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In early 2021, in Denmark: Statens Serum Institut (SSI) Reports Detection of A Novel Flu (Jan. 2021), we saw an unusual report of a Danish citizen infected with a novel swine-variant virus, who had no known contact with pigs.
Just over a year ago, in EID Journal: Reassortant Influenza A(H1N1)pdm09 Virus in Elderly Woman, Denmark, January 2021, we learned that the virus was a novel reassorted H1N1v, comprised of the human A(H1N1)pdm09 virus with the NS gene from an EA-like H1N1 swine virus.
The patient (who had multiple comorbidities) was in pandemic lockdown at the time of her infection and had very little outside contact.
Exactly how she came to be infected isn't known, but the report stated she lived roughly 2 km from a pig farm, and her ". . . residence was downwind of the pig herd most days preceding clinical symptoms."
While controversial, we've seen cases where viable influenza (and other) viruses may have been carried over considerable distance through the air by dust, fibers, and other `non-respiratory' particles (see Nature Comms: Influenza A Transmission Via `Aerosolized Fomites').
In January of this year we saw another report (see Denmark SSI Reports Novel Swine Variant Flu Infection In Slaughterhouse Worker), providing bare-bones information on another case, which occurred in late November of 2021.
The Statens Serum Institut (SSI) has recently detected a case of influenza in a citizen of Denmark with a virus variant that probably originates from pigs. The citizen works at a Danish pig slaughterhouse. It was a serious course of illness in an otherwise healthy person. All indications are that this is a single case of infection. It is not estimated that there is a risk of infection between people.
Today, the CDC's EID Journal published a follow up to this initial report, where we learn more about the patient's severe (and unusual) course of illness - including repeated convulsions - and the genetic characterization of the virus.
Research Letter
Severe Human Case of Zoonotic Infection with Swine-Origin Influenza A Virus, Denmark, 2021
Klara M. Andersen, Lasse S. Vestergaard, Jakob N. Nissen, Sophie J. George, Pia Ryt-Hansen, Charlotte K. Hjulsager, Jesper S. Krog, Marianne N. Skov, Søren Alexandersen, Lars E. Larsen, and Ramona Trebbien
Abstract
During routine surveillance at the National Influenza Center, Denmark, we detected a zoonotic swine influenza A virus in a patient who became severely ill. We describe the clinical picture and the genetic characterization of this variant virus, which is distinct from another variant found previously in Denmark.
Human infections with swine influenza A viruses (IAVs) are sporadically reported (1–4). Increased surveillance has revealed substantial swine IAV circulation within pig herds and frequent reassortment with human seasonal IAVs (5). Despite no sustained human-to-human transmission of variant IAV cases since the 2009 influenza A(H1N1) pandemic, the zoonotic potential is of concern. We report a case of human infection with a swine-origin IAV that resulted in severe illness in a younger, otherwise healthy person employed at a swine slaughterhouse in Denmark. This case was detected 10 months after our previously reported case (4). The patient provided informed consent for publication of this case report.
On November 24, 2021, a person of ≈50 years of age was hospitalized after acute onset of illness characterized by dizziness on the night of November 23, 2021, followed by chest pain, pain radiating toward the left arm, diarrhea, and malaise that developed the next morning, but no fever. The patient called for emergency medical assistance, which arrived shortly. During ambulance transportation and at hospital arrival, the patient experienced repeated convulsions and was admitted to the intensive care unit and put on mechanical ventilation to manage seizures and associated reduced oxygen level.Extensive clinical examination, such as laboratory investigations (i.e., biochemical, microbiological, and immunological assays), multiorgan radiological examinations, and electroencephalography (Appendix 1), identified no cardiovascular, renal, neurologic, or other diseases that could explain the sudden severe illness.
However, a tracheal sample collected and analyzed at the local microbiology laboratory was found positive for IAV (Appendix 1). No other microbiological agents were detected, including SARS-CoV-2 or other respiratory viruses, and the patient showed no signs of pneumonia. The patient received antiviral medication (oseltamivir) and various supportive treatments, and over the next 2 days the clinical condition improved; the patient was soon after discharged from the hospital.(SNIP)The remaining sample material was submitted to the Danish National Influenza Center as part of routine influenza surveillance. The sample was confirmed positive for the pandemic H1N1 strain and was further analyzed by whole-genome sequencing (Appendix 1). Consensus sequences for the virus named A/Denmark/36/2021 were uploaded to GISAID (https://www.gisaid.orgExternal Link; isolate no. EPI_ISL_8786194). WGS confirmed the H1N1 subtype; however, the virus had closer similarity to swine IAVs (Figure) than to other human strains.BLAST (https://blast.ncbi.nlm.nih.gov/Blast.cgiExternal Link) searches revealed no close matches to IAV sequences in GenBank or GISAID, but comparison to in-house sequences from the passive surveillance of influenza viruses in pigs from Denmark revealed close similarity to 2021 swine IAVs (Table). Phylogenetic analyses showed that most gene segments were related to the pandemic H1N1 subtype (clade 1A3.3.2), whereas the neuraminidase and nonstructural segments belonged to the clade 1C Eurasian avian-like swine influenza A(H1N1) (Figure; Appendix 1 Figures 1–7). In contrast, another variant virus found recently in Denmark had a clade 1C nonstructural segment, whereas the 7 other gene segments were related to clade 1A3.3.2 pandemic H1N1 viruses (4).
