https://www.nytimes.com/interactive/2020/04/03/science/coronavirus-genome-bad-news-wrapped-in-protein.html

In a much earlier comment, I said that we should be skeptical of reports that loss of smell or taste are symptoms of Covid-19: Maybe these symptoms, also characteristic of the common cold, should be taken with a grain of salt? But I also raised the possibility of olfactory bulb compromise and, hence, CNS involvement.

Now this:

NEUROLOGICAL COMPLICATIONS OF CORONAVIRUS INFECTIONS
Avindra Nath, MD
NIH–NINDS

Preprint – Neurology (March 30, 2020)

https://www.medpagetoday.com/infectiousdisease/covid19/85746?xid=nl_popmed_2020-04-02&eun=g1138744d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=CoronaBreak_040220&utm_term=NL_Daily_Breaking_News_Active

https://n.neurology.org/content/neurology/early/2020/03/27/WNL.0000000000009455.full.pdf  –

“In 1896, Sir William Osler said, “humanity has but three great enemies, fever, famine and war; of these by far the greatest, by far the most terrible, is fever”. This rings true even today. The newly emerged SARS-CoV2 virus has stricken fear and panic amongst the public, health care workers, patients, politicians and financial markets. Fear strikes the minds of the unprepared. So we must ask ourselves why have we been caught by surprise? In the recent past there have been many major epidemics. This includes Ebola, Zika, Dengue, Chikungunya, acute flaccid myelitis and H1N1 influenza, to name a few. But SARS-CoV2 is different. It struck home! And so very rapidly. It emerged in the region of Wuhan in China around December last year and by March every State in the United States and over a hundred countries have reported cases of the infection with deaths in all the adult age groups. The predictions are dire. The entire healthcare system could potentially be overwhelmed and could crumble. Signs of that are already evident in New York and Washington State. Grocery stores have empty shelves, pharmacies are running out of critical medications and there is scarcity of personal protection equipment and ventilators.”

“The major clinical manifestations of the SARS-CoV2 infection are due to pulmonary complications. While most have mild symptoms, such as fever, headache, cough, dyspnea, myalgia and anosmia, some develop acute respiratory distress syndrome about a week into the illness which can result in death. Rhabdomyolysis can be a late complication of the infection. The mortality rate is about 3-4%. Terminally, patients go into coma which is thought to be due to hypoxia or multi-organ failure. But many unanswered questions remain. Could the headache be symbolic of viral meningitis? There is a report of detection of the virus in CSF of one patient (www.encephalitis.info/blog/coronavirus). Does anosmia suggest involvement of the olfactory bulbs? In mouse models of coronavirus encephalitis, the virus can enter the brain trans-neuronally through the olfactory pathways. Hence this relatively innocuous symptom could be indicative of a potentially more serious complication. Can the respiratory syndrome be due to brainstem involvement? Brain imaging and pathological evaluation of the brain are necessary to understand the full impact of the virus. The elderly and immunocompromised patients are particularly vulnerable. Many have underlying neurological comorbidities. Hypertension and diabetes seem to stand out as the most common comorbidities in patients with more severe manifestations of the infection. An interesting hypothesis has emerged around the use of angiotensin converting enzyme (ACE) inhibitors to treat hypertension and diabetes to explain this phenomenon. ACE2 is the receptor for SARS-CoV2. The use of ACE inhibitors leads to increased expression of ACE2 making the cells more vulnerable to infection with the virus. Clinical studies are underway to test this hypothesis. ACE2 can be found on endothelial cells in the brain and can be induced in neurons raising the possibility that strokes associated with SARS-CoV2 might be directly related to the infection and encephalitis could be a potential complication.”

