Are patients with comorbidities more prone to sequalae in severe COVID-19

Mradul Kumar Daga; Govind Mawari; Siddharth Chand; J Aarthi; RV Raghu; Naresh Kumar

doi:10.4103/injms.injms_37_21

CASE REPORT

Year : 2021 | Volume : 12 | Issue : 3 | Page : 161-164

Are patients with comorbidities more prone to sequalae in severe COVID-19

Mradul Kumar Daga, Govind Mawari, Siddharth Chand, J Aarthi, RV Raghu, Naresh Kumar
Department of Medicine, Maulana Azad Medical College, New Delhi, India

Date of Submission	12-Mar-2021
Date of Decision	07-Apr-2021
Date of Acceptance	08-Apr-2021
Date of Web Publication	09-Jul-2021

Correspondence Address:
Dr. Mradul Kumar Daga
Department of Medicine, Maulana Azad Medical College, New Delhi - 110 002
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injms.injms_37_21

Abstract

Majority hospital admission in COVID-19 is because of pneumonia. Few develop progressive and permanent pulmonary fibrosis. Here, we present three patients of severe COVID-19 pneumonia requiring intensive care unit care. Computed tomography (CT) of the chest of these patients revealed multiple areas of lung involvement at the 4^th week of illness. Follow-up CT scan and pulmonary function test were done after 5 months to look for residual changes. Pulmonary fibrosis induced by COVID-19 is being documented. We need long-term follow-up studies to observe the clinical and radiological course of fibrosis. Corticosteroids and antifibrotic agents in such cases are being looked into.

Keywords: Corticosteroids, COVID-19, sequalae

How to cite this article:
Daga MK, Mawari G, Chand S, Aarthi J, Raghu R V, Kumar N. Are patients with comorbidities more prone to sequalae in severe COVID-19. Indian J Med Spec 2021;12:161-4

How to cite this URL:
Daga MK, Mawari G, Chand S, Aarthi J, Raghu R V, Kumar N. Are patients with comorbidities more prone to sequalae in severe COVID-19. Indian J Med Spec [serial online] 2021 [cited 2023 Mar 26];12:161-4. Available from: http://www.ijms.in/text.asp?2021/12/3/161/321049

Introduction

COVID-19 caused by SARS-CoV-2 virus primarily affects the respiratory system, although other organ systems are also involved. The Chinese Center for Disease Control and Prevention in their study of approximately 44,500 confirmed infections reported mild disease in 81%, severe disease in 14%, and critical disease in 5%.^{^[1]} The overall case fatality rate was 2.3%. From observational studies, it is known that some survivors develop fibrotic pulmonary remodeling and restrictive lung abnormalities, associated with impaired exercise tolerance and poor quality of life at follow-up.^{^[2]} Hence, lung fibrosis may be a possible long-term sequela of COVID-19 pneumonia since there are many similarities between infection caused by SARS-CoV-1 and SARS-CoV-2. Various mechanisms of lung injury in COVID-19 have been described, with both viral and immune-mediated mechanisms being implicated.^{^[3]}

Case Report

Case 1

A 63-year-old male with stable coronary artery disease and no prior history of lung disease presented with SARS-CoV-2 positive by reverse transcriptase–polymerase chain reaction (RT-PCR). He had heart rate of 110 beats/min, blood pressure 124/76 mmHg, respiratory rate of 28/min, oxygen saturation of 85% on room air, and sinus tachycardia on electrocardiogram. The patient was started on oxygen at 10 L/min via nonrebreathing mask and started on ceftriaxone and azithromycin along with Vitamin C and zinc tablets. He was given intravenous dexamethasone and subcutaneous enoxaparin. Chest X-ray [Figure 1]a showed bilateral opacities throughout the lung field predominantly in the lower lobes. The patient's condition deteriorated after 2 days of admission and he was started on noninvasive ventilation-bilevel positive airway pressure (BIPAP) mode. He was administered tocilizumab 600 mg, which was repeated after 48 h. He also received remdesivir for 5 days. He was later weaned off from BIPAP and shifted to oxygen support at 3 L/min. He tested negative for COVID-19 by RT-PCR on days 20 and 24 but remained oxygen dependent, saturation dropping to 87% on room air. Computed tomography (CT) of the chest done [Figure 1]b revealed multifocal areas of bronchocentric consolidation along with tractional bronchiectasis and fibrotic bands. The patient received supplemental oxygen for a month, was gradually tapered off oxygen, and discharged on a steroid inhaler. After 3-month postdischarge from non-COVID care (5 months after testing positive), the patient had complaints of breathlessness on slight exertion. Although oxygen saturation was normal on room air, pulmonary function test was suggestive of restrictive pattern with forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) at 49% and 55% of predictive value. CT scan [Figure 1]c revealed fibrosis and tractional bronchiectasis in both lungs.

