Influenza risk factors

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

Risk Factors

Overview

Risk factors for influenza can be categorized into those that increase the likelihood of acquiring infection and those that increase the risk of severe disease, complications, hospitalization, and death following infection. The CDC and ACIP have established a high-risk list that serves as the foundation for clinical decision-making regarding vaccination prioritization and empiric antiviral treatment.[1] Age is the single strongest predictor of influenza-related hospitalization and death.[2]

Age

The CDC/ACIP identifies all persons aged ≥50 years as a high-risk group, with risk increasing progressively with age.[1] For clinical discussion, adults 50–64 years have intermediate hospitalization rates, while adults ≥65 years consistently have the highest influenza-associated hospitalization and mortality rates across all age groups. Immunosenescence contributes to impaired vaccine responses and increased susceptibility to severe disease in older adults.[2][3]

The CDC/ACIP also identifies children <5 years (especially <2 years) as high-risk.[1][4]

  • Infants <6 months have the highest hospitalization and mortality rates among children but are too young for vaccination, making them dependent on maternal immunization and cocooning strategies.[5]
  • Children <5 years have the highest infection rates among all age groups. In the 2024–2025 season, hospitalization rates in children <1 year were 149.4/100,000 and in children 0–4 years were 100.8/100,000.[5]

Pregnancy and Postpartum Period

Pregnant persons are at increased risk for severe influenza, particularly in the third trimester through 2 weeks postpartum.[2][4] Among women of reproductive age hospitalized with influenza over nine U.S. seasons, nearly 28% were pregnant, and 62% were in their third trimester.[2] Influenza during pregnancy is associated with adverse birth outcomes including preterm birth (aHR 1.34), low birthweight (aHR 1.40), and late pregnancy loss (aHR 10.7).[6][7] Maternal influenza vaccination reduces the hazard of low birthweight (aHR 0.84), preterm birth (aHR 0.83), and extreme preterm birth (aHR 0.59).[6]

Chronic Medical Conditions

The CDC/ACIP identifies the following chronic conditions as risk factors for influenza complications:[1][8]

  • Pulmonary disease: Asthma is the most common underlying condition among children hospitalized with influenza (24–28% of pediatric hospitalizations). COPD and cystic fibrosis also confer increased risk.[3]
  • Cardiovascular disease (excluding isolated hypertension): Congestive heart failure has the highest adjusted rate ratio for influenza-associated hospitalization among specific conditions (aRR 4.2; 95% CI 3.6–4.9) in a recent retrospective cohort study.[9] Influenza is a potent trigger for acute cardiovascular events. A landmark self-controlled case series found a 6-fold increased incidence of acute myocardial infarction within 7 days of laboratory-confirmed influenza (incidence ratio 6.05; 95% CI 3.86–9.50), with highest risk in the first 3 days.[10] A 2025 meta-analysis confirmed moderate-certainty evidence that influenza triggers AMI (IRR 5.37; 95% CI 3.48–8.28) and high-certainty evidence for stroke (IRR 4.72; 95% CI 3.78–5.90).[11]
  • Diabetes mellitus: A meta-analysis of 34 observational studies found that mortality and hospitalization for influenza and pneumonia were significantly higher in individuals with versus without diabetes.[12] Among adults ≥65 years with diabetes, influenza-associated hospitalization rates were 57% higher (RR 1.57; 95% CI 1.43–1.72) compared with those without diabetes.[13]
  • Chronic kidney disease: CKD is associated with more severe influenza illness and higher complication rates.[14] KDIGO recommends annual influenza vaccination for all persons with CKD.[15]
  • Hepatic disease: Patients with liver disease, particularly cirrhosis, have impaired immune function and are at increased risk for influenza-related hospitalization and death. During the 2009 H1N1 pandemic, patients with liver disease had a >5-fold increased risk of hospitalization and 17-fold increased risk of death compared with healthy individuals.[16]
  • Neurologic and neurodevelopmental conditions: These include cerebral palsy, epilepsy, stroke, intellectual disability, muscular dystrophy, spinal cord injury, and conditions that compromise respiratory function or handling of secretions.[8] Among hospitalized children, pre-existing neurologic conditions confer a 3.7-fold increased odds of neurologic complications (aOR 3.7; 95% CI 3.1–4.2), including encephalopathy, seizures, and encephalitis.[17]
  • Hematologic disorders: Sickle cell disease and other hemoglobinopathies increase the risk of influenza complications.[8]
  • Metabolic disorders: Including inherited metabolic disorders and mitochondrial disorders.[8]
  • Heavy alcohol use is associated with increased mortality risk from influenza.[18]

