MERS

Lions And Tigers And…Deer? Oh My!

First it was bats and humans, then domestic cats and dogs, farmed mink, and big zoo cats; now gorillas, hippos, and wild deer that have been infected by the SARS-CoV-2 (CoV-2 for short) virus. Many of these animals have become ill and several have died of COVID-19, most recently three snow leopards in South Dakota and Nebraska zoos. This is quite a wanton virus.

Of course, before CoV-2 and COVID-19 were known to the world, we knew that bats, humans and a few other animals, notably civets and even camels, were ready hosts of several different strains of “‘rona” viruses. We also knew that domesticated animals are also susceptible to their own coronavirus diseases—in fact veterinary coronavirus vaccines have been in use for years. Humans are known hosts for several coronaviruses, including those that cause the common cold, as well as the viruses that cause SARS, MERS, and now COVID-19. And we know that humans often catch these germs from bats and other intermediate hosts as diverse as civets and camels. After we genetically identified CoV-2 and were able to follow its spread, we quickly noticed that domestic pets also could be infected. This was closely followed with news that seven big cats at the Bronx zoo had become infected, and that mink farms across Europe were hotbeds for CoV-2 spread between humans and the animals and back. In fact, mink farms became such a hotbed of CoV-2 zoonotic spread that a couple of European countries completely shut down mink farming and culled all their animals. Several US states have also sharply curtailed mink farming. PETA probably applauds.

More recently two snow leopards at the Lincoln, NE children’s zoo and one in a zoo in South Dakota died from COVID. The Lincoln zoo also had two infected Sumatran tigers who recovered after being treated with steroids and antibiotics to prevent secondary infections and pneumonia. How the animals were infected is uncertain, but the most likely scenario is that they caught the virus from a caretaker. The problem is, none of the caretakers tested positive for the virus. Bats? Something else?

Since April 2020, when a tiger tested positive at the Bronx Zoo, dozens of other animals in zoos around the world have caught COVID. This month, the Denver Zoo reported the first coronavirus cases in hyenas, and the St. Louis Zoo found eight positive cases among its big cats, including two snow leopards. Abroad, the virus has killed a lion in India and two tiger cubs in Pakistan. Big cats seem especially susceptible since three other snow leopards at the Louisville Zoo were infected last December, and another snow leopard tested positive at the San Diego Zoo in July. The virus doesn’t just infect our fuzzy friends either; two hippos, named Imani and Hermien, at a zoo in Antwerp recently tested positive for COVID-19. Zoo keepers were first alerted to a potential problem when they noticed that the colossi had “runny noses.”  One reckons that a runny nose for a hippo is a big deal. One also wonders who gets to dab that nasal maw in order to test for the virus.

In fact, zoo and domestic animal infections have become so prevalent that an animal COVID vaccine developed by Zoetis, a NJ-based veterinary pharma company and former Pfizer subsidiary, has been authorized by the USDA for experimental use. The Cincinnati Zoo, for one, has vaccinated  80 animals, from giraffes to apes, against COVID.

Deer too. Oh my! It is one thing for zoo animals to acquire COVID—their captivity makes it easy to limit their interaction with other animals and humans to prevent spread of contagions, and they seldom complain that their rights are being infringed when they are quarantined. However, COVID in wild animals is a different story, as we have seen with bats and how easily they transmit the virus to humans. Scientists now have evidence that CoV-2 also readily propagates in white-tailed deer. In fact, the virus is already widespread in cervids across the US, which likely has significant implications for the long-term course of this pandemic.

In September of last year, genetic analysis of the gene that encodes the ACE2 protein (i.e., the viral receptors expressed on many cells in the body) in many different animal species suggested that CoV-2 could easily infect deer (and several other animals too). A survey of white-tailed deer in the Northeast and Midwest found that 40% had antibodies against the CoV-2 virus, indicating prior exposure. Between April and December 2020, veterinarians at Penn State found active CoV-2 infections in ~30% of deer tested across Iowa. Then during the winter COVID surge in humans from Nov. 23, 2020, to Jan. 10 of this year, ~80% of the tested deer were infected. The prevalence of the virus in deer was 50 to 100 times greater than in Iowa residents at the time (and the deer reportedly did not wear face masks). The study, published about two months ago, indicates that white-tailed deer have become a permanent reservoir for CoV-2. While it is not fully understood how the virus entered the deer population, genetic sequence analysis of nearly 100 viral samples found that the variants circulating in deer matched the variants circulating in people. This suggests that deer caught the virus from people multiple times in Iowa alone. How that happens is not known since people usually do not have close contact with live deer. More concerning is whether viral variants arising in deer readily pass back to people.

