On 12 January 2020 when the novel coronavirus was first identified as the cause of an outbreak of unexplained pneumonia in Wuhan, China, life carried on as usual for most people. By 9 April 2020, over 1.5 million cases of COVID-19 and more than 80,000 deaths were reported in 184 countries. As we witness the unprecedented speed at which this pandemic has swept across the globe with daily accounts and images of thousands dying, cities becoming ghost towns and healthcare professionals being overwhelmed and themselves stricken by the virus, we ask ourselves if this war can be won.
As new information rapidly becomes available and the understanding of COVID-19 grows daily, opportunities to intervene and establish new treatment options are also emerging. The huge global push towards clinical trials has witnessed an exponential rise in the number of studies being approved by health authorities.
One such strategy is the use of a medication called tocilizumab (known by its trade name Actemra), a medication used to treat rheumatoid arthritis, in the treatment of severe cases of COVID-19. Several independent clinical trials using tocilizumab have already begun globally with promising results.
A study with tocilizumab is scheduled to commence in mid-April 2020 at the University Malaya Medical Centre (UMMC) together with three Ministry of Health Hospitals; Hospital Sungai Buloh, Hospital Kuala Lumpur and Hospital Tuanku Jaafar, Seremban. The study, led by Prof Dato’ Dr Adeeba Kamarulzaman, Dean of the Faculty of Medicine, Universiti Malaya, and an infectious diseases specialist by training, aims to compare the effectiveness of intravenous tocilizumab versus high dose corticosteroids in approximately 300 patients who develop severe forms of COVID-19.
“We are grateful to Kementerian Kesihatan Malaysia (KKM) for their participation in this very important study that has the potential to save many lives and contribute to the urgent search for the best treatment for patients with COVID-19 especially for those with severe disease,” says Prof. Adeeba.
“We know that approximately 80% of patients with COVID-19 have mild to moderate disease and will recover, however 15% progress to severe disease and another 5% will develop critical illness, with death occurring in between 1-3% of patients.” Prof. Adeeba explains. “What is becoming clear is this: in this small group of patients, a dangerous overreaction of their immune system, known as a cytokine storm, overwhelms the patient resulting in respiratory followed by multi-organ failure. So, in these patients, ironically, it is their own immune response to the virus that kills them. And what we need to figure out is how to safely turn off this overactive immune response as soon as it begins,” she adds.
When our bodies are attacked by a virus or bacterium, the immune system is triggered to fight the invader. The fight is led by a complex and intricate network of cells, proteins and molecules called cytokines. When the “invader” or infection has been successfully overcome, the immune system is supposed to shut itself off. But in some cases, instead of shutting off, the immune system continues to release cytokines in an uncontrolled and unregulated manner, resulting in a cytokine storm which can build up and lead to failure of critical organs like the lungs, kidneys and liver.
The current understanding of how a patient with COVID-19 progresses is that after the infection, there may be an asymptomatic initial phase that lasts for a few days. When symptoms of fever, cough and tiredness manifest themselves, the virus is already multiplying in the respiratory tract. Mild symptoms can then progress to become a viral pneumonia. For most infected individuals, particularly those who do not have any pre-existing disease or condition, the body will successfully mount a coordinated immune response and recover. We are beginning to have a better understanding of what happens in the approximately 5% of cases who develop severe disease. After about 1 to 2 weeks of the illness, a second phase ensues where the infected individuals will develop signs and symptoms of a cytokine storm that leads to respiratory failure and the need for mechanical ventilation.
There is growing evidence that interleukin-6 (or IL-6, a specific cytokine) is a critical component of the COVID-19 cytokine storm and that blocking IL-6 may in fact put on the “brakes” that stops the progression of the disease into its most critical stage. This is where tocilizumab exerts its action.
Tocilizumab, a drug specifically designed to block the negative effects of IL-6, has been used for years in the treatment of specific cases of Rheumatoid Arthritis, Giant Cell Arteritis and other conditions where there is excessive inflammation in the body.
Clinicians and scientists are increasingly able to identify many patients who are on the brink of developing COVID-19 cytokine storms. Clinicians and researchers at Yale University in the United States where they have been hard hit with COVID-19 cases, have extensive experience using tocilizumab in treating patients. Professors Altice, Price and Malinas from Yale are joining Malaysian researchers in this innovative trial. Professor Altice, also an Academic Icon at Universiti Malaya, has collaborated with Prof Adeeba and her team for over 15 years.
This proposed study aims to carefully monitor a group of patients and, as soon as there are clinical and laboratory markers of deterioration, they will be treated with either a high dose of steroids or with tocilizumab. Both are known to inhibit inflammation but do so differently. Tocilizumab targets only the IL-6 receptor while corticosteroids broadly block many aspects of inflammation. The aim of this study is to stop the progression of the hyperinflammation process that leads to respiratory failure. By doing so they hope to prevent as many people as possible from needing to be supported on artificial ventilation that is not only in short supply, but leads to multiple other complications.
Our experience using tocilizumab at UMMC with COVID-19 patients who develop the cytokine storm syndrome has been very encouraging. Out of eight patients who were very ill who received tocilizumab, we managed to prevent six from being ventilated. All of these patients are now doing very well. That’s a pretty big deal considering the rate of deterioration described in patients from large centres in China and Italy. In the other two patients, tocilizumab did not work as well as they were already very ill by the time treatment was given. The window of opportunity for response was most probably missed according to Prof. Adeeba.
“While we are excited about the prospects of tocilizumab preventing COVID-19 deaths, we want to know the ideal time to start the treatment and also to carefully monitor for any side effects among Malaysian patients,” says Dr Suresh Kumar, lead clinician at Sungai Buloh Hospital.
The initial funding of RM450,000 to conduct this study was raised from a small group of private donors. “I would like to thank the donors who have contributed generously to make this study a possibility in a relatively short period of time. We hope to raise RM1.5 million for the purpose of this important trial which can help to save lives in our fight against COVID-19,”
“We are also grateful for the donation of tocilizumab by Roche Malaysia that enabled us to treat the first few patients successfully,” said Prof. Adeeba. She estimated that a total of RM1.5 million will be needed for the trial which will be run over a period of 6 months at the 4 hospitals.
Those interested to find out more or who would like to make a contribution towards the study, can contact Dato' Prof. Dr. Adeeba Kamarulzaman, Dean of Faculty of Medicine, and Professor of Medicine and Infectious Diseases, Faculty of Medicine, Universiti Malaya, via email to adeeba@ummc.edu.my.
