What to Know

Unfortunately, with end of the public health emergency, we can no longer see the earliest and best indicator of disease transmission levels – cases (reports to the CDC of all those testing positive by a PCR test performed at a hospital or commercial laboratory). Instead, we now have to resort to wastewater surveillance, hospitalizations for COVID and deaths from COVID, the latter two measures being late indicators of COVID-19 transmission levels. Nevertheless, all three measures are up and increasing leaving little doubt that we are having a new surge (please note that I use surge to denote a measurable and sustained increase in cases, hospitalizations and/or deaths, but the use of the word surge does not in any way indicate the magnitude of the increase relative to baseline or past surges).

Hospitalizations

An increase in hospitalizations due to COVID-19 is certainly an indication that COVID-19 cases have also increased in roughly the week prior. COVID-19 hospitalizations are up in the US and globally, but keep in mind, not only are hospitalizations a late indicator of COVID-19 cases (~ 1 week), but the reporting of hospitalizations is also delayed. I am writing this on August 14, and the most recent data on COVID-19 hospitalizations in the US from the CDC is from July 29, in other words, roughly 2 weeks ago. Further, the reporting to the CDC is not always timely or complete. Thus, there is no way of determining just from the COVID-19 hospitalizations data during a surge, whether the number of cases is still increasing, has peaked, or is even on the decline (we will have to put all of the data together to make that assessment – see below).

In the week ending July 29, there were 9,056 people hospitalized for COVID-19 in the US. That was a 12.5% increase from the week prior. To put this in perspective, the highest number of hospitalizations in the US in a week occurred in the week ending January 15, 20222 with 150,674 COVID-19 hospitalizations (which was high enough to overwhelm many of our hospitals), but keep in mind that it appears that the current surge in hospitalizations may be just beginning and very likely has not peaked yet.

In Idaho, too, there does appear to be a slight uptick in COVID-19 hospitalizations, but it is far less pronounced that what I am seeing nationally, confirming reports that seem to suggest disease transmission may be higher in other parts of the country than the Pacific NW at this time.

Wastewater Surveillance

Detection of SARS-CoV-2 virus has increased significantly in the wastewater testing from every region of the U.S. Currently, levels in the midwestern US are increasing most rapidly, and have overtaken all other areas of the country. It appears possible that wastewater levels of virus have peaked in the eastern US and the southern U.S., while levels in the western U.S. have been lower, but steadily increasing and have now reached the levels seen in the eastern and southern U.S.

In Idaho, reporting is significantly lagging, with the most recent data being roughly 3 weeks old. Keep in mind that the delay from sampling to reporting has historically been about a week, so these data are likely one month old. Nevertheless, it showed that wastewater levels of SARS-CoV-2 virus were increasing in Ada County and steady in all other parts of the state for which wastewater sampling is available. The wastewater surveillance testing/reporting is similarly lagging for the City of Boise (last reported July 24) and that time, I could not discern anything suggesting the beginnings of a surge.

Deaths

The CDC reports that COVID-19 deaths accounted for 1.1% of all deaths in the U.S. and that COVID-19 deaths had increased 10% over the last reported week. That does reflect an increase in COVID-19 deaths in the U.S., however, the numbers remain low on a relative basis, and all of this would be consistent with what would be expected early in a new surge, as we typically don’t see increases in deaths until a couple weeks after we see the increases in cases.

Looking at the Idaho reporting, we are not seeing any increase in COVID-19 deaths over the recent baseline, however, this data is two weeks old.

Variants

It’s a bit challenging to know what variant to attribute to this current surge, although I certainly have my guess. In the past, surges have generally been easily attributed to a single variant that was dominating, and we usually did not see a surge until that variant accounted for over 50% of the genetic sequences recovered and identified from infected persons. However, at this time, in the US, we have at least 18 variants circulating, of which at least 5 appear to be on the rise as a percentage of all the variants circulating. As, I mentioned, I have a guess as to the variant causing the current surge, but it is only a guess, and I base that upon the fact that it is the prevailing variant (perhaps as high as 21% – however, it may be much more now because that was as of August 5) and seems to be the fastest growing variant. That variant is EG.5, another recombinant of two Omicron variants with numerous subsequent mutations.

Unfortunately, the wastewater reporting from the City of Boise is nearly a month old, but interestingly, even then, EG.5 accounted for 11% of the variants detected. The then prevailing variant was XBB.1.9, but I would certainly expect EG.5 to have increased and XBB.1.9 to have decreased by now.

What are the implications of all of this?

There is little doubt that we are in the early part of a new surge. I can’t tell you to what magnitude this surge will manifest, and neither can anyone else. If the wastewater measures truly are peaking in the eastern and southern part of the country, then that is fantastic news and this surge is likely to be rather mild in a relative sense. Even if the surge has not peaked anywhere in the US yet, given what we know about EG.5, we would not expect a surge that would come close to the surges we dealt with in 2020, 2021 and early 2022.

However, we should take the following factors into consideration in reserving judgment as to how significant this surge may or may not be because many factors have changed since these earlier years of the pandemic:

1. We are undeniably dealing with more transmissible and more immune evasive variants now than we did in those earlier years.
2. Schools in many parts of the country will start the new school year over the next couple of weeks. While early on, the evidence seemed to defy logic and experience in that school children did not seem to play a major role in transmitting the virus (children are a significant factor in driving community transmission of most respiratory viruses, especially influenza), but now the data seem clear that in fact children do play a major role in the transmission of SARS-CoV-2), and it is likely that we will see a significant uptick in community spread once schools open.
3. Unlike earlier years when schools were implementing some mitigation measures, from what I can see, it appears that few schools are taking any mitigation measures this school year. This will promote transmission within schools and subsequently within communities. Further, while we know that schools could significantly reduce transmission through changes to their air handling systems, it appears that relatively few schools have adopted these best practices, which could have been subsidized with federal monies that likely are no longer available.
4. Similarly, work places are taking less mitigation measures, and many companies have cut back or ended remote work opportunities. This will undoubtedly promote transmission within work places.
5. Of great concern to me is the fact that up until this year, hospitals required masking in all patient care areas. It was also common for hospitals to limit visitors and screen employees and visitors. Now, many hospitals have abandoned most, if not all, of these measures. We know that as transmission increases in communities, the rate of infections in health care workers increase, as well. Further, while the U.S. does not require reporting of nosocomial SARS-CoV-2 infections (infections that patients acquire while hospitalized), and regrettably, few if any hospitals have been transparent in reporting this data publicly, we know that these infections are well documented in countries that do. It seems all but certain that as community transmission rates increase, it will become more and more dangerous for those who are hospitalized for reasons other than COVID-19.
6. We can all remember the days when masking in the community was not rare, when people avoided large gatherings, and when most larger events were held outdoors. Of course, little of this is the case today. Not only does this increase the risk for exposure to people who are infected when community transmission levels increase, but when in close contact and not masked, the viral dose is increased (the amount of virus that a person inhales), and we have some evidence to suggest that higher viral loads correlate with higher risk of severe disease.
7. Ironically, in 2021 and 2022, we had more treatment options for patients with severe disease.
8. In 2021 and 2022 there was more quarantining of those who were infected and more isolation for those who were exposed by a close contact. Now, people are returning to work and school much sooner and, in many cases, it is likely that they may still be contagious. Contact tracing and isolation are things of the past.
9. Another concerning recent behavior I have seen is that people symptomatic this summer have done a single test that was negative and declared that they have the summer flu. First of all, a single rapid antigen test early on in the development of symptoms is not sufficient to rule out COVID-19. There is a high rate of false negative tests (meaning that the person really is infected despite the fact that the test indicates no evidence of infection) when done early on in the development of symptoms or following an exposure. Thus, serial testing following onset of symptoms is required. Further, while it is possible to acquire a number of respiratory infections, including influenza, during the summer, levels of these viruses circulating in the US during the summer are typically quite low.
10. Finally, keep in mind that in 2021 and 2022, people had fairly regular boosts to their immune protection against SARS-CoV-2 from prior infection, vaccination or both. Today, that immune protection is much less than previously, and keep in mind that only the minority of the population has taken the bivalent vaccine first made available in September of 2022, and even those who did take advantage of that booster have not had another dose of vaccine since. Thus, though we can be grateful for what appears to be long-lasting protection against severe disease, there is not doubt that the immune protection for the majority of our population is waning.