“There are several human coronaviruses. Most cause mild respiratory symptoms and resolve. However, in recent years, new coronaviruses have jumped species and infected humans with devastating consequences. Several acute neurological syndromes have been associated with coronaviruses (Table). SARS-CoV1 has been detected in the CSF of a patient with encephalitis and acute respiratory distress syndrome. MERS-CoV can cause a severe acute disseminated encephalomyelitis and a vasculopathy. A post-infectious brainstem encephalitis and Guillain-Barré syndrome has also been described. HCoV- OC43 can also cause an acute disseminated encephalomyelitis with lesions scattered throughout the brain, cerebellum and spinal cord. Immunocompromised individuals are particularly vulnerable. A fatal encephalitis can occur in immunocompromised patients with HCoV-OV43. In these patients, infection of neurons has been demonstrated at autopsy. A similar concern has been raised with SARS-CoV2. Many patients with autoimmune syndromes such as multiple sclerosis, myasthenia gravis, neuromyelitis optica or sarcoidosis are on a wide variety of immunosuppressive therapies. Drugs that cause systemic immune suppression wound be of concern. It might be prudent for such patients to take extra precautions to prevent exposure to the virus and to re-evaluate the dosages of the medications. However, it may not be advisable to take them off treatment since the underlying illness will surely re-emerge causing serve manifestations in many. With restrictions on travel being imposed and all elective patient appointments being cancelled, there is an urgent cry for teleneurology as a substitute for face to face interactions with patients. However, to make this work, we need to develop a centralized system to license physicians in the entire country and not in each state individually.”

“Seropositivity for coronaviruses has been reported in a variety of neurological disorders which includes encephalitis, optic neuritis, multiple sclerosis and Parkinson’s disease. Virus has also been isolated from CSF and brain of patients with multiple sclerosis. Viruses implicated include HCoV-229E, HCoV- 293 and HCoV-OC43. But the significance of these findings is not clear since these viruses are very prevalent and their causative role in these diseases has not been established.

“In the past century, we have made tremendous progress in the prevention, diagnosis and treatment of diseases. We can dissolve clots in the carotids, we can fix mutated genes before they can cause harm and we can image the brain and its networks with exquisite precision, yet we have been brought down to our knees by the tiniest of organisms; about 60 nanometers in size. We need to retool and rethink how we train physicians in the practice of neurology and physician scientists in the academic neurology, how we prioritize drug development for neurological diseases and we need to enable academia and pharma to develop treatments not based on profits but rather on costs to humanity. While we all recognize the hundreds of viruses that can cause encephalitis and result in devastation to large populations, we have no treatment for any of these organisms except for herpes encephalitis. It is time for us to recognize that we are facing a crisis in neurology. The time to take action is now. “

—————
• As I commented directly above – I’ve stopped MY angiotensin-receptor blocking medication. This is just more justification – f••k the American College of Cardiology.

• Okay, notwithstanding the fact that some of us are self-isolating and/or running around in a panic – and will probably be dead soon – you’ll have to admit:

• This is an utterly fascinating disease. What a cool time to be a YOUNG research neuroimmunologist or pathologist …

ON ANOTHER ISSUE: The Renin-Angiotensin System as it Affects Pulmonary Function and Covid-19 Outcomes

A very hot topic of current medical discussion is the interaction of ACE2 receptors in the lungs with SARS-CoV-2 virions. There is an exploding debate in the best – but (as with all-things -Covid-19, not yet peer-reviewed) – medical literature on this. Some of this literature is new; but much has been peer-reviewed, stemming from the 2002 SARS-CoV-1 pandemic of 2003.

“The renin–angiotensin system (RAS), or renin–angiotensin–aldosterone system (RAAS) is a hormone system that regulates blood pressure and fluid and electrolyte balance, as well as systemic vascular resistance” – https://en.wikipedia.org/wiki/Renin–angiotensin_system

However, the RAS system does far more than play around with your kidneys. It’s a major protagonist with respect to the immune system; it has even been hypothesized that it plays a role in the relative resistance of children to serious Covid-19 disease.

Several Lancet reports from the Wuhan doctors are, to me, very convincing – hypertension patients on ACEIs or ARBs in the ICU fared far worse, with respect to serious morbidity and mortality, than other, age-matched cohorts.

