Post covid 19 pulmonary fibrosis- Is it reversible?
Deependra Kumar Rai*
, Priya Sharma, Rahul Kumar
Department of Pulmonary Medicine, AIIMS Patna, 801505, India
article info
Article history:
Received 12 October 2020
Accepted 5 November 2020
Available online xxx
Keywords:
Covid 19
Pulmonary fibrosis
Antifibrotic
ARDS
abstract
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 clini-
cally tested negative for the disease. As we battle through this pandemic, the challenging
part is to manage COVID-19 sequelae which may vary from fatigue and body aches to lung
fibrosis. This review addresses underlying mechanism, risk factors, course of disease and
treatment option for post covid pulmonary fibrosis. Elderly patient who require ICU care
and mechanical ventilation are at the highest risk to develop lung fibrosis. Currently, no
fully proven options are available for the treatment of post inflammatory COVID 19 pul-
monary fibrosis.
© 2020 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.
1. Introduction
Coronavirus disease 2019 (COVID-19) is caused by a novel
coronavirus, known as severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2). The global pandemic began in
Wuhan, China, in December 2019, and has since then spread
worldwide.1 As of September 30, 2020, the cases of COVID-19
infection continues to soar worldwide with no peak in sight
making total case tally standing at 63,12,585 including 9,40,705
active cases, 52,73,202 cured/discharged/migrated and 98,678
deaths, according to the Ministry of Health and Family Wel-
fare. While whole medical fraternity and researchers across
the world continue to learn more about the novel contagion
and its bizarre array of symptoms, it is becoming clear that the
battle with COVID-19 is not an easy one.
After the COVID-19 outbreak, increasing number of pa-
tients 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 e 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 lung
transplantation due to lung fibrosis, significant cardiac ab-
normalities and stroke leading to significant impairment in
Quality of health. Various studies have reported that around
70e80% of patients who recovered from COVID-19 presents
with persistence of at least 1 or more symptoms, even after
being declared COVID-free.2,3
Considering millions of covid 19 cases worldwide, even
small proportion of post covid lung fibrosis is worrisome.
Many active clinical trials and studies are underway to know
more about the entity post covid pulmonary fibrosis. This
narrative review summarizes current clinical evidence
regarding post COVID-19 pulmonary fibrosis.
2. Materials & Methods
This review was performed to address following questions for
post covid pulmonary fibrosis.
Mechanism
2. Risk factors
3. Clinical course
4. Treatment option
A literature review was performed using different database
(PubMed, Scopus, Science Direct, and Google Scholar) to
identify relevant English-language articles published through
September 25,2020. Search terms included coronavirus, se-
vere acute respiratory syndrome coronavirus 2, COVID-19,
Post covid fibrosis, antifibrotic. The search resulted in 2,567
total articles. Due to the lack of RCTs, we have also included
case reports, case series, and review articles. The authors
independently reviewed the titles and abstracts for inclusion.
Additional relevant articles were identified from the review of
citations referenced. Active clinical trials were identified using
the disease search term coronavirus infection on
ClinicalTrials.gov.
2.1. Mechanism of post COVID pulmonary fibrosis
Various mechanisms of lung injury in COVID-19 have been
described, with both viral and immune-mediated mecha-
nisms being implicated.4 Pulmonary fibrosis can be either
subsequent to chronic inflammation or an idiopathic, geneti-
cally influenced and age related fibroproliferative process.
Pulmonary fibrosis is a known sequela to ARDS. However,
persistent radiological abnormalities after ARDS are of little
clinical significance and have dwindled with protective lung
ventilation.5
It has been found that 40% of patients with COVID-19
develop ARDS, and 20% of ARDS cases are severe.6 The prev-
alence of post-COVID-19 fibrosis will become apparent with
time, but early analysis from patients with COVID-19 on
hospital discharge suggests that more than a third of recov-
ered patients develop fibrotic abnormalities. The pathological
feature of ARDS is diffuse alveolar damage (DAD) which is
characterized by an initial acute inflammatory exudative
phase with hyaline membranes, followed by an organizing
phase and fibrotic phase.7 Previous studies highlight that
duration of disease is an important determinant for lung
fibrosis post ARDS. This study showed that, 4% of patients
with a disease duration of less than 1 week, 24% of patients
with a disease duration of between weeks 1 and 3, and 61% of
patients with a disease duration of greater than 3 weeks,
developed fibrosis.
