Healthcare – The Creative Space

How an Effective COVID-19 Vaccine Could Lead to Better Influenza Vaccines

The Influenza A Virus. Courtesy of the CDC

There is a very high probability that at least one of the many COVID-19 vaccine candidates out there will be successful and help humanity achieve the protection it needs from SARS-CoV-2.

It probably will not happen this year then there is still a lot of work to be done by all the teams involved and the 7 months left will probably not be enough.

A lot of doubters look at the fact that RNA viruses are tough to make vaccines for but we have them – yellow fever, measles, and polio are a few examples. Others look at how difficult it is to make a vaccine against the influenza A and B viruses. That is true but a study of the structure and properties of the flu virus explains why. A comparison of the flu virus with the SARS-CoV-2 virus exposes why we all should be hopeful that an effective vaccine for the latter is possible.

Interestingly, I think the technologies and thought processes driving the development of a COVID-19 vaccine might give us a much better flu vaccine.

One fact that needs to be emphasized over and over again is that COVID-19 is not Influenza. They may share symptoms and some pathology but they are caused by different viruses, have different contagiousness, fatality rates, and clinical pictures.

Both are RNA viruses. Where SARS-CoV-2 is part of the Beta-coronavirus family, the influenza viruses belong to the Orthomyxoviridae family.

The COVID-19 virus is made up of a single strand of RNA. That of the flu is made up of a single strand to but that strand has 8 segments. That is one of the important differences.

Though there are four types of influenza viruses: A, B, C, and D, only Types A and B cause the outbreaks of disease in humans yearly. Flu A is the most dominant and virulent type and the only type that can cause pandemics.

The viral genome of flu A codes for about 14 proteins. Two of these are hemagglutinin (HA) and neuraminidase (N). Hemagglutinin is more numerous than neuraminidase. The two are very important glycoproteins because they are integral to how the virus enters the cell. HA binds to cells of the nasal epithelium that express sialic acid. Once in the cell, the viral genome replicates. It is at this point that neuraminidase facilitates the release of the virions.

Hemagglutinin and neuraminidase are also used to name the different subtypes of the virus.

Originating mainly from birds, there are 18 subtypes of hemagglutinin and 11 subtypes of neuraminidase. Types H1 to H16 and N1 to N9 are found in birds. Types H17 – H18 and N10- N11 were isolated from bats recently. While there are potentially 198 different Influenza A subtype combinations, only 131 subtypes have been detected in nature.

The subtypes currently found in humans are H1N1(the Spanish Flu) and H3N2 (Hong Kong flu). Rarely, H1N2 has been seen. H2N2 was the cause of the Asian flu pandemic in 1957 – 58 and the subtype that caused the Spanish Flu is H1N1.

Flu B is only found in humans. There are 2 subtypes. It also has the hemagglutinin and neuraminidase glycoprotein structures too.

The genome of SARS-CoV-2 is much larger than that of the flu. Where the flu A has 13,588 bases altogether in the 8 segments, SARS-CoV-2 has about 30,000. Both viruses need an RNA polymerase for replication. One hallmark of RNA viruses is how often replication leads to mutations. Whereas the SARS-CoV-2 virus has a proofreader that can excise out mutations in the replicated genome, the flu virus does not have that capability.

Thus flu viruses show a high incidence of mutations, about 50 a year. None of these are proofread and repaired. Moreover, the virus has the ability to exchange pieces of genome between the 8 segments. Also, when two flu A types are present at the same time in a host, they can switch out gene segments, producing a new type. This phenomenon is known as reassortment and is how H1N2 came to be. It resulted from reassortment event between circulating human seasonal influenza A(H1N1) and influenza A(H3N2) viruses.

Thus the high rate of mutations, the ability to exchange genes between the segments (a process called antigen drift), and reassortment lead to an ever-changing structure of the glycoproteins not only in the virus but more importantly, on the viral envelope. The viral hemagglutinin and neuraminidase do not only allow the virus to bind to and enter the cell but they also are the antigens used for Influenza vaccines. This ability to constantly change its genetic identity leads to the vaccines that have very low efficacy, year after year.

The SARS-CoV-2 virus on the other hand does not mutate as much. The vaccine candidates against the virus target the spike glycoprotein on the envelope that has been stable through different types of the virus. The spike protein, but for some minor changes, has stayed grossly the same through SARS-CoV, MERS-CoV, and now SARS-CoV-2. It is thought that its structure will not change significantly to make vaccines as ineffective as with the flu virus.

As mentioned earlier, due to antigen drift, flu vaccines have low efficacy and must be re-engineered annually. Yearly, a global survey has to be done for the flu A strains circulating as well as the nature of the HA antigens. A projection is then made about which strains of flu A and HA antigen types to include in a vaccine, that also contains flu B.

It is no wonder flu vaccines are sometimes only about 20% effective.

One way to improve the antibody response is to use a wide collection of influenza viruses that incorporates the most common amino acids found in hemagglutinin. This technique is known as computationally optimized broadly reactive antigen (COBRA).

Now, as mentioned earlier, the dominant glycoprotein on the envelope of the flu virus is Hemagglutinin (HA). HA is structured like a mushroom, with a stalk and head. The head has the binding sites for the virus and is the dominant antigen in the inactivated, live attenuated, and

recombinant HA vaccines. Unfortunately, it is that part of HA that sees the most mutations. However the stalk, like the spike protein of the SARS-CoV-2 virus, has stayed conserved over the decades. In studies where it was used as the preferred antigen, it produced antibodies that are more broadly reactive.

Instead of presenting it as an inactivated or live version, the genetic material that codes for the stalk could be presented in a vector just like it is being done with COVID-19 vaccine candidates. That will also shorten production time then the present flu vaccines need embryonated eggs for production.

