Om Prakash Gupta, 68, had fever and a cough on April 22. His test results had been mixed up, and it was only on April 27 that he got a call saying he had tested positive and that an ambulance would be coming the next morning to take him to the state-run MR Bangur Hospital in Kolkata. Till that time, he had been home, walking, talking and not complaining of any breathing difficulty. As had been arranged, the ambulance came to pick him up on April 28. He passed away that same evening in the hospital. His son, Raj Gupta, keeps asking how someone who seemed so normal could die so suddenly.
Across the world, there is a growing realisation that COVID-19 is more than just viral pneumonia. It causes death not just by infecting the lungs, but increasingly by triggering a malfunction in the body’s immune response system. There are no visible symptoms of the intense battle between the virus and the immune system within. The progression from moderate to severe can also be sudden, without any noticeable change in symptoms.
Dr Sudhir Bhandari, who is the director of the SMS Hospital in Jaipur and currently has 558 patients in his care, acknowledges as much. “There is a change in our understanding of Covid,” he says. “It enters the upper respiratory tract, yes, but lung infection is not the cause of death.” He attributes the fatality instead to what are called cytokine storms. “When your body senses the presence of a viral cell damaging its healthy cells in the lungs,” he explains, “it produces white blood cells. These cells produce chemicals called cytokines which try to make the body inhospitable for the virus through fever or inflammation.” But Covid, for reasons still being researched, induces some people to have an exaggerated immune response, leading to an overproduction of cytokines. While fever can be controlled, it is the inflammatory tendency of cytokines that starts harming not just the infection but also the human cells in other vital organs. “Patients on ventilator or oxygen support have elevated pro-inflammatory cytokines such as interluken (IL-1 and IL-6),” says Dr Bhandari. Interluken produces fever, inflammation, tissue destruction and, in some cases, even shock or death. Severe patients also show increased levels of the protein fragment D-Dimer and FDP (fibrinogen degradation product) in the blood, which can cause thrombosis, a condition in which the body is unable to dissolve blood clots. Blood clots are lethal, especially when they travel to the lungs, heart, kidney or liver. Of the 50 autopsies of Covid patients in India, many reported pulmonary thrombosis or the presence of microclots in the lungs. “Patients do not die of the fever or cough, they are dying of pulmonary clots, multi-organ failure as a result of inflammation of tissue. These are all a result of chemicals and changes produced in a cytokine storm,” says Dr Bhandari.
Who is at risk?
The percentage of those with very mild, moderate and severe symptoms in India has been the same as the global average of 80, 15 and 5 per cent (of which 2 per cent require ventilator support), respectively. The ones at the highest risk from cytokine storms are those with compromised immune systems or poor health. An April 30 health ministry update put the case fatality rate in India at 3.2 per cent. Fourteen per cent of those who died were under 45 years old, 34.8 per cent between 45 and 60, 51.2 per cent over 60, 42 per cent between 60 and 75, and 9.2 per cent above 75. A significant portion (78 per cent) of the deaths in India were due to conditions of comorbidity, such as hypertension, diabetes and liver illness. The latest deaths show as much: on April 29, a 73-year-old with a history of respiratory disease died in Karnataka; on April 30, a 64-year-old patient in Nanded in Maharashtra died because of undisclosed comorbid conditions; and on May 3, a 65-year-old dialysis patient with hypertension died in Ambala. Deaths of young people with no comorbidities have been rare. Delhi has reported just one death of a person younger than 50 with no pre-existing illness. Mumbai had 14 deaths of people below 35, but there is no information of comorbidity. Doctors attribute such deaths in the young to poor lifestyle choices (smoking, drinking or low nutrition) or, in very rare cases, genes.
“Diabetes and age limit the immune response,” says Dr Sukumar Mukherjee, an internal medicine specialist in Kolkata who is on West Bengal’s 12-member Covid health committee. Deaths in the state stood at 140 on May 6, a sudden spike from just 35 on May 4, making West Bengal’s death rate of 7.57 per cent the highest in the country. Eighty-five per cent of those who died were between the ages of 50 and 60. “The spike protein present in the coronavirus is very dangerous. It helps the viral cells replicate faster. But the immune system of those with comorbidities shows a different reaction, it doesn’t know when to stop producing cells which incite inflammation,” says Dr Mukherjee. A recent audit found that 39 Covid deaths in the state had been due to conditions of comorbidity.