We also must keep in mind that while the focus of the analysis of whether a surge is occurring is based upon hospitalization and death data now that there is so little testing and reporting of data, and while it is true as a general statement that people are less likely to be hospitalized or die today of COVID-19 than in prior years, none of this takes into consideration the risks of potentially life-altering Long COVID (PASC) or the many other potential long-term health effects from infection, and especially repeated reinfections.

Planned Parenthood Greater Northwest, et al. v. Raul Labrador in his official capacity as Attorney General of the State of Idaho, Members of the Idaho State Board of Medicine and Idaho State Board of Nursing, in their official capacities, and County Prosecuting Attorneys, in their official capacities.

Case No. 1:23-cv-00142-BLW

This case was decided on July 31, 2023.

The Background in the U.S.

Of course, the reason that we have seen so many new state abortion laws and legal challenges is that the U.S. Supreme Court overturned the long-standing precedent set out by Roe v. Wade in its decision last year in the case of Dobbs v. Jackson Women’s Health Organization. The result was that there was no longer a federally-guaranteed period of time during a pregnancy in which an elective abortion could be legally performed. Instead, the right to determine under what conditions, if any, abortion would be legal in a state would be returned to the states, and as a result, laws would be expected to vary from state-to-state.

The Background in Idaho

On March 27, 2023, Idaho Attorney General Raul Labrador issued an opinion in a letter with the subject line “Request for AG Analysis” to Idaho Rep. Brent Crane in response to a request from that legislator asking for guidance as to the following:

Do Idaho’s abortion prohibitions preclude:

1. The provision of abortion pills;
2. The promotion of abortion pills; and
3. Referring women across state lines to obtain abortion services or prescribing abortion pills that will be picked up across state lines?

The answer was yes to all of these activities in the Attorney General’s opinion letter. https://www.courthousenews.com/wp-content/uploads/2023/04/labrador-idaho-opinion-letter.pdf. (It is the AG’s response to the third activity that is the subject of this lawsuit.)

The Attorney General subsequently rescinded the letter stating: “It was not a guidance document, nor was it ever published by the Office of the Attorney General, accordingly, I hereby withdraw it.” Idaho AG walks back opinion on prohibiting referrals for out-of-state abortions | The Hill. The state of Idaho on behalf of the AG claimed to the court that the letter was intended to be a private communication, however, the letter was disseminated to and published publicly by a pro-life organization, in part to further its fundraising efforts.

Plaintiffs (Planned Parenthood Greater Northwest, Dr. Caitlin Gustafson, and Dr. Darin Weyhrich) filed suit in federal district court, challenging the Attorney General’s interpretation of Idaho’s criminal abortion statute, Idaho Code § 18-622 and asking the court to enjoin (prevent by legal order) the Attorney General, the Idaho State Board of Medicine and Board of Nursing, and the prosecuting attorneys for every Idaho county from bringing criminal or licensing actions based upon that interpretation of the law. Although the plaintiffs raised a number of legal theories, the case predominantly rested upon the issue as to whether plaintiffs’ First Amendment rights had been violated (making referrals to out of state providers is considered speech and the allegation was that the threat of prosecution for doing so and the threat of suspension of their medical or nursing licenses for doing so were restraints on their exercise of free speech.)

The Attorney General and some of the other defendants filed a motion with the court to dismiss the lawsuit on the basis of some technical legal doctrines concerning justiciability, which in layman’s terms simply mean that the plaintiffs were not in a position to bring a legal challenge and/or the matter was not one that presented a sufficient basis for a court to review it according to the Defendants. That motion was ultimately dismissed by the Judge.

The specific language in the statute in question stated:

“The professional license of any health care professional who … assists in performing or attempting to perform an abortion … shall be suspended ….” (emphasis added)

In addressing the third activity, the AG stated in his letter: “Idaho law prohibits an Idaho medical provider from … referring a woman across state lines to access abortion services …. Idaho law requires the suspension of a health care professional’s license when he or she ‘assists in performing or attempting to perform an abortion. Idaho Code § 18-622(2) (emphasis added). The plain meaning of assist is to give support or aid. An Idaho health care professional who refers a woman across state lines to an abortion provider … has given support or aid to the woman in performing or attempting to perform an abortion and has thus violated the statute.”

The statute allowed for no flexibility on the part of the licensing boards, but rather states that the provider’s license “must” be suspended for six months upon the first offense, and permanently revoked upon the second.

The letter was printed on Idaho State Attorney General office stationery and the title of Attorney General was added below General Labrador’s signature.

The Court’s Decision

The focus of the Court’s analysis rests on the Plaintiffs’ claim that the Attorney General’s interpretation of the criminal statute would violate their First Amendment rights of free speech and the Attorney General’s assertion that there is no threat to Plaintiffs because his letter opinion was withdrawn. 

It was notable to the Court that plaintiffs had previously made referrals for abortion services to out-of-state providers, but stopped doing so after the AG’s letter became public. On the other hand, the AG argued that letter could not constitute a threat of prosecution because it “was sent to one legislator as private legal advice [and] it was not published by the Attorney General or offered as guidance in any capacity.” Further, the state also claimed that there is no threat here because the AG lacks any authority to direct the county prosecutors or prosecute violations of the criminal abortion law.

The Court, however, took note of the fact that the AG’s letter was widely disseminated and became widely available to the public, and further, that this letter was issued and signed by Attorney General Labrador – Idaho’s chief legal officer – and was sent to a member of the Idaho legislature. Whether the guidance was official or not, it was the only guidance provided by the AG, and it nevertheless had a chilling effect on the plaintiffs’ First Amendment rights.

Further, while the state, in representing the AG, asserts that there is no prosecution threat because the AG’s letter was withdrawn, the Court takes notice of the fact that the AG does not disavow that opinion. The Court observed that the AG’s letter was withdrawn just hours before the first status conference in this litigation and appeared only to be for litigation positioning as opposed to a change in view or interpretation of the statute by the AG, and thus the withdrawal was not a disavowal. In fact, when counsel for the state were asked whether the AG or prosecuting attorneys disavowed the legal analysis or conclusion of the AG’s letter, they admitted that there was no such disavowal.

The Court notes that the legal theory upon which defendants seek to have the case dismissed is that of mootness – “when the issues presented are no longer ‘live’ or the parties lack a legally cognizable interest in the outcome.” However, a defendant cannot render a case moot simply by ending its unlawful conduct, because the defendant could simply resume that conduct after the case was dismissed. Instead, to prevail on a motion to dismiss the case for mootness, the defendant “has the heavy burden of persuading the court that the challenged conduct cannot reasonably be expected to start up again.” In the case of a governmental defendant, the defendant must demonstrate that the change in its behavior is “entrenched” or “permanent.” Given that the withdrawal of the AG’s opinion does not reject the statutory interpretation or provide an exception that would exempt the plaintiffs’ free speech from criminal prosecution, the matter before the Court is not rendered moot by the withdrawal of the letter. In fact, there is no evidence that the Attorney General’s position has changed.

Further, although there have been amendments made to the statute, none of those change the relevant language at issue in this case.

For all of these reasons, the Court found that the Plaintiffs were successful in demonstrating that there is a genuine threat of prosecution. The consequence of the threat is a chilling of the Plaintiffs’ Frist Amendment right of free speech. The rescinding of the letter by the AG, without revising or rejecting the legal analysis contained in the letter does nothing to ameliorate this threat or to render the Plaintiffs’ lawsuit moot.

