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Covid-19: a puzzle with many missing pieces

BMJ 2020; 368 doi: (Published 19 February 2020) Cite this as: BMJ 2020;368:m627

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Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2)

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Pneumonitis in COVID-19: parallels with checkpoint Inhibitor related Immune Pneumonitis

Dear Editor

Pneumonitis in COVID-19: parallels with checkpoint Inhibitor related Immune Pneumonitis

Your report rightly highlights the major problem that there are many missing pieces in COVID-19 science.

We write to a highlight a new insight on the type of pneumonia caused by SARS CoV 2 from the many reports on COVID-19.

Pneumonitis of COVID-19 appears to be similar to immune pneumonitis associated with immune checkpoint-inhibitor therapy for cancers.

‘Immune checkpoint’ is a term used for processing of regulatory T lymphocytes in lymph nodes and in peripheral tissues, prior to proliferation or suppression of effector T cells as orchestrated by these regulatory T Lymphocytes.

Two checkpoints exist in the pathway to modulate the immune system. Firstly, a central checkpoint tolerance regulator: Regulation of T cells based on CTLA-4 (Cytotoxic Lymphocyte Antigen) in Lymph Nodes and secondly a peripheral checkpoint tolerance regulator: Regulation of T cells based on PD-1 (Programmed Death-1) in all tissues. Thereafter immune-mediated countering of the pathogenic antigen occurs ( 1,2 ).

Fox et al, have reported findings in COVID-19 post-mortem pathology analysis found CD 8+ and CD 4+ T lymphocytes in the alveoli in patients who died of COVID-19 indicating immune attack in COVID-19 [3].

It has been reported that a rare but major life-threatening complication for checkpoint inhibitor therapy with monoclonal antibodies for cancers is immune pneumonitis [1,2]. Acute colitis, as an immune injury, has also been widely reported as an adverse event [1,2].

Cancer immunotherapy utilises adaptive immunity to attack cancer cells. Naive T lymphocytes are in the Thymus and enter the circulation. The T cell receptors bind to antigens displayed in Major Histocompatibility Complex (MHC) of macrophages.

Cytotoxic T-lymphocyte–associated antigen 4 (CTLA4) and programmed death 1 (PD-1) are receptors in regulatory T lymphocytes which are critical in this process of immune checkpoint assessments. When these receptors are activated, by a binding process, they down regulate T-cell immune function.

Inhibition of these receptors has the effect of activating T-cell receptors (TCR) to antigens displayed in the major histocompatibility complex (MHC) on the surface of an antigen-presenting cells such as macrophages.

Dysregulation of checkpoints would result in proliferation of of specific Cytotoxic Lymphocytes as regulated by regulatory T lymphocytes.

The therapy recommended for Immune Pneumonitis is steroids and Anti Tumour Necrosis Factor ( TNF ). Unlike in cancer therapy, with the potential surge in viral load with steroids and the risk of secondary bacterial infection, steroids are best avoided in viral infections,

Programmed Cell Death-1 (PD-1) molecules have the ability to influence the down regulation of cytotoxic T cells.PD-1 binding inhibits T-lymphocyte proliferation, and resultant interferon-gamma (IFN-g), TNF , and Interleukin ( IL-2 ) production, and reduces T lymphocyte survival.

PD-1 expression is up-regulated in T lymphocytes that have chronically been exposed to the same antigen as in chronic infections (such as Mycobacterium Tuberculosis ).

This has significance for the prevention of cytokine storm, as persistent stimulation in the checkpoint pathway will lead to reduced cytokine responses and could explain the potential benefit of prior BCG vaccination on severity of COVID by a process of being in ‘trained immunity ’ state.

BCG would modulate secretion of TNF that is orchestrated at the peripheral checkpoint by regulatory T lymphocytes through T Lymphocyte-macrophage binding processes. However, such ‘trained immunity 'may also prevent a surge in TNF stimulation with a second viral trigger that has a similar antigen as the system is already active.

The CTLA-4 and PD-1 pathways are considered to be important in different phases of an immune response. CTLA-4 is considered as the key immune molecule that inhibits T cell proliferation when lymph nodes receive thymus primed T lymphocytes [1,2].

Proliferation of T lymphocytes will result in elimination of pathogens by triggering production of cytokines, in particular Interleukin 2 (IL 2).

SARS-CoV-2 virus would appear to trigger an immune over-reaction similar to that produced by checkpoint inhibitors. This is supported by the post pathology reports on several patients who died of COVID-19 (3 )


The preliminary inferences, that can be derived from the similarities between immune pneumonitis in checkpoint inhibitor therapy and COVID-19, are that prior BCG vaccination may be preventative against severe COVID-19 and Anti-TNF biological therapy could be a good therapeutic option for SARS CoV 2 triggered immune-pneumonitis,

Dr Ahran Arnold MBChB MRCP
Clinical Research Fellow Clinical Research Fellow in Cardiology, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0HS, United Kingdom

Dr Nina Stafford MBBS MRCP *
Specialty Registrar in Gastroenterology

Professor Andrew Scurr MBBS FRCA *
Consultant in Intensive Care

Professor Jayantha Arnold MBBS FRCP *
Consultant Physician and Gastroenterologist

*Ealing Hospital, London North West University Healthcare NHS Trust, Uxbridge Road, Southall, UB1 3HW, United Kingdom


1. Buchbinder EI, Desai A. CTLA-4 and PD-1 Pathways Similarities, Differences, and Implications of Their Inhibition. Am J Clin Oncol 2016;39:98–106. doi: 10.1097/COC.0000000000000239.

2. Chuzi S, Tavora F, Cruz M, Costa R, Chae YK, Carneiro BA, Giles FJ. Clinical features, diagnostic challenges, and management strategies in checkpoint inhibitor-related pneumonitis. Cancer Manag Res. 2017;9:207-213. doi: 10.2147/CMAR.S136818

3. Fox R, Akmatbekov A, Harbert J, Li G, Brown Q, Vander Heide RS. Pulmonary and cardiac Pathology in COVID -19; the first autopsy series from New Orleans. medRxiv. doi: 10.1101/2020.04.06.20050575

Competing interests: No competing interests

17 April 2020
Jayantha Arnold
Consultant Physician and Gastroenterologist
Dr Ahran Arnold MBChB MRCP (Clinical Research Fellow in Cardiology, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0HS, United Kingdom), Dr Nina Stafford MBBS MRCP (Specialty Registrar in Gastroenterology), Professor Andrew Scurr MBBS FRCA (Consultant in Intensive Care)
Ealing Hospital, London Northwest University Healthcare NHS Trust, Uxbridge Road, Southall, UB1 3HW.