Figure 1: (a) Chest X-ray at presentation showing bilateral opacities in the periphery predominantly in the lower lobes. (b) CT chest on day 30 demonstrating diffuse ground glass opacities and tractional bronchiectasis and fibrotic bands. (c) Computed tomography chest 5 months after testing positive showing fibrosis and tractional bronchiectasis in both the lungs

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Case 2

A 50-year-old female with type 2 diabetes mellitus, hypertension, hypothyroidism, and no prior history of lung disease presented with complaints of breathing difficulty and fever for 5 days and loose stools for 2 days and tested COVID positive by RT-PCR. She had a temperature – 99.9°F, pulse – 94/min, respiratory rate – 32/min, blood pressure – 138/92 mmHg, and oxygen saturation of 80% on room air, which improved to 90% with high flow oxygen at 10 L/min via a nonrebreathing mask. The patient was given ceftriaxone, azithromycin, intravenous dexamethasone, and subcutaneous enoxaparin. Her chest X-ray [Figure 2]a had opacity in the right upper zone and middle zone and left upper, middle, and lower zones. On day 6, she deteriorated with oxygen saturation falling to 80% with high-flow oxygen and was put on BIPAP ventilation and remdesivir for 5 days. She gradually improved over the next 10 days, maintaining oxygen saturation at an oxygen flow rate of 4–5 L/min. She tested negative for COVID-19 by RT-PCR on days 14 and 16. CT of the chest [Figure 2]b done on day 22 was suggestive of subpleural distribution in the basal segment and bilateral lower lobes of multifocal areas of ground-glass opacities with interlobular septal thickening and subpleural fibrobronchiectatic bands in the bilateral upper lobe. She required oxygen for a total of 8 weeks of illness duration, following which could be discharged on steroid inhalers, without any oxygen requirement. At 24 weeks of testing positive, she was asymptomatic for any breathing difficulty, but a CT scan [Figure 2]c done was suggestive of mosaic attenuation and persistence of ground-glass opacities with minimal fibrosis. Her pulmonary function test was suggestive of a restrictive pattern with FVC and FEV1 at 74% and 70% of predictive value, respectively.

Figure 2: (a) Chest X-ray showing opacities in the right upper and middle zone and left middle lung. (b) Computed tomography chest day 22 showing features of extensive ground-glass opacities and fibrobronchiectatic bands. (c) Computed tomography of the chest 5½ months after testing positive showing persistent ground-glass opacities in bilateral lung fields

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Case 3

A 39-year-old male without any comorbidity and significant past history presented with shortness of breath for 10 days and fever for 4 days. He tested COVID positive by RT-PCR and had received three doses of remdesivir. He presented with pulse rate – 114/min, respiratory rate – 30/min, blood pressure – 120/80 mmHg, and oxygen saturation – 84% on room air which improved to 90% with high-flow oxygen at 15 L/min via a nonrebreathing mask. He was put on high-flow nasal oxygenation (0.7/60 L/min). He was given IV antibiotics, dexamethasone, and subcutaneous enoxaparin along with Vitamin C and zinc tablets. His chest X-ray [Figure 3]a showed fibronodular opacities in the bilateral upper zone and left middle zone. He eventually improved, though remained oxygen dependent and was transferred to the ward after 20 days. He tested negative on days 14 and 20 by RT-PCR. CT of the chest [Figure 3]b done on day 24 was suggestive of fibrotic and fibrobronchiectatic changes in bilateral upper lobes, with inter and intralobular septal thickening along with ground-glass opacities in the lung parenchyma in peripheral predominant location. He was discharged on long-term home-based oxygen therapy. The patient was asymptomatic on his follow-up visit 4 months after testing positive, and the CT scan [Figure 3]c showed few subtle areas of ground-glass opacities and fibrosis in bilateral upper lobes with rest of the lung fields normal. His PFT was normal.

Figure 3: (a) Chest X-Ray at presentation showing fibronodular opacities in bilateral upper zone and left middle zone. (b) Computed tomography chest on day 24 showing fibrobronchiectatic changes in bilateral upper lobe and ground-glass opacities. (c) Computed tomography chest 5½ months after testing positive showing few subtle areas of ground-glass opacities and fibrosis in bilateral upper lobes with rest of the lung fields normal

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Discussion

The risk of chronic respiratory sequelae in survivors of COVID-19 pneumonia is unknown. The possible underlying mechanisms by which lung damage is caused include a hyperimmune response leading to cytokine release syndrome triggered by the viral antigen and high airway pressure and hyperoxia-induced acute lung injury secondary to mechanical ventilation. SARS and Middle East respiratory syndrome coronavirus (MERS) belong to the family of coronavirus and have caused pulmonary infection and syndromes similar to COVID-19 since they are genetically similar. A 15-year follow-up study conducted on 71 patients with SARS revealed that pulmonary functional decline and interstitial abnormalities recovered over the first 2 years following infection and then remained stable. At 15 years, 4·6% (standard deviation 6·4%) showed interstitial lung abnormality in patients infected with SARS.^{^[4]} There is a scarcity of long-term follow-up studies on patients infected with MERS.