COVID-19 has dealt the world a terrible blow but it does have some silver linings. The use of vectors to present genetic material as a vaccine, the choice of conserved parts of the virus as antigens, and the avoidance of inactivated and attenuated viral products may not only give us more vaccine possibilities but also hasten how vaccines are produced.

One possibility is that we may finally get better and more effective Influenza vaccines.

Those RNA Viruses

Note: this a really basic discussion of a very complex and ever-evolving topic.

From Duffy S (2018) Why are RNA virus mutation rates so damn high? PLoS Biol 16(8): e3000003. https://doi.org/10.1371/journal.pbio.300000

The genetic information that codes for traits in all living organisms are found in DNA or RNA or a combination of the two. Even viruses, not really seen as living organisms, have genetic material. They either code them in RNA (RNA viruses) eg. Influenza or DNA (DNA viruses) eg. Herpes.

Where DNA viruses are quite big, RNA ones are much smaller. Also, RNA viruses replicate (multiply) way more than DNA viruses.

(Just a reminder, DNA and RNA are made up of bases called nucleotides).

To exert their disease-making effects all viruses have to enter the cells of the organism they are attacking. So they find a receptor that fits them on the membrane of the cell, fuse with that receptor and then worm their way into the cell.

Once in the cell, a DNA virus finds its way into the nucleus of the cell and fuses with the host organism’s DNA. As it divides and multiples, it uses the organism’s enzymes it needs for multiplication — the polymerases. Ensconced in the nucleus, DNA viruses tend to be more stable over time. They multiply and mutate less and therefore may be easier to treat.

The RNA virus on the other hand, stays in the cytoplasm and divides in there, using its own polymerases. Being smaller, using its own polymerase and away from the influence of the host organism, the RNA divides very fast and often. This leads to the RNA virus being able to switch out the nucleotides in its RNA often resulting in a different strain than what entered the organism — a process we commonly term “Mutation”!

It has been calculated that RNA viruses mutate on an average of once every 50,000 base pairs per infection. DNA viruses do that once every 50,000,000 base pairs per infection.

Now DNA viruses have mutations too but one, they are not as frequent and besides, the organisms polymerases can cut out these renegade nucleotides. The RNA’s polymerases lack this repair ability.

Mutations in RNA viruses are often set off when the environment in the cell changes — like when it senses the presence of a new vaccine or antibodies or medications. This ability to multiply fast and often is the reason why we never seem to get a good enough vaccine for the flu. That is why we sometimes need to treat viral infections like HIV and Hepatitis C with more that one medication.

This ability to mutate often also leads to instability of the RNA virus — it can generate a lot of mutants which do not survive or which may even be more virulent. Much more virulent than the organism that entered the cell.

Now in most normal humans, the body is able to mount a level of immunologic reaction to the vast number of viruses that affect humans. However, if the virus is totally new to humans, that ability is not available for months to even a year. Thus when a novel RNA virus spills over from another mammal into a human, those initial months to a year are very unpredictable. We are dealing with a virus that can mutate into a more virulent strain and against which the body still has no defense.

COVID-19 is an RNA virus that spilled over recently!

The Whistleblowers

I have wondered how Li Wenliang, an ophthalmologist, became the face of the group of doctors in Wuhan I call “The Whistleblowers”. These were the doctors whose warnings about the outbreak of a contagious and novel pneumonia-causing virus in Wuhan, China went unheeded by those in authority.

So I decided to do some digging. Reporting in the WSJ, NYT, and other online publications have been very helpful in this effort.