Bottom line. Clearly, a lot of different animal species can catch Cov-2 and spread it. It is clear that people can spread coronaviruses to pets and other animals, but the FDA says that the reverse, animal-to-human virus transmission, is not common. But, it clearly happens as we have seen with this pandemic, and with many other viruses that cause SARS, MERS, AIDS, Ebola, flu, etc., that spread from animals to humans. The prevalence of CoV-2 infection in so many species of mammals, especially in animals that have close contact with humans, suggests that several animal species, not just bats, can serve as permanent reservoirs for the virus and the jump to humans is something that can happen over and over. This is not unprecedented. It is what we see with influenza, which is carried back and forth between the Northern and Southern hemispheres with migratory birds, in which different flu viruses shuffle their genomes to create the new strains of flu for which we have to vaccinate against each year. This animal reservoir for flu makes it next to impossible to eliminate influenza, and similar animal hosts for CoV-2 likely would make it nigh impossible to eliminate COVID too. I raised this specter some months ago in these pages when reporting that pet dogs and cats can carry the virus. Our furry friends represent a viral reservoir that is in even closer contact with people than bats, deer, and fortunately, hippos and leopards.

We also have to be worried about the CoV-2 virus mutating in the different animal species that harbor and spread it. We know that happens in bats, which makes it almost certain that new strains of the virus will arise in deer and dogs too. We have already seen this on mink farms in the Netherlands and Poland. Farmworkers passed the virus to captive animals where it spread, mutated, and then spilled back into humans. In fact, zoonotic transmission from animals to humans probably happens thousands of times a year. Researchers from the EcoHealth Alliance and from Duke-NUS Medical School in Singapore, estimate that each year many people are newly infected with SARS-related coronaviruses. Many may get sick, but there are many reasons why most of these infections never grow into noticeable outbreaks (for example see my earlier blog post about unusual respiratory infection clusters in China and Los Angeles just before COVID). The researchers also created a detailed map of Asian habitats of 23 bat species known to harbor SARS-related coronaviruses then overlaid it with data on where humans live to create a map of potential infection hot spots. They found that close to 500 million people live in areas where bat-to-human transfer is likely, and this risk is highest in southern China, Vietnam, Cambodia, and Indonesia. Other surveys done before COVID-19 showed that many people in Southeast Asia harbor antibodies against other SARS-related coronaviruses. Blending these data with data on how often people encounter bats and how long antibodies remain in the blood, the researchers calculated that ~400,000 undetected human infections with these viruses occur each year across the region.

That is just for bat-to-human transfer in Southern Asia. It now looks like we will have to also concern ourselves with zoonotic coronavirus transfer from Buddy and Bambi too.

For this reason, researchers are working to develop a universal coronavirus vaccine that will be effective against most viral strains and variants. I will write about this soon. Stay tuned.

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The Long Haul, Part 3: Long Neurological COVID

As I have noted before in this series, acute COVID-19 often appears with neurological symptoms ranging from loss of smell to severe depression to stuttering to brain fog, mania and psychosis. It sometimes has been linked to suicidal ideation. In addition, long haulers often have cognitive symptoms and structural brain changes similar to those seen in aging brains and in those with Alzheimer’s disease. An early survey of 153 COVID-19 patients in the UK and a more recent study of people hospitalized with the acute disease in Italy both found that about a third had neurological symptoms of some kind ranging from sensory problems, motor impairment, and cognitive issues that persist after clearing the acute infection. Other estimates of neuro involvement in long COVID have trended even higher. Many people who survived earlier coronavirus infections such as SARS and MERS also experienced neurological impairments up to 3.5 years after acute infection. Obviously many of these symptoms of long COVID are very serious while others are more annoyances. So, what is going on? Researchers have pretty well cataloged the unusual range of long COVID’s neurological symptoms and now are at the very early stages of understanding their causes and how to treat the problems. Here, I label long COVID that primarily manifests itself with neurological symptoms as “long neuro COVID” in order to distinguish it from other long COVID problems that primarily involve the lungs, heart, or other organs.

