The Kryptonite Hypothesis

By Gabrielle Babbington

Experts say the medical establishment was wrong to dismiss warnings that common obesity-related medications would trigger COVID-19 deaths.

SYDNEY: COVID-19 is trivial for some and deadly for others, which has baffled doctors worldwide; but this enigma could have a simple, yet unwelcome, solution.

Top tier medical journals name at least a dozen drugs that cause cell membranes to become crowded with the enzyme ACE2, the doorway through which the SARS-CoV-2 virus invades cells and causes COVID-19. Most of the drugs are commonly used to treat three health problems related to obesity, namely high blood glucose, high blood pressure, and high cholesterol – and the patients who routinely take a cocktail of the drugs are the same ones who most often die from COVID-19. 

But, faced with the troubling prospect that cornerstone drug treatments might have become hazardous, amid the chaos and uncertainty of the pandemic, the medical establishment closed ranks. Authorities dismissed the warnings of many prominent experts, who still fear the drugs make patients vulnerable to severe COVID-19 – and patients have only heard the prevailing side of the story. Meanwhile, the research rushed through to settle the debate is riddled with flaws that bias the results, but this bad science has been ignored.

“Treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19,” professors hypothesised in the Lancet in March last year; and experts from several medical specialties and countries soon concurred. “With this hypothesis, for many there is plausibility, and for all such ‘believers’, urgency,” Professor Murray Esler, a world leading cardiologist, wrote in Journal of Hypertension last June. “We believe that modulation of ACE2 expression is associated with both infection and mortality rates in COVID-19,” twenty global authorities in diabetes agreed in a separate Lancet paper later that month. “These drugs might promote severe pneumonia and death in the setting of COVID-19, particularly in older individuals who are more likely to be taking these drugs,” Mayo Clinic professors warned. “Attention to this might save countless lives.” 

Medical authorities worldwide have misconstrued the warnings as unsound speculation that suggests doctors should withhold life-saving drugs. But actually, although the issue has divided experts, they all agree on one thing: “Simply discontinuing medication is strongly discouraged and is not an option,” Professor Esler has repeatedly advised for patients with established disease, echoing his fellow proponents. If patients were to forgo the ACE2 stimulating drugs their lives depend on, it would be missing the point, and would carry actual risk, rather than theoretical risk, Professor Esler told Scientific Dissent. Instead, he recommends cautious medication changes when this would be safe, or being extra careful to avoid infection when medication changes would be unsafe. (Cancer doctors have used the same common sense approach throughout the pandemic for patients on chemotherapy.)

The experts’ warnings stem from concerns that, theoretically, the more ACE2 there is on cell membranes, the more suction cups there are for SARS-CoV-2 to stick to and become enveloped by the cell, and the more doorways there are for it to then enter the cell and wreak havoc. The more cells SARS-CoV-2 invades and destroys, the more the virus replicates, the more it ravages the body from one vital organ to the next in a prolonged attack, and the deadlier the outcome. 

As COVID-19 seizes the lungs, it causes the small blood vessels there to leak, allowing the virus to hitch a ride in the bloodstream to seek and destroy new targets. Cells that have ACE2 on their membranes are found in the surface lining of the lungs, heart, blood vessels, kidneys, liver, intestines, adrenal glands, pancreas, mouth, nose, and possibly elsewhere. They are also found in adipose tissue, our fat. COVID-19 can “attack almost anything in the body with devastating consequences”, a Yale University professor told Science. “Its ferocity is breathtaking and humbling.”

When cell membranes are crowded with ACE2, it is referred to as ACE2 overexpression. “Several types of experiment in animals give credence to the idea that human ACE2 expression may be important in COVID-19,” Professor Esler, senior director of the Baker Heart and Diabetes Institute in Melbourne, argued. In animal studies, mice that were genetically modified to have no ACE2 were totally resistant to SARS coronavirus; and mice bred to overexpress human ACE2 were far more likely to become infected with and die from SARS coronavirus than normal mice. The experts fear the latter studies reflect what has happened in humans – except SARS-CoV-2 is worse than SARS coronavirus, its 2003 predecessor, because it is an even better fit for the ACE2 receptor, binding to ACE2 ten to twenty times more readily. This ACE2 affinity is even higher in the especially infectious SARS-CoV-2 variants, such as the Delta strain. 

In what has become a deadly paradox, many of the medications we take to stay healthy might now be our kryptonite. Just as the infamous crystal made Superman vulnerable to enemies he would otherwise defeat, so too might ACE2 stimulating drugs make us vulnerable to SARS-CoV-2. Although COVID-19 vaccines have saved many lives, their waning effectiveness makes them an imperfect shield. A proper investigation of the role that ACE2 expression plays in COVID-19 infectivity and severity might close the book on an otherwise never-ending pandemic. The proponents of the hypothesis that ACE2 stimulating drugs make patients vulnerable to severe COVID-19, hereafter called the kryptonite hypothesis, want the truth no matter its inconvenience.

The implications of the kryptonite hypothesis boil down to this: we are in a grey area, assurances to the contrary are false, and carrying on as normal during the wait for definitive evidence might be a deadly mistake. The kryptonite hypothesis does more than pose a question, it implies a call to action. “Lowering ACE2 expression should be a therapeutic principle applied in COVID-19 prevention and treatment,” Professor Esler, a member of the order of Australia (meaning he has been honoured for his work by Her Majesty Queen Elizabeth II), advised. Making clinical decisions on the basis of a hypothesis is standard practice in medicine: off-label prescribing (using a drug for a purpose other than its intended one) is often informed by anecdotal evidence alone, and accounts for at least one in five prescriptions in the US and Europe

Medication overload: has popping pills made us sitting ducks? 

If intellectual humility and curiosity are the keys to scientific innovation, Professor Esler, of Monash University in Melbourne, must have an especially large dose of both. His pioneering work led to the emergence of the field of cardiovascular neuroscience (how the heart and nervous system interact), as well as revolutionary treatment for severe hypertension (high blood pressure). 

Professor Esler is well acquainted with ACE2, as it is a key component of the renin–angiotensin–aldosterone system, the hormone system that regulates blood pressure. His interest in drugs that stimulate ACE2 piqued when he was surprised by the high prevalence of patients with hypertension among the fatal cases of COVID-19. “Hypertensive patients are really not predisposed to infection at all, so that was very odd,” he said. In over 40 years of specialising in blood pressure disorders, Professor Esler, associate director of the Heart Centre at Alfred Hospital in Melbourne, cannot recall ever losing an hypertensive patient to an infectious cause. For garden-variety infectious pneumonia, it usually works the other way around: pneumonia causes heart problems. 

Professor Esler’s original concerns were the blood pressure drugs ARBs, which can cause a five-fold increase in ACE2 expression, and diuretics (water pills), especially loop diuretics and spironolactone. These drugs cause a drop in body sodium content, which in turn stimulates ACE2. But warnings from other experts led Professor Esler to expand his concern to all common ACE2 stimulating drugs: “There may be a need to think more broadly on this matter,” he wrote in Journal of Hypertension. 