By the second week of December 2019, doctors around Wuhan were seeing patients with symptoms that included fever, coughing, fatigue, and aching limbs. Initially, some doctors thought it was bronchitis but soon most realized the condition was atypical pneumonia. They tried to treat these cases unsuccessfully with antibiotics.
Even though a lot of the patients came from the Huanan Wet Market, the connection was not made until later.
On December 16, an ER doctor named Ai Fen admitted a 65-year-old man to the emergency room at Wuhan Central Hospital whose only symptom was fever. A chest CT showed bilateral lung infections he was given antibiotics and antipyretics. The fever did not break so he was transferred to a tertiary center for advanced care. It was only after the transfer that Dr. Ai learned that the man worked at the wet market.
On December 27, Dr. Ai admitted another patient with similar symptoms. She ordered a chest CT and lab work. By the next day, she had seen 6 more such cases. Four of them worked or were in some way affiliated with the Huanan wet market.
She started to wonder if she was seeing a contagious disease. She notified the hospital leadership, who in turn notified the district CDC office. That office had been getting similar reports from other hospitals and clinics in Wuhan.
On December 30, she got the lab results back from the patient she had seen 3 days earlier. It read “SARS Coronavirus”.
A terrified Dr. Ai notified the hospital leadership of her findings. She also shared a photo of the lab result and a video of a chest CT scan showing pneumonia caused by this new virus with a medical school classmate.
Somehow, this photo and video clip ended up on the phone of an ophthalmologist who also worked at Wuhan Central. His name was Li Wenliang.
That afternoon, he shared it with his group of med-school classmates on WeChat with over 100 members.. (Bear in mind that in China, all social media sites are spied on by the government.) He posted:
“7 SARS cases confirmed at Huanan Seafood Market…Patients quarantined in the Emergency Department of our hospital.”
Another member warned that he could be censored for sharing such information.
He replied:
“Coronavirus confirmed, and type being determined…Don’t leak it. Tell your family and relatives to take care.”
Well, who can avoid sharing such juicy information in this age of social media? By that night, the information was all over WeChat.
The censors showed up shortly thereafter.
The next day he was reprimanded at work. On January 3, he got a visit from the police who warned him and censured him for “making false statements on the internet”. He was made to sign a letter of admonition promising not to do it again.
Reportedly, eight Wuhan doctors in all were admonished by the police for discussing the outbreak on social media in the first week of January 2020.
One of these doctors was Dr. Xie Linka, an oncologist at Wuhan Union Hospital. She learned from her Pulmonology colleagues that the hospital’s respiratory unit was housing many patients with an unknown type of pneumonia. She also later posted on WeChat warning members in her chat groups to wear masks and ventilate areas.
Dr. Liu Wen, a neurologist at Wuhan Red Cross Society Hospital was another doctor who was admonished. He also found out about cases in his hospital and posted about or discussed it on WeChat.
By December 30, doctors who were seeing and treating these patients with the strange new pneumonia knew what the authorities in Wuhan would not accept — that it was contagious and had human-to-human transmit-ability.
On December 31, the Wuhan branch of the National Health Commission issued a statement that confirmed the outbreak of a disease that had so far infected 27 people. It further said:
“The investigation so far has not found any obvious human-to-human transmission or infection of medical staff. The disease is preventable and controllable.”
On January 1st, 2020, Dr. Ai admitted a patient with symptoms of the strange new pneumonia. He ran a clinic near the Huanan market and had been treating a lot of those patients in the preceding weeks. Now he was sick. She alerted the hospital leadership and stressed that she believed the disease was contagious. She asked her staff to put on masks when treating those patients. For that, the hospital leadership admonished her the next day for spreading rumors and destabilizing Wuhan.
Unbeknownst to Dr. Ai, one Dr. Lu Xiaohing, Director of Gastroenterology at the Wuhan Municipal Hospital had received news a week earlier on December 25 2019 of the medical staff at two hospitals in Wuhan who had fallen sick while taking care of patients suffering from new and strange pneumonia. Dr. Lu did share the news but it is unclear if he was also admonished.
These admonishments may have shut up the whistleblowers but not the spread of the virus. With cases mounting not only in Wuhan but in other cities and international concerns increasing, a team led by the SARS expert and renowned epidemiologist, Dr. Zhong Nanshan, was sent to Wuhan. On January 20, 2020, Dr. Zhong would announce what the doctors in Wuhan had known all along — that the virus could be transmitted from human-to-human. At that point, there were 198 cases reported and three deaths.
Sadly, the very group of people who tried to warn the authorities all long that the virus had the ability to be transmitted human-to-human would suffer from this virus because they were not heeded. One of them was one of the whistleblowers — Dr. Li Wenliang.
On January 7, Dr. Li saw a patient with angle-closure glaucoma at Wuhan Central. Unbeknownst to him, the patient was a storekeeper at the Huanan wet market who had the virus. By January 10 he had developed a fever and a cough. On January 12, he had to be admitted because of extreme dyspnea. Dr. Li did not do well. About a month after he contracted the virus from a patient, he succumbed to pneumonia, dying on February 7 at the age of 34. He left behind a pregnant wife and a son.

As of March 4, 2020, China’s National Health Commission reported that more than 3,300 healthcare workers nationwide had been infected and at least 13 have died. Overall, 105, 938 patients have contracted the virus so far worldwide. 3567 people have died and 58,625 have recovered. Whereas the severity in China seems to be waning, the outbreak is on the increase in Iran, South Korea, and, Italy. Also, though the mortality rate looks low, it is very contagious and seems to be still spreading quickly. If millions get infected, even a low mortality rate will still result in lots of deaths.
The outbreak is also having a rather terrible impact on the world’s economies and may lead to a worldwide recession.
This makes me wonder what could have been if only those authorities in Wuhan had listened…listened to those doctors…those whistleblowers.
May Dr. Li Wenliang rest in peace. May all the doctors and nurses all over the world who are caring for patients afflicted by COVID-19 and other infectious diseases be safe.

Not The Last One

“From winter, plague and pestilence, good lord, deliver us!”

– From the play, “Songs from ‘Summer’s Last Will and Testament” by Tom Nashe

Sooner or later, the world will gain control over the COVID-19 outbreak. It will be through containment, effective treatment, a vaccine, or a combination of the three. History teaches that. Even the Black Death ended. Even the incurable HIV/AIDS has been controlled.

History also tells us that sooner or later, human behavior will lead to another epidemic or even pandemic. How is that?

Disease outbreaks occur through uncleanliness, vectors, lack of prevention (Anti-Vaxxers, etc), and zoonotic spillovers.

There are areas of the world that still lack clean drinking water and these areas still have outbreaks of cholera and typhoid.

The mosquito still transmits yellow fever and other viral diseases that are endemic in areas in the Tropics and flare up into epidemics every now and then. Even the bubonic plague broke out not too long ago in Madagascar!

Then is the fact that viruses are spilling over from other mammals to humans causing events like the COVID-19 and SARS outbreaks.

Lastly, refusal by some to get vaccinated means that occasionally, we are going to see diseases like measles and polio break out.

Human behavior does not only lead to the direct breakout of diseases. What we do after these diseases break out will ensure that we will forever see epidemics or even pandemics.

Since time immemorial, the attitude of those in power towards the outbreak of diseases has worsened these events. One can almost predict these reactions and the Chinese authorities epitomized it wonderfully during the initial weeks of the COVID-19 outbreak in December 2019. Instead of appreciating the observations of Li Wenliang and his colleagues that there was a new cluster of patients presenting with SARS-like pneumonia, they censored them.

When a disease breaks out, there are always those, often healthcare workers, who notice the initial cluster of cases and sound the alarm.

Those in power will often deny these reports. Then as the cases mount, they’ll seek to suppress the scientific or observational findings of those who are seeing this cluster swell.

