterns of lung lesions in patients who had recovered from severe COVID-19 pneumonia.Using this method, a 5-7-month follow-up CT scan revealed that over 55% of patients experienced complete or near-complete resolution.Approximately 37.5% of patients still had non-fibrotic lesions, and only 7% had fibrotic lesions (4.4% purely fibrotic and 2.5% post-ventilatory).
The lack of a consistent definition for fibrotic changes in earlier studies resulted in a wide range of reported prevalence for persisting fibrotic lesions.Prior research evaluating CT scans conducted 6-7 months after treatment revealed that the occurrence of fibrotic-like alterations varied between 29 and 70%.The CT characteristics of pulmonary fibrosis, such as the presence of parenchymal bands, reticular pattern, honeycombing, and traction bronchiectasis, were observed with varying frequency [26].
In contrast, a comprehensive examination of 353 individuals revealed that the occurrence of reticulations and interlobular septal thickening was seldom (1%) during the CT scan conducted at the 6-month follow-up [27].Similarly, Wu et al. observed reticular opacities in 13 out of 83 patients (16%) and bronchiectasis in only one patient during the course of repeated CT scans [28].
The radiological patterns are known to vary significantly, similar to clinical progression.Following an average observation period of 10 days, it appears that the majority of cases have shown improvement in lung parenchymal abnormalities, but some patients continue to exhibit modest signs of pulmonary fibrosis [29].

Limitations
We acknowledge the following limitations in our study: The small sample size and the simple spirometry approach are the main limitations of the present study.Additionally, pulmonary function tests before COVID-19 infection are not available for our patients.Due to the acute setting in which the baseline data were gathered and ethical considerations, this study was designed as retrospective observational study rather than an interventional one, till there are recommendations endorsing the use of those anti-inflammatory and anti-fibrotic drugs in PCPF.
Lung diffusion with carbon monoxide (DLCO) test was not available at the time of the study and six-minute walking test (6MWT) was not performed due to nonavailability of the equipment and the small area of post COVID-19 clinic did not allow for accomplishment of this test.Muscle pressures were not assessed as well as corticosteroid-induced myopathy could be a contributing factor to lung function restriction.Due to limitations in our study, we recommend a prospective randomized controlled trial to more rigorously assess the efficacy of different treatments with larger sample size and follow up patients over a longer period to evaluate long-term effects on lung function and radiologic changes.

Conclusions
The use of colchicine added to corticosteroids after acute phase of COVID-19 pneumonia resulted in statistically significant improvement regarding SpO2%, FEV1, FVC, CSS, and TFS changes during follow-up when compared to corticosteroids alone.
The addition of pirfenidone (which is a relatively expensive drug) to corticosteroids and colchicine did not add more statistically significant improvement in functional (when compared to corticosteroids only) and radiological (when compared to corticosteroids only or corticosteroids plus colchicine) assessment during follow-ups.

Fig. 2
Fig. 2 CSS changes in different groups during follow-up

Fig. 3
Fig. 3 TFS changes in different groups during follow-up

Table 1
Socio-demographic characteristics, comorbidities, and severity distribution according to treatment received among the studied cases F One Way ANOVA test , x 2 =Chi-Square test, MC Monte Carlo test , p1 difference between group A & B , P2 difference between group A& C , P3 difference between group B &C, DM Diabetes Mellitus, HTN Hypertension, CVD Cardiovascular Disease, CKD Chronic Kidney Disease, CLD Chronic Liver

Table 2
SpO2 change during follow-up distribution according to treatment received among the studied cases p1: difference between group A & B cases , p2: difference between group A & C cases , p3: difference between group B & C cases , Pa: comparing between baseline and after 1 month after discharge, pb: comparing between baseline and after 3 months after discharge, pc: comparing between 1& 3 months follow up * Significant as P value <0.05

Table 3
Spirometry changes during follow-up distribution according to treatment received among the studied cases F:One Way ANOVA test, p1 difference between group A & B cases, p2 difference between group A & C cases, p3 difference between group B & C cases * Significant as P value <0.05

Table 4 .
Chest CT-severity scoring (CSS) changes during follow-up distribution according to treatment received among the studied cases