A Hypothesis about nCoV2019: Thinking about Patient 1 and Patient 0

As the novel coronavirus outbreak evolves, I have been contemplating and developing various hypotheses. One I think I want to explore in a little more depth involves the timestamp of this outbreak: When did first cases occur? When did this virus end up in humans?

I am asking this because as I look at the trajectory of this outbreak I am beginning to think that maybe this case count reflects large community-based transmission that has been ongoing for some time. I have thought that maybe the cluster at the seafood market was a “red herring” (pun intended) and came to light because of the epidemiologic linkage of patients and I am beginning to increasingly think that it may be the case. The Lancet paper on the 41 seafood market cluster tellingly reveals that patient number 1 had no contact with the market and became ill December 1 — weeks before this outbreak came to light. This suggests that this outbreak had been ongoing since at least November unbeknownst to clinicians. Remember, viral upper respiratory infections and even pneumonias largely go undiagnosed to a specific microbiologic level (to wit, I rounded this weekend and had multiple such cases that defied microbiologic diagnosis even in a nationally renowned quaternary care medical center).

In light of the above, the logical question is: if Patient 1 wasn’t linked to the market, where was the virus acquired? Who is Patient 0? We need serological anitbody-based surveys to see how prevalent exposure to this virus was pre-outbreak detection.

Phylogenetic analysis of the virus suggests a single introduction to humans but little variation in the limited human isolates available so far — they all share a common ancestor. However, does that suggest when the jump to humans occur? There are known rates of coronavirus mutations in humans and that can give some clue to how much divergence has occurred in humans and it appears that it has not diverged much at all. I wonder if this virus, like other coronaviruses, was circulating in the midst of a relatively forceful flu season and not diagnosed or noticed because many of the cases mimic influenza and other respiratory viruses. The data, based on assumed mutation rates, suggests this jumped no earlier than October 29, 2019 which would give the virus an almost 2 month head start to spread comingled in the flu season.The Makona variant of Ebola Zaire, which was the result of a single viral spillover from bats, circulated for 3 months before notice in Guinea.

If this is so, I expect case counts to rise as the virus circulates and deaths to rise as well (though at a much lower rate). Maybe this virus will become another established seasonal coronavirus with severity that is intermediate between the community acquired coronaviruses (OCV43, 220E, NL63, HKU1) and MERS and SARS? (Note that HKU1 can cause severe disease and may be an intermediate coronavirus as well)

I also believe if there is widespread community prevalence of this virus there is likely a significant severity bias in case reporting as well as in conceptualization of this viral syndrome. Imagine if you didn’t know anything about influenza and RSV and scoured adult ICUs and hospital floors. You would get a totally different picture of these diseases than if you were out in urgent care centers and PCP offices?

None of the above is meant to minimize this outbreak but my attempt to make sense of it.

If DA were here, I would ask him and know he would have an answer in a minute. It is at times like these that his giant, reasoned, prescient voice is what the world needs.

The Largely Unknown Story of the once Novel Coronavirus HKU1 is Informative

Like everyone in the field, I am actively following the discovery of a novel human coronavirus in Wuhan that has sickened close to 200 people, killed three, and been exported to three countries. In the last few days, case counts have substantially increased as public health authorities in Wuhan are scouring cases of pneumonia and finding some proportion are positive for the novel virus. Such events — especially the rapid uncovering of cases without links to the market — have caused even more comparisons to SARS to be made. Despite initial reports seemed to have the virus confined to a live seafood market, the discovery of cases with no link to that market argues that at least some level of human-to-human transmission may be occurring (with the caveat that healthcare workers are not being infected).

One hypothesis I am entertaining — and it is a hypothesis that may be quickly overturned — is that perhaps this coronavirus is following a pattern similar to another post-SARS discovered coronavirus: HKU1. The HKU1 discovery story is one that I find is not well known or appreciated so I wanted to explore it in order to put the novel coronavirus into context.

In 2003, after SARS exploded what we knew about coronaviruses — that they were chiefly causes of the common cold and rarely caused severe infection — there were efforts to understand more about coronaviruses and as part of that effort viral discovery efforts were undertaken to uncover new coronaviruses that were causing human infections. Shortly thereafter two novel coronaviruses were isolated from humans, one of which (HKU-1) was a betacoronavirus, the same subgroup that includes among its members MERS and SARS. The first diagnosis of HKU-1 (in 2004) was found in Hong Kong in a 71 year old man who traveled from mainland China and developed a radiographically confirmed pneumonia requiring hospitalization. After this discovery, nasopharyngeal samples from the SARS-era were retrospectively tested for HKU1 and one (from March 2003) returned positive. In the US, specimens from 2001-2002 were also found to contain this virus as well. These findings demonstrated that HKU-1 had been spreading in the global community for at least several months (alongside SARS), unbeknownst to everyone. HKU1 has subsequently found to be circulating all over the world.