When that does not work, they try to argue that things are not so bad.

By the time leaders realize things are bad, the initial outbreak is beyond containment.

We can forgive the lack of scientific knowledge for the reasons leaders in the Antiquity and Middle Ages gave for the epidemics that afflicted them. The Antonine plaque of 165 AD in the Roman Empire was blamed on an angry Jupiter. It was smallpox. The Church claimed The Black Death was due to bad miasma. Others said it was caused by the Jews and slaughtered them for that. It was bubonic plague.

(Looking at how Copernicus and Galileo were treated, I doubt the Church would have listened.)

However, to deny outbreaks, seek to suppress their reporting or make light of their severity has to be unforgivable in our present times. This is especially egregious since early action can contain disease outbreaks. And yet those in power do it.

We saw President Woodrow Wilson and other allied leaders do it during the Spanish Flu epidemic in 1918 leading to 50 million people dying worldwide. They suppressed information about the epidemic so as not to depress morale during the 1st World War.

It happened during the outbreaks of bubonic plague in San Francisco in the early 1900s. 190 people ended up dying.

We saw President Reagan avoid the issue of HIV/AIDs until 1985.

We saw several African Heads of States, like Thabo Mbeki of South Africa, refuse to accept the fact that HIV/AIDs was killing their people in the 1990s and 2000s.

We have seen the Chinese reactions to SARs and COVID-19.

It is not only leaders who misbehave when diseases break out. Among the general population, denial abounds too. That is often compounded by crazy conspiracy theories. This is followed by a period of panic and hysteria. When these reactions do not work, fear sets in. Deep crippling fear. Finally, people learn to accept the new reality and a rational response ensues.

In that regard, we of the present day are no different than the Flagellants in Europe of the 14th century, who whipped themselves bloody to get God to stop the plague during the Black Death.

Another factor that adds to the possibility is the unwillingness of governments to spend the money necessary to prevent these diseases from breaking out. Preventive programs in the hotspots of the world are often underfunded. Even developed nations are cutting back. The US recently axed its Pandemic Team as well as the PREDICT Program – a program made of scientists working around the world to hunt down the viruses, like COVID-19, that could lead to the next epidemic or pandemic.

So yes, human behavior being what it is plus economic policy that often short changes public health, we will continue to see epidemics and pandemics. Even in spite of all the scientific advancements, yes, we will continue to see these events.

If it Walks Like A Duck

There is a saying that goes, “If it walks like a duck, quacks like a duck, and swims like a duck, it is a duck!!! “

It is not a camel, it is not a cat…it is a duck!

We have a novel respiratory virus breaking out in a part of a country where the people are known for capturing, trafficking in, and eating all manner of wild animals, a country with a huge bat population and responsible for two other recent breakouts of respiratory viruses. The previous epidemics were found to be caused by viruses that spilled over from bats, were incubated in rodents, and then jumped over to humans.

Would it not be smart to suspect that this recent outbreak may have followed the same path since the behaviors in that population have not changed?

Walk like a duck, quack like duck!!!

And thus scientists who know and understand the phenomenon of zoonotic spillovers have sequenced the genome of this virus and found it to have 96% similarity to a coronavirus from a bat. 96%!

To the men reading this, if a DNA test had that level of similarity, that child whose paternity you refute would be yours!!!

Yet, in spite of all the evidence, some insist on calling it a zebra instead of a duck. Instead of looking at the science, some insist on wallowing in mind-boggling conspiracy theories.

Look, the COVD-19 is not a lab construct. It spilled over from a bat, going first through another mammal and the earlier we accept that, the sooner we start finding ways to prevent more zoonotic spillovers.

Learn the term: ZOONOTIC SPILLOVER!!!

A team of researchers has taken an intellectual shot at rumors that COVID-19 was engineered. In a paper posted on Monday on the scientific online forum Virological, the scientists – who include top epidemiologists like W. Ian Lipkin from Columbia University; Edward Holmes from the University of Sydney; and Kristian Andersen of Scripps Research – said very important genetic clues indicate that COVID-19 was not created in a laboratory.

The paper states:

“It is improbable that SARS-CoV-2 emerged through laboratory manipulation of an existing SARS-related coronavirus. As noted above, the RBD of SARS-CoV-2 is optimized for human ACE2 receptor binding with an efficient binding solution different from that which would have been predicted. Further, if genetic manipulation had been performed, one would expect that one of the several reverse genetic systems available for beta coronaviruses would have been used. However, this is not the case as the genetic data shows that SARS-CoV-2 is not derived from any previously used virus backbone.”

In other words, the researchers found that the way the virus binds to humans cells is way more efficient than any computer program would have produced.

Also, the “spikes” the virus uses to attach to human cells is based on a structure yet unseen in any lab. If the virus had been engineered, the makers would have used an available backbone used by scientists.

This means that there are two possibilities for COVD-19 origin:

– natural selection in a non-human animal host prior to zoonotic transfer, or

– natural selection in humans following zoonotic transfer.

So in short, COVID-19 IS HIGHLY LIKELY THE RESULT OF A ZOONOTIC SPILLOVER NOT A LAB-MANUFACTURED ORGANISM!!!

No amount of conspiracy theorizing will change that. No novels written in 1981 with predictive passages about Chinese scientists will change that. No statements by irresponsible politicians, nefarious state agents, and clueless media members will change that.

Thus, instead of wasting our time on hollow theories, the world should bring pressure to bear on China to get its people to change their ways.

Historically, the areas around the world’s rainforests have been seen as the hotspots for zoonotic spillovers and two of the deadliest – Ebola and Marburg – came from Africa. Yet, when a group of people actively hunt and capture wild animals from an area of the world with huge bat populations, traffic, sell, and slaughter them on open markets without any control, is the risk in this area not much greater than round the areas around rainforests?