Chief among the other kryptonite drugs are statins for lowering cholesterol, which are the most commonly prescribed drugs in the US, UK, and Australia. Their stimulating effect on ACE2 was backed by the aforementioned twenty world-leading diabetes experts in medical journal The Lancet, with similar mentions in several other papers. Others include the blood pressure drugs ACE inhibitors, which too have had several mentions; and the type 2 diabetes drugs SGLT2 inhibitors and GLP-1 agonists, which were disclosed, and seconded, in Journal of Hypertension. The commonly used anti-diabetic agent metformin is also said to stimulate ACE2, as are the lesser-used ones thiazolidinediones. An Oxford/Cambridge review of the medical literature in BMJ Open found the diabetes drugs insulin and DPP4 inhibitors, the blood pressure drugs calcium channel blockers, and the angina drug ivabradine also stimulate ACE2. 

All of these drugs are preferred treatments for the underlying medical conditions most commonly seen in adults of any age who develop severe COVID-19: hypertension, type 2 diabetes, obesity, high cholesterol, and heart disease. Some of these conditions do weaken the immune system, and predispose patients to severe complications from respiratory viruses like the flu. But COVID-19 is hitting much harder than the flu for patients who take kryptonite drugs, and is sparing patients who do not take the drugs and are usually hit hard by the flu, such as those with mild to moderate asthma (whose inhaled corticosteroid medications might actually lower ACE2 expression).

We know that ACE2 expression increases with age, and young children, with their minimal cell membrane ACE2, are also getting off comparatively lightly. Only about one or two percent of US children with COVID-19 have required a hospital stay, compared with 20-30 percent of US adults over the age over 45, and up to 60 percent of US adults over the age of 75 (these adult figures preceded COVID-19 vaccines and the Delta variant). Conversely, the strongest risk factors for severe COVID-19 in children are type 1 diabetes and congenital heart defects, both of which are treated with kryptonite drugs. 

The elderly commonly take multiple kryptonite drugs; about half of US adults aged over 40 are eligible to take statins; and the ‘off-label’ use of ACE2 stimulating drugs is widespread, often to prevent conditions that have not yet developed, or for non-serious conditions that might fly under the radar in otherwise healthy patients with severe COVID-19, such as hair loss, premenstrual bloating, acne, or infertility. The kryptonite hypothesis can be applied to adults young and old, even those who seem fit and well. Although COVID-19 is most deadly for the elderly, there were reports last year that more than half of affected ICU patients were under the age of 60. 

“I believe the level of drug exposure in communities may be conditioning predisposition to severe COVID-19, and might do the same in the next pandemic,” Professor Esler told Scientific Dissent. US figures show one in five middle aged adults and two in five of the elderly take five or more prescription drugs. “The United States is in the grips of an unseen epidemic of harm from the excessive prescribing of medications,” a Lown Institute report warned in January 2020, just as the COVID-19 pandemic was unleashed. The report said drugs for diabetes and hypertension were often needlessly prescribed to the elderly, and were doing more harm than good – they were hastening death rather than prolonging life. “Both patients and clinicians are steeped in a culture of prescribing, which promotes a pill for every ill,” the authors wrote. Professor Brené Brown, of University of Houston, put it another way: “We are the most in-debt, obese, addicted and medicated adult cohort in US history.” The stage was set for a novel coronavirus that exploits every weakness it finds. 

Although they cannot be taken as proof, emerging trends in COVID-19 mortality dovetail with the kryptonite hypothesis. Men die from COVID-19 more often than women, and are prescribed kryptonite drugs for heart disease more often and more aggressively too. Care home residents, who are overmedicated – one in five of the elderly in the US take ten or more prescription drugs – are overrepresented in COVID-19 deaths worldwide, comprising up to half the fatal cases in several US states. But Professor Esler told Scientific Dissent there are surprisingly few deaths in homeless shelter residents, who are undermedicated. The homeless have poor access to healthcare, so their health problems are often missed, and they have especially poor compliance with prescribed treatment.

When researchers tested all 408 residents of a Boston homeless shelter for COVID-19 last April, just over one third were positive, and almost all of these cases were asymptomatic. None of the residents had severe COVID-19, even though they matched the demographics commonly associated with it: most residents were men aged over 50 years, and about one third were black. (Earlier research found homeless people in Boston also have high rates of obesity.) A follow-up article reported that almost half of Boston’s 1800 strong homeless shelter population had since tested positive for COVID-19, that most cases were asymptomatic, and that only seven residents had died, all of whom had other severe health problems. “It’s a very baffling situation for us,” the researchers said.

The low COVID-19 death toll in Boston’s homeless shelters mirrored reports in other US cities, and is the opposite of what many experts feared would happen, given how vulnerable the homeless are. Juxtaposed against the homeless are the poor but housed, who too are overrepresented in COVID-19 deaths. They are blighted by the lifestyle diseases linked to low incomes (hypertension, type 2 diabetes, obesity, high cholesterol, and heart disease), but have just enough stability to be medicated for them, with kryptonite medications, even if they forgo heating to pay for the drugs, or sometimes skip doses to make each filled prescription last longer.

The low rates of severe COVID-19 among black homeless shelter residents is especially surprising, because US counties with a black majority have had six times more COVID-19 deaths than counties with a white majority. Black people also have much higher rates of hypertension and diabetes than white people, which is said to be a function of obesity – almost half of black adults in the US are obese. The cocktail of kryptonite drugs used to treat these conditions was typically under-prescribed to black people, until treatment guidelines were updated a few years ago (heart disease risk calculators were changed in 2013). But the limited recent research available suggests this gap in treatment has all but closed.

From gold to kryptonite: are hallowed drugs now hazardous?

The lungs are the primary battleground for COVID-19, and its destructive power has startled ICU staff worldwide. “I’ve never seen a microorganism or an infectious process cause such acute damage to the lungs so rapidly,” one ICU respiratory therapist told ProPublica. The SARS-CoV-2 virus replicates inside infected lung cells, which rapidly destroys the cell, and triggers immune responses that cause further damage. The lungs become flooded with a soup of dead tissue; and patients with severe COVID-19 end up “drowning in their own blood and fluids”, the ICU staffer said.

The animal and laboratory evidence that ARBs and ACE inhibitors cause lung cells to become crowded with ACE2 is well accepted, Professor Esler said – and the medical literature confirms this. The medical authorities confirmed it too, but touted one 2005 study by Kuba et al as evidence that, rather than aggravating the pneumonia caused by SARS-CoV-2, using ARBs and ACE inhibitors to produce ACE2-laden lung cells could actually protect infected lungs. But this take on the Kuba study is a misquote, Professor Esler said. The researchers only used a fragment of SARS coronavirus, its spike protein, which cannot get to work invading and destroying cells, rather than active whole virus, which can run rampant. 

