Influenza classification

Jump to navigation Jump to search

Influenza Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Influenza from other Diseases

Epidemiology and Demographics

Risk Factors

Natural History, Complications and Prognosis

Diagnosis

History and Symptoms

Physical Examination

Laboratory Findings

Chest X Ray

Other Diagnostic Studies

Treatment

Medical Therapy

Primary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Influenza classification On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Influenza classification

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Influenza classification

CDC on Influenza classification

Influenza classification in the news

Blogs on Influenza classification

Directions to Hospitals Treating Influenza

Risk calculators and risk factors for Influenza classification

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohammad Braizat, M.S. [2]

Classification

Influenza Virus Types

Influenza viruses belong to the family Orthomyxoviridae and are classified into four types: A, B, C, and D, distinguished by the antigenic properties of their internal nucleoprotein (NP) and matrix (M1) proteins.[1][2]

  • Influenza A infects the broadest range of hosts, including humans, wild waterfowl (the primary natural reservoir), poultry, swine, horses, dogs, marine mammals, and bats. It is the only type that causes pandemics and is responsible for the majority of seasonal influenza morbidity and mortality. Influenza A viruses are further classified into subtypes based on HA and NA surface glycoproteins.[1][3]
  • Influenza B primarily infects humans and is not classified into subtypes but is divided into two antigenically distinct lineages: B/Victoria/2/87 and B/Yamagata/16/88. Influenza B causes seasonal epidemics but has never caused a pandemic. B/Yamagata viruses have not been detected globally since March 2020 and are considered likely extinct.[1][4][5]
  • Influenza C infects humans, pigs, and dogs. It has seven genome segments (compared with eight for types A and B) and possesses a single surface glycoprotein, hemagglutinin-esterase-fusion (HEF), rather than separate HA and NA. Influenza C generally causes mild upper respiratory illness, though it can cause bronchitis and pneumonia in children under 2 years. Six genetic lineages are recognized (C/Taylor, C/Mississippi, C/Aichi, C/Yamagata, C/Kanagawa, C/Sao Paulo).[2][6]
  • Influenza D primarily infects cattle with spillover to pigs and other animals. Like influenza C, it has seven genome segments. It is not known to cause disease in humans, though antibodies to influenza D have been detected in cattle-exposed workers.[1][2]

Influenza A and B viruses are enveloped, negative-sense, single-stranded RNA viruses with eight genome segments encoding at least 12 proteins (some sources cite up to 17 when including accessory proteins). The segmented genome is critical because it enables genetic reassortment during co-infection, a key mechanism for generating novel viruses with pandemic potential.[1][3]

Type Host Range Subtypes/Lineages Genome Segments Pandemic Potential Clinical Significance Refs
A Humans, birds, swine, horses, bats, marine mammals 18 HA × 11 NA subtypes 8 Yes Seasonal epidemics + pandemics [1][2]
B Primarily humans 2 lineages (Victoria, Yamagata) 8 No Seasonal epidemics [1][3]
C Humans, pigs, dogs 6 genetic lineages 7 No Mild illness; severe in young children [2][6]
D Cattle, pigs Not subtyped 7 No (does not infect humans) Not clinically relevant in humans [1][2]

Influenza A Subtype Classification

Influenza A viruses are classified into subtypes based on the antigenic properties of their two major surface glycoproteins:[1][7]

  • Hemagglutinin (HA): Mediates viral attachment to host cell sialic acid receptors and membrane fusion during cell entry. It is the primary target of neutralizing antibodies and the most important antigen for vaccine-induced protection.
  • Neuraminidase (NA): Cleaves sialic acid residues to facilitate release of progeny virions from infected cells. It is the target of neuraminidase inhibitor antivirals (oseltamivir, zanamivir, peramivir).