As Judge Winmill stated in his opinion: “…It would not have been particularly difficult for the State to definitively establish that no case or controversy exists (“case or controversy” has a special legal meaning derived from the U.S. Constitution in conferring jurisdiction upon a court. If there is no case or controversy, then the court has no legal power to hear and decide the case. For example, if someone owes you $10, and refuses to pay you, but over time you reach an agreement that you will accept $5 as payment in full, endorse the check with the statement “Paid in Full,” and deposit the check, but then later decide to sue the person for the $5 balance, there would be no case or controversy since there was a mutual agreement and satisfaction of the debt.). That is, all it would have taken is for Attorney General Labrador to denounce the Crane Letter’s interpretation or make an affirmative statement that he, or his office, will not enforce Idaho’s criminal abortion statute in such a manner. Instead, the Attorney General has strained at every juncture possible to distance himself from his previous statement without committing to a new interpretation or providing any assurances to this Court or the Medical Providers. Attorney General Labrador’s targeted silence is deafening.”

Based upon all of the above, the Court then proceeded to issue a preliminary injunction that prevents Attorney General Labrador from enforcing Idaho’s criminal abortion statute as interpreted in his letter.

Readers are going to hear about a number of important cases that are based upon the First Amendment’s right to free speech. Unlike this case, some very high-profile cases pending before courts currently are using this First Amendment right as a defense to conduct for which they have been charged. Therefore, in future blog posts, we will review the First Amendment right to free speech, how courts have decided these issues in the past, and whether doctors have a First Amendment right to spread disinformation.

I have written many times previously on my blog about Long COVID or PASC (post-acute sequelae of COVID-19 infection), its manifestations and potential pathogenesis. Now, a new paper looks at the immunology of Long COVID: https://www.nature.com/articles/s41577-023-00904-7. In my discussion below, I will include parts of this paper, as well as some other recent information about Long COVID.

Although post-viral syndromes have been known to occur for many decades now, it was surprising early on in the pandemic to see the large number of people who continued to be plagued by persistent symptoms following the apparent recovery from the acute SARS-CoV-2 infection, including those with mild illness, and even including some children.

There is no diagnostic test for Long COVID, and for a long time, there was no widely accepted case definition for the condition. Therefore, there were widely varying estimates of the disease burden, ranging from a low end of around 10% of COVID-19 patients to a high of around 30%.

The World Health Organization definition of Long COVID is:

A condition that occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction and others, which generally have an impact on everyday functioning. Symptoms may be new onset, following initial recovery from an acute COVID-19 episode, or persist from the initial illness. Symptoms may also fluctuate or relapse over time. A separate definition may be applicable to children.

The CDC provides the following additional information about Long COVID:

• Long COVID can include a wide range of ongoing health problems; these conditions can last weeks, months, or years.
• Long COVID occurs more often in people who had severe COVID-19 illness, but anyone who has been infected with the virus that causes COVID-19 can experience it.
• People who are not vaccinated against COVID-19 and become infected may have a higher risk of developing Long COVID compared to people who have been vaccinated.
• People can be reinfected with SARS-CoV-2, the virus that causes COVID-19, multiple times. Each time a person is infected or reinfected with SARS-CoV-2, they have a risk of developing Long COVID.

We did see some differences relative to Long COVID with different variants. For example, comparing long COVID cases from the first wave to those from the Alpha wave, a change in symptomology was observed, with increased muscle aches, brain fog and anxiety, but decreased frequency in loss of smell and altered sense of taste. Despite these minor variations, the fact that a set of common symptoms endures across the different variants and even in vaccinated populations and, thus, across patients with differing viral loads, points to the presence of determinants of pathology that are intrinsic to the SARS-CoV-2 virus.

There are varying hypotheses as to the pathogenesis of Long COVID: (again, I have written about most of these in prior blog posts if you want to dig deeper into these)

• tissue and organ damage caused directly by the viral infection,
  • heart
  • lungs
  • brain
  • kidneys
• persistence or lack of clearance of SARS-CoV-2 and ongoing antigenic stimulation,
  • gastrointestinal tract,
  • testis,
  • a space between the skull and the brain
• an abnormal immune response to acute COVID-19,
  • an overactive immune response resulting in organ damage either in response to a very high viral load or a dysregulated immune response,
  • an inadequate immune response that allows the virus to wreak more havoc or may result in failure to clear the virus
• reactivation of other viruses,
  • Epstein–Barr virus (EBV) reactivation has been the leading candidate (most people have been infected with this virus that causes infectious mononucleosis or sometimes colloquially referred to as the kissing disease), though human herpes virus – 6 has been implicated.
• altered systemic immune responses,
  • We know that we can see various abnormal or exaggerated immune responses during acute infection and in the several months following (e.g., MIS-C, MIS-A – see prior blog posts where I have discussed these if interested).
  • There is intense debate surrounding whether there is potential longer term immune dysfunction and if so, whether it is relevant to the development of Long COVID or apparent susceptibility to other infections following COVID-19 (e.g., RSV, invasive group A strep, etc.). There are other viruses known to cause either temporary (e.g., a temporary loss of humoral immune memory following measles) or permanent immune dysfunction following infection (e.g., HIV). And, of course, there is the confounding factor that not all of the immune disturbance may be the direct effect of SARS-CoV-2 infection, but rather may be in part related to the indirect effect of reactivation of other viruses, such as Epstein-Barr virus, in those patients in which this occurs. One area of intense disagreement is whether COVID-19 results in significant and persistent T-cell exhaustion in some persons. (You can also read about T-cell exhaustion in some of my posts from last year).
• auto-immunity,
  • Many studies have demonstrated that acute SARS-CoV-2 infection can result in the production of a diverse population of autoantibodies, likely a result of viral mimicry (in other words, the virus contains antigens to which the body produces antibodies that are sufficiently similar to other self-antigens that the antibodies not only attack the virus, but the person’s own cells with that similar antigen on their cell surface.
  • Recent studies have identified increasing accounts of antibodies produced against interferon, which is a critical part of the body’s innate immune response in that interferon serves as a cellular warning system that an invading virus has been identified, which in turn, allows nearby cells to take some precautions that make viral entry more difficult.
  • Just a year ago, we concluded that Epstein-Barr virus (EBV) infection can cause multiple sclerosis decades later following infection, likely through an autoimmune mechanism. It is not yet clear whether EBV reactivation during COVID-19 might also contribute to the development of autoimmunity.
  • Of particular concern are autoantibodies that may target various cells of the brain potentially causing or contributing to the wide array of neurological complications seen during and following COVID-19.
• micro-blood clots, and
  • Some autoantibodies are of the type seen in a syndrome characterized by abnormal clotting.
  • Some antibodies may stimulate endothelial cell (the cells that line the inner walls of blood vessels) activation, which itself can promote clotting.
  • There have also been reports of an amyloid-like protein within these micro-clots that may make them more resistant to the body’s normal mechanisms for dissolving clots.
• microbiome dysbiosis (disruption of the normal gut microbiome).

Now we examine what evidence we have at this point in time to correlate immune responses with Long COVID.

As I mentioned, as of yet, we do not have a diagnostic test for Long COVID (in contrast to other diseases such as blood pressure measures for the diagnosis of hypertension or blood sugars for the diagnosis of diabetes). On the other hand, there have been studies that have found biomarkers (these are not diagnostic of Long COVID, but rather predictive of higher risk for the development of Long COVID such as the persistence of abnormal levels of certain cytokines and chemokines (these are chemical messengers of the immune system that may boost or calm the immune response) such as certain interferons or interleukins. One of the chemokines found to be persistently increased in some patients with Long COVID is CCL11, which interestingly and concerningly, has been identified as a mediator of the neurocognitive decline seen with aging.

Recall from my earlier blog posts that the spike protein is referred to as “S” or the S protein, and people will develop antibodies to the S protein with either vaccination or infection. There are other important proteins in the SARS-CoV-2 virus, and one of those is the nucleocapsid protein, which is referred to as N. Antibodies against the N protein are referred to as anti-N antibodies, and we generally only see anti-N antibodies in the case of infection, because U.S. vaccines only include the S protein and not the N protein.