This strategy was deliberate: the researchers wanted to take the viral destruction of cells out of the equation, to see if just a lack of ACE2 affected the severity of SARS-CoV pneumonia. Their curiosity made sense: the ACE2 enzyme inhibits angiotensin II, a substrate that causes inflammation and lung damage when left to accumulate in the absence of ACE2. The researchers had previously found that mice genetically modified to have no ACE2 at all fared far worse than normal mice when their lungs were damaged with acid. Next, they found that both SARS-CoV infection and just SARS-CoV spike protein on its own could decrease ACE2 expression and increase angiotensin II in mouse lung cells. Finally, they found that in mice with acid-injured lungs, treatment with spike protein worsened lung function, whereas treatment with an ARB, a kryptonite drug, improved lung function. 

A lack of ACE2 indeed made mouse lungs more vulnerable, and an abundance of ACE2 indeed bolstered mouse lungs – in the context of acid damage. But the Kuba study did not challenge the body of evidence that severe SARS-CoV pneumonia was primarily a function of the virus destroying lung cells, and the same now goes for severe COVID-19. Rather, the findings suggested that a lack of ACE2 could make matters worse. But Professor Esler argued this finding is irrelevant both for those taking kryptonite drugs, who have a constant oversupply of ACE2, and for those with sparse ACE2 to begin with, who tend to have barely symptomatic COVID-19 (the prime example being children). 

In patients with ACE2 overexpression, the SARS-CoV-2 virion would use up the ACE2 receptors it bound itself to, thereby reducing ACE2 to some extent. But there would be plenty of ACE2 left over on the crowded cell membrane, and the virus would soon destroy the cell anyway, virologist Dr Gary Grohmann, former longtime head of immunobiology at Australia’s drug regulator, the Therapeutic Goods Administration, told Scientific Dissent. “The cell is destroyed, and hundreds of virus particles escape to infect other cells,” Dr Grohmann, expert advisor to the World Health Organisation, said.

The opponents of the kryptonite hypothesis have stretched the Kuba study misquote even further, and claimed that too much angiotensin II does more harm to the lungs than SARS-CoV-2 itself. But if this were true, the patients routinely taking kryptonite drugs would be dying from COVID-19 the least instead of the most, because their ACE2 overexpression would keep angiotensin II at bay, Professor Esler said. 

The opponents are trialling ARBs, ACE inhibitors and statins as treatments for COVID-19 patients in hospital, because, by inhibiting angiotensin II, they reduce inflammation and blood clotting in other critical conditions. It is hoped the drugs will help prevent the extreme and often fatal immune system reactions known as cytokine storms, which result in widespread tissue damage, multi-organ failure and death – and are commonly reported in severe COVID-19. “I anticipate these trials will be harmful, of course. The logic is flawed,” Professor Esler told Scientific Dissent

Even the pre-pandemic research on the drugs’ benefits for more straightforward pneumonias is mixed. In the case of statins, on the one hand they are inexpensive, safe, and readily available; and there is equivocal evidence they improve survival for flu patients. On the other hand, research also suggests statins paradoxically promote inflammation, as shown by a surge in the cytokine interleukin-18, which is in turn linked to increased deaths in patients with severe infectious pneumonia. 

To make a difference for COVID-19 patients, the beneficial effects of statins would have to be potent enough to overcome the ravaging effects of SARS-CoV-2, and the exacerbating effects of ACE2 stimulation. But cholesterol specialist, Associate Professor David Sullivan, head of clinical biochemistry at Royal Prince Alfred Hospital in Sydney, said statins would have a relatively weak effect on preventing cytokine storms in hospitalised COVID-19 patients, and the literature confirms this. So, using statins to treat COVID-19 might be like fighting a blazing inferno with a garden hose in one hand and a flamethrower in the other.

Some opponents of the kryptonite hypothesis have tried to prop up the Kuba study misquote with the argument that patients with severe COVID-19 improve after treatment with the potent anti-inflammatory drugs corticosteroids, especially dexamethasone, precisely because these drugs stimulate ACE2. But they actually might not: the research here too is mixed, with some studies suggesting dexamethasone either reduces ACE2 or binds to it, closing the ACE2 doorway and blocking SARS-CoV-2. 

Moreover, the drugs’ uncertain effect on ACE2 pales in comparison to their two lifesaving effects on patients with severe COVID-19. Firstly, corticosteroids powerfully inhibit proinflammatory cytokines, which calms cytokine storms. Some experts have argued the surge of cytokines in severe COVID-19 is not actually a storm, an immune system overreaction, but is rather a by-product of a high viral load, a legion of virus particles speedily destroying cells, and seriously outpacing the body’s adaptive immune response. When infection destroys cells, cytokines will follow in droves. In obese patients, infection also prompts fat tissue to secrete stored cytokines, adding even more to the swarm. 

Be it a storm or a swarm, the cytokines are a double-edged sword. On the upside, they probably help to finally overthrow SARS-CoV-2 in severe COVID-19, by stripping cell membranes of ACE2 – like slamming on the brakes, right before a car crash. Explaining how is partly guesswork. “Much is still to be understood at the cell level, and we don’t have all the answers yet. Basic research is still catching up,” Dr Grohmann, Adjunct Professor at the University of Sydney, told Scientific Dissent. But it all comes down to Professor Esler’s starting point: sodium. A high sodium level, or hypernatraemia, is the most potent way to reduce ACE2 expression, Professor Esler said. 

In the early stages of COVID-19, as SARS-CoV-2 starts destroying cells, this kicks off cytokines, and patients actually arrive at hospital with low sodium (caused by their kryptonite drugs, and by cytokines), as well as a sudden surge in glucose (caused by SARS-CoV-2 attacking the pancreas, the organ that makes the glucose-regulating hormone insulin, and by cytokines). Both the drop in sodium and the surge in glucose stimulate ACE2 expression even more, accelerating COVID-19. 

But, as the virus destroys more and more cells, and patients deteriorate, the persistently high glucose level, and persistently low oxygen level, in partnership with the accumulated cytokines, all give rise to aldosterone, a steroid hormone that massively increases sodium. Both high aldosterone levels and high sodium levels are commonly seen in ICU patients with severe COVID-19. The patient’s sodium level climbs high enough to obliterate ACE2, leaving SARS-CoV-2 with nowhere to run, and allowing the adaptive immune system’s antibodies to finally catch up with the virus and clear it. 

On the downside, cytokines join forces with their accomplice aldosterone, and the deadly duo deliver the final blows of further tissue damage, blood clotting, organ failure and, ultimately, death. The car crashes head on, leaving no survivors. (Angiotensin II may be a latecomer to the brawl, with the eventual loss of ACE2, but its harms are probably outdone by the cytokines and aldosterone – and studies show angiotensin II levels are not elevated in patients with severe COVID-19.) But, if the timing is just right, dexamethasone can swoop in to mop up the cytokines and save the patient’s life at the crucial moment when SARS-CoV-2 peters out. This only works if the extent of the viral destruction of lung cells is survivable, otherwise a lack of oxygen will cause organ failure long before the cytokines and Co get a chance to. 