Cytokine storm caused by an abnormal immune mecha-
nism may lead to initiation and promotion of pulmonary
fibrosis. Epithelial and endothelial injury occurs in the in-
flammatory phase of ARDS due to dysregulated release of
matrix metalloproteinases. VEGF and cytokines such as IL-6
and TNFa are also involved in the process of fibrosis. The
reason remains unknown as to why certain individuals
recover from such an insult, whereas others develop pro-
gressive pulmonary fibrosis due to accumulation of fibroblasts
and myofibroblasts and excessive deposition of collagen.8
Although ARDS seems to be the main predictor of pulmo-
nary fibrosis in COVID-19, several studies showed that covid
induced ARDS is different (High and low elastance type) from
the classical ARDS. CT findings in many covid cases are also
not suggestive of classical ARDS. Along with, abnormal coa-
gulopathy is another pathological feature of this disease. So,
mechanism of pulmonary fibrosis in COVID-19 is different
from that of IPF and other fibrotic lung diseases, especially
with pathological findings pointing to alveolar epithelial cells
being the site of injury, and not the endothelial cells.
2.2. Risk factor
One of the risk factors for the development of lung fibrosis in
COVID-19 is advanced age and this finding is same as in MERS
and SARS-CoV.9e11
Second risk factor is increased disease severity which in-
cludes comorbidities such as hypertension, diabetes, and
coronary artery disease12 and Lab findings like lymphopenia,
leukocytosis, and elevated lactate dehydrogenase (LDH).7
Serum LDH level has been used as a marker of disease
severity following acute lung injury. It is an indicator of pul-
monary tissue destruction and correlates with the risk of
mortality. According to the World Health Organization, 80% of
SARS-CoV-2 infections are mild, 14% develop severe symp-
toms, and 6% will become critically ill.
Third risk factor is prolonged ICU stay and duration of
mechanical ventilation. While disease severity is closely
related to the length of ICU stay, mechanical ventilation poses
an additional risk of ventilator-induced lung injury (VILI).
Abnormalities of pressure or volume settings underlie this
injury leading to a release of proinflammatory modulators,
worsening acute lung injury, and increased mortality or pul-
monary fibrosis in survivors.13
Smokers are 1.4 times more likely to have severe symp-
toms of COVID-19 and 2.4 times more likely to need ICU
admission and mechanical ventilation or die compared to
nonsmokers.14,15
The World Health Organization (WHO) and the National
Institute on Alcohol Abuse and Alcoholism (NIAAA) have is-
sued communications warning people to avoid excessive
drinking, saying it may increase COVID-19 susceptibility and
severity. Alcohol use disorder increases the risk for compli-
cations of COVID-19.16
2.3. Clinical course
What proportion of covid 19 patients developed lung fibrosis
remains speculative and should not be assumed without
appropriate prospective study. But we can extract data from
SARS and MERS pandemic. Zhanga et al17 followed 71 SARS
patients for 15 years and found 9.4% at beginning of study,
4.6% at one year and 3.2% patients after 15 years had pulmo-
nary lesions visible on CT scans. Similar findings were re-
ported for MERS also. The follow-up of 36 MERS patients for an
average of 43 days showed that lung fibrosis developed in a
significant number of convalescents, and risk was found
highest among patients who were elderly, hospitalised with
severe disease in ICU.18 We have paucity of data for course of
post covid pulmonary fibrosis. In one of the study19 chest CT
scan was performed on the last day before discharge, two
weeks and four weeks after discharge. Compared with the last
CT scan before discharge, the abnormalities (including focal/
multiple GGO, consolidation, interlobular septal thickening,
subpleural lines and irregular lines) in lungs were gradually
absorbed in the first and second follow-ups after discharge.