A study looking at the initial anti-N antibody response during acute infection found an inverse correlation between antibody level and likelihood of symptoms at 3 months or beyond, supporting the view that an inadequate initial antibody response may predispose to Long COVID. [If you are having trouble following that, think about high antibody levels as a vigorous immune response and low antibody levels as a potentially inadequate immune response, but only use this framework early on in an infection, as antibody levels normally decline over time.]

An analysis of a cohort of hospitalized patients of whom roughly 20% would go on to experience Long COVID symptoms at 1-year post-infection found that the Long COVID group showed significantly lower antibody levels to S, with no difference in T cell response. [In this case, the lower antibody levels are to the Spike protein]. Together with the study mentioned directly above, with an association of low anti-N and low anti-S antibody levels with Long COVID, this would naturally cause us to query whether an underwhelming humoral immune response might predispose to the development of Long COVID.

Recall that there are three main parts of the immune response – the innate, the humoral and the cellular immune responses. I liken these to three branches of our military response, e.g., ground troop responses with the Army, a sea response with the Navy and an air response with the Air Force. In the case of immunology, the innate immune response is non-specific and not targeted – continuing with my military analogy, it is like lobbing grenades or dropping bombs from B-52 airplanes like we did decades ago and hoping they get close enough to take out enemy soldiers or tanks, but also realizing there will be a lot of potential collateral damage. The innate immune response is the most immediate immune response.

The humoral and cellular immune responses take days to a week or more longer to develop than the innate immune response. The humoral immune response is your antibody response – these are like laser-guided or heat-seeking missiles that are specifically targeted to the invading enemy. The cellular immune response is incredibly complicated, but in simple terms, antibodies can only capture enemy virus before they enter and infect cells. Once inside cells, we need specialized immune cells that can recognize that a cell is harboring fugitive virus inside and then have orders to take the entire cell out and kill everything in it. [If you are totally geeking out on this and must know what these specialized cells are, these are the cytotoxic T-cells or CD8+ cells].

So far in COVID-19, our limited understanding is that neutralizing antibody levels (a subset of all antibodies, these antibodies are capable of preventing the virus from entering and infecting cells, as opposed to other antibodies that bind to the virus, but do not block cell entry, which we broadly refer to as binding antibodies) correlate with protection from infection and cellular immune responses protect against severe disease. The reason that the COVID vaccines help prevent severe disease is that they provide you with a supply of neutralizing antibodies and stimulation of the cellular immune capability prior to getting infected so that your immune system is already primed and ready, as opposed to infection in unvaccinated persons where the virus gets a 3 – 7-day head start before the immune response can catch up to the virus. Unfortunately, as we have allowed uncontrolled transmission of the virus with subsequent development of progressively more transmissible and immune evasive variants, the neutralizing antibody response from either prior infection or vaccination is less effective and shorter lasting, but fortunately, we have seen the cellular immune response be much more durable lasting in most people at least 8 months and perhaps even longer.

However, a study looking at SARS-CoV-2-specific antibodies and T cell responses at 1–2 months post-infection and 4 months post-infection showed minimal differences between individuals with persistent symptoms and those without. When I see conflicting results from studies, we either have to consider other explanations such as perhaps not all persons with Long COVID have the same immune profiles, but as of now, we cannot conclude a unifying explanation for the development of the disease such as the hypothesis that perhaps those with inadequate humoral immune responses are those that are at risk for developing Long COVID.

Still, in other patients with Long COVID, there is evidence for an enhanced immune response, which may lend support for persistent antigenic stimulation from uncleared virus or virus particles.

Frankly, while this may frustrate readers that results seem to be all over the board, this just suggests to me that Long COVID may very well be a spectrum of disease, manifesting in different ways related to a number of potential pathogenic mechanisms by which Long COVID may result (e.g., perhaps in some patients Long COVID is related to latent Epstein-Barr virus reactivation, but in others it is related to auto-immune responses).

Results of studies that might support this hypothesis include those that show that individuals who went on to report persistent respiratory symptoms showed low serum cortisol, whereas those going on to develop neurological symptoms had an elevation of proteins involved in circadian regulation of the sleep cycle. Also, evidence of Epstein-Barr virus reactivation during acute COVID-19 was a predictor for the development of persistent fatigue.

We have yet to find a unifying immune profile that can be attributed to the development of Long COVID. That could be because Long COVID is not a result of immunopathology or is only such a result in some patients, or there are various profiles involved that account for the variation in how Long COVID manifests. This requires more research because we do have a range of targeted therapies that can treat specific aspects of the immune response. We can remain hopeful that as we better understand Long COVID, we will be able to offer more options to patients.

Crimean-Congo hemorrhagic fever (CCHF) is a vector-borne disease (recall that this means transmission by an insect rather than human-to-human transmission or animal-to-human transmission (zoonotic transmission). However, unlike the several diseases I discussed in the last three posts that are transmitted by mosquitoes, this disease is transmitted by a tick. The virus responsible for this disease is called CCHF virus, a Nairovirus, a member of the Bunyavirus family. The CCHF virus causes severe viral hemorrhagic fever outbreaks with a case fatality rate (CFR – recall that this is determined by dividing the number of people who die with the disease by the number of diagnosed cases of the disease and then expressed as a percentage as opposed to the infection fatality rate or IFR, which is the number of deaths due to the disease divided by the estimated number of people infected when there are cases that may be missed due to mild or asymptomatic cases that may never be diagnosed as cases) of 10–40%.

[Note: We still refer to the disease as vector-borne even when the tick or mosquito feeds on an animal, acquires the virus and then transmits it to a human through a bite (in other words, we would not refer to that as a zoonotic transmission). Similarly, we still refer to the disease as vector-borne when the tick transmits the virus to a human and then the virus is then passed on to a fetus by a pregnant mom or to another human through sexual contact, a blood transmission or an organ or tissue donation. In this case, we would still refer to the main transmission as being vector-borne, but acknowledge that there can be limited subsequent human-to-human transmission.]

CCHF is endemic in Africa, the Balkans, the Middle East and Asian countries south of the 50th parallel north – the geographical limit of the principal tick vector.

Unfortunately, there are a wide range of potential hosts of the virus, including cattle, sheep and goats. And, while the virus does not appear to infect most birds, it does infect ostriches, and ostriches have been reported to be the source of infection for humans even though ostriches generally show no evidence of being ill.

While the primary transmission route is via tick bites, CCHF can also be transmitted by close contact with the blood, secretions, organs or other bodily fluids of infected animals when humans slaughter the animals or those of a human in a household or healthcare setting. The majority of cases have occurred in people involved in the livestock industry, such as agricultural workers, slaughterhouse workers and veterinarians.

A tick may transmit the virus to animal, in which the virus may circulate in the animal’s blood for as long as a week. During that time, another tick may feed on the animal’s blood, which may result in the tick carrying the virus to yet another animal or a human and transmitting the virus as it feeds on the animal or human.

Following infection by a tick bite, the incubation period is usually one to three days, with a maximum of nine days. The incubation period following contact with infected blood or tissues is usually five to six days, with a documented maximum of 13 days.

The onset of symptoms is often sudden, with fever, muscle aches, dizziness, neck pain and stiffness, backache, headache, sore eyes and sensitivity to light. Patients can develop a fast heart rate, swollen lymph nodes and a rash that first may be dominated by small, bright, red dots that may then evolve to areas of bruising. In some cases, patients develop swelling and tenderness in the right upper part of their abdomen due to swelling of the liver.

Severely ill patients may experience rapid kidney deterioration, sudden liver failure or respiratory failure after the fifth day of illness.

Patients who recover from this infection generally show improvement by day 9 or 10 of the illness, whereas those who die from the disease most often die during the second week of illness.

The World Health Organization has identified its top 9 list of “priority diseases,” which in the assessment of the WHO present the greatest public health risks. CCHF is on this list. [That list contains Crimean-Congo hemorrhagic fever, Ebola virus disease and Marburg virus disease, Lassa fever, Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS), Nipah and henipaviral diseases, Rift Valley fever, and Zika.]