Secondly, corticosteroids resolve adrenal insufficiency, a fatal complication often found in critically ill patients, who can become too worn out to produce enough stress hormones to fight their foe. Whether or not corticosteroids stimulate ACE2, their two lifesaving effects can only be a good thing in patients whose cells were already crowded with ACE2 anyway, because they had long been taking kryptonite drugs, and in whom SARS-CoV-2 had already run rampant for long enough to land them in ICU. Using corticosteroids to treat severe COVID-19 might be like fighting a blazing inferno with two high pressure hoses in one hand, and a sparkler in the other. 

Another argument used by opponents of the kryptonite hypothesis is that research in humans shows ARBs and ACE inhibitors do not increase ACE2 expression, but these studies actually measured soluble ACE2 in the blood or urine, which is different to ACE2 expression on cell membranes – one is not a proxy for the other, Professor Esler said, and the medical literature confirms this. 

The other kryptonite drugs have also been shown to stimulate membrane ACE2 in animal and laboratory studies, but the results are mixed once again. Most of the drugs have not been well studied in humans to determine the extent, and location in the body, of their stimulating effect on cell membrane ACE2. The studies require tissue biopsies, so animals are used in favour of humans, Professor Esler explained. The drugs stimulate ACE2 through various physiological mechanisms, some of which are well understood, and some of which remain a mystery. Some of the drugs are meant to stimulate ACE2, some do so accidentally. There are still more questions than answers, and nothing is clear cut. 

Adding further complexity are the other kryptonite drugs mentioned in the medical literature, including the pain and fever remedy ibuprofen, oestrogen replacement therapy, vitamin D, and the vitamin A derivative all-trans retinoic acid (also known as tretinoin). There might be more. Some physiological changes also stimulate ACE2, such as when the body is depleted of sodium, or when the body suddenly becomes too high in glucose (but persistent high blood glucose reduces ACE2). Fever due to everyday viral illnesses increases ACE2 expression in the nose. Smoking might also stimulate ACE2, but this is unclear

Closed ranks and straw men: how scientific is the ARB/ACEi debate?

Professor Esler co-wrote his warning about ACE2 stimulating drugs with his daughter Dr Danielle Esler, a public health doctor playing a key role in Australia’s pandemic response. “Most of my clinical colleagues, even friends, are not too happy about the Esler and Esler paper,” he told Scientific Dissent. “Even though some are distinguished clinical scientists, they find it hard to think that their beloved drugs might now be harmful in this new environment,” Professor Esler said. “They closed ranks and spoke as the voice of the medical establishment. None have engaged me in conversation on this matter.”

Some opponents of the kryptonite hypothesis barely conceal their ire. A group of kidney disease experts referred to the warnings about ACE2 stimulating drugs as “unjustified extrapolations” in The Clinical Journal of the American Society of Nephrology; and the same group has been active on Twitter, referring to academic papers that support the kryptonite hypothesis as “fake news”, and accusing the medical journals that publish them of being “irresponsible” and “creating panic, fear, and irrational behavior”. They also have a blog dedicated to refuting the hypothesis. “This premature hypothesis has generated confusion”, and could lead to a situation whereby “the medical community makes recommendations for patients to withhold potentially life-saving drugs”, some of the group wrote in a letter to the Lancet. Scientific Dissent contacted a key member of the group, who did not respond. 

Associate Professor David Sullivan, of the University of Sydney, identified with the opponents of the kryptonite hypothesis. “We start in a COVID-19 free setting, where ACE2 is definitely a good guy, and drugs that support it aren’t kryptonite, they are gold. COVID-19 comes along and turns everything on its head: it uses ACE2 to get into our bodies,” he told Scientific Dissent. “Everyone is trying to act in the best interests of patients and the population at large, but we are faced with two diametrically opposed sets of advice, and the data to guide the advice is accumulating in uncontrollable circumstances,” Professor Sullivan said.

The dispute over ARBs and ACE inhibitors has probably been fuelled by the profound uncertainty doctors have faced in the pandemic. “Decisions now in the pandemic need to be made on incomplete evidence. That is uncomfortable for most, including me,” Professor Esler told Scientific Dissent. “Falling back on the apparent certainties of medical treatment guidelines is a common response of doctors and, in fact, of their learned national and international medical societies,” he said, and the medical literature supports this. But Professor Esler resists the urge to uphold medical orthodoxy: “I see the need to at least wonder whether some of our most treasured drugs have lost their lustre in these special times.”

At least a dozen medical societies worldwide lost no time dismissing the idea that ARB and ACE inhibitor (ACE-i) drugs have been harmful in the pandemic. “This speculation about the safety of ACE-i or ARB treatment in relation to COVID-19 does not have a sound scientific basis or evidence to support it,” Professor Giovanni de Simone, chair of the European Society of Cardiology’s Council on Hypertension, wrote in a position statement, which was backed by the International Society of Hypertension. Like its counterparts, the statement was brief, it did not address the arguments put forward by the proponents of the kryptonite hypothesis, and it only listed one counterargument, based on a misquote of the Kuba study (as discussed earlier).

“There is no clinical or scientific evidence to suggest that treatment with ACEi or ARBs should be discontinued,” Professor de Simone wrote in the statement – even though the proponents of the kryptonite hypothesis have not actually made this untenable recommendation, this non sequitur, but rather, have insisted from the outset that patients keep taking the medications their lives depend on. “Patients who may deteriorate rapidly if treatment with ACE inhibitors or ARBs is stopped, including those with heart failure or poorly controlled hypertension, should probably continue to take them, even during active infection,” clinical pharmacologists, and proponents of the kryptonite hypothesis, Dr Jeffrey Aronson and Professor Robin Ferner, wrote in the British Medical Journal. The medical societies are refuting their own misrepresentation of the kryptonite hypothesis. This is an act of straw man fallacy, a type of flawed logic used in controversial debates to discredit opposing views – and the result of short-sightedness and defensiveness, bioethics experts say. 

Like the medical societies, patient support organisations worldwide have also dismissed the warnings on ARBs and ACE inhibitors, with the American Heart Foundation claiming they are “misinformation” and a “rumour” that has been “debunked”. But, far from being false content circulating on social media platforms, the warnings are the expert opinion of many international figures in medicine, as published in top-tier medical journals. “Their message is not direct to me, but to doctors and the general public, from their elevated offices: ‘This is not true. Do not change or stop your medication’,” Professor Esler told Scientific Dissent. The news media, in turn, has reported the message with uncritical reverence instead of scrutiny

The medical establishment’s one-sided advice to millions of patients worldwide, that their ARB and ACE inhibitor medications pose no threat to them, belies the plausible risk that the drugs make patients vulnerable to severe COVID-19. In the absence of definitive evidence, the medical authorities have misconstrued expert warnings, withheld potentially lifesaving information, given patients false reassurance, and failed to tell them about the whole gamut of ACE2 stimulating drugs. This is arguably a breach of the International Code of Medical Ethics, which states: “Physicians shall deal honestly with patients.” 