After this discovery, HKU1 was the subject of several important studies. One of these, a retrospective and prospective study conducted in Hong Kong is very interesting. In this study, nasopharyngeal samples obtained between March 22, 2003 (the start of SARS cases in Hong Kong) and March of 2004 collected from community acquired pneumonia cases that were SARS negative were screened for the presence of HKU1. Strikingly, HKU1 was found to account for 2.4% of the community acquired pneumonias during that period. If HKU1 was such a common cause of community acquired pneumonia, it clearly had been widespread despite only being “discovered” in 2004. I suspect the number would have been even more substantial if upper respiratory tract infections were included as well.

Another important study, conducted in the US city of Cleveland in 2016, tested over 1000 respiratory samples from patients in all settings (inpatient and outpatient) and found 1.8% to be positive for the novel HKU1 with 54% of cases hospitalized and 29% requiring intensive care unit admission — the standard indicator of critical illness. So, not only was HKU1 a newly discovered coronavirus but it was also widespread and capable of causing critical illness — again something that no one had appreciated.

Trying to integrate the story of HKU1 with the novel virus in Wuhan, I wonder if this virus will subsequently be shown to be part of the coronavirus repertoire that was just unidentified. Pneumonia cases are not always diagnosed to the specific microbiologic level and many go undiagnosed, including those requiring ICU care.

I don’t what happened in December at that market to bring this virus to light. Was it a big animal spillover? Was it a focal point of transmission from an animal species? Was it the site of a superspreading event? These are all important question that remain desperately unanswered. I wonder, thought, could whatever occurred at the market be an indicator that this virus was already present in human populations at some level — like HKU1 — and only coming to light with the aid of this concentrated outbreak? Phylogenetic analysis seems to indicated that, based on the lack of genetic diversity seen in the limited number of sequences that are available, this was a recent event. However, doing serological surveys for specific antibodies would really help determine the extent of spread as would testing older samples from unexplained pneumonia cases (as was done with HKU1).

This is not to minimize the events in Wuhan but to provide some context for how difficult the first stages of an outbreak investigation may be and how understanding the historical context of related viruses may help understand the emergence of a novel member of the family. I also wonder how many coronaviruses (as well as other viruses and other microorganisms) circulate surreptitiously because of lack of diagnostic capacity and lack of diagnostic curiosity.

Now that advanced technologies exist, illuminating the biological dark matter that exists in every hospital (whether in Cleveland or in Wuhan) in cases of sepsis, pneumonia, meningitis, and encephalitis in which a specific microbiologic diagnosis has not been made is a task I believe should be a priority not only for patient care but for pandemic preparedness..

A Book by Any Other Name Would Be as Sweet a Read: A Review of Superbugs

Of the many books written on the topic of “superbugs” many focus on listing the greatest threats faced by infectious disease physicians, difficult patient anecdotes, warnings, and proposed solutions. The other type of infectious disease books involve exotic locales and explosive outbreaks. The latest book I read is different from these and, in my estimation, is a worthy addition to the shelves or ipads of those who like this topic. Superbugs: The Race to Stop an Epidemic by Cornell infectious disease physician Matt McCarthy is a book ostensibly about a clinical trial but has a lot more of value in it.

McCarthy begins the book’s prologue with a patient anecdote but quickly moves to what I see as the essential focus of the book: the ins and outs of an antibiotic trial. Along with this trial McCarthy peppers in a lot of interesting aspects regarding infectious diseases and the day-to-day of an academic infectious disease physician. Besides himself, the chief protagonist is his mentor, the renowned mycologist Thomas Walsh, and their interactions provide a really enjoyable perk of the narration.

The book does cover the initial development of antibiotics — the stories of Domagk and Fleming — but adds an often neglected aspect: the crucial and undervalued role of pharmaceutical companies. He quotes Tony Fauci to make this point:

You don’t want the federal government to be a pharmaceutical company because you’d have to build an entire industry...If the federal government tried to re-create Merck it would cost billions of dollars. The expertise of production, filling, packaging, and lot consistency. People take that for granted, but that’s an art form that has been perfected by these companies, not the government

He also notes that, contrary to what those who villainize antibiotic manufacturers may say, the net present value (NPV) of an antibiotic is just $42 million compared to the $1 billion for other pharmaceutical products. He later points to another analysis showing the NPV may be negative $50 million.

The focus of McCarthy’s clinical trial is on dalbavancin, an interesting long acting gram positive injectable antibiotic. The drug had a little bit of a tortured history being passed from Pfizer to Durata to Actavis to Allergan (Durata was acquired by Actavis which bought Allergan and kept the name). At that time, Allergan was one of a few remaining major pharmaceutical companies involved in antibiotic development (it has since tried to sell its infectious disease unit). While dalbavancin isn’t a breakthrough antibiotic on par with some others, it has an important niche in treating MRSA infections, avoiding hospitalization, and avoiding the use of long term intravenous lines. The book uses this trial as backdrop to discuss topics such as institutional review boards (IRBs), informed consent, FDA oversight, and patient recruitment. All of this makes for worthwhile reading.

