Article No. 370
13 August 2020
Early this year, soon after it had completed its Rare Disease Day activities and COVID 19 news was beginning to take over the mainstream media, Global Action published it first news blogs about aHUS and COVID 19 ( Articles 331 and 332) .
Our ears had pricked up on reports that the serious cases of COVID 19 were being caused more by an “overactive immune response” than the virus itself. That was something those with aHUS could identify with.
Nothing specific said about Complement at that time. Although a doctor in New York thought it was involved . Global Action did use “ Infection TMA” to describe what COVID 19 might be.
Website COVID 19 articles then turned to how the virus might impact on existing aHUS patients because of their immunosuppressed state.
As months went on, more information appeared about the characteristics of those who were faring worse from the infection and the processes that led to their serious condition. But nothing much still which suggested that Complement was much to do with it. In recent months thinking has begun to change.
The bigger, even more central, role that Complement may be playing in making the COVID 19 a serous life-threading condition is now seen as a key factor in the course of the disease.
This is best exemplified by a paper by Java et al which was published in June. Its title –
“The Complement system in COVID 19 – Friend and Foe?” The full article can be read HERE.
Dr Anuja Java
Anuja’s group rely on the scarce evidence provided by autopsies of non survivors The remains of high level Complement activity have been found in those whose COVID-19 clinical course became serious. With a mixture of evidence found in previous coronavirus epidemics plus recently discovered knowledge about the extent to which Complement is intertwined with other parts of innate immune and coagulation systems, the investigators view COVID 19 as an infection TMA but with an overlap with Complement. Even going as far as saying it is like a Complement TMA.
Those who may recall the Vienna Group model of TMA classifications ( it featured and was the basis of a series of website article “ aHUS is its end nigh?”) will see infection TMA ( including E.coli and Streptococcus Pneumoniae) as something different from Complement TMA .The first being an acquired secondary TMA and the latter a genetic disorder that is aHUS, a primary TMA.
Complement is in at the beginning when dealing with the virus. Its job is to recognise it and play an early part in the immune response, I.e. messaging other parts of the innate immune system for action against that specific virus.
Sometimes viruses can evade that initial detection by using a number of strategies. There is no evidence yet that COVID 19 deploys such devious strategies.
Studies have shown that complement is activated at all levels and pathways.
It is important that along with Complement’s destruction of invaders powers, the natural antibody response takes place, but as COVID 19 is a new virus there is unlikely to be something specific for COVID 19 available yet.
The person with COVID19 is now infected, but the normal immune response is engaged with the viral load ,which may reduce or grow from here.There are likely to be symptoms after a few days which just reveal that the body is fighting something. The success of that fight to clear the viral load is pivotal to what happens next.
Evidence from tests on COVID 19 patients suggest that Complement can be seen everywhere and that it suggest a high level of unregulated Complement, even genetic variants in Complement control factors CD 55 and CFH have been found. Unlike aHUS however the apparent COVID 19 mediated Complement activation, resulting from Lectin Pathway as well as the Alternative Pathway, impacts on a wider number of organs especially the lungs. Also, no hemolysis ( red blood cell destruction) that is a feature of aHUS has been observed.
It is here where the story gets serious. What could have been a common cold running its course takes a different turn. The battle moves to the cellular lining of the kidneys, lungs and other organs. There is a thrombotic microangiopathy moment with complement mediated injury of the endolethium.
Preexisting conditions like diabetes, hypertension , obesity and other cardiovascular conditions which exasperate endolethial dysfunction, make such patients at higher risk of a more serious COVID infection outcome.
The damage to endolethial cells leads to clotting at micro and macro levels. Coagulation activity elevates too , with Complement the potential driving force as it would with aHUS and TTP.
Simultaneously in COVID 19 there is excessive inflammation in the lungs and the notorious “cytokine storm”. Activated Complement throws off fragments C3a and C5a which nudge the components of inflammatory response into activity.
And finally Complement could be up to no good not just outside cells but inside them too.Recently evidence has been found that Complement has an immunity role inside cells. Called the “complosome” by the Java Group. Many cells have the ability to take in Complement from the outside.
Another discovery that Complement protects human airway surface cells from inside is pertinent to COVID 19 disease.This is particularly important when barriers are breached. That can lead to a plasma leak and its serious consequences.
The group also describe the potential of Complement inhibitors in the treatment of serious cases of COVID 19 disease. Therapies include eculizumab, Ravulizumab, IFX-1, Avdoralimab and narsoplimab. The timing of such inhibition is vital. Not doing so when Complement is helping to reduce the viral load but as early as possible once it starts to over respond.
So in COVID 19 the Java group are saying that Complement
– is active at all levels, which is normal and good
– becomes excessively activated, that is not so good
-exacerbates endolethial damage of blood vessels, makes things serious
– then stimulates high levels of clotting , very serious
-promotes an excessive inflammatory response, even more serious
– works on the inside and outside of cells and which is important in the cell lining of the lungs;
-may need inhibiting when it becomes the problem, though timing is important.
By the end of all this Java and her colleagues suspicions about COVID 19 will no doubt be proven one way or the other. Maybe if it is such a big player Complement will get even more awareness. More complement awareness could be beneficial to those with aHUS.
Without detracting from its serious and complex content , this reads like a detective novel. A criminal investigation involving laboratory forensic evidence and hypothesis about the suspects. An Agatha Christie scenario with diverse characters on the COVID Immunity Express. With a character called Mr Complement hiding in full sight as a benign sort of fellow eventually becoming a prime suspect, though with all the travelers as accomplices.
The investigation continues as this update article from the University of Washington Missouri reveals click here