Although bioethics expert Professor Paul Komesaroff, of Monash University in Melbourne, admitted the one-sided advice was unethical, he backed away from criticising it, as he did not want to politicise the scientific debate around ACE2 stimulating drugs and COVID-19. “It is important that discussions within science are argued out on the basis of the ideas, concepts and evidence, and are separated from the effects of power and local interests,” he told Scientific Dissent. But the powerfully influential medical societies politicised the debate from the outset, by referring to the kryptonite hypothesis as unsound speculation, by countering it with misquoted evidence and straw man fallacy, and by telling patients it is a false rumour that has been debunked.

“Professional medical associations can be highly problematic, and their guidelines may be subject to personal biases, including political conservatism, but there is no conspiracy of controlling forces to ensure that a particular view prevails,” Professor Komesaroff said. “While pharmaceutical companies have strong vested interests they are committed to defending, that is unlikely to be the case with the multiple professional associations and clinicians who have expressed scepticism about the hypothesis,” he told Scientific Dissent

But pharmaceutical policy expert Associate Professor Joel Lexchin, of York University and the University of Toronto, disagreed. “Medical societies usually have strong links to drug companies, and receive financial support from them, and so medical societies may take positions that are favourable to drug companies,” he told Scientific Dissent. Professor Lexchin is co-author of a study published in the British Medical Journal that found the majority of medical society leaders received substantial payments from Big Pharma. 

“There may be a link between receiving industry funding for speaking, consulting, or research and the publication of apparently promotional opinion pieces,” experts in pharmaceutical marketing from Georgetown University wrote. The pharmaceutical industry has also manipulated medical debates by funding many partisan reviews and commentaries, often ghostwritten, for publication in medical journals, which “may be designed to convey specific, but subtle, marketing messages”, they wrote. (Notably, the authors of influential papers that claim angiotensin II plays more of a role in severe COVID-19 than the viral destruction of cells, and hence that severe COVID-19 should be treated with kryptonite drugs, are on the Big Pharma pay roll.)

Here we go again: how predictable is the rejection of the hypothesis?  

The strong financial ties between medical societies and pharmaceutical companies is concerning, because professional medical associations greatly influence medical research, education, and practice. “Their agenda is so wide-ranging, involving almost all aspects of medicine, that scientific integrity, objectivity, and independence are essential,” wrote medical historian, Professor David Rothman. But the medical establishment’s disregard for warnings that preferred drug treatments might now be hazardous is perhaps better explained by psychology than conspiracy. Resistance to change in medicine long predates the rise of Big Pharma, dating as far back as the contentious introduction of hand-washing in the mid-1800s. 

Professor Komesaroff, an endocrinologist, experienced such resistance firsthand in the 1990s, when medical authorities believed prescribing long-term hormone replacement therapy (HRT) to postmenopausal and elderly women reduced their risk of heart disease. “In some clinical circles, it was argued that it was unethical not to prescribe HRT,” he told Scientific Dissent. The practice was based on observational studies and aggressive Big Pharma marketing. It had taken off in the mid-1960s with the publication of the best-selling pro-HRT book Feminine Forever, which was financed by the same pharmaceutical company whose HRT product Premarin was the most frequently prescribed drug in the US in the early 1990s. “During this time, my efforts to raise the alarm that the therapies were being oversold attracted a great deal of personal acrimony against me,” Professor Komesaroff said. 

But by 2002, definitive research in the form of a randomised controlled trial of 16,608 healthy postmenopausal women with a uterus, one of the trials in the Women’s Health Initiative research project, vindicated Professor Komesaroff’s view: it found HRT did more harm than good – so much so that the trial had to be stopped early. Combined estrogen and progestin therapy actually increased rates of heart disease, as well as stroke, blood clots, and breast cancer. (It decreased rates of hip fracture, and bowel and uterine cancer.) The medical authorities who closed ranks and dismissed Professor Komesaroff’s warnings were proven wrong. 

(Having said that, the evidence has since changed again. The Women’s Health Initiative trials targeted women aged 50 to 79, as elderly women were often prescribed HRT at the time to treat ageing in general. But studies have since found that HRT can be beneficial for newly menopausal women in their 50s – it is older women who should avoid HRT.)

Professor Komesaroff’s experience with HRT is an example of medical reversal: when a new and superior clinical trial contradicts current clinical practice, revealing it to be ineffective or harmful – a result of missteps. “Although this phenomenon should be rare in the age of evidence-based medicine, it is ubiquitous,” professors wrote in Yale Journal of Biology and Medicine, citing many other examples of medical reversal. Discredited practices often remained in place for years, sometimes decades, even in cases involving no financial conflicts of interest, due to “the mere wish to defend one’s practice, procedures, and scientific beliefs”, the experts wrote. “Reversal harms patients who undergo the contradicted therapy during the years it was in favor, and in the lag time before a change in medical practice,” they wrote.

This lag time can be catastrophic. For example, the medical establishment spent 20 years falsely reassuring pregnant women it was safe to check their babies’ placement with an x-ray, despite hard evidence to the contrary. In the mid-1950s, the epidemiologist Dr Alice Stewart published her unequivocal finding that the children of women who were x-rayed while pregnant had an increased risk of developing cancer. “Her finding that there was danger in receiving even such a low dose of radiation was met with outrage by doctors and the nuclear industry, and Dr. Stewart had difficulties obtaining financing for other studies. But by the mid-1970’s, other scientists had duplicated her findings on prenatal X-rays, and the practice ended,” the New York Times wrote in Dr Stewart’s obituary. 

The medical profession is founded on the ethical principles of beneficence, or doing good, and nonmaleficence, or doing no harm. The heroism, selflessness and compassion doctors have shown during the pandemic attests to this. But doctors are only human. “Human beings are deeply unwilling to change their minds,” social psychologists Carol Tavris and Eliot Aronson, authors of the book Mistakes Were Made (But Not by Me), wrote in The Atlantic. “As people justify each step taken after the original decision, they will find it harder to admit they were wrong at the outset. Especially when the end result proves self-defeating, wrongheaded, or harmful,” they wrote. This resistance is due to cognitive dissonance: “What we feel when the self-concept – I’m smart, I’m kind, I’m convinced this belief is true – is threatened by evidence that we did something that wasn’t smart, that we did something that hurt another person, that the belief isn’t true,” Carol Tavris told the New York Times

“The construct of cognitive dissonance is very relevant to the clinical context,” researchers wrote in the journal Medical Education. Doctors often encountered new beliefs that conflicted with long-held ideas and behaviours; and they often made autonomous decisions that, if wrong, would have potentially horrific consequences, they wrote. “People can become entrapped in continuing down a suboptimal path, escalating their commitment to a choice even in the face of evidence that outcomes are poor,” the researchers wrote.