A virologist at the well-respected Karolinska Institute in Sweden, said that the ticks carrying the CCHF virus were “moving up through Europe due to climate change, with longer and drier summers.” In fact, Spain reported a case of CCHF last year. Iraq has been experiencing a prolonged outbreak of CCHF since last year. Already this year, 100 cases and 13 deaths have been reported. There have also been outbreaks in Namibia and Pakistan. Just this month, Turkey is reporting at least two cases.

Again, the point of this blog piece is:

1. There are many outbreaks occurring other than just the SARS-CoV-2 pandemic.
2. Many of these outbreaks are occurring in countries where these diseases have not been endemic, nor seen other than in international travelers who traveled to the south of the 50^th parallel north.
3. We need to commit to more research of these diseases, the development of therapies and the development of safe and effective vaccines.

This is part IV of a blog series that examines recent U.S. outbreaks of diseases that are not yet endemic to the U.S. and for which we usually do not see cases in the continental U.S. other than in international travelers.

In part I, I reviewed the history of some of these outbreaks. In part II, I discussed dengue fever and in part III, I wrote about Zika virus disease. The common denominator was that dengue and Zika are both flaviviruses; the diseases they cause are both vector-borne meaning that these viruses are transmitted to humans primarily through an insect – in the cases of these viruses, a specific species of mosquitoes – rather than human-to-human transmission or zoonotic transmission (animal à human) as are so many of the diseases that I have previously written about; the outbreaks have occurred in the southern U.S.; and given the fact that these viruses generally are endemic in tropical and subtropical areas of the world, these recent outbreaks may be, at least in part, related to climate change making previously less favorable environments in the northern hemisphere more hospitable for the mosquitoes that transmit these diseases.

In this part IV blog piece, I will discuss chikungunya. No doubt you are already wondering where this strange name came from and what it means. I’ll explain below.

The chikungunya virus is an alphavirus in the Togavirus family (this is a different group of viruses than that to which dengue virus and Zika virus belong). It was first identified in Tanzania in 1952, however, it received little attention, research interest or efforts at containment until it did two concerning things – (1) adapted to be able to be transmitted by an additional species of mosquito, allowing for greater spread of the disease and (2) relatedly, began causing disease in the northern hemisphere. [I know you are wondering, so here you go. There are about 3,000 different species of mosquitoes and approximately 200 species can be found in the U.S.]

Since its emergence in Tanzania, the virus has been detected in other countries of Africa and Asia. The first recorded outbreaks in urban areas were in Thailand in 1967 and in India in the 1970s.

Prior to 2006, we rarely identified chikungunya infection in U.S. travelers who travelled abroad.

Between 2006 and 2013, we would detect evidence of recent chikungunya in about 28 Americans on average per year who travelled to Africa, Asia or areas surrounded by the Indian Ocean.

In 2013, chikungunya virus was detected in Central and South America, the Caribbean islands and some U.S. territories.

Beginning in 2014, we began receiving reports of chikungunya virus disease among U.S. travelers returning from Central and South America, but more concerningly, we began seeing local transmission (this means the mosquitoes and virus were circulating in these areas) in Florida and Texas as well as Puerto Rico and the U.S. Virgin Islands.

Given the fact that we did not conduct much research into this virus and the disease it causes until relatively recently, unfortunately, it is now a public health threat for which we have many knowledge gaps, no known effective treatments and no vaccine available.

Chikungunya virus is transmitted by the same mosquitoes that transmit the dengue virus and the Zika virus.

Chikungunya infection causes high fever and disabling joint pains of varying duration. This is where the name of chikungunya comes from. Kimakonde is the language spoken by the Makonde, an ethnic group in the southeastern part of Tanzania. You will recall that Tanzania was where chikungunya was first identified. Also recall from part II of this blog series that people called dengue fever – breakbone fever – a reference to the intensity of bone, joint and muscle pains. The Makonde named this virus chikungunya – the Kimakonde word that means “to become contorted,” another reference to the intensity of the musculoskeletal pain associated with infection.

The onset of symptoms with chikungunya infection is usually 4 – 8 days, but can be as short as 2 or as long as 12 following the mosquito bite. Fortunately, not everyone develops severe symptoms. The most severe cases tend to be in the very young and the elderly. Most often, when patients are symptomatic, the first symptoms are fever and joint pain, usually with a rather abrupt onset. The joint pain is generally so disabling that people are largely bed-ridden in their homes or a hospital. These pains may last only a couple or few days, but unfortunately, in some, the pains may last weeks, months, or even years. Patients also often experience muscle pains and headache. Some will develop swelling of their joints. As with dengue fever, some will develop a rash.

Most patients fully recover, though eye, heart and neurological complications have been reported. Fortunately, at this time, the evidence supports lasting immunity against repeat infection.

Fortunately, and for not entirely clear reasons, cases of locally-contracted chikungunya have declined rapidly in the continental U.S. with no cases reported since 2015, but slower in the U.S. territories, with the last reported cases in 2019.

As with our discussion of these other vector-borne outbreaks, there are no specific precautions for Americans to undertake unless travel is planned to areas where these infections are endemic. My purpose in writing about these disease outbreaks is to raise the level of concern as I believe that these are warning signs that should promote more preparedness, testing capabilities, and research into treatments and vaccines for all of these vector-borne diseases.

In my last two blog pieces, I began a blog series addressing the fact that we have seen a number of diseases that are not endemic to the U.S. pop up and cause outbreaks. Some of these are infections that we have not previously seen people acquire in the continental U.S., but rather were involving international travelers who acquired the infection elsewhere, then traveled to the U.S., became ill, and were diagnosed with the illness here.

In part I, I reviewed a short history of a number of these outbreaks focusing on those that have occurred since 2020 to illustrate that this is not just one or two diseases, nor ancient history.

In part II, I discussed the dengue virus that caused an outbreak in Florida in 2020 that was of note because we rarely see locally contracted infections in the continental U.S.

In this blog piece, I will discuss the Zika virus. Zika virus belongs to the same family of viruses as the dengue virus – flaviviruses. As I mentioned in my last blog piece, flaviviruses are vector-borne diseases, meaning that instead of human à human transmission or animal à human zoonotic transmission, these viruses are transmitted through the bites of mosquitoes (although there is some evidence that Zika can be transmitted through sexual contact, blood transfusions, and perhaps even tissue or organ donation, though these are all less common routes of transmission. Nevertheless, WHO recommends that men returning from an area with active Zika transmission use protection or abstain from sex for a period of 3 months after their return to protect their sexual partners and that women engage only in protected intercourse or abstain from sex for a period of two months following their return from an endemic area). The same type of mosquito that transmits dengue virus and the Chikungunya virus also transmits Zika virus, and thus we tend to see Zika infections in tropical and subtropical regions of the world.

Zika virus was first identified in Uganda in 1947 in a Rhesus macaque monkey followed by evidence of infection and disease in humans in other African countries in the 1950s. During the 1960s through the 1980s, Zika disease predominantly occurred in Asian and African countries. since 2007, outbreaks of Zika virus disease have been recorded in Africa, South and Central America, Asia and the Pacific rim countries that are in the southern hemisphere, where the Aedes mosquitos abound.

In 2015 and 2016, large outbreaks of Zika virus occurred in Central and South American countries, resulting in an increase in travel-associated cases detected in US states, and widespread transmission in Puerto Rico and the US Virgin Islands. In July of 2016, the first outbreak in the continental United States was identified in the Wynwood area of Miami-Dade County, Florida.

While like dengue fever, most cases of Zika virus disease are mild, in early outbreaks we observed an increased frequency of Guillain-Barre’ syndrome (GBS), a disorder that can range from a brief duration of mild weakness and abnormal sensation, to an ascending paralysis that can be severe and progressive enough to require a ventilator for respiratory support until the condition resolves, which it does in most cases. GBS can evolve rapidly over hours, or more slowly over days or even weeks.

