Vaccine- induced interstitial lung 
disease: a rare reaction to 
COVID- 19 vaccination

Alison M DeDent, Erica Farrand

After  millions  of  deaths  worldwide  and 
months of widespread social and economic 
devastation,  the  first  vaccine  against 
SARS- CoV- 2 
(COVID- 19)  was  given 
emergency  use  listing  by  the  WHO.1 
Approved  only  1 year  after  the  virus  was 
first  identified  in  Wuhan,  China,  this 
historic  achievement  was  the  result  of 
public  and  private  institutional  partner-
ships,  as  well  as  decades  of  foundational 
scientific  research.  Two  of  the  earliest 
vaccines  authorised  for  widespread  use 
were  the  BNT162b2  (Pfizer/BioNTech) 
and  mRNA- 1273  (Moderna)  messenger 
RNA  (mRNA)  vaccines,  demonstrating 
95%  and  94.1%  efficacy,  respectively,  in 
phase  II/III  clinical  trials.  Notably,  both 
vaccines  have  strong  safety  profiles,  with 
the most common adverse events including 
injection  site  reactions, 
fever,  chills, 
fatigue,  headache,  and  muscle  and  joint 
aches.2  3  Postauthorisation  reports  of 
severe  reactions,  including  anaphylaxis, 
have  been  extremely  rare,  occurring  in 
only 4.5 reported cases per million doses.4
In  this  issue  of  Thorax,  Park  and 
colleagues5 present the first published case 
of  COVID- 19  vaccine- related  interstitial 
lung  disease  (ILD).  An  86- year- old  man 
developed  an  acute  onset  of  fever,  weak-
ness, shortness of breath and hypoxaemia 
requiring  high- flow  nasal  cannula  1 day 
after  receiving  a  dose  of  a  COVID- 19 
mRNA  vaccine.  He  had  no  history  of 
ILD,  connective  tissue  disease,  tobacco 
use or exposure to offending medications. 
CT  of  the  chest  showed  bilateral,  diffuse 
ground glass opacities, with areas of focal 
consolidation  and  centrilobular  nodules. 
Evaluations  for  alternative  aetiologies, 
including  nasal  and  sputum  testing  for 
COVID- 19  and  other  infectious  diseases, 
an  ECG,  a  brain  natriuretic  peptide  test, 
and  serological  testing  for  connective 
tissue  diseases,  were  normal  or  negative. 
The  patient  declined  to  undergo  bron-
choscopy  or  surgical  lung  biopsy.  Based 

Department of Medicine, Division of Pulmonary and 
Critical Care Medicine, University of California San 
Francisco, San Francisco, California, USA

Correspondence to Dr Alison M DeDent, 513 
Parnassus Ave, HSE 1314, Box 0111, University of 
California San Francisco, San Francisco, California CA 
94143, USA;  alison. dedent@ ucsf. edu

on the time course and available informa-
tion, he was diagnosed with drug- induced 
ILD  and  treated  with  high- dose  methyl-
prednisolone,  with  rapid  improvement 
in  his  clinical  condition  and  imaging.  He 
was  discharged  on  a  steroid  taper,  and 
follow- up  imaging  nearly  3 months  after 
discharge  confirmed  resolving  ground 
glass opacities and consolidations without 
the development of fibrosis.

tumor  necrosis 

Drug- induced ILD is a rare disease, for 
which  the  true  incidence  and  prevalence 
are  unknown.  The  severity  of  illness  can 
range  from  subclinical  disease  to  severe 
acute respiratory distress syndrome, and it 
is a diagnosis of exclusion, with a differen-
tial  that  includes  infection,  haemorrhage, 
oedema  and  exacerbation  of  an  under-
lying  ILD.  In  the  absence  of  an  alterna-
tive  diagnosis,  drug- induced  ILD  should 
be  suspected  if  a  temporal  association 
between symptom onset and an offending 
agent can be identified. The most common 
medications associated with drug toxicity 
of  the  lungs  include  chemotherapeutic 
rheumatological  medications 
agents, 
(disease modifying antirheumatic drugs(D-
MARDs)  and 
factor 
(TNF)- alpha  inhibitors),  amiodarone  and 
nitrofurantoin,6  although  a  complete  list 
of medications that may cause pulmonary 
toxicity can be found on the website Pneu-
motox ( www. pneumotox. com). Symptoms 
may  include  cough,  shortness  of  breath, 
fever and hypoxaemia, and both imaging 
and  histology  findings  are  non- specific, 
often overlapping with other types of ILD. 
While more invasive testing, such as bron-
choscopy and surgical lung biopsy, is often 
non- diagnostic, it may aid with the exclu-
sion  of  alternative  diagnoses  and  should 
be  considered  on  an  individual  basis.7 
Risk  factors  vary  and  are  poorly  under-
stood;  however,  older  age,  underlying 
pulmonary  disease  and  tobacco  use  have 
been most commonly reported. Treatment 
depends on the degree of disease severity, 
and high- quality evidence is lacking. Mild 
cases may resolve with medication discon-
tinuation  alone,  while  corticosteroids  are 
often added to treat more severe cases.6

The  pathogenesis  of  drug- induced  ILD 
is incompletely understood, although both 
cytotoxic and immune- mediated pathways 