That medications meant to help might now be doing harm is a bitter pill for doctors to swallow, and their resistance to the idea also raises the well-documented problem of psychological biases in medicine. There are several types, and of particular relevance is status quo bias, an emotionally driven preference for the current state of affairs, and an aversion to the losses associated with change. “This bias can facilitate clinician inertia, for example, when clinicians do not step down treatments, even when it is indicated,” the authors of a recent paper on doctors’ cognitive biases wrote in the British Medical Journal. Closely related, omission bias is judging actions that lead to harm as much worse than sitting on your hands, even if doing nothing leads to equally harmful outcomes. 

With cognitive dissonance and psychological bias comes false reassurance: that nothing has changed, that no action is required, that there is no new threat. “What you have to do in healthcare is to reassure everybody that everything is going to be alright. Reassurance is deeply embedded in the practice of medicine,” observed Guardian columnist Dick Vinegar. “Everything, we have to be reassured, is for the best in the best of all possible worlds. The outcomes of the need for reassurance are endless cover-ups.” 

Muddying the waters: can the pandemic research be trusted?

We do not yet have definitive evidence on the risk posed by kryptonite drugs, and Professor Esler is concerned by the quality of research thus far in the pandemic. “Research at the moment is being done on the run, often in rather chaotic circumstances. Science is best not done on the run,” he told Scientific Dissent

“I fear the principles of evidence-based medicine have been abandoned,” clinical pharmacologist Dr Jeffrey Aronson, of Oxford University’s Centre for Evidence-Based Medicine, told Scientific Dissent. “In the face of a mindless virus, we have become mindless,” he wrote for the British Medical Journal, adding that COVID-19 research was often poorly designed, and failed to report clear results. “Instead of looking for strong hypotheses and testing them, researchers are positing weak hypotheses and trying to prove them,” he wrote. But Dr Aronson, president emeritus of the British Pharmacological Society, took no issue with the kryptonite hypothesis – he supported it in the British Medical Journal. “The concerns are legitimate, and should be given equal airing alongside the opposing opinions,” he told Scientific Dissent

Experts wrote in BMJ Evidence-Based Medicine that the “race to publish” during the pandemic meant COVID-19 papers were marred by aberrant data collection, poor statistical analysis, erroneous conclusions, and limited scrutiny during the editorial and peer review process. One prominent US study on the effect of ARBs and ACE inhibitors on COVID-19 was retracted due to concerns about the validity of the data; and experts raised concerns that another such study had “severely skewed results” due to a type of research bias called immortal time bias. Most COVID-19 studies, including those on kryptonite drugs, were also replete with another type of research bias called collider bias, experts warned in the journal Nature Communications – adding that unbiased research was “urgently required to provide reliable evidence”. 

Professor Lyle Gurrin, of the Centre for Epidemiology and Biostatistics at the University of Melbourne, is among several experts in research methods who have refuted the findings of studies that found kryptonite drugs neither increased patients’ risk of developing severe COVID-19, nor their risk of dying from it. Professor Gurrin said the researchers had ignored the likelihood that patients were taking multiple kryptonite drugs at once, and had thus failed to pinpoint the true effect on COVID-19 of any individual drug yet studied. “Without knowing what other medications people took, it is not possible to draw any meaningful conclusions from the results,” he told Scientific Dissent

The lifestyle-related risk factors that lead to disease (an unhealthy diet, being sedentary, being overweight or obese, stress, smoking, drinking too much alcohol), are more or less the same for all of the underlying medical conditions most commonly seen in patients who succumb to severe COVID-19. So, these conditions often occur in tandem as comorbidities, and the kryptonite drugs that treat them are taken together more often than not. A blood pressure drug, a diuretic and a statin is one routine kryptonite drug cocktail, for instance – and this is just the start for patients with type 2 diabetes, who also take at least one, and often three or four others. 

Each kryptonite drug probably stimulates ACE2 to varying degrees, and in varying sites in the body; and when taken together their discrete effects on COVID-19 severity are all mixed into a concoction of risk that is hard to separate. In research, this mixing in of effects is called confounding, a type of bias that can seriously skew results. Confounding bias can falsely make factors appear to be linked or unlinked, or to have stronger or weaker links than they really do. 

Scientific Dissent contacted the researchers behind two widely-publicised US studies on the effect of ARBs and ACE inhibitors on COVID-19, who admitted they did not account for the confounding effects of all the other ACE2 stimulating drugs in their analysis. When asked if they would redo their analysis with the other kryptonite drugs in mind, the Reynolds et al group did not respond, but the Mehta et al group said, “Accounting for all other medications that modulate with the ACE2 receptor is an important task, and as we progress into the pandemic, we need to keep revisiting this question.” But this has not yet happened.

The ACE2 stimulating effect of all the other kryptonite drugs was on record before the ARB and ACE inhibitor studies commenced; and researchers have ignored this obvious confounding bias in the face of counterintuitive results: after fiddling with numbers that often initially suggest the the drugs are harmful, researchers conclude the drugs are harmless, or beneficial, even though they open the door to a deadly virus, and are taken by those who consistently die from this virus the most. “Better to do something that from the point of view of improving human health is useless or, even worse, wrong, because we can, rather than think about what we would need to do to achieve something useful that we can’t do now,” Professor Gurrin said of the pandemic research efforts thus far. Compounding the problem, multiple media outlets have taken the research at face value, instead of interrogating the evidence.

Experts are especially concerned by studies that suggest ARBs, ACE inhibitors, and statins have a protective effect on COVID-19. “In many papers, you will see that the crude unadjusted data show an apparent risk causing effect of the drugs, which quickly moves close to the null after adjustment for age and sex. The further adjustment – in my opinion over-adjustment – for cardiac risk factors creates an apparent protective effect that I don’t think is real,” evidence-based healthcare expert, Professor David Henry of Bond University in Queensland’s Gold Coast, told Scientific Dissent. “To see such adjustments flip a risk-elevating relationship to a significant protective effect is unusual,” Professor Henry, a pharmaco-epidemiologist, wrote in the journal Heart. Incorrect statistical adjustment is another research flaw that can bias study results – and it might not stop at cardiac risk factors. Given both age and sex are factors that affect the number and dose of kryptonite drugs a patient takes, and given the drugs might play a greater role in causing severe COVID-19 than age and sex per se, overzealous adjustments for age and sex might also bias study results: they might cause the exposure more than the outcome. 

The questionable protective effect of ARBs and ACE inhibitors can also result from collider bias, biostatistics experts wrote in the journal Nature Communications. Like confounding bias, collider bias can also falsely make factors appear to be linked or unlinked, or to have stronger or weaker links than they really do. When the participants in a study are not representative of the general population (as in studies that only include COVID-19 patients in hospital), collider bias can seriously skew results if the same risk factor (taking kryptonite drugs) influences both the likelihood that a patient will be included in a study (by making patients more likely to require hospital treatment for COVID-19), and the outcome being studied (COVID-19 death). “In many circumstances, this can lead to a risk factor for disease onset that appears to be protective for disease progression,” the experts wrote. With collider bias, kryptonite drugs can falsely appear to protect patients from dying of COVID-19.

Safeguarding the vulnerable: what medication changes are needed?