Patients requiring long-term oxygen therapy have been described in the Indian setting.^{^[5]} One study from the UK reported severe functional deficit with an interstitial deficit in 5% recovered patients.^{^[6]} Shortness of breath and pulmonary fibrosis have been reported in patients who had recovered with no oxygen requirement.^{^[7]}

In our series, we see that patients who are old and have multiple comorbidities have worse respiratory outcomes. They are more likely to have persistent lung changes and be symptomatic. This may be because of dysimmune response leading to increased fibrosis. Young patients even if suffering from severe illness are more likely to recover without any residual changes.

In the 2009 swine flu pandemic caused by H1N1, few developed pulmonary fibrosis. In a study conducted by Mineo et al.,^{^[8]} 20 patients affected by H1N1 influenza were followed up for a period of 1 year, which showed that 25% of cases developed acute respiratory distress syndrome (ARDS) which progressed to pulmonary fibrosis in 10%. One of them showed a late appearance of initial signs of pulmonary fibrosis characterized by reticular thickening of the interstitium and traction bronchiectasis with peripheral distribution on day 68, which showed regression at 10^th month follow-up imaging. In another patient, a CT scan done on day 15 revealed signs consistent with fibrotic evolution; however, complete regression of the signs of interstitial lung disease was seen at the 4-month follow-up. A similar pattern of clinicoradiological evolution of H1N1 influenza was observed in a case reported by Singh et al.^{^[9]} Two patients who developed post swine flu fibrosis were followed up for 5 years, both of them did not show a progression of disease both radiologically and on pulmonary function tests.

Lung injury during the acute phase of COVID-19 pneumonia is mainly due to the inflammatory response to viral infection. Endothelial dysfunction and microvascular damage by local thromboembolic events are other possible determinants of lung damage.^{^[10]} A histopathological progression similar to SARS has already been observed in COVID-19 pneumonia, with intra-alveolar and interstitial fibrin deposition and chronic inflammatory infiltrate, already a few weeks after the initial diagnosis.^{^[11]} The predominance of pro-fibrotic pathways in the wound repair response and invasive ventilation-associated mechanical stress^{^[12]} is involved in long-term remodeling. Notably, lung fibrosis is promoted by coronavirus infection by two mechanisms: (a) transforming growth factor-beta (TGF-b) signaling, which is a powerful pro-fibrotic stimulus that is mediated and enhanced by the nucleocapsid protein of SARS-CoV-1.^{^[13]} Although the nucleocapsid protein of SARS-CoV-2 is over 90% similar to that of SARS-CoV-1,^{^[14]} possibility of COVID-19 sharing this similar feature as that of SARS is unknown. (b) There is a downregulation of angiotensin-converting-enzyme-2, reducing angiotensin II (Ang II) clearance in the lungs, probably induced by a coronavirus. Ang II could then upregulate TGF-b and connective tissue growth factors.^{^[15]}

A hyperactive immune response may be responsible for scarring. Once immunologic complications such as cytokine storm occur, lung damage ensues because of the inflammation and fills the alveoli with pus. In the worst-case scenarios, inflammation caused by this damage is so severe that a thickened scar tissue in honeycomb-shaped clusters is left behind – something similar also seen in SARS and MERS. Three complementary strategies to reduce the likelihood of development of lung fibrosis are (a) a more intense and prolonged inhibition of viral replication; (b) a long-standing inhibition of the inflammatory response; and (c) the administration of antifibrotic drugs.^{^[16]} To date, it is unknown whether the above-mentioned strategies may prevent lung remodeling. There is still conflict regarding prolonged administration of low-dose corticosteroids for few weeks to months which may prevent long-term respiratory sequelae in survivors of ARDS. The conflict is due to the benefit–risk ratio of these drugs, especially in patients with comorbidities such as diabetes mellitus, hypertension, and chronic heart failure.^{^[17]} Use of either angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers may halt the progression of lung fibrosis and subsequent chronic consequences since Ang II may be a key player also in the development of lung fibrosis, although this point is still to be clarified.^{^[18]} Antifibrotic drugs used in the treatment of idiopathic pulmonary fibrosis, such as pirfenidone and nintedanib, may be of some help in preventing lung fibrosis secondary to COVID-19 infection. These antifibrotic drugs seem to have some anti-inflammatory effects as well, thus supporting their use even in the acute phase of COVID-19 pneumonia.^{^[19]}

Currently, a 4-week course of pirfenidone is being tested by a multicenter, randomized, open clinical trial (ClinicalTrials.gov identifier: NCT04282902) on the effects it has on CT findings and gas exchanges in patients with COVID-19. The use of serial PFT and/or imaging tests may outline the actual pulmonary outcomes of COVID-19 survivors. Moreover, should the risk of long-term lung fibrosis be confirmed, the identification of risk factors and early markers of lung fibrosis would become crucial, favoring the implementation of preventive strategies in the subset at higher risk.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

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