Pulmonary Fibrosis in post COVID-19 follow up cases

Introduction

The World Health Organization (WHO) officially announced COVID-19 as a pandemic disease in March 2020.1 This infectious disease is highly contagious and mainly spreads by coughing, talking within proximity, or sneezing.2 A large proportion of infected COVID-19 cases had very mild symptoms - such as loss of taste or smell, fever, fatigue, and dry cough - or are completely asymptomatic. However, in about 14% of the cases, acute respiratory distress syndrome (ARDS) can develop which is a potentially fatal condition.3 ARDS can especially develop in patients predisposed to certain risk factors, such as diabetes mellitus, old age, and hypertension etc.4 COVID-19 is primarily considered a respiratory condition however it is a systemic disease as it can adversely affect various organs, including the cardiovascular, gastrointestinal, nervous, hematopoietic, and cardiovascular systems; This can be due to the angiotensin-converting enzyme 2 (ACE2)'s abundant presence in many organs of the body.5

After the COVID-19 outbreak, increasing number of patients worldwide who have survived COVID-19 continue to battle the symptoms of the illness, long after they have been clinically tested negative for the disease. They are called as long – haulers. As we battle through this pandemic, the challenging part is how to manage this COVID-19 sequelae which may vary from mild in terms of fatigue and body aches to severe forms requiring long term oxygen therapy and even lung transplantation due to lung fibrosis or significant cardiac abnormalities and stroke leading to impairment in quality of health.6, 7

The severe lung involvement can lead to ARDS. The pathological correlate of ARDS is the diffuse alveolar damage (DAD) which is characterized by an initial (acute inflammatory) exudative phase with edema, hyaline membranes, and interstitial acute inflammation, followed by an organizing phase with loose organizing fibrosis mostly within alveolar septa, and type 2 pneumocyte hyperplasia. A potent third stage of ARDS may be the fibrotic stage.8 Abnormal immune mechanism initiates and promote pulmonary fibrosis, possibly as a consequence of a cytokine storm. Dysregulation release of matrix metalloproteinases during the inflammatory phase of ARDS causes epithelial and endothelial injury. VEGF and cytokines such as IL-6 and TNF alpha are also implicated in fibrosis process.

Our medical college hospital during the pandemic became a dedicated Covid tertiary care centre (DCH) and patients who recovered were coming with various post covid symptoms so this study was carried out here to evaluate and manage these patients.

Materials and Methods

Study design- A prospective observational study was carried out in patient who are COVID cases (RTPCR positive/ RAT positive/CT scan of thorax suggestive of covid infection) and were recovered from COVID infection and come for follow up in post COVID care clinic of Respiratory Medicine at C.R. Gardi Hospital, Ujjain. Recruitment of the patient according to the inclusion and exclusion criteria. The patient and/or relatives had been explained about procedure and informed and written consent was taken from the patient and/or relatives.

Results

In our study of 119 patients, 29 (24.4%) were females and 90 (75.6%) were males of which, 15 (22.4%) females and 52 (77.6%) males in fibrotic group. Of total, 51(42.85%) patients were below 50yr of age and 68(57.1%) patients were above 50yr of age, while in fibrotic group, 20(29.85%) patients were below 50yr of age and 47(70.14%) patients were above 50yr of age (p=0.0240). Mean age of 54.9701(±12.5493) years was higher in patient with post covid lung fibrosis compared to non-fibrotic group (45.7885±14.5108) (p=0.0003).

Only 6(5.0%) patients were in home isolation and 113(95.0%) patients had been admitted in hospital during Covid (p=0.0043). The duration of hospital stay (days) was significantly higher in fibrotic group [17.1045±7.5741] compared to non-fibrotic group [12.3913±5.4792] (p=0.0004).

In fibrotic group, only 1(1.49%) patient was of mild Covid infection, 18(26.86%) were patients of moderate Covid infection and 48(71.64%) patients had severe Covid infection. On the evaluation it was found that in fibrotic group, only 1(1.49%) patient was on room air, 6(8.95%) patients were on nasal prong, 11(16.41%) patients were on face mask, 16(23.88%) patients were on NRBM, 3 (4.47%) patients were on HFNC and 30 (44.77%) patients were on BiPAP/NIV. So maximum patient in fibrotic group had received oxygen support during hospitalization.

In this study of 119 post covid patients, 109(91.6%) patients have received corticosteroids (p=0.0020), 48 (40.3%) patients had received Remdesivir (p<0.0001) and 5(4.2%) patients had also received Tocilizumab (p=0.0441) for their Covid management according to severity of lung damage.