In fact, all of humanity needs to be wary about encroaching on the habitats of these bats and/or hunting and eating all manner of wild animals nilly-willy.

Imagine the COVID-19 virus had not been a respiratory virus but one that causes hemorrhagic fever like Ebola? Just imagine!

Don’t think it can happen?

Well, we have had SARS, MERS, Ebola, Marburg, Nipah, Hendra spillover in just the last 50 years from bats and they have 60+ other viruses they are willing to share!!!

Let’s wise up!!!

When We Encroach

He is seen as the first patient who got sick but some researchers believe the virus had already started raging earlier than that December 1st when he was admitted to a hospital in Wuhan, China with pneumonia. By December 10, there were 3 more patients and by the end of the month, there were 40 cases.

Soon the world would hear of a virus that was making people sick in Wuhan, China, and was going to spread even beyond China.

Initial work by Chinese virologists soon showed what the causative agent was – a coronavirus not found in humans. Now there are several strains of the coronavirus. Four types are found in humans and they usually cause the common cold. The ones found in other mammals are the ones that cause severe disease in humans. The two known ones are severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East respiratory syndrome coronavirus (MERS-CoV). Whereas the coronavirus that caused SARS was isolated from a civet, the source of MERS is thought to be a camel.

The strain causing the people of Wuhan to get cases of pneumonia was named 2019-nCoV (novel coronavirus). Further work showed it shared 79.5% percent of the structure of another non-human coronavirus that had caused an epidemic in 2002-2003 – the SARS-CoV – and was 96% identical at the whole genome level to a bat coronavirus.

So a virus found in bats is causing disease in humans.

Now this phenomenon is not new. Pathogens from vertebrate animals that cause disease in humans are called “Zoonoses”. The process whereby the pathogen (bacteria, prions, protozoa, fungi, worms, viruses) springs over from the animal to the human is termed a “Spillover”.

Roughly 80% of viruses, 50% of bacteria, 40% of fungi, 70% of protozoa, and 95% of worms that infect human beings are zoonotic. Most of the identified reservoirs are mammalian in nature (roughly 80%). More than 60% of the roughly 400 emerging infectious diseases that have been identified since 1940 are zoonotic. Thus zoonoses are of particular public health interests.

We all know the famous ones like HIV-AIDS, Ebola, the flu, SARS, and even rabies. We get these diseases through direct contact with the body fluids of an infected animal, exposure to their habitats, through vectors like mosquitoes, and from eating contaminated meat.

Of all the pathogens, viruses seem to be the most lethal. They are simple creatures that mutate easily and are unaffected by antibiotics.

These diseases that reside in animals and have the ability to infect humans can be the cause of serious epidemics and even pandemics as seen with the Spanish Flu and HIV. They are also more difficult to eradicate than those pathogens whose final reservoir is the human, like smallpox and polio. One mammal that seems to get implicated in all this is the bat. It has been implicated in the spillovers of several zoonoses like Ebola, SARS, Nipah, and the ongoing 2019-nCoV outbreak. With an immune system that makes them able to harbor a lot of viruses without getting sick, they are the reservoirs of about 60 zoonotic viruses. It is estimated that each bat species harbors 1.79 zoonotic viruses. (The coronaviruses that caused both SARS and MERS are thought to have originated from bats, then infected the civet and camel respectively, and then humans).

Although it is impossible to predict when the next zoonoses spillover or what even allows certain pathogens to spill over, there are characteristics of these phenomena that allow epidemiologists to predict the areas on the planet which are hot spots for zoonotic spillovers.

In a 2012 paper by Morse et al in the Lancet, they teased out several hallmarks of zoonotic spillovers.

First, the frequency of emergence of new pathogens is on the increase. This increase seems to correlate strongly with increasing population density. Thus the expansion of human habitation, agriculture, travel routes, trade, and general changes in land use may be leading to humans getting exposed to more pathogens. We are encroaching on the habitats of these animals. This also means that areas with more biodiversity will see more of these zoonotic spillovers. So areas in the world with high population densities and biodiversity are more prone to see these events.

Based on these hallmarks of zoonotic spillovers, a few models have been created to depict how a new disease emerges. The 3-stage one by Morse et al really simplifies it. The first stage sees humans encroaching into the habitat of these wild animals through changes in land use or even caving (bats). Through contact, the pathogen spills over causing disease locally. This can range from small clusters of human cases to large outbreaks, some with the limited person-to-person transmission (eg, Ebola virus) and some without (eg, Hendra virus in Australia). The third stage is the large spread leading to a pandemic.

Also based on these same hallmarks, certain areas of the world are seen as hotspots. These are areas around the world’s rain forests – Latin America, West, and Central Africa, Southeast Asia, and the Pacific Islands. This is quite understandable due to the biodiversity of these forests and the fact that they are being encroached on actively for commercial purposes as well as due to population growth. Thus we first saw Zika come from Brazil and Ebola from Sudan and the Congo simultaneously in 1976.

Another important hotspot has spawned the present 2019-nCoV epidemic and also gave us SARS – Southern China.

The area has a huge population of bats. Moreover, it is also famous for the culinary culture of “Yewei” or “Wild Flavor” Cuisine. This involves “such exotic fare as camel hump, dried tiger penises, and bear bladders”.

Like Karl Taro Greenfeld writes in the book “The China Syndrome”, “Yewei” has become the perfect symbol of China’s newfound wealth; the Chinese would even call the period of the economic boom in the South “the Era of Wild Flavor.”

Some also attribute the attainment of sexual prowess and therapeutic effects from eating these exotic meats.

