The news every morning is grim. With the number of cases rising exponentially in all countries, the infection rate of Covid-19 (Corona Virus Induced Disease 2019) does not appear to be slowing down. A daily dose of numbers infected in each province with total deaths only adds to the anxiety and uncertainty that has gripped not only our country, but the entire world.
We had been dealing with intermittent outbreaks of polio across the country, had barely recovered from the HIV epidemic in Larkana, and had just about dusted ourselves off (albeit not completely) from a dengue outbreak in Punjab, and here we are now: facing another crisis. Only this time the transmission is unclear, knows no bounds, and it is not quite as simple and easy as spraying your garden to eliminate the vector because it is not a mosquito, it is us.
Covid-19 is new and as aptly referred to, novel. We are still trying to understand it. What makes the virus scarier than many other infectious diseases is that no approved medical treatment exists currently. Moreover, there are no vaccines in the market that will prevent humans from acquiring the infection in the first place.
In the absence of these modalities, healthcare professionals have no other choice but to provide supportive care (which simply manages the symptoms of the disease) to patients afflicted with Covid-19.
How does the virus cause disease?
The virulence of a particular virus is often associated with the immune response it encounters in the human body. For Covid-19, the immune response has been divided into two phases. The initial phase is thought to involve the development of a specific adaptive immune response required to eliminate the virus, and stop progression of the disease. Therefore, it becomes important to provide treatments that boost immune responses early in the infection, such as antibodies and immunomodulators.
Immune responses however tend to weaken with age, which is why the elderly are particularly vulnerable.
If the immune response is weak or impaired because of other comorbidities such as cardiovascular diseases and diabetes, the virus multiplies and can lead to tissue damage. The second phase of the immune response leads to damaged cells inducing inflammation in the lungs.
This is where the infection enters its dangerous phase, since lung inflammation causes life-threatening respiratory disorders, making it difficult for individuals to breathe on their own. Different therapies being tested work at different stages of the disease which is why it is important to identify which phase a patient is in before you initiate treatment.
In the face of this pandemic, several new experimental therapies are being proposed and tested by medical researchers, including anti-viral drugs which can kill viruses. Other drugs include immunomodulators that modify the ability of the immune system to fight viruses. Researchers have also looked into medicines used to fight other infections such as the anti-malarial choloroquine, which is thought to help prevent the virus from infecting cells.
Many of the therapies being investigated currently are regarded as "experimental" since they have no proven efficacy in fighting off this variant of the coronavirus.
Experimental therapies or treatment are not recommended except in the setting of clinical research. Such treatments, under ideal circumstances, should not be provided to the general public until safety and effectiveness has been established through rigorous systematic research.
However, amidst these desperate times with Covid-19 related deaths increasing every day, the natural inclination is to make use of any novel intervention that provides even the tiniest glimmer of hope.
Plasma therapy: What is it and how does it work?
One such intervention that has been the talk of the town is convalescent serum transfusion, commonly referred to as "plasma therapy". This treatment modality has previously been used as a desperate last resort step during Ebola outbreaks of 2014, and also in the Severe Acute Respiratory Syndrome (Sars) and Middle East Respiratory Syndrome (Mers).
The procedure of plasma therapy involves collecting blood from someone who has recovered from Covid-19 and transfusing separated plasma to a critically sick patient. Plasma is the clear part of blood that is left when blood cells have been removed and contains antibodies and other proteins. The transfusion of plasma with its antibodies provides a form of 'passive immunity' to the sick recipient to fight the infection. The protection offered by passive immunisation however is short-lived, usually lasting only a few weeks or months.
The science behind plasma therapy and passive immunisation, per se, is not new or novel considering that the concept, introduced by a German immunologist Emil von Behring, has existed since 1890, and has been widely applied for the treatment of different infectious diseases including mumps, measles and polio etc.
The donor of the plasma must have been previously diagnosed with laboratory-confirmed Covid-19 and subsequently test negative for Covid-19 and other respiratory viruses, as well as for Hepatitis B virus, Hepatitis C virus, HIV, and syphilis at the time of donation. The donors must be otherwise healthy for at least 10 days, with a high level of Covid-19 specific antibodies.
Will plasma therapy treat Covid-19 patients?
We don’t know. Medical researchers and scientists all over the world are now grappling with this question.
Experience from China
Preliminary data from China is promising, reporting some positive outcomes of convalescent serum transfusions to desperately sick Covid-19 patients. However, there is no robust evidence to consider this as a "miracle cure".
There are multiple reasons for this. First and foremost, one of the studies from China that reported successful outcomes of this experimental therapy involved a small group of critically ill Covid-19 patients. Furthermore, the authors of this research themselves acknowledged several limitations, including the fact that the patients were also on multiple other treatments (including steroids and antiviral agents) and they cannot be sure what helped, given the very small number of patients.
Other researchers have also critiqued this investigation, calling it an "anecdotal case series". This means that the conclusions from the China experience cannot be generalised since they are inconclusive.
