3. Outbreak of the novel coronavirus nCoV-19 (SARS-CoV-2) - first reported
in Hubei province, China1
Globally, as of 6:17pm CEST, 6 October 2021, there have been 23,56,73,032 confirmed cases of
COVID-19, including 48,14,651 deaths,, reported to WHO2
1. QJM: An International Journal of Medicine 2020: 837–838
2. https://covid19.who.int/ Accessed on 6th October 2021
4. Long Haulers-
Increasingly number of
patients who survived
covid 19, continued to
battle the symptoms of
the illness, long after they
have been clinically tested
negative for the diseases
Ann Clin Microbiol Antimicrob (2021) 20:35
11. Age
Illness
severity and
associated
comorbidities
Length of ICU
Stay and
Mechanical
Ventilation
Levels of
LDH
Smoking
Chronic
Alcoholism
Risk Factors for
Pulmonary Fibrosis
following SARS-CoV-2
Infection
Pulmonary Medicine Volume 2020, Article ID 6175964, 10 pages;
Lung India 2020
12. Predictors of Pulmonary Fibrosis
Retrospective study of 32 confirmed COVID-19 patients
Clinical and Lab
predictors
• Older
• Levels of C-reactive protein
• Interleukin-6
• Longer-term of
hospitalization
• Pulsed steroid therapy and
antiviral therapy
• More dyspnea and higher
respiratory rate
HRCT Imaging
• Interstitial
thickening
• Irregular interface*
• Coarse reticular
pattern and
• Parenchymal band*
* predicts the formation of pulmonary fibrosis early Korean J Radiology 2020
Advanced disease
• More segments
involved
• Larger lesion
diameter manifested
14. Three complementary strategies to reduce the likelihood of
development of lung fibrosis may be proposed:
European Journal of Preventive Cardiology 2020, Vol. 27(13) 1442–1446
15. TREATMENT OF POST-COVID FIBROSIS
i. Steroids
• RECOVERY Trial- In hypoxic patients in ICUs across the world
modest doses of 4–6 mg dexamethasone for no more than 10 days
• Fibrosis still reported in few
• Steroids should be continued on discharge if the CT scan prior to discharge
continues to show significant GGOs and the patient remains hypoxic
• No more than 20–30 mg of prednisolone at discharge and tapering it on
follow-up depending on the patient’s response
Lung India 2020
16. TREATMENT OF POST-COVID FIBROSIS
Critical points of
reciprocal influence for
COVID-19 and
IPF
J. Proteome Res. 2020, 19, 4327−4338
17. TREATMENT OF POST-COVID FIBROSIS
ii. Antifibrotics:
• Useful in patients with acute exacerbations of ILD (both IPF and
other fibrotic ILDs).
• Fibrosis with fibroblasts and honeycombing has clearly been demonstrated in
autopsies and explanted lungs of patients with SARS-C0V-2.
Lung India 2020
18. The excessive inflammatory state, associated with the presence of fibrotic tissue induced by SARS-CoV-2, has been
shown to play a key role in clinical cases considered more critical.
In the more severe stages of viral infection, excessive release of pro-inflammatory mediators, such as
cytokines, leads to lung damage with extensive fibrosis and rapid onset of respiratory distress syndrome.
The use of agents to prevent or reduce fibrotic status, as pirfenidone, may be therapeutically effective in
preventing serious or fatal complications. Pirfenidone is the drug of choice in the treatment of idiopathic pulmonary
fibrosis (IPF) and with a pleiotropic mechanism of action reduces the fibrotic and inflammatory state of lung tissue.
19. • inhibit apoptosis
• downregulate ACE receptors
expression,
• decrease inflammation by several
mechanisms and
• ameliorate oxidative stress and
hence protect pneumocytes and other
cells from the COVID-19 invasion and
cytokine storm simultaneously
Pirfenidone could be a safe add on to the current protocols of COVID-19
treatment, with trivial side effects and plenty of potential benefits
20. Pirfenidone: Post Covid Lung Fibrosis
Anti-inflammatory effects of
pirfenidone
• Inhibits TNF-α secretion and decrease a
large number of other inflammatory
cytokines
• Ameliorates lipopolysaccharide induced
pulmonary inflammation and fibrosis by
blocking NLRP3 inflammasome
activation
Anti-fibrotic effects of pirfenidone
• Inhibits TGF- β,Down-regulating of
profibrotic gene expression and
collagen secretion
• Collagen I fibril formation and causes a
reduction in collagen fibril bundles
• Pleiotropic actions- immune system
and extracellular matrix (ECM);
regulates tissue injury and repair
Medical Hypotheses Volume 144, November 2020,
21. Nintedanib improves pulmonary fibrosis by inhibiting the
action of PDGF, FGF-2, and vascular endothelial growth factor
The arrow size indicates the degree of contribution to pulmonary fibrosis suggested by the published data.
