Post Covid-19 Recovery - Incidence of Pulmonary Sequelae - Hype or Fact?
Coronavirus disease 2019 (COVID-19) announced in March 2020 as a pandemic by the World Health Organization (WHO) with the causative agent of COVID-19 identified as the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Months later, longer-lasting COVID-19 cases started gaining attraction among social support groups, like Long Haul Covid Fighters, Body Politic Covid-19 Support Group. At first, doctors dismissed their concerns as symptoms related to mental health, such as anxiety, in a phenomenon called "medical gaslighting".(1)
Early data suggested a shorter recovery (eg, two weeks) for those with mild disease, and a longer recovery (eg, two to three months or longer) for those with more severe disease.
However, this scenario changed soon. The term long-haul COVID-19 (or post-acute COVID-19) started gaining recognition in the scientific and medical communities(2)
The recovery process from COVID-19 exists on a continuum(3)
1) Acute COVID-19: Symptoms of COVID-19 for up to 4 weeks following the onset of illness
2) Ongoing symptomatic COVID-19: Symptoms of COVID-19 from 4 to 12 weeks following the onset of illness
3) Post-COVID-19: Symptoms that develop during or after COVID-19, continue for ≥ 12 weeks, not explained by an alternative diagnosis
PATHOPHYSIOLOGY (4)
COVID-19 virus is enveloped which infects the host through a series of viral spike proteins. Host protease TMPRSS2 reveals the fusion domain of the spike protein which allows attachment to the angiotensin-converting enzyme-2 (ACE2) receptor on the host cell. It allows endocytosis to release the viral genome into the host cell. Virus attacks the host cellular machinery to replicate and release viral particles extracellularly subsequently causing infection of neighbouring cells. The virus is believed to infect several target cells, including type II pneumocytes, and alveolar macrophages in the lungs.
INCIDENCE OF LUNG FIBROSIS IN POST-COVID19:
A study by Wu C et.al showed that 40% of patients with COVID-19 pneumonia develop acute respiratory distress syndrome (ARDS), and nearly 20% of patients have severe ARDS. Duration of disease along with severity are important determinants for the development of lung fibrosis post-Covid 19 pneumonia. Lung fibrosis was observed in about 4% of patients with a disease duration of less than 1 week as compared to 61% of patients with a disease duration of greater than 3 weeks.(5)
MECHANISMS OF PULMONARY FIBROSIS
Some of the proposed mechanisms for the development of lung fibrosis in Covid 19 include(6)
1) Cytokine release syndrome triggered by the viral antigen
2) Drug-induced pulmonary toxicity, and high airway pressure
3) Hyperoxia induced acute lung injury secondary to mechanical ventilation.
RISK FACTORS FOR PULMONARY FIBROSIS
Some of the risk factors associated with the development of lung fibrosis include(7)
1) Age
2) Disease severity
3) Duration of ICU stay and ventilatory support
4) Smoking
5) Chronic alcoholism
RISK REDUCTION STRATEGIES
Due to high morbidity and poor quality of life in patients with pulmonary fibrosis, there should be a greater focus on strategies to reduce the risk. Strategies should be directed at reducing the factors that worsen the cycle of lung injury, inflammatory response, and fibroproliferation.
Some of them include(7)
1) Use of antiviral and immunomodulatory medications
2) Ventilator-induced lung injury to be minimized with protective lung ventilation (low tidal volumes and low inspiratory pressures)
3) Continuous lung injury has been considered a major factor in the development of lung fibrosis. Therefore, patients should be educated to limit exposure to environmental factors and encouraged for smoking cessation.
CLINICAL COURSE AND DIAGNOSIS
Clinical manifestations of COVID-19 have ranged from asymptomatic/mild symptoms to severe illness and mortality. Most of the mild and moderate cases recovered completely but a small proportion of severe cases with acute respiratory distress syndrome continued to remain hypoxemic despite adequate treatment.
There is a paucity of data for course of post covid pulmonary fibrosis. A study conducted at Italy (between April 2020 to May 2020) assessed persistent symptoms in 143 patients who were discharged from the hospital after recovery from COVID-19. Patients were assessed at a mean of 60. 3 days after the initial onset of COVID-19 symptom; at the time of evaluation, only 18 (12.6%) were completely free of any COVID-19–related symptom, while 32% had 1 or 2 symptoms and 55% had 3 or more. None of the patients had fever or any signs or symptoms of acute illness. Worsened quality of life was observed among 44.1% of patients.(9)
Another follow up study which studied the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery enrolled 55 patients and found different degrees of radiological abnormalities in 39 patients.(10)
Many studies have shown that most common abnormality of lung function in discharged survivors with COVID-19 is impairment of diffusion capacity, followed by restrictive ventilatory defects, both associated with the severity of the disease.(11)
Chest imaging of this subset of patients revealed fibrotic changes in the form of traction bronchiectasis, architectural distortion and septal thickening similar to the changes seen in other fibrotic lung diseases.
TREATMENT OPTIONS FOR FIBROSIS
Two medications, nintedanib and pirfenidone, have been shown to slow disease progression. Both COVID-19 and IPF share many common demographic factors. Autopsy studies showed fibrosis with fibroblasts and honeycombing in patients with SARS C0V 2. Hence, it is assumed that antifibrotic drugs may have a potentially valuable role in treating patients with post-COVID-19 lung fibrosis setting.(12)
REFERENCES:
1) Rubin R. As Their Numbers Grow, COVID-19 "Long Haulers" Stump Experts. JAMA. 2020 Oct 13;324(14):1381-1383.
2) Greenhalgh T, Knight M, A'Court C, Buxton M, Husain L. Management of post-acute covid-19 in primary care. BMJ. 2020 Aug 11;370:m3026.
3) COVID-19 rapid guideline: managing the long-term effects of COVID-19. London: National Institute for Health and Care Excellence (UK); 2020 Dec 18.
4) McDonald LT. Healing after COVID-19: are survivors at risk for pulmonary fibrosis? Am J Physiol Lung Cell Mol Physiol. 2021 Feb 1;320(2):L257-L265.
5) Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934e943.
6) George PM, Wells AU, Jenkins RG. Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. Lancet Respir Med. 2020 Aug;8(8):807-815. doi: 10.1016/S2213-2600(20)30225-3.
7) Ojo AS, Balogun SA, Williams OT, Ojo OS. Pulmonary Fibrosis in COVID-19 Survivors: Predictive Factors and Risk Reduction Strategies. Pulm Med. 2020 Aug 10;2020:6175964.
8) Liu D, Zhang W, Pan F, Li L, Yang L, Zheng D, Wang J, Liang B. The pulmonary sequalae in discharged patients with COVID-19: a short-term observational study. Respir Res. 2020 May 24;21(1):125.
9) Carfì A., Bernabei R., Landi F. For the Gemelli against COVID-19 post-acute care study group. Persistent symptoms in patients after acute COVID-19. J Am Med Assoc. 2020;324(6):603–605.
10) Zhao Y.M., Shang Y.M., Song W.B. Follow-up study of the pulmonary function and related physiological characteristics of COVID-19 survivors three months after recovery. EClinicalMedicine. 2020;25:100463. doi: 10.1016/j.eclinm.2020.100463.
11) Nusair S. Abnormal carbon monoxide diffusion capacity in COVID-19 patients at time of hospital discharge. Eur Respir J. 2020 Jul 23;56(1):2001832. doi: 10.1183/13993003.01832-2020
12) Udwadia ZF, Koul PA, Richeldi L. Post-COVID lung fibrosis: The tsunami that will follow the earthquake. Lung India. 2021 Mar;38(Supplement):S41-S47
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