Editorial

of  injury  have  been  described.  Cytotoxic 
injury may occur directly to pneumocytes 
or  the  alveolar  capillary  endothelium, 
and  immune- mediated  reactions  occur 
through  T  cell  regulation.7  Whether  one 
or  both  of  these  pathways  are  involved 
in  COVID- 19  vaccine- induced  ILD  is 
unknown;  however,  reports  of  vaccine- 
induced  ILD  after  influenza  vaccination 
may  suggest  a  shared  mechanism  of  lung 
injury  that  is  not  specific  to  the  molec-
ular  composition  of  the  vaccine.  While 
more  studies  are  needed,  the  presence  of 
lymphocyte  sensitisation,  demonstrated 
using  in  vitro  drug  lymphocyte  stimu-
lation  testing  after  exposure  to  various 
types  of  vaccines,  could  possibly  support 
a  common  immune- mediated  mechanism 
of lung injury.7

There  are  important  limitations  for 
clinical practice that accompany published 
case  reports.  First,  while  reporting  and 
recognising potential adverse events in the 
postauthorisation  period  are  essential,  a 
causal  relationship  cannot  be  established 
from  a  single  case  report.  Further,  these 
findings  cannot  be  generalised  to  any 
specific  risk  group  or  population.  While 
the authors note that other potential cases 
of ILD due to COVID- 19 vaccination were 
identified in VigiBase, a drug safety data-
base managed by the WHO,8 the accuracy 
of these reports must be interpreted with 
caution due to differences in international 
coding criteria, errors, lack of transparent 
diagnostic criteria, and lack of distinction 
between  a  new,  acute  ILD  and  the  exac-
erbation of an existing ILD. Nevertheless, 
continuous  monitoring  of  both  patients 
and international drug safety databases for 
pulmonary toxicity from these vaccines is 
warranted.

In 

clinicians 

conclusion, 

should 
consider  drug  toxicity  in  their  differen-
tial  of  any  unexplained  acute  respiratory 
failure  or  ILD  and  should  be  aware  of 
this  reaction  as  COVID- 19  vaccination 
efforts continue. However, the benefits of 
widespread COVID- 19 vaccination in the 
general  population  continue  to  strongly 
outweigh  the  risks.  COVID- 19  vaccina-
tion is the most effective and safe method 
for preventing COVID- 19- related serious 
events.

Twitter Erica Farrand @ericafarrandMD

Contributors  AMD drafted the initial version of the 
manuscript, and AMD and EF participated in drafting all 
revisions. Both authors approved the final manuscript 
submitted for publication.

Funding  The authors have not declared a specific 
grant for this research from any funding agency in the 
public, commercial or not- for- profit sectors.

Competing interests  None declared.

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DeDent AM, Farrand E. Thorax January 2022 Vol 77 No 1

Editorial

Patient consent for publication  Not required.

Provenance and peer review  Commissioned; 
externally peer reviewed.

This article is made freely available for use in 
accordance with BMJ’s website terms and conditions 
for the duration of the covid- 19 pandemic or until 
otherwise determined by BMJ. You may use, download 
and print the article for any lawful, non- commercial 
purpose (including text and data mining) provided that 
all copyright notices and trade marks are retained.

© Author(s) (or their employer(s)) 2022. No commercial 
re- use. See rights and permissions. Published by BMJ.

To cite DeDent AM, Farrand E. Thorax 2022;77:9–10.

Accepted 24 August 2021
Published Online First 11 September 2021

 ► http://  dx.  doi.  org/  10.  1136/ thoraxjnl- 2021- 217609

Thorax 2022;77:9–10.
doi:10.1136/thoraxjnl-2021-217985

REFEREnCEs
 1  "WHO issues its first emergency use validation for a 

COVID- 19 vaccine and emphasizes need for equitable 
global access." WHO, 2020. Available: https://www. 
who. int/ news/ item/ 31- 12- 2020- who- issues- its- first- 
emergency- use- validation- for- a- covid- 19- vaccine- and- 
emphasizes- need- for- equitable- global- access [Accessed 
6 Aug 2021].

 2  Polack FP, Thomas SJ, Kitchin N, et al. Safety and 

efficacy of the BNT162b2 mRNA Covid- 19 vaccine. 
N Engl J Med 2020;383:2603–15. doi:10.1056/
NEJMoa2034577

 3  Baden LR, El Sahly HM, Essink B, et al. Efficacy and 

safety of the mRNA- 1273 SARS- CoV- 2 vaccine. N Engl J 
Med 2021;384:403–16.

 4  Gee J, Marquez P, Su J, et al. First Month of COVID- 19 
Vaccine Safety Monitoring - United States, December 
14, 2020- January 13, 2021. MMWR Morb Mortal Wkly 
Rep. 2021;70:283–8.

 5  Park JY, Kim J- H, Lee IJ. COVID- 19 vaccine- related 
interstitial lung disease: a case study. Thorax 
2022;77:103–5.

 6  Skeoch S, Weatherley N, Swift AJ, et al. Drug- Induced 

interstitial lung disease: a systematic review. J Clin Med 
2018;7. doi:10.3390/jcm7100356. [Epub ahead of 
print: 15 Oct 2018].

 7  Matsuno O. Drug- induced interstitial lung disease: 

mechanisms and best diagnostic approaches. Respir Res 
2012;13:39.

 8  Uppsala Monitoring Centre. "Vigibase.". Available: 

https://www. who- umc. org/ vigibase/ vigibase/ [Accessed 
7 Aug 2021].

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DeDent AM, Farrand E. Thorax January 2022 Vol 77 No 1