Amidst the great excitement around the phase-three trials of a number of vaccines throughout the world as well as in India, we must not forget what this new tiny spiky virus has taught us about ourselves over the last one year. Covid-19 has already claimed more than 1.5 million lives worldwide out of more than 67 million registered cases. The global case fatality rate is hovering around 2.3 per cent.
India has registered close to 140,000 deaths out of close to 10 million cases. Yes, the case fatality rate in India is indubitably much lower -- around 1.5 per cent as compared to the global data. A number of causal conjectures have been laid out and are being explored by scientists, mostly based on the age-old “hygiene hypothesis”, which says a life history replete with exposure to a variety of infectious agents makes the immune system more efficient in dealing with new infections -- the so-called “trained immunity”.
The sub-tropical biodiversity as well as a social life closer to nature compared to the West are also being explored as plausible explanations. This is definitely good news for us Indians. But there is also some bad news lurking as we delve deeper into the details of those who are dying of the coronavirus and of those who are at a higher risk of contracting it.
Why do people die from Covid-19 and to what extent is the virus itself responsible for these untoward outcomes? The symptoms that patients who were able to realise they had come down with Covid presented at clinics around the world have led to the description of this disease in two distinct phases. Most of the symptomatic patients suffer from mild flu-like symptoms with fever, malaise or at times brief episodes of diarrhoea, followed by uneventful recoveries. Physicians have named this “mild Covid.”
Some patients progress to the second phase of the disease, a more severe one, in which their lungs fail to deliver sufficient oxygen to the circulation, leading to falling oxygen saturation levels in the blood. As a result, most of these patients feel distressing shortness of breath and require immediate oxygen therapy. An even more dangerous situation arises in some patients as they never feel any drop in their oxygen saturation levels. Doctors have termed this condition “happy hypoxia”. Unless oxygen saturation in the blood is measured, for example, using a finger-clip device called a pulse oximeter, this cannot be detected until very late. This acute respiratory distress syndrome is what precedes most of the fatal outcomes in Covid-19 and this later phase of the disease is referred to as severe Covid.
Research done in different parts of the world has also made it clear that severe Covid is less due to the viral load the patient is carrying. It stems more from aberrant hyperactivity of the immune system, which was no doubt triggered by the infection but creates problems more due to dysfunctional braking mechanisms. Continued activation of the immune system leads to a sustained flood of proteins called cytokines in the circulation that drives organ damage. This phenomenon is frequently referred to as the “cytokine storm”. But returning to the question of how much the virus is responsible for sustaining this “cytokine storm,” it’s assumed to be to a far lesser extent than factors associated with the host body. In other words, the infected individuals who develop this severe form of Covid more often seem to have pre-existing conditions that predispose them to it. What are the discernible characteristics of such predispositions?
It is reported from large studies that people with pre-existing medical conditions (or co-morbidities), like chronic lung diseases, obesity, hypertension, ischemic heart disease, chronic kidney diseases, chronic liver diseases and type 2 diabetes, are over-represented among patients who develop severe Covid.
Those factors linked most consistently to worse outcomes have been obesity, type 2 diabetes and hypertension. These observations started coming in from China right at the start of the epidemic. One report from Tongji Hospital in Wuhan recorded almost one-in-four of severe Covid patients were diabetic. And it held true for all countries as the epidemic touched them. In Italy, diabetes had been the second most common co-morbidity associated with death -- one-in-three -- after hypertension. France’s CORONADO study which only studied diabetic patients with Covid found that more than one in five of them required ventilator support and more than one in ten died.
If we now go back to the issue of the lower case fatality rate recorded in most south Asian countries, it’s been argued that a large part of this can be explained by demographic characteristics. These countries have a much higher proportion of younger individuals in the population compared to the West.
Now if we consider the comorbidity situation in India, our experience has not been much different.
More importantly, possibly, is the fact that the number of severe Covid patients having pre-existing metabolic co-morbidities is much higher. Our own experience, taking a rather small cohort of patients while working in a single centre in eastern India in a plasma therapy trial, was the finding that almost one-in-two severe Covid patients had diabetes. This tells you that in the absence of pre-existing ailments, the Indian case fatality rate perhaps could have been even lower.
Over the past few decades, India has been experiencing a steadily progressing prevalence of non-communicable diseases, especially diabetes. More importantly in contrast to the West, where obesity is more often associated with the development of type 2 diabetes, in this part of the world non-obese individuals are also affected by this condition in large numbers. Several population-level studies over the past few years have shown this and it is also evident from the National Family Health Survey data. Regular personal physical health check-ups are not usual for most of the Indian citizens so the absence of any physical appearance usually thought to be associated with diabetes, such as obesity, also precludes early diagnosis. Thus, we’re also experiencing a silent epidemic of diabetes in the country, as for a large number of people, the first diagnosis leading to the start of medical therapy has to wait till some of the later complications are noted.
In a large number of severe Covid cases, diagnosis of high blood sugar or hyperglycemia came as a coincidental finding, with the patients having no prior knowledge of having diabetes. It is true that there have been propositions about de novo incidence of hyperglycemia associated with the virus infection or due to corticosteroid therapy. But these factors only apply to a handful of patients. A large number of patients, apparently healthy in terms of chronic diseases, only came into contact with the medical system due to Covid. It turns out that this pandemic is revealing a number of pre-existing medical conditions, most often type 2 diabetes, that had been unattended until now. A number of these patients are progressing to severe Covid as expected from the already established susceptibility. In addition to the menace of “happy hypoxia” which is delaying medical attention, this ignorance about pre-existing co-morbidities is also playing a big role in the fatalities that could be otherwise prevented if the patients had known before being diagnosed with Covid. It took a viral pandemic to unmask another silent one and it's time we pay heed to that.
Covid is not the first infection that makes diabetics more susceptible. Rather, the susceptibility here is of a different sort, leading to hyperactivation of the immune system. Diabetics are known to have a weaker immune system and, thus, higher susceptibility to infections. For example, diabetics have been a major victim of another, much longer-standing pandemic, that of tuberculosis. A number of questions remain unanswered though. One relates to why the immune system suffers in diabetics and if ways can be found for an “a priori” assessment so that diabetics who are more susceptible to immune dysfunctions can be detected. This needs support for focused scientific studies. On the other hand, in the public health domain, greater efforts should be made to screen the population for diabetes much before complications arise. This would be another very critical tool in being prepared for other epidemics that we may have to face in the future.
Dipyaman Ganguly is a physician-scientist and immunologist working in CSIR-Indian Institute of Chemical Biology, Calcutta and is actively engaged in studying Covid-19 patients.