In-depth interviews with the patient revealed occupational exposure to swine in a pig slaughterhouse in Denmark, which appears the most likely place of infection. The patient handled live pigs, carcasses, and meat during the slaughtering process while wearing protective equipment including gloves and gown but no face mask. The patient was previously healthy, had no underlying diseases or immune deficiencies, and had received the recommended quadrivalent seasonal influenza vaccine in October 2021.
No other cases of influenza had been reported at the patient’s workplace or among close contacts. In the 2021–22 influenza season, 16,160 cases of influenza A virus occurred among 244,184 tested samples in Denmark; the H3N2 subtype was dominant. No other human cases of swine-origin influenza virus were detected during this period. Genetic analyses and antigenic characterization of the virus (Appendix 1 Table 1, Figure 8) showed several genetic and antigenic differences and suggested poor reactivity to the contemporary human seasonal influenza vaccine.
This reported case is considered independent of the previously reported variant infection in Denmark (4), because the 2 viruses are genetically distinct (Table). The symptoms were also different; the earlier case was in an elderly patient with comorbidities who experienced classical influenza-like illness, but in this case, a previously healthy adult of younger age experienced unusual severe and sudden illness. Influenza-associated convulsions in adults are rare (6) and mostly accompanied by fever or encephalitis, which was not observed in this patient.
The identification of variant IAVs emphasizes the zoonotic potential of these strains and highlights the importance of continued monitoring of both human and swine IAVs. The reported case suggests a need for focusing on early registration of swine exposure for humans with influenza-like illness, as well as increased measures to reduce the swine IAV exposure risk for people with occupational contact with swine.
Ms. Andersen is a PhD student at the Department of Health Technology, Technical University of Denmark and at the National Influenza Center, Statens Serum Institut, Denmark. Her research interests are the genetic evolution of influenza A viruses at the human/swine interface and using bioinformatics to identify genetic markers of zoonotic transmission.
Although it is possible that the positive IAV sample was incidental to - and not the direct cause - of this patient's severe illness, it is apparent that after excluding other possibilities, the doctors treating him regard it as the most likely diagnosis.
We've seen atypical influenza symptomology in the past (see Atypical Influenza (H5N1,H7N9, pH1N1) Presentations), but the lack of fever and pneumonia in such a sick individual is quite unusual.
Because of limited testing and surveillance, we don't really know how often swine-origin viruses spillover into humans, but it is undoubtedly far more common than the numbers we have suggest.
This year (2022) the CDC reports:
A total of ten human infections with variant novel influenza A viruses have been reported in the United States in 2022, including five H3N2v (Michigan, New Mexico, West Virginia (3)) and five H1N2v (Georgia, Michigan, Ohio, Oregon, Wisconsin) viruses. When an influenza virus that normally circulates in swine (but not people) is detected in a person, it is called a “variant” influenza virus. Most human infections with variant influenza viruses occur following exposure to swine, but human-to-human transmission can occur. It is important to note that in most cases, variant influenza viruses have not shown the ability to spread easily and sustainably from person to person.
And as we've discussed often in the past (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?) - swine flu viruses are viewed as having a bit of an advantage in the pandemic sweepstakes, as only H1, H2, and H3 influenza subtypes are known to have sparked a human influenza pandemic in the last 130 years.
This doesn't mean we couldn't see an avian (H5, H7, H9, etc.) flu pandemic, only that swine viruses have less far to evolve to adapt to humans. Which is why we track these sporadic species jumps from swine to humans.
The CDC's IRAT (Influenza Risk Assessment Tool) lists 3 North American swine viruses as having at least some pandemic potential (2 added in 2019).
H1N2 variant [A/California/62/2018] Jul 2019 5.8 5.7 ModerateH3N2 variant [A/Ohio/13/2017] Jul 2019 6.6 5.8 Moderate
H3N2 variant [A/Indiana/08/2011] Dec 2012 6.0 4.5 Moderate
In 2021 the CDC ranked a Chinese Swine-variant EA H1N1 `G4' as having the highest pandemic potential of any flu virus on their list (see EID Journal: Zoonotic Threat of G4 Genotype Eurasian Avian-Like Swine Influenza A(H1N1) Viruses, China, 2020).
So far, the good news is that currently circulating swine variant viruses haven't become biologically `fit' enough spark a pandemic. In order to be successful, they need to be able to replicate and transmit on par with already circulating human flu viruses.
The bad news is there are hundreds of swine-variants spreading - and reassorting - among hundreds of millions of pigs around the world, and most of that goes on out of our sight.
And like with the last swine-flu pandemic, the first sign that a virus has made the leap to a pandemic virus may not come until days or even weeks after the virus has begun its world tour.