But this does not mean all elderly people or those with comorbidities are at serious risk from Covid. Dr Avinash Bhondwe, president of the Indian Medical Association (IMA) in Maharashtra, where the number of deaths touched 617 on May 6, explains, “Covid’s severity has been noticed more in the elderly and those with pre-existing diseases. But it also ties in with long-term health. There have been many with comorbidities who have recovered. If you’ve maintained your sugar, your heart condition or your overall health over a few years, your immune response will most likely not go into overdrive.”
In Gujarat, which reported 368 deaths on May 6, the severity of the disease is also being linked to the viral strain and stage of diagnosis. At 4.6 per cent, the state has the second highest death rate in the country. “We are studying the reasons for this, it could be a more virulent strain of the virus. But from initial reports, it also seems to be a case of late diagnosis. If patients are not coming to the hospital on time, we can miss a critical window for treatment,” says Dr Chandresh Jardosh, president of the Gujarat IMA.
Fear has led to people self-medicating. Unfortunately, the mildness of symptoms nearly always betrays the severity of internal damage, and patients often test for Covid late. For example, Neha Bhasin (name changed), a 42-year-old patient in Delhi, waited almost 10 days before going for a Covid test despite fever and a cough. “I didn’t feel sick at all. But one day, I was suddenly not able to breathe. They rushed me straight to the ventilator. After a week, I recovered,” she says.
Last month, the CDC (Centre for Global Health and Prevention) and ICMR (Indian Council of Medical Research) added more Covid symptoms that could signify an infection and quicker diagnosis. “It isn’t just fever or cough,” says Dr Om Srivastava, head of the infectious disease department at Mumbai’s Jaslok Hospital, a private-run Covid facility. “With vessel inflammation, you could get mild skin rashes. Chills and shivering have been noticed too, as have muscle aches or loss of taste or smell.” The Mumbai district had 9,945 cases and 387 deaths as on May 6, the country’s highest. “RNA viruses like Covid are very cunning. Just when a person thinks they are getting better, the virus steps up its attack on human cells. It is critical to understand the internal progression of Covid because the external symptoms are very different and difficult to catch. We have to catch the virus in the golden period before the onset of a cytokine storm. The exact golden period is still not known, but Day 5 to Day 10 are critical,” he says.
A self-limiting disease, Covid dies out on its own. Thus, in many European countries, only paracetamol and IV fluids, not antibiotics or antivirals, are given in the initial stages. In India, antibiotics such as Azithromycin or Augmentin are given so far to treat flu symptoms. In the severe stage, a combination of anti-HIV and anti-malaria drugs is being used to tame cytokine storms and limit virus replication. However, with the disease leapfrogging in severity and causing death, medical directors are now relying on early diagnosis, oxygen and organ monitoring, along with managing blood clots, inflammation and cytokine response.
“A concerning cause of death is reporting the infection too late. By that time, the cytokine onslaught has begun, and chances of controlling lung damage, organ inflammation or blood clots start diminishing depending on a person’s health,” says Dr Ajay Goenka, head of the Chirayu Hospital in Bhopal. It starts showing in the oxygen levels and damage to organs. “Within six hours of a patient being admitted, we run tests for the heart, liver, kidney, lung and blood. If there are already signs of organ damage, we start immediate treatment,” he says. Then comes oxygen monitoring with a pulse oximeter.
According to Dr Bhandari of Jaipur’s SMS Hospital, a person may not immediately notice a fall in oxygen levels, a condition known as silent hypoxia. “But it is a sign that conditions are worsening. We observe a 24-48-hour window from when oxygen levels fall, and it is critical we start oxygen therapy and treatment in this time.”
Extensive research is being done around the world, and by ICMR in India, to understand what precipitates cytokine storms only in some people, and drugs which can stall and treat them. With the efficacy for a reliable treatment yet to be proved, early diagnosis, long-term health and close monitoring of oxygen levels are currently our most reliable weapons in the fight against Covid.