When Zika emerged in the Americas with a large outbreak in Brazil in 2015, we noticed an alarming association between Zika virus infection in pregnant women and congenital microcephaly (an abnormally small head) of the infants delivered from these mothers. Infants with complications from their mothers’ Zika infection during pregnancy are said to have congenital Zika syndrome. This appears to occur in 5 – 15% of pregnancies during which the pregnant mom becomes infected (some reports are as high as one-third of infants born to mothers with Zika infection during pregnancy will develop microcephaly), even when the mother is completely asymptomatic and unaware that she was infected. Besides the microcephaly that is generally quite obvious and devastating on its own, this syndrome can include limb contractures (where the arms or legs are unable to move the full normal range of motion), abnormal muscle tone, eye abnormalities and hearing loss. Also tragically, some babies will become non-viable and the mother will experience fetal loss or the baby may be a stillbirth. Zika infection during pregnancy can also result in premature birth.

There is a study following the infants born with congenital Zika syndrome in Brazil following the large outbreak in 2015 that shows these infants have an 11-fold higher mortality risk during the first year of life.

Like with dengue fever, most persons who are infected with Zika virus do not develop symptoms or develop only mild symptoms. Those that do become symptomatic generally do so between days 3 and 14 following infection. Many of the symptoms are similar to those of dengue fever – headache, fever, muscle and joint pain and rash. The symptoms generally last 2 – 7 days.

Other complications of Zika virus disease tend to occur in older children and adults and include Guillain-Barre’ Syndrome (discussed above), peripheral neuropathies (loss of proper nerve functioning of one or more nerves to the extremities), or myelitis (an inflammation of the spinal cord).

Like dengue fever, there are no specific treatments or therapies for Zika virus disease; but unlike dengue fever, there is no vaccine against Zika.

Again, there is nothing in particular that Americans need to do in regard to Zika unless you are planning to travel to an endemic area, however, our public health planning needs to take into account these increasing occurrences of outbreaks of vector-borne diseases occurring in the southern U.S. that we have not previously dealt with in terms of locally acquired infections.

We have had outbreaks in 2016 (Zika), 2020 (dengue fever) and 2023 (malaria). We must consider these as warning signs. In my next blog post, we will discuss Chikungunya.

In my last blog piece, I wrote that we have seen a number of diseases that are not endemic to the U.S. pop up and cause outbreaks. Some of these are infections that we have not previously seen people acquire in the continental U.S., but rather were involving international travelers who acquired the infection elsewhere, then traveled to the U.S., became ill, and were diagnosed with the illness here.

Dengue virus is endemic to over 100 countries in the southern hemisphere, predominantly those in tropical and subtropical regions of the world. While we do occasionally see outbreaks of dengue fever in the U.S. territories of American Samoa, Puerto Rico, and the U.S. Virgin Islands, and the freely associated states, including the Federated States of Micronesia, the Republic of Marshall Islands, and the Republic of Palau, cases in the continental U.S. have historically been in international travelers or travelers from these territories.

In 2020, there was an outbreak of locally-acquired dengue fever in Florida (72 cases), which might be less of a concern if it were not for the pattern of emerging outbreaks of other diseases for which we generally have not seen locally acquired infections in the past, but now have resulted in local outbreaks, especially in Florida – e.g., zika, chikungunya prior to the dengue fever outbreak and most recently malaria (while we have historically had local transmission of malaria, we had eliminated malaria from the U.S. back in 1951). It is interesting to note that the common denominator for these four infections is that they are all transmitted through mosquito bites.

Dengue virus is a flavivirus and flaviviruses cause vector-borne diseases in humans. Vector-borne means that the virus is transmitted to humans through the bite of an insect – typically a mosquito, flea or tick. Dengue virus is transmitted by mosquitoes. Other mosquito-transmitted flaviviruses include the yellow fever virus, Japanese encephalitis virus, the West Nile viruses, and Zika virus.

The mosquitoes that are capable of transmitting dengue virus are of the Aedes species. Modelling studies show that Aedes aegypti and Aedes albopictus mosquitoes could potentially extend their natural habitats in the southern hemisphere up to some areas of the U.S., particularly the southeastern parts of the country.

We may miss cases of dengue fever in the U.S., because in some people (estimated to be about 75% of cases), the illness is mild or even asymptomatic. Those with mild symptoms may attribute them to a cold or the flu, or be seen, but not tested for dengue fever given that this is not something most U.S. doctors have seen before.

Dengue fever can manifest as a severe disease, in fact, it is estimated that 22,000 people die from dengue annually across the globe. Classic dengue fever is characterized by high fever and intense muscle, joint and bone aching, and even muscle spasms, giving rise to its colloquial name, “breakbone fever.”

In classic dengue fever, the first phase of the illness lasts 2 – 7 days. In addition to fever and the muscle, joint and bone pain, some patients will complain of headache, nausea and vomiting and some may experience bruising, bloody nose, or bleeding from their gums. On or about the third day of the illness, most people who are symptomatic with dengue will develop a red rash, that may be smooth, may have tiny bumps, or both. In most cases, the rash does not itch. Some patients will get a rash all over their body, while others will have patchy rashes. When the rash is generalized, it generally begins over the tops of the feet and the back of the hands and then spreads to the arms, legs, abdomen and chest. There is much variation in the possible rashes and in some cases, the particular manifestation of rash tells us what the major underlying pathological process is (e.g., immune reaction versus disruption to the proper functioning of the blood and blood clotting system).

While most people recover within about a week, some people do deteriorate and require hospitalization (about 1 out of every 20 cases). Those at highest risk for severe disease are infants, pregnant moms and those with a reinfection of the virus. They can experience profound fluid losses or maldistribution of these bodily fluids, internal bleeding (sometimes called dengue hemorrhagic fever) and potentially can develop shock (sometimes referred to as dengue shock syndrome).

While many lay people are under the false impression that the initial infection of any illness is the worst, and that subsequent infections will always be milder, this is not always the case, and dengue fever is the classic exception. In the case of dengue reinfections, a phenomenon called antibody-dependent enhancement (ADE) can occur. In essence, what takes place is that the initial infection triggers an immune response. Part of that response is the production of antibodies against the virus. When non-neutralizing antibodies are produced (e.g., antibodies that attach or bind to the virus, but do not interfere with or prevent the virus from entering and infecting cells), there are some cases in which these weak antibodies can actually promote the viral cell entry and infection, often also stimulating an intense inflammatory process, a condition we refer to as ADE.

There is no specific treatment available for treating dengue fever. The efforts to develop a vaccine against this infection has been hampered by the potential for ADE. However, there is a vaccine, though it is not licensed in all countries where dengue virus is endemic.

For now, Americans need not take any specific precautions unless you are planning travel to countries where dengue is endemic. However, we need to be mindful of our own changing and evolving public health situation in the U.S.

With climate change, we may see more and more diseases that are not endemic in the U.S. migrating northward. Further, if we continue to exercise a great deal of complacency against other disease outbreaks in the U.S. such as SARS-CoV-2 and monkeypox, we risk allowing these diseases to become endemic, especially, as we allow new variants to emerge and allow infections to transmit among our wildlife and domesticated animals. We often have an opportunity to eliminate infectious diseases, but that window does not stay open for indefinite periods of time. Further concerning is the fact that after going to the efforts to eliminate a number of vaccine-preventable illnesses in the U.S., we have allowed these diseases to reemerge in outbreaks due to the uncontrolled misinformation, disinformation and anti-vax campaigns that are undermining vaccine confidence in the U.S. and globally.

