Covid-19: Why do some patients fare so badly?

If we can get some insight into this, we can try out various strategies to address the factors that make this group of patients so much more ill. Jeyakumar Devaraj shares some thoughts on the clinical management of coronavirus patients.

The latest coronavirus Covid-19 is a new pathogen and the medical profession hasn’t fully worked out why exactly it affects some people worse than others.

From data emerging from China, it appears that about a third of persons infected with the virus do not even show any symptoms (Josephine Ma et al, South China Morning Post, 22 March 2020). It has not yet been ascertained whether such asymptomatic individuals can transmit the virus to others.

Clinical spectrum

Of those who develop symptoms, it appears that:

• 80% recover without any specific medical treatment. These patients have various intensities of fever, cough, sore throat and body aches, but they generally recover within two weeks of the onset of symptoms. Some of them might have post-infective tiredness that may last for weeks
• 15% develop shortness of breath. Tests might show that the level of oxygen in their blood is diminished. But most of them will feel better with oxygen delivered by nasal prong, where the percentage or concentration of oxygen inhaled (FiO2) is 28% compared to room air of 21%. Or oxygen could be delivered by ventimasks with the concentration of oxygen inhaled at 30-100%, depending on the type of mask and the oxygen flow-rate and whether an oxygen reservoir is deployed with the mask. [The fraction of inspired oxygen or FiO2 is the volumetric fraction of oxygen in the inhaled gas. Oxygen-enriched air, has a higher-than-atmospheric FiO₂. Natural air includes 21% oxygen, which is equivalent to an FiO₂ of 0.21.] The more serious among them would benefit from intensive care unit (ICU) management. The time this set of patients take to recover is usually longer – about four to eight weeks
• the most seriously affected 5% will go into respiratory failure even with the highest concentration of oxygen that can be delivered by masks. This group will need intubation and ventilation for a few weeks. Sometimes even ventilation does not correct the oxygen deficiency in the blood and the only way to keep them alive is by using the heart-lung machine normally used for open-heart surgery (termed extra-corporeal membrane oxygenation). The patient’s blood is drawn from a major vein and passed through the heart-lung machine to pick up oxygen and then is pumped back to a major artery in the patient’s body. This obviously is quite a desperate measure

Why do some patients fare so badly?

This is the crucial question. If we can get some insight into this, we can try out various strategies to address the factors that make this group of patients so much more ill.

We know that older people do worse and so do people with underlying illnesses such as heart failure and diabetes. That is understandable. But we also have young people succumbing to the virus as well eg Dr Li Wen-liang, the 33-year-old ophthalmologist who sounded a warning regarding this virus on 30 December 2019.

I am not sure if any of the data collected in China, Italy or elsewhere hold answers to this question. Perhaps the answer lies in how the patient’s immune system responds to the virus.

Viruses cause disease by taking over our cells and “hijacking” our cell’s mechanisms to produce more copies of themselves. This new virus copies and then spreads in tissue fluids and through the bloodstream to infect even more cells.

Our body fights the infection by producing antibodies that circulate in the bloodstream and in tissue fluids to inactivate any virus found there. This is essential to prevent the virus from spreading and attacking more cells.

The body also produces killer cells that attack and destroy our own cells (in the case of the coronavirus, the cells in our lungs) that have been taken over (hijacked) by the virus, because these cells have become factories producing thousands of virus particles. [CD8+ T cells, also known as killer cells, are cytotoxic. This means they are able to directly kill virus-infected cells and cancer cells. CD8+ T cells can also use small signaling proteins, known as cytokines, to recruit other cells when mounting an immune response against cells identified as foreign.]

If the immune system was a bit slow in starting off its counter-attack, the coronavirus would have infected many more lungs cells, requiring the destruction of all these cells to eradicate the virus.

The other possibility is that the killer cells produced by the patient are too “trigger happy”, and they attack some of the lung cells which are not harbouring the virus, causing the extensive damage that leads to respiratory failure.

We see this phenomenon of extra damage because of activation of the immune system in several bacterial and viral infections.

It is well recognised that leprosy patients often develop new nerve lesions in the first month of treatment. [Erythema nodosum leprosum (ENL) is an immune-mediated complication of leprosy, characterised by the presence of multiple inflammatory cutaneous nodules and systemic symptoms such as fever, malaise, arthritis, iritis, neuritis and lymphadenitis.] They require medicines to modulate the immune response. Interestingly, thalidomide is one of the drugs used to treat this reaction.

Chronic Hepatitis B patients often develop a flare-up of their hepatitis and a deterioration of liver function when specific anti-viral therapy is commenced.

The life-threatening complications of leptospirosis are believed to be due to overactivity of the immune system. And there are many more examples.

Some clinicians and researchers speculate that Covid-19 infection can be divided into two main stages – virological and immunological:

• The first week of the infection is characterised by multiplication of the virus and its spread to more and more lung cells
• The development in the second week is defined by how the patient’s immune system attacks the cells containing the virus

Clinical significance of such speculation

Such speculation has a bearing on treatment strategies. If the rapid spread of the virus in the first few days of the illness (resulting in more cells to be infected) is a major cause of a more serious illness, then measures to damp down this virological phase should be instituted early in the disease.

