Post by Nadica (She/Her) on Jul 26, 2024 14:01:22 GMT
Mortality of H5N1 human infections might be due to H5N1 virus pneumonia and could decrease by switching receptor - Published July 24, 2024
The increasing host range and ability of avian influenza viruses to spread between mammals and humans raises concerns about a potential pandemic risk.1 This pandemic risk is a concern as the mortality was 458 (52%) of the 876 influenza A(H5N1) cases reported in Europe since 2002.2 The haemagglutinin protein is the host-range determinant as it mediates virus binding to the sialic acid receptors.
Here we argue that the high mortality might be due to a H5N1 virus pneumonia, and should the H5N1 switch to the upper airway receptor for human influenza (H1, H2, and H3), α2,6-sialic acid (SA α2,6), we hypothesise that the mortality would be lower because most infections would be rescricted to the upper respiratory tract infections and only in rare cases pneumonia.
The current outbreak of influenza A(H5N1) in dairy cattle in the USA has raised concerns of increased risk for sustained human-to-human transmission.3 As of July 12, 2024, 151 dairy herds and 99 million poultry are affected and H5N1 has been found in 9528 wild birds.3 Five humans cases have been reported and in three, the symptoms reported included conjunctivitis.4
The influenza virus hemagglutinin protein binds to sialic acid receptors on the host cells, which can be either SA α2,3 or SA α2,6.5, 6 SA α2,3 is found on specific human tissues especially lung alveoli and conjunctiva, while SA α2,6 is predominantly found in the upper respiratory tract of humans.6 The avian influenza's uses the SA α2,3 receptor whereas the three human influenza viruses (H1N1, H2N2, and H3N2) use the SA α2,6 receptor.6
Avian influenza can occasionally cross the species barrier from animals to humans. This transmission likely requires exposure to a high number of avian influenza viruses for the virus to reach the SA α2,3 receptor in the alveoli, after which the infected person will develop diffuse, double-sided pneumonia. Receptor distribution also explains why conjunctivitis has been reported in at least three of the five reported human H5N1 cases infected from cattle in the USA.3
Our experience from the 2009 H1N1 pandemic was that admissions to intensive care were due to a H1N1 pneumonia.7 The mortality rate was five (23·8%) in 21 patients and three (33·3%) in nine patients receiving extracorporeal membrane oxygenation treatment.7 These rates might not be considerably different to the 52% mortality reported by the European Food Safety Agency,2 given the variance between centres in Europe.
Therefore, we hypothesise that if the H5N1 virus switched receptor preference from SA α2,3 to the human upper respiratory receptor SA α2,6, the virus might cause a less severe upper respiratory infection and the mortality rate would decrease because most cases would no longer be due to influenza virus pneumonia.
A 2012 study showed that a reassortant H5 H1N1 virus with four mutations was capable of droplet transmission in a ferret model. The transmissible H5 reassortant virus preferentially recognised human-type receptors, replicated efficiently in ferrets, caused lung lesions and weight loss, but was not highly pathogenic and did not cause mortality.8 These findings agree with another study using an A(H5N1) virus modified by site-directed mutagenesis. The genetically modified A(H5N1) virus ultimately became airborne transmissible in ferrets; however, none of the recipient ferrets died after airborne infection.9 Four amino acid substitutions in the host receptor-binding protein hemagglutinin, and one in the polymerase complex protein basic polymerase 2, were consistently present in airborne-transmitted viruses.9 These two studies support our hypothesis, that a with a H5N1 receptor preference switch from SA α2,3 to SA α2,6, the pathogenicity could decrease.
Nevertheless, people in close contact with H5N1 infected dairy cattle and poultry are at risk of being infected and developing H5N1 pneumonia with high mortality. Consequently, Finland, as the first country, has introduced immunisation with a H5N1 vaccine to people 18 years and older who are at increased risk of being infected with avian influenza because of their work or other circumstances.10
Even if mortality were lower due to receptor switching, widespread transmission could still lead to a substantial health-care burden and morbidity and mortality due to potentially high numbers of concurrent cases.
LS and EP are supported by a grant from the Danish National Research Foundation (grant number DNRF170). We declare no competing interests.