The dotted line indicates that very little data was available.
Core Evid. 2015;10:89-98
22.
23. Nintedanib was associated with shorten lengths
of mechanical ventilation
N= 60 , 30 patients received nintedanib
interventional study in which adult patients with COVID-19 requiring
mechanical ventilation (MV)
Nintedanib was not
associated with decreased
28-day mortality
24. Caution
• Increased risk of acute pulmonary embolism in patients with COVID-19 and
anticoagulant therapy might be associated with improved outcomes in
patients with severe COVID-19 and coagulopathy.
• Nintedanib - increases risk of bleeding when concomitantly
administered with full-dose anticoagulation.
Lancet Resp Med 2020; 8(8):807-815
25. Oxygen support at home
Pulmonary rehabilitation – Once shifted out of the
ICU and continued at home
Lung transplant
Anticoagulation
OTHER TREATMENTS FOR POST-COVID FIBROSIS
Lung India 2020
26. FOLLOW –UP : resource-strapped countries
• 6 monthly lung function, walk tests
• QOL questionnaires
• Annual HRCT
Should be done for all patients till clinical, physiological, and
radiological stability has been documented
Lung India 2020
27. Key Take Home Messages
• The risk factors for severe COVID-19 are shared with idiopathic pulmonary fibrosis
(IPF), suggesting that this group of patients will be at increased risk of severe
COVID-19.
• There is therapeutic rationale for the use of licensed antifibrotic therapy in acute
exacerbations of IPF, including those triggered by viral infection.
• Available antifibrotic therapies have broad antifibrotic activity regardless of
aetiology and these drugs might have a role in attenuating profibrotic pathways in
SARS-CoV-2 infection.
Cytokine storm, severe inflammation, oxidative stress, and reactive
oxygen species damage and increased permeability of vascular bed are
responsible for the development of ARDS
An initial phase of lung injury is followed by acute inflammation
as well as an attempt at repair [3]. This process can result
in the restoration of normal pulmonary architecture, or it
may lead to pulmonary fibrosis with architectural distortion
and irreversible lung dysfunction. The repair process
involves regeneration by native stem cells and connective
tissue deposition to replace areas of defect [7]. Alveolar
macrophages play a central role in this process by phagocytizing
alveolar debris and the production of cytokines and
growth factors involved in the repair [8].
The process of repair involves angiogenesis, fibroblast
activation, and collagen deposition [9]. In the presence of
alveolar exudates, organization occurs which is identified by
fibroblastic invasion of the alveoli and transformation into
myofibroblasts leading to the deposition of an organizing
fibroblastic extracellular matrix (ECM) [9]. Epidermal
growth factor (EGF) and transforming growth factor-alpha
(TGF-α) stimulate proliferation of bronchiolar stem cells to
replace damaged alveolar epithelium [10]. Vascular endothelial
growth factor (VEGF) and fibroblast growth factor (FGF)
stimulate the migration and proliferation of uninjured endothelial
cells leading to pulmonary capillary angiogenesis [11].
The degradation of organizing fibroblastic tissue by the
fibrinolytic system or remodeling into the interstitium
coupled with epithelial and endothelial proliferation is sufficient
for the repair process if the basement membranes are
intact [4, 12]. However, in severe or persistent injury with
damage to the basement membranes, fibroblastic activities
persist, converting organizing into fixed and/or progressive
fibroblastic tissue [4, 13]. The formation of this scar tissue,
either focal or diffuse, results in disorganized alveolar architecture
[14]. Excessive deposition of extracellular matrix is
therefore central to the process of lung fibrosis. It manifests
as an irregular interlobular septal thickening and reticular
pattern with traction bronchiectasis on chest CT scan [15].
The process described is typical of pulmonary fibrosis following following
acute lung injury such as those occurring in severe acute
respiratory syndrome (SARS) with diffuse alveolar damage,
acute fibrinous, and/or organizing pneumonia [14]. It must
be noted, however, that pulmonary fibrosis could occur in
the absence of a clear-cut inciting agent and without a
clinically obvious initial acute inflammatory phase. This is
known as idiopathic pulmonary fibrosis (IPF) or cryptogenic
fibrosing alveolitis.
ACE receptors are the major COVID-19-SARS virus receptor in humans.
Trials that targeted the inhibition of these receptors with antibodies
are under investigation [52]. Surprisingly, it has been shown
that pirfenidone inhibits the AT1R/p38 MAPK pathway, decreased
angiotensin-converting enzyme (ACE), angiotensin II, and angiotensin
II type 1 receptor expression, and strongly enhanced liver X receptor-α
expression [21]. This will not only protect cells from developing fibrosis
(LXR-α) also by decreasing the ACE receptor expression decrease entrance
of the COVID-19-SARS virus into cells