Thus in provinces like Guangdong, where SARS developed and, Hubei, where Wuhan is, there are thousands of wild animal markets or “wet markets” where one can buy all manner of animals including chickens, snakes, raccoons, dogs, civets, cats, monkeys, otters donkeys, sheep, pigs, foxes, badgers, bamboo rats, hedgehogs, and pangolins.

So inasmuch as these “wet markets’ have become symbols of China’s growing affluence, they may also be a vulnerability. They may be breeding grounds for zoonotic spillovers.

Between 2000 and 2003, Lee, Lau, and Chan, researchers from Hong Kong surveyed these markets in Guangdong and Shenzhen. This is an excerpt from their report:

“The animals are packed in tiny spaces and often in close contact with other wild and/or domesticated animals such as dogs and cats.”

Animals are stacked vertically so waste rains from one species to the other and since they are often slaughtered in the markets, blood joins in the fray.

The team further wrote, “The markets also provide a conducive environment for animal diseases to jump hosts and spread to humans”.

Interestingly, it was during this period that SARS broke out. This makes southern China a potent hotspot for zoonotic spillovers. The situation is further complicated by a political system that discourages sharing information and reporting such incidences.

Even as I write, the 2019-nCoV zoonotic spillover is looking more and more like it has the hallmarks of a pandemic. It has spread to 23 countries, sickened over 14,000 people, and killed 299 in China and one person in the Philippines.

It has been shown to be transmitted from human-to-human, even in cases where there are no symptoms, and even may survive on inanimate objects. A vaccine is at least a year away but with all the efforts being made worldwide, there is hope that the outbreak can be brought under control.

It will not be the last zoonotic spillover the world will see. Not as long as we keep encroaching on the habitats of wild animals and keep enjoying wild and exotic meats.

Echoes From the Hallway

Just sometimes, the practice of medicine becomes onerous. Just sometimes the pulmonary embolisms are too stifling, the myocardial infarctions too pressurizing and those hip fractures too achy. With one case following the other, one’s empathy and compassion get buried beneath the units of blood, chest compressions, epinephrine boluses, endotracheal tubes and measured urine outputs.
After hours of patient care, one reaches a point where thoughts of the warm couch and a cold one are so intrusive that, they threaten to sweep away the right doses one has memorized for starting a patient on Amiodarone.
Sometimes, the practice wears on the body and the soul.

Recently, I had such a day. Finally, after some 13 or so hours, I scurried off to the locker room to change and head home. I was so relieved to be able to finally leave it all behind. Or so I thought.
I changed faster than a Broadway artiste and headed for the door.
Now, the locker room has two main doors. One leads into the operating rooms suite while the other leads to a long hallway that is flanked by a ward, two intensive care units and waiting rooms for family members. The hallway also leads to a stairwell that leads to a door that lets one out of the hospital.

As I neared the into-the-hallway-leading locker room door, I heard a curious sound coming from the hallway. For a minute I thought someone was crying but the walls muffled the sound. I opened the door and made the left turn into the hallway and was immediately greeted by a most heartbreaking sight.
In the hallway were maybe 20 people who seemed to be related and they were all crying really uncontrollably.

It is not uncommon to see the family members of patients in either intensive care units hanging around in the hallway instead of staying in the waiting rooms. The reasons they do that are myriad. The most common is that the waiting rooms are full. Another is that a patient was just admitted, so the family members are still finding their bearings. Other times, the patient might not be doing well and the loved ones are all trying to see him or her before it is too late. Then, there is also the instance where a family member dies in one of the units.
As I stopped momentarily, frozen by the display of grief around me, I knew this was one of those instances where a patient had died and the family members were grieving openly in the hallway. It was not the first time I had seen patient family members crying in that hallway but never had I witnessed that number of weeping and heartbroken visitors.
For a minute I thought of using another route to the parking garage but something made we walk down that hallway between all those sobbing people and a chaplain, trying unsuccessfully to console them. The sobs bore into my very soul and their tears seemed to just flow. For what seemed like an eternity, I walked down that hallway, legs and heart quite heavy.
Finally, I turned the corner, went down the stairs and out of the hospital.

I walked briskly to my car, opened it and sat down. I noticed I was breathing rather fast. I tried to catch my breath and thoughts. Suddenly, my tiredness felt so secondary. Suddenly, the long day felt so unimportant and the warmth of my couch was not such a pressing need.
The empathy came flooding back. The compassion rolled over me.

I had seen grief and sensed loss and they made life so much more important. They put what I did, what we do within those walls in perspective. They humanized the pulmonary emboli, the strokes, the dissections, the fractures. I sat in the car and realized that I could not let my empathy and compassion be buried under units of blood, chest compressions, epinephrine boluses, endotracheal tubes, and measured urine outputs. That I had to reach in there and fish them out as soon as I realized they were drowning in the busy-ness of the day. Then behind those people we call patients, behind those people who make us work really hard and miss out on warm couches and beds are the lives they have left behind and hope to return to. Lives that include people who love them and will cry uncontrollably in a cold hallway if these patients do not make it.

I started the car, reversed and drove off. The radio came on and an old Stevie Wonder song was playing but even that could not keep the echoes away – the echoes of those visitors crying in the hallway. Death really has a way of reminding us about life and a special style of putting it all in perspective.