References
1.Kang M Li HP Tang J et al.
Changing epidemiological patterns in human avian influenza virus infections.
Lancet Microbe. 2024; (published online July 6)
doi.org/10.1016/S2666-5247(24)00158-7
2.European Food Safety Authority, European Centre for Disease Prevention and Control, European Union Reference Laboratory for Avian Influenza, et al
Avian influenza overview April–June 2023.
EFSA J. 2023; 21: e08191
3.US Centers for Disease Control and Prevention
H5 bird flu: current situation. March 25, 2024.
www.cdc.gov/bird-flu/situation-summary/index.html
Date accessed: July 14, 2024
4.US Centers for Disease Control and Prevention
CDC reports fourth human case of H5 bird flu tied to dairy cow outbreak. July 3, 2024.
www.cdc.gov/media/releases/2024/p-0703-4th-human-case-h5.html
Date accessed: July 14, 2024
5.Kang M Wang L-F Sun B-W et al.
Zoonotic infections by avian influenza virus: changing global epidemiology, investigation, and control.
Lancet Infect Dis. 2024; (published online June 12)
doi.org/10.1016/S1473-3099(24)00234-2
6.Thompson AJ Paulson JC
Adaptation of influenza viruses to human airway receptors.
J Biol Chem. 2021; 296: 100017
7.Petersen E Keld DB Ellermann-Eriksen S et al.
Failure of combination oral oseltamivir and inhaled zanamivir antiviral treatment in ventilator- and ECMO-treated critically ill patients with pandemic influenza A (H1N1)v.
Scand J Infect Dis. 2011; 43: 495-503
8.Imai M Watanabe T Hatta M et al.
Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets.
Nature. 2012; 486: 420-428
9.Herfst S Schrauwen EJA Linster M et al.
Airborne transmission of influenza A/H5N1 virus between ferrets.
Science. 2012; 336: 1534-1541
10.Finnish Institute for Health and Welfare
Avian influenza vaccinations begin–vaccine to be offered to persons at increased risk of infection. June 25, 2024.
thl.fi/en/-/avian-influenza-vaccinations-begin-vaccine-to-be-offered-to-persons-at-increased-risk-of-infection
Date accessed: July 14, 2024
The increasing host range and ability of avian influenza viruses to spread between mammals and humans raises concerns about a potential pandemic risk.1 This pandemic risk is a concern as the mortality was 458 (52%) of the 876 influenza A(H5N1) cases reported in Europe since 2002.2 The haemagglutinin protein is the host-range determinant as it mediates virus binding to the sialic acid receptors.
Here we argue that the high mortality might be due to a H5N1 virus pneumonia, and should the H5N1 switch to the upper airway receptor for human influenza (H1, H2, and H3), α2,6-sialic acid (SA α2,6), we hypothesise that the mortality would be lower because most infections would be rescricted to the upper respiratory tract infections and only in rare cases pneumonia.
The current outbreak of influenza A(H5N1) in dairy cattle in the USA has raised concerns of increased risk for sustained human-to-human transmission.3 As of July 12, 2024, 151 dairy herds and 99 million poultry are affected and H5N1 has been found in 9528 wild birds.3 Five humans cases have been reported and in three, the symptoms reported included conjunctivitis.4
The influenza virus hemagglutinin protein binds to sialic acid receptors on the host cells, which can be either SA α2,3 or SA α2,6.5, 6 SA α2,3 is found on specific human tissues especially lung alveoli and conjunctiva, while SA α2,6 is predominantly found in the upper respiratory tract of humans.6 The avian influenza's uses the SA α2,3 receptor whereas the three human influenza viruses (H1N1, H2N2, and H3N2) use the SA α2,6 receptor.6
Avian influenza can occasionally cross the species barrier from animals to humans. This transmission likely requires exposure to a high number of avian influenza viruses for the virus to reach the SA α2,3 receptor in the alveoli, after which the infected person will develop diffuse, double-sided pneumonia. Receptor distribution also explains why conjunctivitis has been reported in at least three of the five reported human H5N1 cases infected from cattle in the USA.3
Our experience from the 2009 H1N1 pandemic was that admissions to intensive care were due to a H1N1 pneumonia.7 The mortality rate was five (23·8%) in 21 patients and three (33·3%) in nine patients receiving extracorporeal membrane oxygenation treatment.7 These rates might not be considerably different to the 52% mortality reported by the European Food Safety Agency,2 given the variance between centres in Europe.