Although there is currently insufficient evidence to prove ACE2 stimulating medications are a risk factor for severe COVID-19, there is enough to make stopgap recommendations, lest doing nothing proves to be doing harm. “I know of family members of international figures in medicine who have changed their medication, as a safeguard,” Professor Esler told Scientific Dissent. This is an option for patients with stable hypertension, who could switch to beta-adrenergic blockers. 

But medication changes would be unsafe in patients with heart failure, kidney disease, type 2 diabetes or fatty liver disease, who should shield, or opt for protective self-isolation at home, until fully vaccinated. “Your ‘home fortress’ is the final barrier,” Professor Esler told Scientific Dissent. Shielding has been criticised for causing anxiety and depression (and for being of little use in a pandemic), but doctors have been making it work for years to keep cancer or transplant patients, or premature babies, free from infection. Health professionals know how to mitigate the practical and psychosocial downsides of shielding; and they know entire households can learn and follow infection control guidelines to protect their loved one. 

There is no one-size-fits-all option – except to ensure that any medication changes are overseen by the treating doctor. In the case of patients who take kryptonite drugs to prevent a disease they do not yet have, or off-label for non-serious health problems, Professor Esler said they could elect to have a drug holiday, if the risks of treatment outweighed the benefits during the pandemic. For example, some patients take the diuretic spironolactone off-label for acne, baldness, hairiness, athletic performance, PMS bloating and weight loss. “Stopping the drug for these indications would be justified,” Professor Esler said. Statin treatment is more complicated to stop, Associate Professor David Sullivan said, but the literature describes alternatives for some disease-free patients. 

Patients who are obese – one third of the US population are in this category – could lose a modest amount of weight through healthy eating and exercise as a means to phase out treatment with kryptonite medications, under medical supervision, if they were yet to develop the diseases that come with the territory. Losing five pounds can lower blood pressure; and a sustained seven percent reduction in body weight can lower blood sugar levels

Professor Esler also advised against sodium depletion, as a reduction in body sodium content stimulates ACE2. This can happen in many ways, including: gastroenteritis, deliberate purging, eating disorders, a diet very low in sodium and high in its antithesis potassium, drinking too much water after heavy exercise, taking the recreational drug Ecstasy, and initiating treatment with antidepressants. If any of the above goes on for at least a week, and if the lost sodium is not replaced, ACE2 overexpression can result, Professor Esler said. This means overrun health workers, who are forced to skip meals and wear hot and sweaty personal protective equipment (PPE) during long shifts for days on end, are also at risk of sodium depletion. 

There are some potential ACE2-related treatment options for COVID-19, but they are yet to be properly tested. “If I get COVID-19, I will take fludrocortisone (Florinef), a prescription drug,” Professor Esler said, recommending a daily dose of 0.1 mg. Fludrocortisone reduces ACE2 expression by decreasing the amount of sodium the body excretes in urine, he said. “Reducing the activity of ACE2 in cell membranes could theoretically reduce the ability of SARS-CoV-2 to penetrate cells,” clinical pharmacologists Dr Jeffrey Aronson and Professor Robin Ferner wrote in a paper for Oxford University’s Covid-19 Evidence Service. 

Experimental evidence shows dietary sodium loading also decreases ACE2 expression, so eating sodium-rich food or taking sodium tablets might be worth a try for people who do not have high blood pressure, heart failure or kidney disease – bearing in mind these conditions are underdiagnosed, and it might be prudent to check with the doctor first. “The ACE2 change I expect would take no less than one week. Would it be too late once symptoms have started? Hard to be sure, given individual differences between people in the speed of onset of the disease,” Professor Esler told Scientific Dissent.

The medical literature does not clearly identify prescription drugs that reduce ACE2 expression, but research suggests age old essential oils might hold promise. One laboratory study found geranium oil substantially reduced ACE2 on cell membranes; and Mayo Clinic research showed geranium oil was safe for adults to use in the nose (mixed with sesame oil), where SARS-CoV-2 begins its advance; while some patients with bronchitis benefit from adding geranium oil to their inhaled treatments. Eucalyptus oil is another potential preventative option, given its antiviral properties – it can be added to a saline nasal spray. For children, both oils can be diffused, keeping safety in mind: inhaling essential oils triggers asthma attacks in some, and swallowing essential oils can be fatal.

These essential oil approaches have the added benefit of helping to ward off other everyday viruses, which might help protect against COVID-19: viral illnesses that cause fever give rise to cytokines called type I interferons, which in turn increase ACE2 expression in the nose. This effect occurs in everyone, including infants and children, who might then become vulnerable to COVID-19, especially if their viral fever is treated with the kryptonite drug ibuprofen. Children’s hospitals report that their young patients often have other everyday ‘piggyback’ viruses. Influenza vaccines might also help prevent COVID-19 in the same way, as might antiseptic mouthwash (which might help reduce SARS-CoV-2 viral loads in the early stage of COVID-19). But other cold and flu remedies are best avoided, excepting probiotics, which studies suggest might be a beneficial adjunct treatment for COVID-19. 

Melatonin, a popular natural sleep-aid, might also help prevent COVID-19, Cleveland Clinic research suggests, and trials are underway to see if this holds true. Several papers have argued that melatonin has potent anti-inflammatory, anti-oxidant, anti-viral, and anti-obesity properties, and is safe to use. Melatonin also inhibits calmodulin, a substance that helps ACE2 stick to cells, and this effect sheds ACE2 from the cell membrane, professors wrote

Professor Paul Zimmet AO, honorary president of the International Diabetes Federation, and contributor to the landmark Lancet paper on diabetes and COVID-19 that supported the kryptonite hypothesis, said the over-the-counter cough medicine bromhexine hydrochloride (Bisolvon, Chesty Forte in Australia) was a possible therapy against COVID-19, and had few side effects. It blocks a substance called TMPRSS2, which helps SARS-CoV-2 get through ACE2 doorways and into cells. (Bromhexine hydrochloride is not safe for young children, but research suggests children have lower levels of TMPRSS2 than adults, anyway.) “I’ve told friends about it, it’s cheap, it’s over-the-counter; and if there is a study that comes out and confirms it has a beneficial effect on COVID-19, then I think it’s worth considering it,” he told Scientific Dissent

But this highlights another gap in the COVID-19 research. “Prophylactic and therapeutic approaches have not been particularly supported around the world, which is really unfortunate,” Dr Gary Grohmann told Scientific Dissent. “We are absolutely swamped by groupthink on vaccinations, so all the money has gone into vaccine development all around the world,” Dr Grohmann said. High cost treatments are now starting to emerge, but low cost options remain elusive. 

The rule of thumb on COVID-19 vaccines is that they protect you, not others; they stop most severe cases, but not new cases. Saving lives, for now at least, might be as good as it gets: many experts argue that COVID-19 vaccines do not stop the spread of dominant SARS-CoV-2 variants, making herd immunity unachievable. (Herd immunity happens when the vaccinated many prevent infection in the unvaccinated few.) “These vaccines do not break the lines of transmission,” Dr Grohmann said, of the two-dose regime. Delta data shows that, although cases might initially drop in a freshly vaccinated population, they will inevitably rise again, as vaccine effectiveness against infection wanes. 