I’m not a medical doctor, and the only times I play one is when triaging and treating myself. So I’m not qualified to give any medical advice; to do so would be both pretentious and unethical.

However, if you (or anyone you care about is on one of these medications), ask your PCP (or cardiologist or nephrologist of infectious disease doc, if you have one) for personally tailored advice.

Currently, these three sources should give you a sense of the poles – though not the messy in-betweens – concerning positions taken vis-à-vis this intensifying controversy:

• https://www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19

versus

• https://academic.oup.com/jtm/advance-article/doi/10.1093/jtm/taaa041/5809509

versus

• https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaa235/5810479

Keep in mind, official policy recommendations, such as that of the American College of Cardiology, always lag behind the data. So consider yourselves fortunate indeed if can keep up with the most current science and evaluate your best course of action.

A very personal note: I am the furthest thing possible from a neutral observer. I am at major risk of dying from Covid-19 should I become sick. Not only because of so-called “pre-existing conditions” [Is not life itself, by definition, a ‘pre-existing CONDITION for us all?], but also hypertension that is well controlled with valsartan (an ARB) and three (!) other medications. I have been resuscitated and served extended time on an ICU ventilator – several times. (Spoiler alert: NOT the most enjoyable four-week ‘vacation’!!!).

My hopefully well-informed personal decision has been to discontinue my ARB. I will increase the dosages of my other BP meds, as I deem empirically advisable, until this pandemic either kills me. or subsides.

https://www.ft.com/coronavirus-latest

So further update. The sigmoid plots are converging to a final Australian tally of around (and very possibly below) 10,000 cases at plateau. The measures taken by the government are now clearly manifesting ever more strongly in the daily data. I would reiterate that if they hadn’t dithered for several weeks we’d see even less, but when I look at the mess that is the USA I am glad that I live in a First World country and not an authoritarian wannabe dictatorship run by an ignorant group of incompetents and narcissistic sociopaths…

Short answer — I didn’t start with one. I modeled based on raw figures, not proportions, and let the solver estimate the rates of movement between the three populations from that.

I used the number of recorded USA cases from early Feb through the second week of March as my initial data. Did the solving in R (the statistics software) with the deSolve library.

I haven’t had time to go back and update with latest numbers — going to all classes online takes a bit more time.

Dean, I’m curious about how you arrived at a figure for the proportion of susceptible individuals…

Since I did the eyeballing last week I’ve pressed some non-logistic sigmoid fits to the Australian data: the assumption of a logistic curve’s symmetry around the point of inflection really can’t be defended in such a complex scenario, especially when we can’t apply China’s draconian control measures to our own society.

At the moment models with floating points of inflection aren’t easily able to come up with a credible fit. A Gompertz curve (my preferrred for terrestrial poikilothermic vertebrates) still whips around like a firehose with just a few dozen cases added to a daily update, but overall there seems to be an indication with the passing of days that we’ll land somewhere between 20-40 thousand cases between the beginning and end of June, before we approach a plateau. Not great, but at least it’s not in the hundreds of thousands or the millions. Still, if our government had acted with greater alacrity the number might have otherwise been half of what will be realised.

I’ll try a Richard’s fit soon, to see if that can project further with greater accuracy.

One thing that has concerned me is that media commentators are quoting mortality by dividing the total number of deaths by the latest tally of infections. Given that a mortailty rate based on deaths realised to date should be predicated on the number of infections at the time that the deceased contracted their infections, the denominator should probably be the number of cases 7-10 days prior to the latest death count. On this basis Australia can expect 1-2% mortality – so somewhere between 200 to 800 dead based on the weekend’s rubbery projections. I’m just glad that it’s not the US’s death toll, which is already screaming upward past ten times that ball-park…

All eyes on China then, as restrictions are loosened tentatively.

I modeled things here (USA) with a simple SIR model. The results were clear: if we don’t continue with the steps we’re beginning to take as a nation, we’re royally fucked.