Therefore, we hypothesise that if the H5N1 virus switched receptor preference from SA α2,3 to the human upper respiratory receptor SA α2,6, the virus might cause a less severe upper respiratory infection and the mortality rate would decrease because most cases would no longer be due to influenza virus pneumonia.
A 2012 study showed that a reassortant H5 H1N1 virus with four mutations was capable of droplet transmission in a ferret model. The transmissible H5 reassortant virus preferentially recognised human-type receptors, replicated efficiently in ferrets, caused lung lesions and weight loss, but was not highly pathogenic and did not cause mortality.8 These findings agree with another study using an A(H5N1) virus modified by site-directed mutagenesis. The genetically modified A(H5N1) virus ultimately became airborne transmissible in ferrets; however, none of the recipient ferrets died after airborne infection.9 Four amino acid substitutions in the host receptor-binding protein hemagglutinin, and one in the polymerase complex protein basic polymerase 2, were consistently present in airborne-transmitted viruses.9 These two studies support our hypothesis, that a with a H5N1 receptor preference switch from SA α2,3 to SA α2,6, the pathogenicity could decrease.
Nevertheless, people in close contact with H5N1 infected dairy cattle and poultry are at risk of being infected and developing H5N1 pneumonia with high mortality. Consequently, Finland, as the first country, has introduced immunisation with a H5N1 vaccine to people 18 years and older who are at increased risk of being infected with avian influenza because of their work or other circumstances.10
Even if mortality were lower due to receptor switching, widespread transmission could still lead to a substantial health-care burden and morbidity and mortality due to potentially high numbers of concurrent cases.
LS and EP are supported by a grant from the Danish National Research Foundation (grant number DNRF170). We declare no competing interests.
References
1.Kang M Li HP Tang J et al.
Changing epidemiological patterns in human avian influenza virus infections.
Lancet Microbe. 2024; (published online July 6)
doi.org/10.1016/S2666-5247(24)00158-7
2.European Food Safety Authority, European Centre for Disease Prevention and Control, European Union Reference Laboratory for Avian Influenza, et al
Avian influenza overview April–June 2023.
EFSA J. 2023; 21: e08191
3.US Centers for Disease Control and Prevention
H5 bird flu: current situation. March 25, 2024.
www.cdc.gov/bird-flu/situation-summary/index.html
Date accessed: July 14, 2024
4.US Centers for Disease Control and Prevention
CDC reports fourth human case of H5 bird flu tied to dairy cow outbreak. July 3, 2024.
www.cdc.gov/media/releases/2024/p-0703-4th-human-case-h5.html
Date accessed: July 14, 2024
5.Kang M Wang L-F Sun B-W et al.
Zoonotic infections by avian influenza virus: changing global epidemiology, investigation, and control.
Lancet Infect Dis. 2024; (published online June 12)
doi.org/10.1016/S1473-3099(24)00234-2
6.Thompson AJ Paulson JC
Adaptation of influenza viruses to human airway receptors.
J Biol Chem. 2021; 296: 100017
7.Petersen E Keld DB Ellermann-Eriksen S et al.
Failure of combination oral oseltamivir and inhaled zanamivir antiviral treatment in ventilator- and ECMO-treated critically ill patients with pandemic influenza A (H1N1)v.
Scand J Infect Dis. 2011; 43: 495-503
8.Imai M Watanabe T Hatta M et al.
Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets.
Nature. 2012; 486: 420-428
9.Herfst S Schrauwen EJA Linster M et al.
Airborne transmission of influenza A/H5N1 virus between ferrets.
Science. 2012; 336: 1534-1541
10.Finnish Institute for Health and Welfare
Avian influenza vaccinations begin–vaccine to be offered to persons at increased risk of infection. June 25, 2024.
thl.fi/en/-/avian-influenza-vaccinations-begin-vaccine-to-be-offered-to-persons-at-increased-risk-of-infection
Date accessed: July 14, 2024