What is long neuro COVID like? In the early days of the pandemic, a newly minted English MD worked on the front lines in a COVID ward and soon became a patient herself. Being 35 and healthy she expected to quickly recover but underwent the long haul, which she has written about. The acute phase of the disease lasted about two weeks, but by 4-5 weeks, she was experiencing new persistent problems including tachycardia with a resting heart rate of 140 bpm (normal is 60-100) that would increase to 170 after minimal exertion such as getting a glass of water. She also was breathless with a resting respiratory rate of 20-24 (12-16 is normal), saying it felt like her “body forgot to breath.” She described cyclic bouts of pins and needles in all four extremities, and whole-body shaking as violent as if she were having a seizure. There were feelings of impending doom, and, despite extreme mental and physical exhaustion, she was unable to sleep, which eventually led to hallucinations. Those symptoms slowly subsided over a few months only to be replaced by intense pain very deep in one ear. This ultimately led to tinnitus and some hearing loss and a diagnosis of encephalitis. Ten months later, she wrote that  she was recovering but was far from normal. She suspected that these symptoms were driven by a dysfunctional autonomic nervous system, a condition called dysautonomia. The autonomic nervous system is what regulates your organs and allows you to breath, your heart to beat, your gut to move food through it, and controls your blood pressure without you having to think about it all. Since her experience in early 2020, it has been confirmed that long neuro COVID can wreak havoc with both the peripheral and central nervous systems.

 

After two years of long COVID, we now know that long neuro COVID symptoms are wide ranging; some are devastating, like stroke, encephalitis, and even psychosis or mania, or even suicide. Other neuro symptoms are more subtle such as cognitive decline, loss of smell, hearing loss, balance problems, fatigue, memory problems, and difficulty concentrating or brain fog. Others are bizarre, such as stuttering. This seemingly unrelated range of symptoms suggests that there might be several different subtypes of long neuro COVID, possibly arising from distinct pathologies.

Back in July 2020, one of the first studies was published describing neurological symptoms that appeared long after the initial COVID disease. This since has been followed by several other reports of neurological or neuropsychiatric problems long after recovering from acute COVID disease. One study by Oxford scientists published last February, found that about 33% of post-COVID patients are left with long term mental health or neurological symptoms including brain fog, headaches, dizziness, and cognitive problems such as difficulty doing simple math. Some studies have shown an elevated incidence of PTSD, and seizures or movement disorders  long after COVID recovery. Other post-COVID patients have new-onset depression, psychosis, and suicidal behavior as reported in JAMA Psychiatry by a Columbia University research team this past spring. In this large study investigators examined electronic health records of more than 236,000 COVID-19 patients, mostly in the US. The researchers compared their records with records from those who experienced non-COVID respiratory tract infections during the same time frame and found an increased incidence in anxiety and mood disorders in post-COVID patients. More than three months after diagnosis, these common psychiatric diagnoses were found in about 34% of COVID survivors. Other studies confirmed that having the disease led to doubled risk for anxiety, depression and sleep disorders.

Importantly, researchers did not see an increased incidence of other neurological problems such as Parkinson’s disease or Guillain-Barré syndrome in long COVID patients, both of which sometimes follow viral infection. This suggests that long neuro COVID involves a select subset of neurological problems rather than an indiscriminate neurological malady.

Similarities between long COVID and Alzheimer’s disease. The cognitive issues seen in many long neuro COVID patients share intriguing similarities with Alzheimer’s disease (AD) and normal aging. Thus, an international group of researchers found that more than half of patients 60 or older who had been infected with the CoV-2 virus showed acceleration of Alzheimer’s-like symptoms such as cognitive decline. Other researchers at the University of Texas Health Science Center, San Antonio studied more than 200 older adults from Argentina who had COVID-19. Those who had a persistent loss of smell were more likely to experience AD-like cognitive issues. Importantly, the area of the brain affected in AD overlaps with the area that processes smell. It also might be relevant that the sense of smell, which is often lost in COVID patients, is also often reduced in AD patients.

