Hantavirus and An Explainer on the Current Outbreak

The hantavirus was first identified as the cause of what was then called Korean Hemerologic Fever in 1978. The virus was isolated from small infected field rodents. It is so named because these rodents were near the Hantan River in South Korea. Due to its virologic properties, it was added as a new member of the Bunyaviridae family of viruses, some of which are transmitted by arthropod vectors (e.g., mosquitoes and ticks) and others (like the hantaviruses) are transmitted through the excrement (feces, urine and saliva) of rodents.

The hantaviruses are RNA viruses (there are now at least 21 different stains and 30 genotypes identified) and fall generally into two groups: (1) Old World hantaviruses (i.e., those endemic to the eastern hemisphere) that cause viral hemorrhagic fever with renal syndrome (HFRS) with case fatality rates up to 15 percent and (2) New World hantaviruses, those found in North, Central, and South America and cause a condition called hantavirus pulmonary syndrome (HPS) with case fatality rates up to 50 percent (but generally in the range of 35 – 38 percent). 

While first thought to be limited in distribution to the eastern hemisphere, in 1993, an outbreak of hantavirus in the four-corner region of the Southwestern U.S. (where Arizona, Colorado, Utah and New Mexico intersect) in which people developed serious respiratory distress led to the discovery of hantavirus in the western hemisphere that causes the pulmonary syndrome rather than the hemorrhagic fever illness typical of the eastern hemisphere. In that outbreak, the virus was found in the common deer mouse.

We see sporadic cases (about 15 – 40 per year) in many states across the country, but very prominently dominant in the western part of the U.S. (94% of cases occur west of the Mississippi River), particularly in those four corner states. We have had a total of 890 confirmed cases from 1993 – 2023 in the U.S (25 were in Idaho). The strain of hantavirus that we see in the U.S. is predominantly the Sin Nombre virus. The historical case fatality rate has been 35 percent.

Hantavirus got some publicity in the U.S. last year, when the bodies of actor Gene Hackman and his wife, Betsy Arakawa, were found dead in their home in New Mexico. Betsy was infected with Hantavirus, but Gene did not appear to be. That does make some sense because as far as we know, all strains of hantavirus other than the Andes strain (the strain involved in the latest outbreak) appear to most likely be the result of the virus being aerosolized from the rodent excrement (for example, when people are sweeping areas where rodents may have been residing) rather than human-to-human transmission and suggests that perhaps Betsy contracted the infection outside the home.

The Andes strain, which causes HPS and is found in Argentina and Chile is unique among the hantavirus strains in that multiple studies have confirmed person-to-person transmission, usually with close contact that is more than fleeting, including household clusters and nosocomial spread (within health care settings). To date, there has been no evidence that hantavirus has ever caused community spread and transmission as we see with SARS-CoV-2 and our usual seasonal respiratory viruses. We have no data to suggest that there is efficient transmission in casual contact settings except when prolonged and in poorly ventilated spaces. The current pandemic potential for any hantavirus, including the Andes strain is considered low by the CDC and WHO, and I concur with that assessment.

On the other hand, the Andes virus has been labeled as “barely transmissible” by many, and that is clearly unsupported. As mentioned below, in one outbreak, the reproductive number was 2.12 before mitigation measures. That certainly suggests sufficient transmission to lead to expanding numbers of infections. The reason we have not seen larger outbreaks is that this virus has generally been thought to not have presymptomatic infectiousness, which has allowed for successful containment measures. Were this to change, and we have to be open to this possibility with increasing numbers of infection over time given this is an RNA virus, then the transmission dynamics could create much more spread. We need to explore the potential for and be vigilant to the possibility of presymptomatic, early symptomatic and pauci-symptomatic transmission in the current outbreak, as well as in future ones, especially in light of an outbreak on a cruise ship which may create different epidemiological risks than the environments of past outbreaks.

Latest Outbreak

A week ago, we got word of an outbreak of hantavirus on a cruise ship that originated in Argentina and was offshore of Cape Verde, South Africa on its way to its intended destination of Antarctica, but was rerouted to the Canary Islands. However, apparently, some passengers ended their cruise at St. Helena, an island in the Atlantic Ocean, and they would have likely already returned home to their country of origin, thus this will potentially cause cases to pop up across the globe.

This story caught my attention because, to my knowledge, this was the first outbreak of hantavirus to occur on a ship of any kind, and second, because cruise ships give us a somewhat unique opportunity to learn more about the transmission characteristics of a virus that we don’t have a lot of experience with. At the time of the earliest reports, we were told of three deaths (two involving a married couple), one person in critical care, and three suspected cases that were not critically ill at the time (total of 7 cases). Two cases had testing that confirmed hantavirus infection. An eighth patient was among those who disembarked at St. Helena and returned home and then became ill. That patient is in a Swiss hospital. A ninth patient (woman in her 20s) became symptomatic on her flight home from the Canary Islands and now is in France on life support. A tenth case is a patient in Spain who is asymptomatic, but testing positive. There is an eleventh patient who is on life support. As of the time of this writing there are 11 cases, 3 of whom have died and two are critically ill on life support (ventilators). That leaves 4 symptomatic, but not severely ill patients as of right now and two who are asymptomatic as of now, but testing negative.

Sequencing

Genetic sequencing has confirmed that the virus causing this outbreak is the Andes strain of the Hantavirus. Thus, this is the strain of Hantavirus that is capable of human-to-human transmission.