To date, 18 HA subtypes (H1–H18) and 11 NA subtypes (N1–N11) have been identified. Of these, 16 HA (H1–H16) and 9 NA (N1–N9) subtypes are enzootic in avian species, primarily wild waterfowl. Two additional HA subtypes (H17, H18) and two NA subtypes (N10, N11) have been identified exclusively in bats through RNA detection, though infectious virus has not been isolated from bats.[1][3][7]

The HA subtypes are phylogenetically divided into two groups:[7]

  • Group 1: H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17, H18
  • Group 2: H3, H4, H7, H10, H14, H15

This grouping is clinically relevant because broadly neutralizing antibodies targeting the conserved HA stem region tend to be group-specific, which has implications for universal vaccine development.[7]

Currently circulating seasonal human influenza A subtypes are A(H1N1)pdm09 and A(H3N2). These two subtypes have co-circulated since 1977, with the relative dominance of each varying by season and geography.[1][8]


Influenza B Lineage Classification

Influenza B viruses are not classified into subtypes. Instead, two antigenically distinct lineages diverged in the 1970s–1980s and have co-circulated globally since approximately 2001:[9][10]

  • B/Victoria/2/87-like (B/Victoria)
  • B/Yamagata/16/88-like (B/Yamagata)

The two lineages differ in their HA antigenic properties, with most B-cell responses being lineage-specific rather than cross-reactive. This antigenic distinction was the rationale for the introduction of quadrivalent influenza vaccines in 2012–2013, which included representatives of both lineages.[11][4]

B/Yamagata probable extinction: B/Yamagata viruses have not been detected in global surveillance since March 2020. The probable extinction is attributed to the combined effects of COVID-19 pandemic non-pharmaceutical interventions (NPIs) reducing transmission, a depleted susceptible population following the large 2017–2018 B/Yamagata outbreak, and the lineage's slow antigenic evolution.[5][4] In response, the WHO recommended removing B/Yamagata from influenza vaccines, and all U.S. influenza vaccines reverted to trivalent formulations beginning with the 2024–25 season.[12] As of 2025–26, only B/Victoria is included in seasonal vaccines.[8]

B/Victoria viruses continue to undergo genetic diversification, with HA deletion variants (e.g., clade V1A.3a.2) dominating recent seasons.[13]

WHO Strain Nomenclature

The WHO established a standardized nomenclature system for influenza viruses in 1971, revised in 1980, that remains in use. Each strain designation includes:[14]

1. Antigenic type (A, B, or C) 2. Host of origin (omitted for human isolates) 3. Geographic origin (location of first isolation) 4. Strain number 5. Year of isolation 6. For influenza A: subtype designation in parentheses (HxNx)

Examples:

  • A/California/7/2009 (H1N1) — human influenza A, H1N1 subtype, isolated in California, strain 7, year 2009[15]
  • A/duck/Alberta/35/76 (H1N1) — avian influenza A from ducks in Alberta
  • B/Victoria/2/87 — human influenza B, isolated in Victoria, strain 2, year 1987

Clade and Subclade Nomenclature for Genomic Surveillance

Beyond the subtype/lineage level, influenza viruses are further classified into clades and subclades based on phylogenetic analysis of HA and NA gene sequences. A dynamic nomenclature system has been developed by the Nextstrain team in collaboration with WHO Collaborating Centres and is now widely used by the GISRS system, vaccine manufacturers, and researchers.[16]

Current nomenclature for the three circulating seasonal lineages uses hierarchical subclade designations with letter aliases to keep names manageable:[16]

  • A(H1N1)pdm09: Aliases A–D (initialized from clade 6B.1A.5a, ~2018)
  • A(H3N2): Aliases A–K (initialized from clade 3C, ~2012)
  • B/Victoria: Aliases A–C (initialized from clade V1A, ~2008)

The nomenclature is updated approximately four times per year and is implemented in the Nextclade web tool for rapid sequence classification.[16] For example, the A(H3N2) subclade K (alias for J.2.4.1) emerged in mid-2025 and showed rapid global spread with multiple HA substitutions compared with the 2025–26 vaccine virus, raising concerns about antigenic mismatch.[17]