Countries with high vaccine uptake, such as Iceland and Singapore, have still had large Delta outbreaks, with most of the cases in fully vaccinated people. Health officials from both Israel and Singapore have said their whole-population data shows mRNA vaccines are only about 40 percent effective at preventing infection – the less recent the doses, the less protection they offer against infection. Vaccine protection against severe disease lasts longer, as seen in the UK’s dramatic drop in hospitalisation rates this year, but this too wanes after about six months in older adults and other clinically vulnerable groups. 

Several countries have now introduced COVID-19 vaccine boosters, especially for the clinically vulnerable. But vaccine rollout remains uneven, and the people who need their doses the most are at the back of the queue to get them. The same social disadvantage that gives rise to the lifestyle diseases treated with kryptonite drugs, also results in poor access to information, healthcare services, and online booking systems. These access problems are further amplified by language barriers, disability, geographical remoteness, and incarceration. “Disadvantaged [people] face triple jeopardy – low vaccination rates, greater likelihood of being infected with COVID-19, and higher risks of serious disease and death from COVID-19,” Australian academics wrote.

Protecting the vulnerable against an airborne pathogen means facemasks, good ventilation, and air purifiers remain important. Eye protection might also help stop the spread of SARS-CoV-2, which can linger in the air, land on the surface of the eye, and sneak through the tear duct to infect the respiratory system, gut, and circulation, experts wrote in The Lancet. In the hands of experts, far-UVC lamps might also stop SARS-CoV-2 in its tracks, but safe household models are not yet available. 

The rule of thumb on facemasks is that they protect others, not you: they stop you sharing your germs, but they do not stop you inhaling others’ germs. So, it is important that everyone, even those who are fully vaccinated, wears a valve-free face mask over their mouth and nose indoors, and in congested areas outdoors, to prevent the spread of COVID-19. “The evidence is quite thin that a face mask will stop you from getting a virus infection, but the evidence is reasonably good that a face mask stops you transmitting the virus, because your breath and saliva will hit the mask, and that will definitely halt any transmission through the air,” Dr Gary Grohmann said. Respirators on the other hand, such as the P2 and N95 masks worn by frontline health workers, do offer good protection against SARS-CoV-2, experts wrote in the Medical Journal of Australia. A study by Cambridge University NHS Hospitals Foundation Trust found FFP3 respirators might provide complete protection against COVID-19. 

In conclusion: where to from here?

It was probably impossible to provide a right-first-time response to the COVID-19 pandemic, and the medical establishment might have dug itself into a hole. Proponents of the kryptonite hypothesis have called on medical societies to reconsider the effect of ACE2 stimulating drugs on COVID-19 severity, and to make an about-turn on their recommendations. 

“Although it’s difficult, changing our minds is not impossible. The challenge is to find a way to live with uncertainty, make the most informed decisions we can, and modify them when the scientific evidence dictates,” social psychologists Carol Tavris and Eliot Aronson wrote. “Admitting we were wrong requires some self-reflection – which involves living with the dissonance for a while rather than jumping immediately to a self-justification.” They advised asking: “Why am I believing this? Why am I behaving this way? Have I thought it through or am I simply taking a short cut, following the party line, or justifying the effort I put in to join the group?” 

Some of the medical societies have expressed a willingness to change their minds on ACE2 stimulating drugs, if and when they see convincing evidence. But access to the requisite research funds is not a level playing field. The billions of dollars that go into academic medical research each year are allocated through a process of  expert peer review, and merit is rarely the deciding factor, studies repeatedly show. One study found that expert evaluators tended to misconstrue and downgrade any research proposal that sought to explore new ideas, such that potentially game-changing insights would never see the light of day. 

Moreover, reports published in the British Medical Journal have revealed that much of the available funding for medical research comes either directly from pharmaceutical companies, often for studies run by medical society leaders, or from private foundations like the Wellcome Trust or the Gates Foundation, both of which have hundreds of millions of dollars invested in pharmaceutical companies. The same foundations are influential in government, multilateral and public-private partnership decisions on medical research funding. So, the definitive research required to change minds, might not be possible without changed minds – a catch-22 situation. 

Although the kryptonite hypothesis could be the solution to the enigma of what makes people susceptible to severe COVID-19, its proponents are quick to point out that there is probably a complex network of factors at play. To definitively determine the precise role of each ACE2 stimulating medication (and physiological state) in severe COVID-19, experts have made an urgent call for the very studies that have so far eluded us: research that asks the right questions, is designed to avoid bias, and is independently funded. “Big Pharma involvement would ensure the research findings had no credibility,” biostatistics expert Professor Annette Dobson, of the University of Queensland, told Scientific Dissent

Epidemiologist Dr Ben Goldacre, of the University of Oxford, and author of the books Bad Science and Bad Pharma, told a UK parliamentary inquiry there was “extensive and longstanding evidence” that Big Pharma routinely buried unfavourable studies, or parts of studies. “This is an important source of bias, and can lead to exaggeration or misrepresentation of the true effects of a treatment,” Dr Goldacre said. A systematic review of the evidence by the world-leading research nonprofit Cochrane found: “Industry sponsored drug and device studies are more often favorable to the sponsor’s products than non-industry sponsored studies due to biases.” 

There are differing opinions on the type of research required to shed light on the kryptonite hypothesis. “What we need is a large, randomised, double-blind, preferably placebo-controlled trial of ACE inhibitors and ARBs, in which other medicines are evenly distributed between the groups,” Dr Jeffrey Aronson of Oxford University told Scientific Dissent. “We need to determine whether those taking the drugs in advance of an infection are benefited or harmed by doing so.” But Professor Esler warned such trials might prove harmful, and instead recommended a study using existing patient data that takes all relevant factors into account – perhaps easier said than done. “I think many of the COVID-19 databases are rather chaotic, given the social distress. I hope the quality of some databases are up to the task,” he said. “It may be difficult to test this hypothesis. Do we as clinicians just live with it, leaving prescribing unchanged?” 

The usually ordered world of medical academia is currently flooded with papers rushed to print without proper scrutiny. Warnings that contradict the go-to sources of trusted knowledge, the international medical societies, are unlikely to be heeded. But when the stakes are as high as more than five million recorded COVID-19 deaths, and when the request to reconsider the kryptonite hypothesis comes from multiple fields of medicine, and from eminent experts, is refusing to budge an act of reason or bias? 

Last updated 8 November 2021

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Scientific Dissent originally published The Kryptonite Hypothesis as an essay, on December 16, 2020. The author subsequently rewrote the piece in a longform investigative journalism format, and Scientific Dissent republished it as a special report on 18 January 2021. It is continuously updated. 

A handful of professors from both sides of the ACE2 debate have okayed the factual and technical accuracy of the special report, and news editors have commended it. But it is not to be taken as medical advice, and readers should discuss any concerns with their treating doctor.