The lung lesions of 64.7% discharged patients were fully
absorbed after 4-week follow-up. It indicated that the damage
to lung tissue by COVID-19 could be reversible for the common
COVID-19 patients. It also suggested that the prognosis of
non-severe patients is favourable, and the clinical interven-
tion should be conducted in time to prevent common COVID-
19 patients from worsening to severe patients.
Another study2 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-19erelated
symptom, while 32% had 1 or 2 symptoms and 55% had 3 or
more. None of the patients had fever or any signs or symp-
toms of acute illness. Worsened quality of life was observed
among 44.1% of patients. They also found that most common
symptom persistent beyond discharge was fatigue (53.1%),
dyspnea (43.4%), joint pain, (27.3%) and chest pain (21.7%).
Another follow up study20 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. Blood Urea nitrogen concentration at admission was
associated with the presence of CT abnormalities.
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 disease21,22 Both decreased alveolar volume and KCO
contribute to the pathogenesis of impaired diffusion capac-
ity.23 At 3-months after discharge, residual abnormalities of
pulmonary function were observed in 25.45% of the cohort
which was lower than the abnormal pulmonary function in
COVID-19 patients when discharged.10 Lung function abnor-
malities were detected in 14 out of 55 patients and the mea-
surement of D-dimer levels at admission may be useful in
prediction of impaired diffusion defect.16
2.4. Treatment of post COVID 19 pulmonary fibrosis
Currently, no fully proven options are available for the treat-
ment of post inflammatory COVID 19 pulmonary fibrosis.
Various treatment strategies are under evaluation. It has been
proposed that prolonged use of anti-viral, anti-inflammatory
and anti-fibrotic drugs diminish the probability of develop-
ment of lung fibrosis. However, it is yet to be ascertained
whether early and prolonged use of antiviral agents may
prevent remodeling of lung or which of the available antiviral
is more effective. Though risk-benefit ratio should be assessed
prior to use, prolonged low dose corticosteroid may prevent
remodeling of lung in survivors.24 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.25 Pirfenidone exerts anti-fibrotic, anti-
oxidative and anti-inflammatory effects. Pirfenidone could
attenuate ARDS induced lung injury as it reduces LPS-induced
acute lung injury and subsequent fibrosis by suppressing
NLRP3 inflammasome activation.26 There are few concerns
regarding antifibrotic in acute phase. Many covid 19 patients
have hepatic dysfunction in the form of raised transaminases
and both antifibrotics pirfenidone and Nintedanib cause
hepatotoxicity. Nintedanib is associated with increased risk of
bleeding as most of the covid 19 patients are on anticoagulant.
Evidence is present regarding use of pirfenidone, azi-
thromycin and prednisolone in the management of pulmo-
nary fibrosis post-H1N1 ARDS, based on data from a case
report of three patients.27 Now the literature supports the use
of antifibrotic by the first week of ARDS onset to prevent
consequences such as lung fibrosis. Thus, there is urgent need
for the identification of biomarkers early in the disease course
to identify patients who are likely to progress to pulmonary
fibrosis. The rationale for using antifibrotic therapy should be
personalized and the role of precision medicine assumes
prediction of high-risk population, better understanding of
pathophysiology and prevention of disease worsening or/and
lung fibrosis development.
Rehabilitation in the acute stage and particularly in the
recovery stage is beneficial. It improves respiratory function,
exercise endurance, self-care in daily living activities and
psychological support.28 However, scientific research is
required for concluding its definite benefits.
3. Conclusion
Considering huge numbers of individuals affected by COVID-
19, even rare complications like post covid pulmonary
fibrosis will have major health effects at the population level.
Elderly patient who require ICU care and mechanical venti-
lation are the highest risk to develop lung fibrosis. Currently,
no fully proven options are available for the treatment of post
inflammatory COVID 19 pulmonary fibrosis.
Financial support and sponsorship
Nil.
Conflicts of interest
The authors have none to declare.