Pain Pays the Income of Each Precious Thing

Of all the rotations I had to do as a resident, my least favorite was Pain Management. I never enjoyed that specialty. Pain being a rather subjective sensation, it is almost impossible to measure. What a patient says must be taken at face value unless there are circumstances and clinical signs that contradict his or her story. No matter how much empathy one has, there is always the feeling that some patients are not being truthful and that pain was being used as a bargaining chip. A chip to obtain narcotics and not work. Don’t get me wrong – there were patients who were truly in chronic pain but more often than not, those patients found a way to lead a life that was not totally ruled by their suffering.
It was during that rotation that I learnt the term, “Pain pays” and came to realize how true it is.
For the patient, pain brings attention, an excuse from working, doting on by a loved one and pain medications that often lend a high.
For the physician, it is cash from perform pain-alleviating procedures on these patients and the lure of a “pill mill”.
For the drug companies, selling all those pain pills spells profits.

Pain pays!
Shakespeare uses the term in his 1594 narrative poem, “The Rape of Lucrece”.
The poem tells the story of Tarquin, the son Lucius Tarquinius, King of Rome. Tarquin was a soldier in his father’s army besieging Ardea. One night, all the men bragged about how chaste and virtuous their wives were. To prove their claims, they all secretly retuned to Rome to see if each other’s wife was as described. The only wife who proved chaste, virtuous and was incredibly beautiful was Lucerne, wife of the soldier, Collatinus, a friend of Tarquinius’. Her chastity and virtue sparked something in Tarquinius. When they all retuned to Ardea, he stole back to Rome and went to Collatinus’s home.
Lucrece, seeing her husband friend and the king’s son, welcomed him and allowed him to spend the night. In the middle of the night, he entered her room, raped her and fled.
Prior to the act, he debated with himself whether he should commit the dastardly act. As he comes to the door of her bedroom he says to himself:

“Pain pays the income of each precious thing;
Huge rocks, high winds, strong pirates, shelves and sands,
The merchant fears, ere rich at home he lands.”

Lucrece summoned her father and husband the next day back to their home in Rome. She asked them to avenge what had happened to her, told them the story and then stabbed herself to death. Her husband and father carried her body to the public square and told the people of Rome what had happened. The Tarquinius family was chased out of Rome, ending the monarchy.

Did pain really pay?
For a while, Tarquinius may have enjoyed the bitter fruits of his act but his win led to death and misery for all involved.

Before the 1990s, doctors used opioids rather sparingly. One can say that pain was under-treated. Narcotics were mainly given to cancer patients. Then in 1980, Hershel Jick published a study claiming that the use of narcotics in 11,882 in-patients led to only 4 cases of addiction. Six years later, Portenoy published his study looking at the use of narcotics in non-cancer patients. He claimed there were no adverse effects. He studied 38 patients on which he based his claims!
Even though both studies were highly flawed, they dramatically changed medical thinking and then practice. Portenoy formed the American Pain Society and preached that the risk for opioid addiction was less than 1% – a number he would later confess that he grabbed out of thin air!
The society came up with “Pain as a 5th vital sign” slogan and it caught on.
Into this fray was dropped the drug Oxtcontin by Purdue Pharma in 1996. With aggressive marketing, they promoted this new drug.
The Joint Commission got behind pain the 5th vital sign. By 2004, doctors who under treated pain faced sanctions. Opioids were being prescribed to all, even outpatients. Later Endo Pharma and Johnson & Johnson would join the opioid party with their own portfolio of synthetic opioids.
Purdue Pharma claimed that oxycontin was a slow-release formulation and would never lead to addiction. Well, we know better now. They had to pay $635 million in fines in 2007 for misbranding and reformulate the dug but by then it was too late.
By 2012, sales of opioids were more than $9 billion a year and in 2013, opioid overdose surpassed car accidents as the number one cause of accidental death.
These patients are now not just sticking to prescribed narcotics but using heroin, cocaine as well as illegally made fentanyl and karfentanyl of unknown potency!

Like Tarquinius, pain did pay the income of each precious thing. The drug companies got rich. Doctors ran “pill mills” where they prescribes opioids like candy… and got rich. Whatever misgivings these players may have had was only like “ the merchant who fears, ere rich at home he lands”.
Like Tarquinius, doctors and the pharma companies took from these patients something really valuable. Almost as valuable as what was taken from Lucrece. They took away their will to not fall prey to opioid addiction. They took away their independence and sense of worth. They made them dependent. All those years of easy narcotics made all these patients highly susceptible to addiction to heroin and cocaine.
Lucrece killed herself shortly after her defilement. These patients are however dying slowly albeit in large numbers. However the misery their fading lives cause is as profound as that which Lucreces’ father and husband felt.

How his all this going to end?
Are the drug companies and doctors going to get banned from our cities?
Already, states like Ohio are suing the drug companies to force them to finance the care of all these addicts. Will doctors be held liable too?
Whatever happens, I hope we all learn that pain is not a means to amass wealth but rather a sign that the sufferer needs help.

