Community Spread of nCoV2019: Is Endemicity Possible?

Lately, one of the questions I’ve been asked is how I see the novel coronavirus outbreak ending. It is a complicated question that is hard to answer. One outcome that I think is worth exploring, as a thought experiment, is that the novel coronavirus outbreak ends with the virus become one of the coronaviruses we deal with perennially (i.e. it becomes endemic as a human viral respiratory virus). The trajectory of the virus has demonstrated its capacity for sustained human-to-human spread at a rate higher than SARS. As such, I believe this virus is spreading akin to a community-acquired coronavirus such as OC43, 229E, HKU1, or NL63. With those coronaviruses, a winter/spring seasonality is present. Thus, I wonder if this virus — absent control efforts currently underway that may dampen the seasonality or smooth it— would exhibit this type of seasonality. It has clearly no need, currently, for whatever animal reservoir(s) it jumped to humans from.

It is hard to completely understand severity yet as very limited data is available but it is evident from observing case counts and death counts that this virus has at maximum an intermediate coronavirus fatality rate. That is, it lies between the community acquired coronaviruses and below SARS. I have seen some estimate it’s fatality rate to be 1/50th of that of MERS. It does appear, from early case studies, that deaths cluster in older adults with comorbidities.

The WHO today stated that they believe control measures are still thought capable of halting transmission and perhaps these efforts will be aided by the natural coronavirus seasonality. However, if transmission isn’t entirely stamped out and low-level transmission continues it could be the case that next winter the novel coronavirus appears again as part of the viral respiratory virus cast. If that happens could it be we will just have another sometimes severe respiratory virus to contend with (of course containment should be the goal so long as it is possible). We have examples of these potentially perilous infections in adenovirus 14, adenovirus 7, the AFM-induced EV-D68, and several others. These viruses are hazards to be dealt with seasonally and are challenging with high burdens of illness in some individuals. Another important example is that of the 2009 H1N1 influenza A strain that emerged in the spring of 2009 and displaced the prior H1N1 strain to transition from a novel pandemic strain to an endemic seasonal strain.

I don’t know how the emergency phase of this outbreak will end or how quickly events will either support or reject this idea I proposed but I think there is more than a zero probability that a 5th community-acquired coronavirus has appeared.

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..