Since 1996, when a highly pathogenic avian influenza (HPAI) virus H5N1 of the lineage A/Goose/Guangdong/1/96 (GsGd) emerged in domestic geese, this lineage has spread worldwide. Even though the 1997 avian epidemic was controlled, the virus persisted in birds, and two decades later, it has spread extensively among birds throughout Asia, reaching Africa, Europe, the Middle East, South America, and Antarctica for the first time. Human infection with avian influenza A(H5N1) usually occurs after close contact with infected birds, other infected animals, or highly contaminated environments. In this study, the authors from Canada reported a severe avian influenza A(H5N1) illness in a 13-year-old adolescent.
Previous data suggest that differences in the presentation of influenza A(H5N1) virus infection in current human cases may be due to numerous factors, including changes in the viral genome or the effect of prior immunity to H1N1 strains that were prevalent after 2010. Some authors suggested that older people may have partial immunity to H5N1 because of their childhood exposure (“imprinting”) to seasonal H1N1 and H2N2 viruses, whereas younger people born since the 1968 H3N2 pandemic may be more susceptible to severe H5N1 disease. A certain degree of cross-reactivity between H5N1 and the avian-origin N1 neuraminidase that has circulated in humans since the 2009 pandemic may also provide partial protection. https://doi.org/10.1038/s41586-024-08054-z
Case report
On November 4, 2024, a 13-year-old girl presented to an emergency department in British Columbia with a 2-day history of conjunctivitis in both eyes and a 1-day history of fever. In medical history, she had mild asthma and a body mass index greater than 35. She was discharged home without treatment.
On November 7, she returned to the emergency department with a cough, vomiting, and diarrhea. A reverse-transcriptase polymerase chain reaction (RT-PCR) test for influenza A(H5)2 was positive on the day of admission. Specimen testing revealed a relatively high viral load. She was diagnosed with respiratory distress and hemodynamic instability, and the next day was transferred to the pediatric intensive care unit with respiratory failure, left lower lobe pneumonia, acute kidney injury, thrombocytopenia, and leukopenia.
Oseltamivir treatment was started on November 8. The next day, respiratory deterioration and progression to acute respiratory distress syndrome with complete bilateral opacification of both lung fields on chest radiographs prompted tracheal intubation and the initiation of Extracorporeal Membrane Oxygenation (ECMO).
Continuous renal replacement therapy was initiated on November 10. Combined antiviral treatment with amantadine (started on November 9) and baloxavir (started on November 11) was added to ongoing treatment with oseltamivir. After starting antiviral treatment, RT-PCR testing showed a decrease in viral RNA load in serum and samples from the upper and lower respiratory tract.
Chest radiographs, one day apart
The authors noted that respiratory samples from the lower respiratory tract had consistently higher viral concentrations than those from the upper respiratory tract. These findings are consistent with the results of a recent study comparing the attachment patterns to the human upper or lower respiratory tracts of the H5N1 virus of clade 2.3.4.4b, the H5N1 virus of clade 2.1.3.2, and a seasonal H3N2 virus. In the human lower respiratory tract, the H5N12022 virus was found to attach more abundantly to the apical side of ciliated and non-ciliated epithelial cells of the trachea, bronchus, and bronchiole, and alveolar type-I and type-II pneumocytes compared to the H5N12005 virus. The H5N12005 virus only attached to alveolar type-II pneumocytes and less abundantly to the other aforementioned cell types, whereas the H3N22003 virus attached most abundantly to ciliated and non-ciliated epithelial cells in the airways and alveolar type-I pneumocytes, but not to type-II pneumocytes. According to these data, the H5N12022 virus is attached to both the upper and lower human respiratory tract more abundantly than the H5N12005 virus. This suggests an expanded receptor binding repertoire for the H5N12022 virus. https://discovermednews.com/the-attachment-pattern-of-the-h5n1-virus/
Similar results were found in a study that compared the viral attachment pattern between two human influenza viruses (H1N1 and H3N2) and the avian H5N1 virus in the respiratory tracts of humans, mice, ferrets, cats, and pigs. In contrast to human influenza A viruses, the attachment of avian influenza viruses was rare in the trachea, but it gradually increased towards the bronchioles. The avian influenza virus preferentially attached to different cell types compared to the human influenza A viruses: to acinar cells in the tracheal and bronchial submucosal glands, to nonciliated cuboidal cells in the bronchioles, and alveolar type II pneumocytes and alveolar macrophages. (van Riel D, et al, Human and Avian Influenza Viruses Target Different Cells in the Lower Respiratory Tract of Humans and Other Mammals. The American Journal of Pathology, Vol. 171, No. 4, October 2007)
The patient received plasma exchange treatment from November 14–16. On November 16, the RT-PCR result for serum was negative for the first time. Since the patient’s respiratory status improved, ECMO was discontinued on November 22, and the patient was extubated on November 28.
The clade 2.3.4.4b, genotype D1.1 virus isolated from a tracheal-aspirate specimen on November 9 (eight days after the onset of symptoms) was most closely related to viruses found in wild birds in British Columbia at the same time. In the tracheal-aspirate specimen collected on November 9, sequencing detected three mutations potentially associated with adaptation to humans: the E627K mutation in the polymerase basic 2 gene and E186 and Q222 in the H5 hemagglutinin (HA) gene. The mutations in the H5 HA gene have previously been shown to increase binding to α2-6-linked sialic acids, which function as receptors that facilitate viral entry into cells of the human respiratory tract and enable viral replication.
Conclusion
This report presented a severe avian influenza A(H5N1) illness in a 13-year-old adolescent. This is the first report of a critically ill pediatric patient with HPAI (H5N1) virus infection in North America. The authors emphasize that the detection of HA changes that could increase binding to human airway receptors is concerning.
This article was published in The New England Journal of Medicine.
Journal Reference
Jassem AM, Roberts A, Tyson J, et al. Critical Illness in an Adolescent with Influenza A(H5N1) Virus Infection. The New England Journal of Medicine. December 31, 2024 (Open Access). https://www.nejm.org/doi/full/10.1056/NEJMc2415890