Antigenic Drift and Antigenic Shift

Two distinct mechanisms of antigenic variation drive influenza virus evolution and have direct clinical implications for vaccine effectiveness and pandemic risk:[1][3]

Antigenic drift is a continuous process affecting both influenza A and B viruses. It results from the accumulation of point mutations in the HA and NA genes, driven by antibody-mediated selective pressure and the high error rate of the viral RNA-dependent RNA polymerase (which lacks proofreading ability). Antigenic drift enables the virus to escape immunity from prior infection or vaccination, necessitating annual updates to vaccine composition and annual immunization. In H3N2 viruses, five canonical antigenic sites (A–E) on the HA globular head have been mapped, encompassing approximately 131 residues; antigenic changes in these sites can result from substitutions in a relatively small number of key positions near the receptor-binding domain.[17][18]

Antigenic shift is an abrupt, major change in the HA (with or without NA) of influenza A viruses, producing a virus antigenically distinct from previously circulating strains. It occurs through:[1][3]

  • Genetic reassortment during co-infection of a single host with two or more different influenza A viruses. Pigs are considered "mixing vessels" because they express both avian-type α2,3-linked sialic acid receptors (predominant in the avian gastrointestinal tract) and human-type α2,6-linked sialic acid receptors (predominant in the human upper respiratory tract), enabling co-infection with avian and human viruses.[3]
  • Direct adaptation of an avian influenza A virus to efficient human infection, requiring changes in receptor-binding specificity from α2,3 to α2,6-linked sialic acids.[3]

This receptor-binding distinction is clinically important: avian influenza viruses preferentially bind α2,3-linked sialic acids, which are abundant in the avian gastrointestinal tract and the human lower respiratory tract. This may explain why avian viruses like H5N1 and H7N9 cause severe lower respiratory disease but do not transmit efficiently between humans, as efficient human-to-human transmission requires binding to α2,6-linked sialic acids in the upper respiratory tract.[1]

Antigenic shift can produce a novel virus to which most of the human population lacks immunity, creating the potential for a pandemic. All four pandemics of the past century (1918, 1957, 1968, 2009) resulted from antigenic shift events.[3][19]

Avian Influenza Pathogenicity Classification

Avian influenza A viruses are classified by their pathogenicity in poultry into two categories, which has important implications for zoonotic risk assessment:[20][21]

  • Low pathogenicity avian influenza (LPAI): Causes mild or asymptomatic infection in poultry. The HA cleavage site contains a monobasic motif, restricting HA cleavage to trypsin-like proteases found primarily in the respiratory and gastrointestinal tracts.
  • Highly pathogenic avian influenza (HPAI): Causes severe systemic disease with high mortality in poultry. HPAI viruses arise from LPAI precursors through acquisition of a multibasic (polybasic) cleavage site in the HA protein, which allows cleavage by ubiquitous furin-like proteases, enabling systemic viral dissemination.

HPAI conversion has been documented exclusively in H5 and H7 subtypes in nature. Between 1959 and 2019, at least 42 independent LPAI-to-HPAI conversion events were documented globally.[21] The HPAI H5Nx lineage descended from A/goose/Guangdong/1/1996 (Gs/GD) has been the most consequential, with clade 2.3.4.4b causing unprecedented global spread in wild birds, poultry, and mammals since 2020.[22]

This pathogenicity classification applies specifically to poultry and does not directly predict disease severity in humans, though HPAI viruses (particularly H5N1) have generally caused more severe human disease than LPAI viruses.[23][24]

Zoonotic and Variant Influenza Viruses

Zoonotic avian influenza viruses that have caused confirmed human infections include H5N1, H5N6, H5N8, H7N9, H7N7, H7N3, H7N2, H7N4, H9N2, H10N3, H10N7, H10N8, H6N1, and H3N8.[23][25] The subtypes of greatest public health concern are:

  • H5N1: Sporadic human cases since 1997; high CFR in earlier clades (~50–60%), lower in clade 2.3.4.4b (~0.7%). Between March 2024 and May 2025, 70 human HPAI A(H5N1) cases were reported in the United States, predominantly among dairy and poultry workers, representing the first documented bovine-to-human transmission of H5N1 and the largest cluster of human H5N1 cases in U.S. history. This reinforces the importance of ongoing surveillance of H5 clade 2.3.4.4b as a pandemic preparedness priority.[23][26]
  • H7N9: 1,568 confirmed human cases with ~40% CFR (2013–2019); no cases since 2019[3]
  • H5N6: Sporadic cases in China with high severity (75% fatality among hospitalized cases)[24]
  • H9N2: Sporadic mild infections; important as a gene donor for other zoonotic reassortants[3]

Variant influenza viruses are swine-origin influenza A viruses that infect humans. The CDC designates these with a "v" suffix (e.g., A[H3N2]v, A[H1N1]v, A[H1N2]v). Since 2011, over 470 variant virus infections have been reported in the United States, predominantly in children with swine exposure at agricultural fairs. Most cause mild illness, but they represent a pandemic risk through potential reassortment with seasonal human viruses.[3][25][27]

High-Yield Clinical Pearls

  • Only influenza A causes pandemics; influenza B causes epidemics but never pandemics.[1][3]
  • Only two influenza A subtypes (H1N1pdm09 and H3N2) currently circulate seasonally in humans. H3N2-dominant seasons are generally associated with higher morbidity and mortality.[1][3]
  • Antigenic drift (point mutations) drives seasonal epidemics and the need for annual vaccination; antigenic shift (reassortment or direct adaptation) creates pandemic risk — this distinction is fundamental to understanding influenza epidemiology.[1][3]
  • The LPAI-to-HPAI conversion occurs only in H5 and H7 subtypes and requires acquisition of a polybasic HA cleavage site — this is the molecular basis for the heightened pandemic concern surrounding H5 and H7 viruses.[20][21]
  • Variant viruses (swine-origin, designated with "v") are reportable to the CDC and represent a distinct pandemic preparedness concern from avian influenza.[25]