Incubation Period

Hantaviruses have long incubation periods (the time between infection and the development of symptoms), ranging anywhere from 1 week to 8 weeks depending, at least in part, for the strain of virus. Long incubation periods can allow for the possibility of post-exposure vaccination to prevent infection, but in this case, we do not have a proven, approved vaccine for hantavirus. On the other hand, a long incubation period, especially with a wide range, makes epidemiologic investigation and contact tracing much more difficult. If the incubation period was short, then it would be clear that the infection was transmitted while on the cruise, and now the schedules of the passengers involved would merely have to be reviewed to see if they were onboard that entire time, or whether there were excursions at ports of calls that might be implicated. In this case, investigators have to sort out whether the initial infected person was possibly infected prior to boarding. However, given that the cruise departed on April 1 (5 weeks ago), we certainly must consider it likely that the infection was acquired on the ship or at one of the ports of call if passengers left the ship for an excursion.

Reproductive Number

This is the number that reflects how many other people one infected person is likely to infect while infected. When this number is less than one, the outbreak cannot be sustained and will subside on its own. If greater than 1, then the likelihood is that the outbreak will grow without containment efforts. In the epidemiologic investigation of a 2018 outbreak of the Andes strain in Argentina, the reproductive number was 2.12 before control measures were implemented and it diminished to 0.96 when those measures (quarantine/isolation) were implemented. The dynamics of this outbreak suggest that in this setting, the reproductive number might very well be much higher.

Symptoms

Importantly, we have established that there can be asymptomatic/presymptomatic infection and this presents a problem for containment of the outbreak if these individuals are infectious (which has not yet been established). This was shown in an American who was being flown home by the government who was asymptomatic, yet tested positive. Previous studies had suggested a correlation between infectiousness and onset of symptoms and accompanying liver inflammation.

Although we do not have complete information as of yet, this current outbreak seems to be predominated by symptoms of fever and shortness of breath.

[For Clinicians] Pathogenesis

In severe Hantavirus Pulmonary Syndrome resulting from the Andes strain, the virus infects endothelial cells and capillary leak syndrome and pulmonary edema result.

There is also enhanced inflammatory signaling by TLR-4 (Toll-like receptor 4) and NF- ĸB (Nuclear Factor Kappa B) that likely contributes to the endothelial dysfunction as well as amplifies cytokines.

Prevention

In the usual setting of infection in the U.S., the virus is excreted into barns, sheds and other facilities that may be prone to rodent habitation. The virus is then aerosolized with cleaning activities leading to inhalation by a human with resulting infection. Thus, applying disinfectants or bleaches to moisten the dust or debris prior to sweeping, vacuuming or blowing may reduce the aerosolization that would otherwise result. Further, wearing a respirator such as a N-95 mask can help prevent inhalation of virus.

In a setting where there are already known cases, the most successful containment strategies are to quarantine those who are symptomatic or testing positive and to isolate those who have been close contacts.

Due to the long incubation period and serial interval (the time from the development of symptoms in the close contact to the time of development of symptoms in the other close contact, which in prior studies has been roughly just over three weeks), it is important not to discontinue isolation prematurely based on a negative test that was performed prior to the full incubation period.

There is no currently available and approved vaccine.

So, where do things go from here and what questions should we hope to answer:

1. The first patient (index case) unfortunately died. That may make it less likely that we can determine his point and manner of infection, but we hold out hope until the epidemiologic investigation is completed.
2. The serial interval in this outbreak (time from symptom onset in the index case to symptom onset in those he infected) appears to be 22 days, which is consistent with prior studies. The important thing now will be to see if there are new cases and how many cases there are in 22 days from when this group of people became infected that presumably resulted from contact with the index case occurred. That will be in about 8 days from the posting of this blog piece. That will give us an idea of whether containment efforts began early enough to prevent further spread or not. Similarly, we will want to look for infections developing roughly three weeks from when this next group of infections occurs. Hopefully, we will see few, if any infections, indicating that this outbreak is becoming under control.
3. I am concerned about those who disembarked early and took flights home before quarantine and isolation procedures were put in place. We need to make sure those countries are following up on these cases to determine how many became ill and ensuring that persons on the flights or family members did not become infected.
4. We have a great opportunity here to assess the frequency and significance of asymptomatic infection by testing everyone who was on the cruise. We then can perform contact tracing to hopefully confirm that we did not see asymptomatic transmission of disease, as that could be a game changer.
5. We also have an opportunity to perform sequencing on those who test positive to determine the rate of accumulation of mutations in the virus and to begin to assess the impact of mutations.
6. If we confirm what prior studies have suggested that infectivity is correlated with viral load, I hope we can explore the viral load trajectory in those persons who do show up newly infected in just over a week from now and compare those viral loads to asymptomatic individuals to see if we can predict the infectious period in infected individuals to help give us information at to peak risk period for transmission and when quarantine can be safely lifted.
7. We also have the opportunity to study real-time factors that tend to predict severe disease since this unique cruise ship situation has identified plenty of persons for the possibility of asymptomatic or pauci-symptomatic disease that we would not ordinarily have.
8. This might also be an opportunity to study the immune responses of those who were infected, but with mild or asymptomatic disease. What is the long-term immune response? Is there evidence of protection against future infection? Could convalescent serum be a therapeutic option? Can we identify neutralizing antibodies?
9. Finally, I hope that there will not be any immunocompromised individuals infected, but if so, we should take the opportunity to determine whether they are at risk for more severe disease, whether they can clear the virus, and if not whether the virus undergoes significant mutation during the chronic infection.

We still have so much to learn.