He also discusses fungal infections, which often get short shrift to our detriment, one of the passions of his mentor. He tells of the discovery the first antifungal, nystatin, by two female researchers, which I had never heard before and recounts that it was named for the New York State (NYS) Department of Health. He also covers the emergence of Candida auris and the quest for new treatment options.

I found the book very enjoyable to read and think it is an important contribution because it demonstrates what it is to be an infectious disease physician in the modern era, concretizing the daily battles, the insoluble and endless puzzles, and the exhilarating rush one gets from figuring things out.

Concretizing Influenza Then & Now With the Help of A Mütter Museum Exhibit

This year’s flu season is well into effect though somehow I have yet to diagnose a case myself. This season is marked by an early dominance of influenza B which will be interesting to see, from a virological standpoint, remains sustained. The last time a season was dominated by influenza B was my senior year of high school (I didn’t miss any days). Markers of severity are all below epidemic thresholds.

With this year’s flu season in mind, I recently visited an exhibit that detailed a very cataclysmic event: the 1918 pandemic the Mütter Museum in Philadelphia (maintained by The College of Physicians in Philadelphia) currently has two exhibits devoted to infectious disease. One is entitled Going Viral: Infections Through the Ages. This exhibit importantly takes the viewer through the various explanatory stages for infectious diseases: from the humoral stage to miasmas to the culmination of the germ theory of disease. This progression is really crucial to understanding the history of infectious disease and how science progresses.

The other is Spit Spreads Death, a special project that details the experience of Philadelphia during the 1918 pandemic. Interactive displays demonstrating the spread of the flu, newspaper headlines, photographs , and personal anecdotes are included.

As people forget about how dangerous a virus influenza is, exhibits like these help concretize the power of this infectious disease and are well-worth visiting for both the general public and infectious disease experts alike.

Rage Against The Machine: A Brief Review of Randall's Black Death at the Golden Gate

Several weeks ago news headlines carried stories of a spattering of plague cases in China. To those who follow infectious disease, it was not surprising as parts of Asia is considered the home of plague and cases occur there with regularity. But despite these facts, media headlines invoked the Black Death. The Black Death, which occurred over 500 years ago, was a calamitous outbreak of plague that likely killed one-third of Europe’s population.

The news stories about these latest cases almost universally left out the context of the Black Death — no supportive care, no antibiotics, and malnutrition. They also did not mention that though person-to-person spread of plague involving the lungs — pneumonic — is possible, it is rare (and the cases reported were bubonic which should prompt little in the way of special measures).

While this was all happening, i was in the middle of a new book on the topic of plague entitled Black Death at The Golden Gate: The Race to Save America from the Bubonic Plague. This book, published in 2019, by David Randall tells the story of the turn-of-the-century outbreak of bubonic plague in San Francisco. This subject has been told before in books but Randall’s approach, to me, appeared fresh and full of details that I hadn’t quite recalled from prior reading on the subject.

In brief outline, the story of plague in San Francisco is one that is familiar to anyone who knows the history of infectious disease: a cycle of denial, overreaction, and bureaucratic interference. The backdrop of the events that occurred in San Francisco occurred in the midst of a power struggle between the US Surgeon General Walter Wyman and rising public health luminary Joseph Kinyoun who was exiled to the Angel Island quarantine station. At the time, plague had just raged in Hawaii leading to the literal burning of Honolulu’s Chinatown — an ominous development that Kinyoun did not want to occur in San Francisco

Plague first appeared in San Francisco as a single case in Chinatown prompting a draconian quarantine of the entire region and then, when tests were not fully completed, a reversal and then another quarantine. Randall also details the baffling stories of how plague deaths were hidden from authorities (which including propping dead bodies up to make them look alive). The book details the bureaucratic machinations that Kinyoun faced — including interference from President McKinley and the California governor (Gage) — and ultimately how he was replaced.

In the end, plague established itself in the US after public health measures failed to contain it and the book illustrates how failing to heed the warnings of public health authorities can prove disastrous. I think these themes are timeless and have been repeated countless times in outbreaks small and large from HIV, to hepatitis A, to SARS, to Ebola. I was struck by the lone brilliance of those like Kinyoun who were, instead of being rewarded, were punished for their foresight.

Randall also weaves in a great deal of the history of California, San Francisco, and the Chinese Six Companies into the narrative. He also highlights some of the anti-Chinese immigrant sentiment that permeated area even prior to the outbreak including mayoral candidates campaigning to keep California “white” and threats of violence against those that employed Chinese immigrants.

I highly recommend this book as a great introduction to the history of plague in the modern era but even more so as a great case study of how public health and infectious disease authorities face not only the microbe but often a hostile public and government leadership that must also be navigated with equal precaution.