In fibrotic group, 33(49.3%) patients had diabetes mellitus (p=0.0016), 29(43.3%) patients had hypertension (p=0.0011), 2(3.0%) patients had asthma and COPD (p=0.7139). 27 (40.3%) patients were smokers (p=0.0137) in fibrotic group.

In our study 119 post Covid follow up patient had various symptoms persisting as 101(84.9%)weakness, 44 (37.0 %) cough, 21 (17.6 %) expectoration, 12(10.1%) fever, 64(53.8%) breathlessness, 14(11.8%) chest pain, 12(10.1%) joint pain, 31 (26.3%) insomnia, 10(8.4%) sore throat, 1(7.1%) abdominal pain, 2(14.3%) constipation, 1(7.1%) dry mouth, 1(7.1%) gum weakness, 1(7.1%) headache, 3(21.4%) haemoptysis, 1(7.1%) neuropathy, 2(14.3%) running nose, 1(7.1%) skin rash and 1(7.1%) vertigo. These symptoms were more severe in fibrotic group compare to non-fibrotic group.

In our study of 119 post covid follow up patients, only 67(56.3%) patients had bilateral infiltrate and reticular shadows on chest X-ray (p<0.0001) and these patients also had interstitial fibrosis, intra and inter septal thickening on HRCT thorax (p<0.0001). On follow up of these 67 patients of pulmonary fibrosis, only 3(4.47%) patients had residual fibrosis and in rest the fibrosis resolved between 2-5 months. We found that in our study, wCRP (<5) was significantly higher in [96.6418±242.1744] the fibrotic group compared to non-fibrotic group [25.2423±60.9711] (p=0.0403) also D-Dimer (<500) values were significantly higher in fibrotic group [1260.1940±992.9654] compared to non-fibrotic group [312.8846±695.9704] (p<0.0001).

It was found that in our study of 119 patient, 45 (37.8%) patients had been given anti-coagulants in post Covid follow up (p<0.0001. In the present study out of the 119 patients, all of the 67(56.3%) patients who had developed post Covid lung fibrosis had also received Pirfenidone(anti-fibrotic) to prevent lung fibrosis. Out of these 67 patients, 51 patients had been given anti-fibrotic for 2 to 3 months, 13 patients had received it for 4 to 5 months and only 3 patients had developed residual fibrosis for which anti fibrotics were continued(p<0.0001).

Discussion

The clinical manifestations of COVID-19 can range from mild symptoms to severe illness that lead to permanent lung damage or even mortality.9 Most of mild and moderate cases were completely recovered as seen in non-fibrotic group of our study but only few of severe cases with acute respiratory distress syndrome (ARDS) continued to remain hypoxemic despite receiving adequate medical treatment, developed post-COVID pulmonary fibrosis was one of the important sequalae.10 Many theories were discussed as a potential cause of post-COVID pulmonary fibrosis; older age, severity of illness, prolonged ICU stay, mechanical ventilation, history of smoking, comorbidities are the risk factors for its developments.11 But later on, it was found to be in most cases to be broncho vascular bundle distortion, fibrotic strips, architectural distortion, subpleural curvilinear atelectasis which resolved over time.12 As in our study, out 67 patients of pulmonary fibrosis, only 3 patients had developed residual fibrosis while other improved.13 This may be due to as they had received anti-inflammatory drugs like steroids, Tocilizumab etc and anti-fibrotics in covid.14 Also, patients presented with various symptoms in post-covid phase.15

Conclusion

Covid pandemic has gradually spread around the world with lots of mortality. Based on limited data from our study of 119 patients, the evaluation of long-term consequences of acute COVID-19 has shown that these had post covid sequelae like pulmonary fibrosis were seen in 67(56.3%) patients of which only in 3(4.47%) patient residual lung fibrosis was developed. Post covid HRCT findings showed interstitial fibrosis, intra and inter septal thickening which were later found to be actually broncho vascular bundle distortion, fibrotic strips, architectural distortion, subpleural curvilinear atelectasis. So, the patients who had lung fibrosis were fewer than expected (<5%) as this could be due to the use of anti-inflammatory medication and the use of anti-fibrotics. These sequelae were mostly occurring in the elderly patients with comorbidities, having longer duration of hospital stay, severity of covid infection and smoking are the other risk factors for its development. Post Covid patients had various symptoms like weakness, cough, breathlessness, ghabarahat, joint pain, palpitation, brain fogging etc which required symptomatic management.

Source of Funding

None.

Conflict of Interest

None.