Previous research on plasma transfusions used for diseases other than Covid-19 indicate that this procedure is certainly not risk free, and may lead to side effects in recipients, including but not limited to severe allergic reactions, acute lung injury, and circulatory overload in patients with cardiorespiratory disorders.
Current situation of plasma therapy
Plasma therapy may yield promising results in the future but at this point in time, it is imperative to recognise that we are sailing in unchartered waters. Convalescent serum transfusion is an experimental therapy.
Presently, Covid-19 convalescent plasma is either being used as part of a clinical trial (a form of rigorous systematic investigation) or being provided as an Emergency Investigational New Drug (eINDs) to individual patients.
The latter falls within an ethical framework known as Monitored Emergency Use of Unregistered Interventions (MEURI). During the 2018 Ebola outbreak in West Africa, the World Health Organisation (WHO) established a set of criteria for access to investigational therapies for individual patients outside of clinical trials in emergency, life threatening situations.
The first requirement is that it can be used as MEURI if no other treatment exists. This holds true for Covid-19. Another important criterion includes an approval from a qualified scientific advisory committee. This has been done in the case of United States, where the Food and Drug Regulatory Authority (FDA) has approved the use of this therapy for critically ill patients a couple of days back. Approval from an ethics committee is another essential requirement. Within this context, obtaining informed consent from patients who are provided this experimental therapy is necessary. The patients must know that what they are being offered is an experimental therapy which itself can have significant short-term and long-term side effects. Investigators are of course required to document the results and share them in a timely manner with the wider medical and scientific community.
Preliminary reports from MEURI use of plasma will continue to add important information. However, the critical next step is moving to a much more scientific clinical trial design of investigation since this is what is needed to draw conclusive evidence regarding this treatment modality.
Plasma therapy in Pakistan
The technology for using plasma therapy exists in Pakistan, but only at a handful of places. Therefore, wider use across the entire country may not be possible.
There is also an assumption that every convalescent patient will be willing to donate. The media glare and the hype created may actually pressurise recently recovered Covid-19 survivors to feel obliged to donate. This is not like any ordinary blood donation and carries its own risks for the donor. This donation involves taking approximately 400 ml of plasma using a procedure called "apharesis" in which the donor’s blood is passed through a machine to collect plasma, the plasma is extracted and the blood cells returned.
This process may require the insertion of a wide catheter, called a double lumen line, and can take up to two hours. The side effects may include allergic reactions, fatigue, dizziness and nausea etc. While these side effects are usually mild and stop once the procedure ends, it is important that donors are informed about them.
Against this backdrop, it is important keep public expectations in check. There are real dangers in the way plasma therapy has been publicised in the media, particularly within the context of Pakistan.
While providing hope in times of despair is essential to boost morale, it is also the ethical responsibility of the scientific and medical community, as well as the media, to provide full information to the general public.
Regulation of research
Physician-researchers must adhere to proper protocols as they attempt to use this experimental therapy within Pakistan. This requires scientific approval from a regulatory authority which, in this case, includes Drug Regulatory of Pakistan (Drap) and ethical approval from institutional research ethics committees and the National Bioethics Committee (NBC) of Pakistan.
The NBC is providing rapid turnaround reviews of Covid-19 related research proposals within 72 hours in order to ensure that studies can be initiated as quickly as possible while ensuring safety and welfare of patients. Ethical oversight is always essential when human subjects are part of medical experimentation, and this becomes even more important in times of crises when populations are rendered more vulnerable to possible exploitation.
When experimental modes of treatment, such as convalescent therapy are being used, patients and family members must be adequately informed of not only the benefits, but also the possible risks/complications that this therapy may entail. It is imperative that patients and their families are not misled in their understanding of participation in research and realise that this is not proven therapy. Such steps ensure greater transparency and help in maintaining public trust.
Responsibilities of media
Media has a key role in providing relevant and pertinent information to the public, and not create false hypes by claiming convalescent therapy as a miracle.
Caution also needs to be exercised in providing incomplete information to the public without ascertaining all the facts. Research is always done in a certain context. When a researcher reads a research study and looks at the results, she or he will interpret findings based on multiple factors. However, when media accesses the same articles, chasing deadlines, they tend to start putting pieces of the puzzle together that are still missing. The consequence is that an incomplete set of often grossly misleading information is shared with the public.
The pitfalls of doing so were illustrated when the use of the anti-malaria drugs was touted to be a miracle cure for Covid-19 leading to a global shortage for the drug and several fatal and non- fatal toxicity reports.
Amidst a growing crisis, with increasing morbidity and mortality, there is a sense of urgency to do whatever it takes. However, we have a responsibility to adhere to established professional and ethical standards, for the safety of the public.
Scientific research and advancements ought not to be discouraged but in Friar Lawrence's warning to the impulsive Romeo, who represents the voice of reason and caution in Shakespeare's Romeo and Juliet (Act 2, Scene 3), "Wisely and slowly. They stumble that run fast."
We must proceed but wisely so that we do not stumble.
Opinions expressed are those of the authors and not necessarily of the institutions they are employed with.