These might include the following:

• Interferon which is a substance that our body produces to stimulate our own immune system to fight viruses. This could be administered to patients upon diagnosis. Interferon is already being used for the treatment of Hepatitis B. Cuba has reportedly produced lots of Interferon and is making it available for coronavirus treatment
• Anti-HIV drugs reduced the mortality of Sars patients by about 85% in retrospective analysis of some clinical data. [“Upfront treatment with liponavir/ritronavir combined with ribavirin reduced mortality to 2.3% compared to 16% in the untreated group”, a paper by Chan et al quoted in King’s Critical Care Evidence Summary for Clinical Management of Covid 19.] Liponavir/ritronavir blocks the replication of certain viruses. But are they effective against the latest coronavirus Covid-19? Various combinations of anti-HIV drugs have been tried out in this Covid-19 epidemic – in China, in Thailand, South Korea and Japan. We need to look at all the data to see if any of the combinations used had a beneficial impact
• Reports mentioned that plasma from recovered patients was used to treat new cases of Covid-19. [China National Biotec Group collected and prepared plasma from recovered patients and used this to treat several critically ill patients. The Star 15 February 2020.] That would work as the plasma of recovered patients would have high levels of antibodies against Covid-19. We could collect blood from recovered cases, separate the red blood cells and transfuse those back to the donor and keep the plasma to treat new Covid -19 cases (after screening for HIV, Hepatitis B and C, and other pathogens). They attempted this in Wuhan, but did they find it useful? If it wasn’t that beneficial, was it because they were using this modality at the wrong phase of the illness – on the critically ill patients (ie during the immunological phase) when ideally this modality would have the most impact early in the virological phase of the illness?

If immunological “exuberance” by the patient’s immune system is a major factor causing a poor outcome, we need to look for ways of toning down the immune system without stopping it from destroying the cells that are really infected.

Chloroquine has been mentioned (even by Donald Trump) as an anti- Covid-19 drug. Apart from being an anti-malarial medicine, cloroquine is also used in the treatment of auto-immune conditions such as rheumatoid arthritis. It is believed to reduce the hyperactivity of the immune system.

What about the other drugs used in auto-immune diseases? There are a whole set of them including steroids, azathioprine, sulfasalazine and many others. Other clinicians in East Asia surely would have looked at these. What did they find?

Would a treatment strategy focusing on reducing the viral spread in week one and toning down the immunological response in week two reduce the percentage of patients requiring ventilation? If it did, that would be most welcome as then we would have fewer desperately ill patients requiring ventilation.

Prognostic markers

We know that 20% of patients do not do well and about 5% of them do badly. So we should focus an active treatment strategy on this high-risk group. But how do we identify at the outset itself who are at greater risk apart from age and the presence of comorbidities?

Is viral load per cubic millimetre of blood a prognostic factor? Did any country test viral loads of their Covid-19 patients? Was there any correlation to the severity of the disease? We have to compare viral loads at the same point of the illness, for I think when the immunological phase kicks in, viral loads will be quite low. We need data on viral loads on day two of the clinical illness and see whether this correlates to respiratory impairment, ventilation and death.

How about C-reactive protein? King’s Critical Care Evidence Summary for Clinical Management of Covid-19 mentions that high C-reactive protein levels correlate with a worse prognosis. Would a lung CT scan finding on day three of the clinical illness give us a clue how severe the infection will turn out to be?

Do our human leukocyte antigen (HLA) genes have anything to do with disease severity? [The (HLA) system or complex is a gene complex encoding the major histocompatibility complex (MHC) proteins in humans. These cell-surface proteins are responsible for regulating the immune system in humans. The HLA gene complex resides on a 3 Mbp stretch within chromosome 6p21.] The HLA genes determine the antigens that are expressed on the surfaces of our cells.

Is it possible that some HLA antigens mimic the antigens expressed on the surfaces of Covid-19 infected cells? This is wildly speculative but should be considered. Rheumatic heart disease, which was prevalent in the pre-antibiotic era, is caused when antibodies produced to fight certain species of streptococcus cause collateral damage to heart valves because of some similarity in antigens. Has any treatment centre looked into this possibility? Worth ruling out, I would think.

It would be a game-changer if doctors could, on day two or day three of diagnosis, identify the subset of patients who have a greater chance of ending up really ill.

So developing a set of clinical and lab criteria to risk stratify our patients would enable us to target specific therapy on those at highest risk. Treatment modalities like plasma transfusion will face supply issues. So it would have to be used judiciously.

Let’s not reinvent the wheel

Many clinicians are grappling with this new pathogen. Most of them are so caught up in keeping their patients alive that they hardly have any time to review the experience of other centres in their own country and other countries.

Shouldn’t we set up a team of doctors to collect and look at all the data of treatment strategies tried by various countries in treating Covid-19 patients?

This research team should also define questions that will help improve prognosticating indicators and treatment strategies. If some of these questions have not yet been answered rigorously, then perhaps some necessary data should be generated from patients coming to our hospitals.

Countries around the world should collaborate to develop an effective protocol for treating Covid-19 patients. Data should be gathered from the different centres, and perhaps trials focusing on some of the unanswered questions should be carried out in treatment centres in the various countries handling Covid-19 cases.

Covid-19 isn’t going to go away for a while. Even if our movement control order brings new cases down to single digits, we will still continue to get clusters of cases from domestic and imported cases from time to time.

This will continue until an effective vaccine is found and made available. Even when that happens, there is a danger that Covid-19 will do what the influenza virus is doing – mutate to strains that the vaccine is ineffective against.

So Covid-19 will be with us for some time. We would be much better off if we could learn more about the disease process and fine-tune our management.

In the meantime, stay indoors and keep safe!

The views expressed in Aliran's media statements and the NGO statements we have endorsed reflect Aliran's official stand. Views and opinions expressed in other pieces published here do not necessarily reflect Aliran's official position.

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