It should be concerning to everyone that is paying attention that we are experiencing disease outbreaks in the US of diseases that we generally shouldn’t see outside of international travel. In some cases, these are the emergence of diseases that are endemic to other countries of the world, but not the US, and frustratingly, others are the resurgence of diseases that we previously eliminated from the U.S. Consider the list of these diseases in just in the past three years (if we went back further, we could add other infectious diseases to the list such as zika and chikungunya):

2020 – SARS-CoV-2 (novel virus)

              Dengue fever (endemic in the southern hemisphere)

2022 – Monkeypox (previously endemic to only African countries)

              Polio (eliminated from the US in 1979)

              Candida auris

              Measles (eliminated in the US in 2000)

2023 –   Malaria (eliminated from the U.S. in 1951)

The reasons are many, including:

1. The world is failing to appreciate that infectious diseases that appear limited to poor and developing countries are a threat to all countries given international travel and trade (including wildlife).
2. The world is not investing enough in research of novel viruses, antiviral development and better vaccines (durability and the induction of mucosal immunity) with broader coverage against families of viruses that pose epidemic and pandemic threats.
3. The world is not doing enough to minimize the risks of zoonotic (animal à human) transmission of novel viruses. It is estimated that roughly 75% of all newly recognized infectious agents are the result of these spillover events to humans.
4. Climate change and the resulting geographic changes in habitats of animals and vectors (e.g., mosquitos and ticks) that transmit infections to humans.
5. The rampant spread of medical misinformation and disinformation, including the well-organized, well-coordinated and well-funded antivax campaign, that has undermined vaccine confidence, and as a result, vaccination rates, is leading to a resurgence in vaccine-preventable diseases.

I have already written extensively about SARS-CoV-2 previously, so in my next blog post, I will cover Dengue fever and subsequently, the other diseases on this list.

If we were to ask Americans what disease outbreaks the world has experienced in the past 3 years, I suspect almost everyone would be able to identify COVID-19 (caused by the SARS-CoV-2 virus). Probably a large number, but certainly less would also be able to name influenza, likely by using its colloquial name of the “flu.” My guess is that if we pressed for more, a minority of Americans would be also able to identify RSV (respiratory syncytial virus) and possibly monkeypox (recently renamed by the CDC as MPox). I would be impressed if more than a handful of people would be able to recall the health alerts in the U.S. for Candida auris, drug-resistant gonorrhea, increased rates of syphilis, the drug-resistant bacterial infections (Pseudomonas aeruginosa) with artificial tears and eye drops, the outbreaks of norovirus, the hepatitis of unknown etiology in children, or the most recent outbreaks of malaria in Florida and Texas. I suspect that no lay person would realize that we had a larger than usual outbreak of human metapneumovirus infections at the beginning of this year and into the spring, unless they were one of the many infected with this virus.

Of course, there have been many more outbreaks than this that have received relatively little attention in the media and press, including outbreaks that we have had in the U.S., specifically polio in New York and measles in Ohio.

Among the many other outbreaks that occurred in parts of the world such as Marburg virus disease and Lassa fever, there was one that really caught my attention and caused me to do a double-take, and yet, I doubt any one other than infectious disease experts, public health experts or virologists knows anything about this virus.

In August 2022, a novel henipavirus named Langya virus caused an outbreak in China among 35 farmers and local residents that likely contracted the infection from shrews. The virus was isolated from patients with severe pneumonia. We already knew about two other henipaviruses – Nipah virus and Hendra virus. The case fatality rate for henipavirus infections in humans is approximately 70%. Hendra virus was first identified in 1994 in specimens taken mostly from horses, but also some humans with respiratory and neurologic disease in Australia. The source of the virus is flying fox bats (aka fruit bats). Hendra virus is not of significant pandemic concern because the virus primarily infects horses and humans are generally only infected by contact with the secretions or tissues of infected horses. Further, no human-to-human spread has been identified.

Nipah virus is a different story. Nipah (pronounced “Nee-paw”) is also transmitted by fruit bats, but it infects humans and pigs. It can cause inflammation and swelling of the brain, a condition doctors refer to as encephalitis. The illness can range from mild to severe, including death. Outbreaks have historically occurred in India and Bangladesh.

Nipah virus presents more of a potential pandemic threat than Hendra virus because while the earliest outbreaks appear to have resulted from transmission from bats à pigs à humans with little, if any, human-to-human transmission, human-to-human transmission regularly occurs in more recent outbreaks. Close contact with a person with Nipah virus disease can cause transmission through body fluids – nasal secretions, respiratory droplets, blood and urine. Transmission most often occurs within families and within health care settings.

However, Langya virus presents more a of potential pandemic threat in my mind than the other henipaviruses for the following reasons:

• The first known spill-over event was in August of 2022. (In case you don’t understand why that would increase the pandemic threat relative to the other two viruses in its family – Hendra and Nipah viruses – it is because the other two viruses have been circulating in the animal and human population much longer, and therefore, have already had more opportunity to develop more efficient transmission in humans and to have caused a major outbreak by now, but haven’t yet.
• Rats and shrews can serve as intermediate hosts for Langya virus and are distributed globally, which greatly increases the risk of infections in humans, as people living in large metropolitan areas are far more likely to encounter rats than pigs (Nipah virus) or horses (Hendra virus).
• The fruit bat is migratory, which means that it can carry the virus with it to new geographic areas.
• The Langya virus is a novel and antigenically distinct from its cousins, Nipah and Hendra viruses, which means that there is no significant pre-existing immunity, nor is there likely much cross-over protection (in other words, antibodies to Nipah virus are unlikely to be protective against Langya virus.

What this means is that we need to conduct more research into these novel viruses to better understand their pathogenesis, to develop treatments and hopefully develop effective vaccines.

I have been preparing for pandemics for more than two decades in my roles as a leader of a major teaching hospital in the Texas Medical Center and subsequently as the President and CEO of the largest health system in Idaho.

In pandemic planning, I have found it useful to consider past outbreaks, epidemics and pandemics to consider which pathogens were not eliminated and have the potential to recur. For example, I didn’t spend much effort worrying about smallpox (the only virus we have eliminated from the world as a natural infection) because the only way we would see that would be as a result of a state-sponsored bioweapon attack. I also crossed the original SARS virus (2003) off my list because to our knowledge, that virus never was introduced into an animal reservoir before we contained the spread of the outbreak in humans (very much unlike what has happened with the second SARS virus – SARS-CoV-2 (2019). Further, while we still have cholera outbreaks in the world, they tend to be isolated to locations without proper water treatment and in locations following natural disasters that lead to flooding and disruption of the infrastructure. Further, person-to-person transmission of cholera is minimal and unlikely to propagate the spread to other areas of the world.

We must keep in mind that the majority of emerging infectious diseases in humans are the result of zoonotic transmission (animal à human). More than 70% of these pathogens arise in wildlife.

Looking a past epidemics and pandemics, the pathogen that would rise to the top of the list for causing a new pandemic would be an influenza A virus with zoonotic transmission to humans and mutations that would increase its virulence as well as its efficient spread from person-to-person. That has happened three times in the 20^th century – 1918 (the so-called Spanish flu – H1N1), 1957 (the so-called Asian flu- H2N2), and 1968 (the so-called Hong Kong flu- H3N2). Currently, we are watching the alarming spread of H5N1 avian influenza among multiple species of mammals causing significant mortality. Normally, there is a genetic protection of humans from these avian viruses, however, with increasing transmission among mammals, the potential for significant mutations (specifically, influenza viruses tend to develop the most profound genetic modifications from reassortment of their genes – a swab of genes from one virus to another), is concerning for the potential to develop a new mechanism by which the virus can infect humans with better onward human-to-human transmission.

As I wrote in Preparing for the Next Global Outbreak, https://www.press.jhu.edu/books/title/12896/preparing-next-global-outbreak, we must expand our readiness and preparedness for novel viruses as:

• the frequency of human-wild animal interactions increases with:
  • human expansion into wild animal habitats;
  • wet markets continue to operate in various countries;
  • non-domesticated animals are exported for research purposes or as part of black-market trade; and
  • the world becomes increasingly interconnected through international travel.