Common Pitfalls

  • Stating there are only "3 types" of influenza — there are now four recognized types (A, B, C, D).[1]
  • Using the outdated count of "16 HA and 9 NA subtypes" — the current count is 18 HA and 11 NA.[1][7]
  • Assuming influenza B is clinically insignificant — influenza B accounts for approximately 23% of seasonal influenza cases globally (based on 2001–2018 data) and can cause severe disease, particularly in children. Post-pandemic proportions may differ given B/Yamagata extinction.[28]
  • Confusing LPAI/HPAI pathogenicity classification (which applies to poultry) with human disease severity — LPAI viruses like H7N9 can still cause severe human disease with ~40% CFR.[3][21]
  • Assuming that B/Yamagata is still circulating and that quadrivalent vaccines are still standard — all U.S. influenza vaccines are now trivalent.[12][8]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 Uyeki TM, Hui DS, Zambon M, Wentworth DE, Monto AS (2022). "Influenza". Lancet. 400 (10353): 693–706. doi:10.1016/S0140-6736(22)00982-5. PMID 35965100 Check |pmid= value (help).
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Shimizu K, Kawakami C, Matsuzaki Y; et al. (2024). "Monitoring Influenza C and D Viruses in Patients With Respiratory Diseases in Japan, January 2018 to March 2023". Influenza and Other Respiratory Viruses. 18 (6): e13345. doi:10.1111/irv.13345. PMID 39007387 Check |pmid= value (help).
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 Paules C, Subbarao K (2017). "Influenza". Lancet. 390 (10095): 697–708. doi:10.1016/S0140-6736(17)30129-0. PMID 28640221.
  4. ↑ 4.0 4.1 4.2 Marchi S, Bruttini M, Milano G; et al. (2024). "Prevalence of Influenza B/Yamagata Viruses From Season 2012/2013 to 2021/2022 in Italy as an Indication of a Potential Lineage Extinction". Influenza and Other Respiratory Viruses. 18 (9): e13359. doi:10.1111/irv.13359. PMID 39363725 Check |pmid= value (help).
  5. ↑ 5.0 5.1 Han W, Zeng J, Shi J; et al. (2025). "Unraveling the Mechanism Behind the Probable Extinction of the B/Yamagata Lineage of Influenza B Viruses". Nature Communications. 16 (1): 10440. doi:10.1038/s41467-025-65396-6. PMID 40133118 Check |pmid= value (help).
  6. ↑ 6.0 6.1 Liu R, Sheng Z, Lin T; et al. (2020). "Genetic and antigenic characteristics of a human influenza C virus clinical isolate". Journal of Medical Virology. 92 (2): 161–166. doi:10.1002/jmv.25589. PMID 31671003.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 Focosi D, Franchini M, Senefeld JW; et al. (2024). "Passive immunotherapies for the next influenza pandemic". Reviews in Medical Virology. 34 (3): e2533. doi:10.1002/rmv.2533. PMID 27064508.
  8. ↑ 8.0 8.1 8.2 Del Riccio M, Caini S (2026). "Global Influenza Epidemiology After 2020: Patterns of Circulation, Epidemic Timing and Duration, and Implications for Vaccination Strategies". Euro Surveillance. 31 (21). doi:10.2807/1560-7917.ES.2026.31.21.2500743. PMID 39753470 Check |pmid= value (help).
  9. ↑ Rosu ME, Lexmond P, Bestebroer TM; et al. (2022). "Substitutions Near the HA Receptor Binding Site Explain the Origin and Major Antigenic Change of the B/Victoria and B/Yamagata Lineages". Proceedings of the National Academy of Sciences of the United States of America. 119 (42): e2211616119. doi:10.1073/pnas.2211616119. PMID 36209948 Check |pmid= value (help).
  10. ↑ Virk RK, Jayakumar J, Mendenhall IH; et al. (2020). "Divergent Evolutionary Trajectories of Influenza B Viruses Underlie Their Contemporaneous Epidemic Activity". Proceedings of the National Academy of Sciences of the United States of America. 117 (1): 619–628. doi:10.1073/pnas.1916585116. PMID 31647048.
  11. ↑ Chan WM, Wong LH, So CF; et al. (2020). "Development and evaluation of a conventional RT‐PCR for differentiating emerging influenza B/Victoria lineage viruses with hemagglutinin amino acid deletion from B/Yamagata lineage viruses". Journal of Medical Virology. 92 (3): 382–385. doi:10.1002/jmv.25607. PMID 31736027.