Those Miracles

When one looks at US Health Care from a global perspective, the numbers are not pretty. Compared to other industrialized nations, the US spends way too much money on healthcare but has some of the worst outcomes. Where the US shines though is in cancer care, where only Japan and Sweden do better.
The mortality from ischemic heart disease is especially galling. Looking at 2013 figures, the US mortality is about 128/100000 (0.128%) versus 35/100000 (0.035%) for Japan. Out of 12 nations looked at, the US did only better than New Zealand. This is however easy to explain when one looks at the lifestyle choices of most Americans versus the Japanese as well as access to primary health care in both nations.
In spite of these discrepancies, those of us who work in the system see the effort that most healthcare workers put in daily to achieve good outcomes. Every now and then, some of these outcomes makes one think of a miracle. Someone may even wonder if a Deity has a hand in these miraculous outcomes. Yet if one sits back and analyzes what it took to achieve some of these really amazing outcomes, one sees the expenditure of something more than just faith and prayers.
Now imagine a 60-year-old man, who is a smoker, obese, with uncontrolled diabetes and high blood pressure. He shows up in an ER with an ST-elevation myocardial infarction and is looking rather bad. In less than an hour, a top-rate cardiologist has him in the cardiac catheterization unit and diagnoses severe 3-vessel disease and congestive heart failure that needs surgery. In no time, the cardiac team is ready and the poor fellow is the operating room getting prepped for coronary artery bypass surgery. He has the best cardiac surgeon in the hospital, an excellent cardiac-trained anesthesiologist, a tip-top perfusionist and just amazing nurses and scrub techs. Surgery goes well but his left ventricle has taken a hit so he ends up needing an Intaraortic Ballon Pump (IABP) and then a Left Ventricular Assist Device (LVAD) to make it out of the operating room. The team is worried about his prognosis.
In the intensive care unit, he is cared for by a cardiac nurse with awesome experience and nursed around the clock. A well-trained lntensivist hovers over it all.
The patient stabilizes. The LVAD and IABP are taken out a few days later. About a week later, he is out of his induced coma, has no other complications and is extubated. On post-operative day 8, he is in a chair, looking like nothing happened. His family, expecting the worst now look at him like he is Lazarus walking out of the tomb. He is a miracle!
Which brings me to that something other than faith – Money! This poor man was saved because there were resources to save him and those resources were bought with and paid for by money. He lives in a society that can buy him a miracle! Sure, the prayers of his family may have improved his outcome but those same prayers will be of no use if he had this myocardial infarction in a Third World country!
Now let’s look at the cost of this miracle (these are averages):
The ER visit cost about $2000.
Diagnostic Cardiac Catheterization cost about $2600.
Cost of coronary bypass surgery is about $70,000 to $200,00 (with his complications and assist devices, more like the upper end).
ICU stay cost about $10,000 a day for the ventilated patient, so about $80,000 in his case. I have not even added the cost of the LVAD and IABP.
The above charges are mainly hospital charges. Drugs are not included. Neither are some personnel and ancillary charges.
This was one expensive miracle, only possible in the developed nations of the world. Even in these countries, one has to ask if it is really feasible to spend so much resources on one person. Most people would want such care for themselves and family members if ever in such a situation. Who wouldn’t? is it feasible though in the long term? Can any nation afford this, even the mighty USA?
A British economist, Lionel Robbins, once gave the classic definition of economics. He stated that “it was the study of the use of scarce resources which have alternative uses.
I borrow that definition as I ask the question:
“Can we continue to use the resources we have, which may not be scarce but could have alternative uses, to achieve these medical miracles without any consequences?”
Most patients do not really care but I think we as providers should. Even in the US, nothing last forever.

The Physiology of Anger

“You will not be punished for your anger, you will be punished by your anger.”
– Buddha

Anger is a strong emotional response to a perceived slight, threat and hurt. It impacts the whole body and mind.
Emotions are controlled by the limbic and autonomic nervous systems. Whereas the limbic system seems to be the engine of emotions, the autonomic nervous system carries out the effects of our emotions eg. fight or flight.
The complex set of structures called the limbic system are situated on both sides of the thalamus, just under the cerebrum. It includes the hypothalamus, the hippocampus, the amygdala, and several other nearby areas. The amygdala are two almond-shaped structures that are responsible for our emotions.
They identify threats or hurts and send out a warning sign to the autonomic nervous system. The efficiency of the system is such that it can get us to act before the cortex can modify it’s commands. Why is that important? Well, if we react to emotions as directed by the limbic and autonomic nervous systems, our actions are without thought and judgement. Our actions are without consideration of consequences. It is the cortex that gets us to consider our actions.
Thus an angry person runs the risk of action without thought and judgement.
As one gets angry, the muscles tense up. Epinephrine (adrenaline) is released giving one a burst of energy and the desire to take immediate action. The focus narrows, the heart rate and blood pressure increase, blood flow to the arms and legs go up. More neurotransmitters are released putting the angry person in a state of very high arousal. One is ready for a fight.
It is at this point that the cortex is supposed to step in and get one to asses the reasonableness of the planned reaction and consequences. The ability to step back from this angry state and look at things sanely takes some training. It can come from our upbringing, our belief systems or techniques one has learnt (breathing exercises).
If one is able to step back, reassess the situation and take control of the emotion, the cool down phase starts. Now this phase takes a while to get one to the resting, calm state of affairs. It can take days. The problem is, if the cause of the anger re-emerges in this phase, the threshold for getting angry is much lower. The intensity is higher and the chances of acting on the emotion increases.
Beside getting one to act without reason and judgement, anger also makes people think in more negative and prejudiced terms about outsiders. It makes one deal more in stereotypes and hinders analytical thinking, unlike sadness or fear. There is the tendency to place blame on another person for one’s misery. Angry people also tend to find causes for issues that are charged with anger. So an angry person is wont to listen to the pundit who preaches anger-illiciting reasons for societal ills.
Anger is however not wholly a negative emotion. When harnessed well, it can lead to positive action due to arousal. Arousal is a very important human condition. Human action of any sort is preceded by arousal. Every athlete will tell you that a certain level of arousal is needed prior to competition. Moderate arousal levels help the brain to learn and enhance memory, concentration, and performance. So controlling one’s anger stems the hasty action but leaves a level of arousal that can be harnessed to effect real change, create or even learn. When arousal is excessive as in the angry state, it limits our ability to concentrate, learn and remember. Any surprise most do not remember an angry outburst?
Also, anger can be feigned as a strategy to manipulate or even affect the outcome of a negotiation.
The powerful emotion that is anger is meant really to be a force for good. This force can only be realized if we can tame it through the right coping strategies like behavioral therapy and meditation. Then one angry person may have minimal effects socially, but an angry populace can have massive detrimental societal ramifications.