In addition, we must also anticipate diseases showing up in the US that were previously endemic only to poor and developing countries due to the increase in international travel. One example was the case of a man who traveled from an African country to the U.S. with Ebola virus disease who developed symptoms once he was in the U.S. and subsequently presented to a hospital in Dallas on September 25, 2014. This one patient had 48 contacts, 6 of whom would be considered close contacts, prior to his death from Ebola. Two nurses caring for this patient before he was diagnosed became infected. Ultimately, 147 health care workers were involved in the care of the initial patient and the two infected nurses. It is easy to see from this how one person can potentially expose many people if the person is not so sick as to be incapacitated or the disease has not been identified and people are not using proper protection. Just last year, we had another wake-up call. Monkeypox was first identified in 1958. There have been outbreaks of disease in humans since 1970, primarily in African countries. With lack of appreciation of the global risk presented by novel viruses that first appear in low income and developing countries, the world largely ignored these outbreaks and did little to study the virus, to develop antiviral treatments and to develop vaccines. Then, in 2022, a global outbreak with monkeypox developed.

Finally, health care leaders must also consider diseases endemic to countries in the southern hemisphere that may now present in the U.S. due to climate change (e.g., Chikungunya outbreaks in Florida and Texas in 2014 and Zika in 2015 and 2016, and malaria in 2023).

For the past three years, I have been warning that SARS-CoV-2 (COVID-19) will not be our last pandemic. Just in the past two decades we have had an epidemic or pandemic with novel viruses at intervals of 6 years, 3 years, and 7 years.

The World Health Organization prepared a list of pathogens that it considers to pose the highest risk for a future outbreak or potentially, a pandemic in 2018. That list turned out to be quite prescient (as you can see that outbreaks with almost every virus listed have occurred since then) and contains the following infectious diseases:

• Crimean-Congo hemorrhagic fever (there is currently an outbreak in Afghanistan involving more than 100 people, with 6 deaths reported so far);
• Ebola virus disease (there was an outbreak from September 20, 2022 until January 10, 2023 in Uganda with more than 160 people infected, 77 of whom died);
• Marburg virus disease (an outbreak was declared on 2/13/23 in Equatorial Guinea. It infected 16 people, 12 of whom died. It was contained and declared over on May 15, 2023);
• Lassa fever (there have been outbreaks in Nigeria and in Ghana. The outbreak in Ghana began in February 2023 and was contained rapidly with no new cases since March 2023, with 27 people in total infected, one of whom died);
• Middle East respiratory syndrome (MERS) (there were three cases reported between December 2022 and May 2023, involving 1 death);
• Nipah virus disease (between January 4, 2023 and February 13, 2023, there have been 11 cases resulting in 8 deaths in Bangladesh);
• Rift Valley fever (there was an outbreak in Mayotte, France between November 2018 to July 2019 involving 142 confirmed cases); and
• Zika (in March 2015, Brazil reported a large outbreak that was soon thereafter determined to be Zika virus disease. In 2015 and 2016, there was widespread transmission of Zika in Puerto Rico and the U.S. Virgin Islands, as well as limited local transmission in Florida and Texas. Only counting cases that were locally acquired (not cases in travelers from other countries to the U.S., between 2015 and 2017 when the last case occurred in the continental U.S., there were a total of 231 cases in the continental U.S. and 37,041 cases locally acquired in U.S. territories (Puerto Rico and US Virgin Islands).

I have never advocated for living in fear. But, worse, in my opinion, is living in ignorance. I believe in doing risk assessments and then prioritizing those risks based upon the likelihood of the threat coming to pass versus the magnitude of harm that would result if the risk materialized. I illustrate how to do this and make decisions based upon this assessment on pages 277 – 280 in the book – Preparing for the Next Global Outbreak.

Fortunately, some of the viruses with the highest mortality rates (70+%) are less likely to cause pandemics than other viruses with lower mortality rates. However, that is for viruses that we know about today, and even if that were still the case for all new emerging novel viruses, there are still plenty of viruses that have mortality rates 10 – 20 times what we saw with SARS-CoV-2 that under the right circumstances could efficiently spread and cause a pandemic.

We must increase our surveillance, improve our response to outbreaks and promote cooperative international research into passive immunity treatments, vaccines that can provide durable, mucosal immunity; antiviral therapies that are effective against an entire family of viruses; rapid and inexpensive tests for these viruses that can be rapidly deployed, and research to identify the main antigenic targets for each of these vaccines that might allow for the rapid development of effective vaccines.

There has rightly been a lot of focus on bats, particularly in southern China and in Saudi Arabia because 3 novel coronaviruses capable of causing severe acute respiratory syndrome have been identified in those countries in the past 20 years – SARS-CoV (2003) – China, MERS-CoV (2012) – Saudi Arabia and SARS-CoV-2 (2019) – China. We know that bats often carry coronaviruses and that we have only yet begun to sample and characterize al the coronaviruses they carry and can transmit to animals such as palm civets, raccoon dogs, camels, pangolins, and many others that can then serve as potential intermediate hosts for zoonotic transmission to humans.  A major route of transmission of coronaviruses from bats to animals is thought to be through fruit. The bats feast on fruit and in doing so can contaminate the fruit with coronaviruses, or alternatively can contaminate the ground with coronaviruses passed through their guano (excrement). The partially eaten fruit often falls to the ground, where animals, such as those mentioned above, forage for food, eating the residual fruit or ingesting the guano-contaminated vegetation exposing themselves to coronaviruses left by the bats.

Recently, researchers have reminded us that not all worrisome coronaviruses will necessarily arise out of Asian or Middle Eastern countries. A team of researchers from the Imperial College of London and the University College of London sampled 48 fecal specimens from 16 of the 17 species of bats that reside in the UK.

From these 48 specimens, they recovered 9 whole coronavirus genomes (i.e., a complete copy of their genetic material), which allows for identification of the coronavirus. Coronaviruses are divided into 4 genera based upon certain biological characteristics– alpha- and beta-coronaviruses infect mammals and gamma- and delta-coronaviruses primarily infect birds, but there is a gamma-coronavirus that infects whales and a delta-coronavirus that infects pigs.) Of these 9 coronaviruses:

• 4 were alpha-coronaviruses (you may recall my earlier blog piece discussing human coronaviruses in which I indicated that common cold coronaviruses 229E and NL63 are alpha-coronaviruses)
• 5 were beta-coronaviruses:
  • One was a merbecovirus – (the sub-genus to which MERS-CoV belongs)
  • 4 were sarbecoviruses, which are in a sub-genus to which SARS-CoV and SARS-CoV-2 belong. At least one of the novel sarbecoviruses can bind the ACE-2 receptor to infect human cells as SARS-CoV-2 does, though it does so sub-optimally. In addition, these sarbecoviruses were only one mutational step away from a development (a furin cleavage site) that would significantly enhance virus receptor binding and potentially infectivity. (Note that it was the fact that SARS-CoV-2 did have a furin cleavage site that many used to justify that SARS-CoV-2 was genetically engineered or modified, but this (and other findings) demonstrate that a furin cleavage site can be a result of natural viral evolution.)

2 of the coronaviruses identified were previously unknown coronavirus strains – i.e., novel coronaviruses (one of the alpha-coronaviruses and the merbecovirus).

The key takeaways are these:

1. There will continue to be future outbreaks, epidemics and even pandemics.
2. Outbreaks that occur anywhere in the world threaten every other part of the world due to international travel and trade.
3. Most new, emerging infectious diseases are zoonotic in origin (transmitted by animals to humans).
4. Increasing human expansion into wildlife areas is increasing the risk for zoonotic events.  
5. Climate change is causing introductions of infectious diseases into some more northern geographic locations where these infectious diseases had previously not been circulating.

We must prepare now. For a full discussion of preparation see Preparing for the Next Global Outbreak, https://www.press.jhu.edu/books/title/12896/preparing-next-global-outbreak. Preparation includes increased surveillance, improvement in our response to outbreaks and promotion of cooperative international research into passive immunity treatments; vaccines that can provide durable, mucosal immunity; antiviral therapies that are effective against an entire family of viruses; rapid and inexpensive tests for these viruses that can be rapidly deployed, and research to identify the main antigenic targets for each of these vaccines that might allow for the rapid development of effective vaccines.