  12. ↑ 12.0 12.1 Fisman D, Pérez-Rubio A, Postma M, Smith DS, Mould-Quevedo J (2025). "Maintaining the Value of Influenza Vaccination - The Shift From Quadrivalent to Trivalent Vaccines: An Expert Review". Expert Review of Vaccines. 24 (1): 499–508. doi:10.1080/14760584.2025.2515597. PMID 40462760 Check |pmid= value (help).
  13. ↑ Ichikawa Y, Saito R, Chon I; et al. (2026). "Molecular Epidemiology and Genetic Diversity of Influenza B Viruses Based on Whole‐Genome Analysis in Japan and Myanmar, 2016–2020". Influenza and Other Respiratory Viruses. 20 (2): e70234. doi:10.1111/irv.70234. PMID 39973388 Check |pmid= value (help).
  14. ↑ WHO (1980). "A Revision of the System of Nomenclature for Influenza Viruses: A WHO Memorandum". Bulletin of the World Health Organization. 58 (4): 585–91. PMID 6998651.
  15. ↑ Coates BM, Staricha KL, Wiese KM, Ridge KM (2015). "Influenza A Virus Infection, Innate Immunity, and Childhood". JAMA Pediatrics. 169 (10): 956–63. doi:10.1001/jamapediatrics.2015.1387. PMID 26248444.
  16. ↑ 16.0 16.1 16.2 Neher RA, Huddleston J, Bedford T; et al. (2026). "Nomenclature for Tracking of Genetic Variation of Seasonal Influenza Viruses". Influenza and Other Respiratory Viruses. 20 (2): e70230. doi:10.1111/irv.70230. PMID 39973394 Check |pmid= value (help).
  17. ↑ 17.0 17.1 Zambon M, Hayden FG (2025). "Influenza A(H3N2) Subclade K Virus". JAMA. doi:10.1001/jama.2025.25903. PMID 40915905 Check |pmid= value (help).
  18. ↑ Wiley DC, Wilson IA, Skehel JJ (1981). "Structural identification of the antibody-binding sites of Hong Kong influenza haemagglutinin and their involvement in antigenic variation". Nature. 289 (5796): 373–8. doi:10.1038/289373a0. PMID 6957527.
  19. ↑ Ziegler T, Mamahit A, Cox NJ (2018). "65 years of influenza surveillance by a World Health Organization-coordinated global network". Influenza and Other Respiratory Viruses. 12 (5): 558–565. doi:10.1111/irv.12570. PMID 29774955.
  20. ↑ 20.0 20.1 de Bruin ACM, Funk M, Spronken MI; et al. (2022). "Hemagglutinin Subtype Specificity and Mechanisms of Highly Pathogenic Avian Influenza Virus Genesis". Viruses. 14 (7): 1566. doi:10.3390/v14071566. PMID 35893190 Check |pmid= value (help).
  21. ↑ 21.0 21.1 21.2 21.3 Lee DH, Criado MF, Swayne DE (2021). "Pathobiological Origins and Evolutionary History of Highly Pathogenic Avian Influenza Viruses". Cold Spring Harbor Perspectives in Medicine. 11 (2): a038679. doi:10.1101/cshperspect.a038679. PMID 32631861 Check |pmid= value (help).
  22. ↑ Dabrera G (2024). "H5 and H9 Avian Influenza - Potential Re-Emergent Zoonotic Threats to Humans". Current Opinion in Infectious Diseases. 37 (5): 431–435. doi:10.1097/QCO.0000000000001019. PMID 39030393 Check |pmid= value (help).
  23. ↑ 23.0 23.1 23.2 Philippon DAM, Wu P, Cowling BJ, Lau EHY (2020). "Avian Influenza Human Infections at the Human-Animal Interface". The Journal of Infectious Diseases. 222 (4): 528–537. doi:10.1093/infdis/jiaa105. PMID 31589916.
  24. ↑ 24.0 24.1 Jiang H, Wu P, Uyeki TM; et al. (2017). "Preliminary Epidemiologic Assessment of Human Infections With Highly Pathogenic Avian Influenza A(H5N6) Virus, China". Clinical Infectious Diseases. 65 (3): 383–388. doi:10.1093/cid/cix334. PMID 28504386.
  25. ↑ 25.0 25.1 25.2 Valleau M, Szablewski CM (2024). "Influenza". CDC Yellow Book. PMID 24919060.
  26. ↑ Rolfes MA, Kniss K, Kirby MK; et al. (2025). "Human Infections With Highly Pathogenic Avian Influenza A(H5N1) Viruses in the United States From March 2024 to May 2025". Nature Medicine. doi:10.1038/s41591-025-03905-2. PMID 40712649 Check |pmid= value (help).
  27. ↑ Gao R, Pascua PNQ, Chesnokov A; et al. (2024). "Antiviral Susceptibility of Swine-Origin Influenza a Viruses Isolated From Humans, United States". Emerging Infectious Diseases. 30 (11): 2303–2312. doi:10.3201/eid3011.240892. PMID 39756640 Check |pmid= value (help).
  28. ↑ Caini S, Kusznierz G, Garate VV; et al. (2019). "The Epidemiological Signature of Influenza B Virus and Its B/Victoria and B/Yamagata Lineages in the 21st Century". PloS One. 14 (9): e0222381. doi:10.1371/journal.pone.0222381. PMID 31520047.
Retrieved from "https://www.wikidoc.org/index.php?title=Influenza_classification&oldid=1745210"