Three to six months after they were infected, more than half of these patients still struggled with AD-like cognitive challenges including persistent forgetfulness, difficulty sequencing tasks, and forgetting words and phrases. How sick a patient was with acute COVID-19 was not an indicator of whether they would experience this cognitive decline. In other words, AD-like symptoms also occurred in people who only had mild COVID.

COVID-19, of course begins as a respiratory disease and investigators have long been tuned in to the potential links between respiratory diseases and the brain. For example, AD-like changes in cognition and behavior were also observed in people with Severe Acute Respiratory Syndrome (SARS) and with Middle East Respiratory Syndrome (MERS). Infection with other respiratory viruses can also increase the risk of Alzheimer’s.

Together, these findings suggest that some patients with long neuro COVID might have an acceleration of Alzheimer’s-related symptoms and pathology, but it is too soon to conclude that long neuro COVID causes AD, or even that AD and COVID-related cognitive dysfunction are even related. A major distinction between classical AD and AD-like long COVID is that the latter do not show the amyloid brain plaques which are pathognomonic of AD, which suggests that these could be distinct cognitive maladies with overlapping symptoms. Furthermore, other studies showed that worse cognitive scores in long COVID patients correlated with patients who had lower oxygen saturation during a 6-minute walk test. This makes it possible that persistent oxygen deprivation in the brain due to lung compromise during COVID could cause cognitive difficulties in these patients.

At this point, these observations simply raise many unanswered questions on whether there is a real overlap with COVID and Alzheimer's disease. But, it is too soon to say that COVID-19 increases a person's risk for Alzheimer's vs causes a different neurological problem symptomatically related to AD.

What causes long neuro COVID? Long COVID represents a broad category of over 200, often unrelated symptoms encompassing 10 organ systems. It likely consists of multiple different maladies with manifold causes, of which long neuro COVID is at least one broad category. Based on its biology and range of symptoms, long neuro COVID also likely entails more than one specific problem. It makes sense then that the many different manifestations of long neuro COVID would arise from different causes. Such seems to be the case. Researchers have cataloged several genetic, structural, inflammatory, and infectious correlates to the various symptoms, painting a complicated picture. Then things get really confusing since viral infection of neurological tissues and/or the attendant inflammatory responses could cause the observed structural changes and all this could be predisposed or mitigated by genetics. In other words, things are as clear as mud right now about what causes long neuro COVID. Investigators are just now making basic observational correlates between the neurological changes and long neuro COVID symptoms, and these correlations will be followed by the harder studies to learn just how these changes might cause the plethora of symptoms that have been documented.

On the genetic front, a Stanford U team found that long neuro patients manifest widespread changes in gene expression in the region of the brain involved in complex processing of human thought. These genetic changes affected genetic pathways that play a role in mental illnesses such as schizophrenia and depression. Although these results were made in the brains of patients who died of acute COVID disease, such fundamental changes in gene expression in the brains of patients with acute COVID would plausibly lead to long-lasting post-COVID effects. Similar changes in gene expression were not found in the brains of people who died from flu or from nonviral causes, which strengthens a possible cause and effect relationship of gene expression changes to some long neuro COVID symptoms.

But, what causes changes in brain gene expression? Is it directly due to viral infection in the brain or secondarily due to the immune inflammatory response to the virus? Maybe both? Or is something else involved? Evidence exists for all these possibilities.

One report on 111 unvaccinated patients from the Chicago area showed that 56 who had long neuro COVID cognitive problems showed a particular immunological signature that was not found in people who cleared the acute infection without long term problems. The severity of cognitive deficits correlated with reduced memory T cell responses to certain parts of the virus, and with enhanced antibody (or B cell) responses to one of the viral proteins. Furthermore, it has been observed that females are more prone to devleop long neuro COVID. Since women also are more likely to get autoimmune disease, some have put these observations together to suggest that there might be an autoimmune component to some long neuro COVID symptoms.

