Easter Monday, 13/04/20; An Australian Chest Physician’s Reflections on the Covid-19 Pandemic. “Misery acquaints a man with strange bed-fellows”. ACE2, Covid-19 and sarcoidosis.
Letters from Australia. No.6 by Prof. Roger KA ALLEN (www.sarcoidosis.com.au)
The strange nature of Covid-19 lung involvement
I have observed over the past weeks that the medical profession has been on a steep learning curve in the management of Covid-19 and yet again, today, I read that there have been serious doubts expressed over the role of ventilators. From what I have read, the inflation pressures of the lungs with patients with severe Covid-19 lung involvement have not been particularly high e.g. around 13 cmH2O which is a pressure we would often see in patients on CPAP for sleep apnoea. In other words, the lungs are not as stiff as we usually see in ARDS (Acute Respiratory Distress Syndrome) and viral pneumonia e.g. influenza pneumonia. The notable difference is the lower oxygen levels in Covid-19 and often more severe than the clinical symptoms suggest. A normal lung does not take much pressure to inflate but as the lung becomes more infiltrated with inflammatory cells and fluid, it becomes stiffer e.g. less compliant like trying to inflate a brick compared to a balloon.
However there is something unusual happening in Covid-19 pneumonia and we think it is to do with the small blood vessels in the lungs which normally interact with the capillaries to exchange oxygen from the air and to get rid of carbon dioxide from the tissues. Each capillary wraps around the alveolar sac a bit like your hand grasping a tennis ball with each finger representing a capillary branch and the ball representing an air sac or alveolus. So far there have been very few autopsies from patients dying from Covid-19 and this may be from the danger to pathology staff and this to me is a major draw-back as detailed a post-mortem examination tells us much. Indeed, post-mortem rates have been dropping world-wide since I graduated, mainly due to cost.
Nevertheless, from my reading of the literature on a daily basis, I glean that something unusual is happening to the blood vessels in the lungs, resulting in disproportionately low arterial blood gases for the degree of lung involvement. It’s all out of proportion. In severe cases there is a very high level of D-dimer, a breakdown product of the clotting system and some even develop a very serious clotting disorder called DIC (Disseminated Intravascular Coagulation) which is treated, ironically, with heparin, a drug which makes one’s blood less likely to clot. Cardiac involvement can also occur.
Patients may present with very low oxygen levels manifest as blue lips (cyanosis) out of proportion to their breathlessness and this usually triggers the medical staff to intubate the patient and put them on a ventilator. However, more and more ICU specialists in Italy and including in New York have expressed the view that ventilatory support in some cases may be putting the patient at even more risk with a resultant high mortality verging on 80% in the some centres and at best about 50%.
A patient presenting with an oxygen saturation of 60% is equivalent to being at Base Camp at Mt Everest at 20,000 feet and I see many patients with obstructive sleep apnoea who desaturate to this level all night without dying and do this night after night, year after year. However, when awake, their oxygen levels are normal or near normal. I also understand that patients are being intubated with oxygen saturations around 90 to 80% which is not really that bad at all but it is a warning that the lungs are being affected and may get worse quickly.
The ventilator, particularly if excessive pressure are needed may open up parts of the lung (called “recruitment”) which are still not being well perfused with blood resulting in what is called a “shunt” i.e. blood goes straight through the lung without picking up oxygen a bit like an express train going through a station without stopping to unload passengers e.g. CO2, or picking up new ones i.e. oxygen. Thus, it appears to me that some patients may do better just with high-flow oxygen or even non-invasive ventilatory support (BiPAP or CPAP) with oxygen than with invasive ventilatory support with survival about 50% and higher mortality, depending on a range of other factors including co-morbidities, age, ethnicity, obesity etc.
