Monday, May 25, 2020

CMAAO CORONA FACTS and MYTH BUSTER 104 Immuno hyper inflammation

Dr K K Aggarwal

President Confederation of Medical Associations of Asia and Oceania, HCFI, Past National President IMA, Chief Editor Medtalks

926: IMA-CMAAO Webinar on “Update on Covid-19 -Immuno-hyper inflammation”

23rd May, 2020


Dr KK Aggarwal, President CMAAO
Dr Rajan Sharma, National President IMA
Dr RV Asokan, Honorary Secretary General IMA
Dr Ramesh K Dutta
Dr Jayakrishnan Alapet
Dr Sanchita Sharma


Dr Rohini Handa
Senior Consultant Rheumatologist, Apollo Hospitals, New Delhi
Former Prof, Dept of Rheumatology, AIIMS, New Delhi


·        The Covid-19 virus is behaving differently in different people. Up to now, we have seen 7 different manifestations of the coronavirus.

1.    It is a viral illness, so it is self-limiting disease; antiviral drugs are effective
2.    It has bacterial activity, procalcitonin is high in some persons; antibiotics like doxycycline, azithromycin may work.
3.    It has some HIV like properties, as there is lymphopenia (viruses usually cause lymphocytosis), decrease in CD4 cell count; anti-HIV drugs may be effective.
4.    It causes immuno-inflammation: rise in acute phase reactants (ESR, CRP, ferritin and platelet count). Hydroxychloroquine may work.
5.    It causes thrombo-inflammation: Increase in d-dimer and fibrinogen; anticoagulation may be important.
6.    Silent hypoxia (walking dead phenomenon): Hypoxia (oxygen 60-70%) without loss of consciousness.
7.    Cytokine storm and ARDS

·        The mortality in Europe is 10-12%, in US 6-7% and in India it is 3-4%. In Europe, we are seeing multisystem inflammatory disease in children with multiorgan involvement (Kawasaki like).
A progressive in d-dimer levels with fall in leukocytic count is a sign of high mortality.

Inflammation is the protective response of the body to noxious stimuli resulting in containment of that insult at the site of injury, which can be cuts, innocuous injuries, infection, toxins etc.
Inflammation, in itself is not bad; it is the unchecked chronic inflammation, which creates problems.

Many diseases now have been identified to have inflammatory components e.g. bronchial asthma, atherosclerosis, obesity, rheumatoid arthritis.

Immunoinflammation is a subset of inflammation where the trigger is a dysregulated immune response. Immune-mediated inflammatory diseases are RA, SLE, systemic sclerosis, Sjogren, ANCA-associated vasculitides. The major trigger in these diseases is the aberrant immune response.

The host inflammatory response phase, which comes into play in some patients, is the major contributor of mortality.

·        Strictly speaking, in Covid-19, it is a hyperimmune response and not immunoinflammation.
·        In a dysfunctional immune response, the virus elicits a hyperimmune response, which is out of proportion to the inciting event in some people. This triggers a systemic cytokine storm, which is responsible for multiorgan failure and mortality.

·        In a healthy immune response, the virus is inactivated by the neutralizing antibodies. There is minimum inflammation and lung damage. This is how most people with viral infection, including Covid-19, recover.

·        But in a subset of people, the dysfunctional immune response goes on unchecked, called “hyperinflammation”, excessive infiltration of macrophages, monocytes and T cells, which leads to an inflammatory cascade, which triggers the cytokine storm, where a number of cytokines come into play leading to pulmonary edema, pneumonia and resulting in widespread inflammation and multiorgan damage.

·        Thrombo-inflammation is another manifestation of Covid-19, where there is interplay of coagulation and inflammation. The procoagulant pathway is triggered which produces microthrombi formation, seen in autopsy samples of Covid-19 patients who have succumbed to the disease.

·        The multiplicity of pathways is the reason why a variety of drugs are being tried.

·        Covid toes, thromboembolism, right heart involvement, Kawasaki-like multisystem inflammation have been seen, but without lung involvement (no ARDS and cytokine storm). So, there must be a separate pathway for hyperinflmmation other than cytokine crisis.  This means that hyperinflammation is only one part of the story; we have a long way to go before we understand the pathobiology of the infection and the pathogenetic mechanisms and the host response.
·        The stage at which the sample is collected will give different findings. This is a challenge.
·        Immuno-mediated inflammatory diseases like Rheumatoid, Sjogren’s, lupus, are no different from that encountered in the West. E.g. many people with history of joint pains, low levels of rheumatoid factor, no deformity are labeled as Rheumaotid, but they are actually Sjogren’s – no questions about dry eyes, dry mouth, caries are asked in these patients. We need to connect the dots.

·        Giant cell arteritis is extremely uncommon in India, Takayasu’s is more common.
·        In children, juvenile idiopathic arthritis (JIA), earlier known as juvenile rheumatoid arthritis, is the commonest type of immuno-inflammatory disease in children. But, it gets labeled as rheumatic fever in India.

·        If there is deforming arthritis in a child, which is not getting better, and Echo is normal, rethink about rheumatic fever. Not all aches and pains in a child are rheumatic fever.

·        Could a virus be linked to autoimmune disorder? The trigger of autoimmunity is not known yet. But it has been believed for long that a virus could trigger an autoimmune disorder. The classical example is parvovirus, which was thought to cause arthritis and now there is Chikungunya. It is believed that Chikungunya may unmask latent autoimmune disorder.

·        Registry data has shown that rheumatoid arthritis patients, who are on a moderate immunosuppression, do not get Covid-19 more than their counterparts and behave similarly, unless they are taking high dose of steroids, or cyclophosphamide.

·        Joint manifestations are not a prominent feature of Covid-19 so far.

·        Pre-existing rheumatoid may flare up with viral infection. But, there is no specific data on Covid-19.

·        Monoclonal antibodies are derived from single cell line; these are biologics as they are derived from living cell systems. They target all three components of the inflammatory pathway: cytokines, receptor and the cell. MAbs target one process and not a large group of cytokines. We do not know yet which is the key cytokine.

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