The above study assessed the anti-CoV-2 immune responses of T and B cells from the peripheral blood but not from the brains of the patients. In other words, it did not address whether the immune response in the body affects brain function or whether an antiviral immune response directly occurs in the brain affecting cognitive function. Other researchers have shown that the virus can indeed enter the brain via the nose and spread from the olfactory lobe to the frontal and temporal lobes of the brain. Other confirmatory studies have found viral protein expression in cortical neurons of autopsied brain tissues, and have directly shown that the virus can infect neurons in tissue culture. While these findings are consistent with direct infection of the brain and the possibility of immunological damage to the organ, they do not settle the question of whether viral infection itself might directly damage the central nervous system, or whether it is the immune reaction to the virus that causes the problems.

Perhaps confounding all of this are the results of a large study on gross brain structure conducted by researchers at the University of Oxford and at the NIH. In this study, researchers used the UK Biobank, an existing database, which contains brain imaging data from >45,000 people in the UK going back to 2014. This means that there was pre-COVID baseline imaging data the researchers could compare to post-COVID brain images. New images were collected from 394 of these patients who caught COVID and compared to their pre-COVID images and to 388 controls who did not catch COVID-19. The groups were otherwise matched based on age, sex, common disease risk factors, etc. The results showed that those who caught COVID suffered significant loss of gray matter in the frontal and temporal lobes on the left side of the brain. This brain loss was found regardless of COVID disease severity. Those who were COVID-free had no brain tissue loss. Interestingly, these regions of the brain are responsible for smell, taste, memory, and emotion, all of which can be affected in long neuro COVID patients. We also often talk about the left temporal lobe in the context of aging and Alzheimer’s disease because that is where the hippocampus is located, which plays a key role in memory and other cognitive processes associated with aging and AD. While it is normal to see reduction in gray matter with age, the COVID-linked changes were greater than that typically seen during normal aging. All of this raises questions about how COVID might affect the natural aging process in the brain.

In addition to these genetic, immunological, and structural changes in the central nervous system of COVID patients, autopsies also have revealed clotting in multiple organs including the brains of many patients. About one in 50 COVID brains showed evidence for an ischemic stroke, which is when a blood clot interrupts blood flow to a region of the brain downstream from the clot. Ischemic strokes in COVID patients tended to be more severe and more likely to result in severe disability or death than stroke in non-COVID individuals. Again, while these findings were made on autopsies of patients suffering from acute COVID, these ischemic strokes would have caused long term manifestations presenting as long neuro COVID.

There are other, very specific and very peculiar neurological symptoms that might arise from more specific neurological abnormalities. For example, some long COVID patients display hearing loss and or balance problems which suggest vestibular involvement that could be due to CoV-2 infection of the inner ear. Scientists at MIT and Stanford found that the ACE2 protein, which is the cell receptor for the CoV-2 virus, is expressed on certain inner ear cells obtained from surgery patients. Since inner ear tissue is difficult to obtain, the researchers directed stem cells to develop into inner ear cell precursors or that could assemble into primitive inner ear  organoids in tissue culture and showed that the CoV-2 virus could infect them. Together, these observations support, but do not prove, that infection of the inner ear is a cause of hearing and balance issues in some long neuro COVID patients. It is relevant to note that it is not unusual for hearing loss and balance disorders to be caused by other viral infections of the inner ear.

Then there also are the rare long COVID patients who develop an odd stuttering problem. Typically, stuttering originates in the complex circuity of the brain that controls speech and this speech disruption usually appears when children are learning to talk. However, “neurogenic stuttering” can arise in adults after brain trauma. Since only a few researchers are investigating long COVID-associated stutter, the cause is not well understood, but, the link between neurogenic stuttering and brain injury raises the possibility that inflammation and/or micro-clotting caused by the virus or by the immune response to the virus in the brain microvasculature could lead to the neurological damage that causes stuttering.

Bottom line. These many new findings, while provocative, do not yet fully tell us how long neuro COVID arises, or how to treat it. But, they raise many new questions: What do these COVID-related brain changes mean for the process and pace of brain aging in long COVID patients? Over time does the brain recover? How do we medically deal with these patients? Can we prevent long neuro COVID? Etc.

Stay tuned, we will see.

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