ACE2 in Covid-19; strange bedfellows
As a young doctor I was asked by my professor if I would like to write a paper on the use of serum angiotensin-converting enzyme (serum ACE) as a test for sarcoidosis and which I duly did and published this in 1980 as this enzyme which was found to be an integral part of blood pressure homeostasis also went up in sarcoidosis. Around that time the first ACE-inhibitor was discovered in the venom of the South American pit-viper, Bothrops jararaca, which uses the venom to drop the blood pressure of the prey. Thus captopril, the first ACE-inhibitor blood pressure medication was born. This later stimulated my desire to research this topic more deeply and which led to my being awarded a NH&MRC Research Scholarship for a doctor of philosophy and led to a life-long dedication to the study of sarcoidosis and to the investigation and management of those afflicted with this complex condition. Ironically, one my examiners of my thesis was a specialist in Denmark with expertise in sarcoidosis and many of the early pioneers were Scandinavian as was one of my great-grandfathers. Subsequently I learnt Norwegian and feel privileged to have some insight into their Scandinavian world.
Although the name of my thesis was “The Role of Angiotensin-Converting Enzyme in Sarcoidosis: A Clinical and Laboratory Study” (University of Melbourne, 1990), I felt that after five years, I never fully understood why it is found in this disease due to the withering complexities the enzyme had on inflammation, blood pressure control and other mechanisms still imperfectly understood e.g. the kinen-kallikrein system. Sometimes the missing pieces of the jigsaw puzzle are found much later due to advances in laboratory techniques, discoveries in seemingly unrelated areas and serendipity. Time does not allow me to elaborate further on ACE in sarcoidosis, but Covid-19 has recently revealed another piece of the puzzle twenty years later.
To understand a little of what I am talking about requires some reading about the renin-angiotensin system. Nevertheless, it has been found that the Corona virus binds onto cells by the ACE2 receptor on cells and through this it gains entry to the cell to replicate. “Misery acquaints a man with strange bed-fellows”. (The Tempest, Act 2, Scene 2). This is one smart virus. Why it does this, I am not sure we know but this may explain why Covid-19 patients with hypertension do particularly badly as the ACE which I studied, converts angiotensin-I to angiotensin-II as well as breaking down bradykinin, as part of the blood pressure regulatory system and in regulation of inflammation. It also may explain, at least imperfectly, why patients with severe Covid-19 pneumonia have uncharacteristically low oxygen levels, possible shunting etc. I shall not engage in more conjecture other than to say, that this shows us once again, that everything is interconnected and incredibly complex and that simplistic, mechanistic view of medical research are naïve. “We see through a glass darkly.”
Sarcoidosis
This brings me to sarcoidosis and the pandemic. As one managing many patients with sarcoidosis, I have recommended that patients continue on their current treatment which is often hydroxychloroquine (Plaquenil) or methotrexate as I try to avoid oral prednisolone as much as possible as it is not a good drug for the long haul due to side-effects. There is some evidence that hydroxychloroquine may offer some benefit with Covid-19 but the jury is still out notwithstanding Mr Trump’s enthusiasm for it. I have had advice from an immunologist that methotrexate may not greatly increase the risk of contracting Covid but in the event of this, serious consideration needs to be given regarding a temporary cessation. On the other hand, it is better I think to keep sarcoidosis stable with these medications as treatment reduction may be followed by new symptoms such as cough and breathlessness or a flare up of cardiac symptoms. In this case, it would invoke the possibility that Corona virus was causing the symptoms, thus creating a need for testing, medical assessment and even hospitalisation. In a nutshell, reducing or ceasing treatment would seriously muddy the waters.
Patients still need to have their monthly blood tests while on methotrexate and have six monthly optometry checks while on hydroxychloroquine. As we don’t know if the latter works reliably in Covid-19, I recommend that no one start on this drug just because of possible Covid infection. In summary, stay the course, maintain disease stability and remain “bunkered down” until this storm passes and until a vaccine is available. Influenza vaccine is also important to prevent unnecessary infection which will burden the health system and put you at risk of contracting Corona virus in hospital.
Time and space do not permit my elaboration on Corona virus, ACE2 receptors on cells and sarcoidosis but there are ideas fermenting in my head, perhaps for a later time.