Cumulative Risk of Multiple Comorbidities

The cumulative number of CDC-defined high-risk conditions is a strong predictor of influenza-related medical encounters. A 2024 study found that the odds of influenza-related hospitalization increased progressively with each additional high-risk condition: OR 1.8 for 1 risk factor, OR 3.4 for 2 risk factors, and OR 6.4 for ≥4 risk factors.[19] A 2025 study confirmed that adjusted rate ratios for influenza-associated hospitalization increased with each additional underlying medical condition, and that hospitalization rates would have been approximately 60% higher without vaccination.[9]

Obesity

Extreme obesity (BMI ≥40 kg/m²) is recognized by the CDC/ACIP as a risk factor for severe influenza.[1] A prospective cohort study found that obese adults (BMI 30–40) had 27% higher influenza incidence (aHR 1.27) and 57% higher hospitalization risk (aHR 1.57), while very obese adults (BMI 40–50) had 69% higher incidence and nearly 5-fold higher hospitalization risk (aHR 4.81).[20] Obesity dysregulates pulmonary antiviral immune responses and is the third most common underlying condition among children hospitalized with influenza (13–16%), associated with worse prognosis including ICU admission and death.[5]

Immunocompromised States

Immunosuppression from any cause increases the risk of severe influenza, prolonged viral shedding, nosocomial transmission, and antiviral resistance.[1][21] Among 35,348 adults hospitalized with influenza (2011–2015), 10% were immunocompromised. After adjustment, immunocompromised adults had 46% higher mortality (aOR 1.46; 95% CI 1.20–1.76), longer hospitalization, and higher rates of mechanical ventilation (aOR 1.19).[21] Immunocompromised patients may have atypical presentations (absence of fever) and prolonged viral shedding, facilitating nosocomial transmission.[22]

Aspirin/Salicylate Use in Children and Adolescents

Children and adolescents aged 6 months through 18 years receiving aspirin- or salicylate-containing medications are at risk for Reye syndrome following influenza infection.[1][8] Reye syndrome is characterized by encephalopathy and fatty degeneration of the liver, typically following influenza or varicella. Historical data (1981–1997) reported a case fatality rate of 31%; modern rates may differ given improved ICU care and the rarity of the condition, though no updated large-scale data exist.[23] Only inactivated influenza vaccine should be administered to children on chronic aspirin therapy.[24]

Genetic Susceptibility

Host genetic factors contribute to variability in influenza severity, though their clinical utility for risk stratification remains limited. The IFITM3 rs12252-C polymorphism is the most consistently replicated genetic risk factor, with a meta-analysis showing an overall OR of 1.52 (95% CI 1.06–2.17) for severe influenza, though effects vary by ethnicity.[25][26] Other implicated genes include TMPRSS2 (viral entry), IRF7/IRF9 (interferon signaling), and pulmonary surfactant-associated proteins.[2][27]

Neurologic Complications in Previously Healthy Children

During the 2024–2025 season, 109 cases of influenza-associated encephalopathy (IAE) were identified, with 41% mortality among acute necrotizing encephalopathy (ANE) cases. Notably, 55% of children with IAE were previously healthy, and only 16% had received the influenza vaccine.[28][5] This demonstrates that severe neurologic complications can occur in otherwise healthy children and underscores the importance of universal pediatric vaccination.

Demographic and Socioeconomic Risk Factors

Race and Ethnicity

Significant racial and ethnic disparities exist in influenza severity in the United States.[29][30] From 2009–2019, age-adjusted influenza hospitalization rates were highest among Black persons (68.8 per 100,000), followed by American Indian/Alaska Native, Hispanic, and White persons.[30] Among children ≤4 years, hospitalization rates were 2–3 times higher in Black (RR 2.21), Hispanic (RR 1.87), and American Indian/Alaska Native (RR 3.00) children compared with White children. In-hospital death rates were 3–4 times higher in Black, Hispanic, and Asian/Pacific Islander children.[5][30] The CDC now explicitly identifies Black, Hispanic, and American Indian/Alaska Native persons as populations disproportionately affected by severe influenza.[4]

Socioeconomic Status and Poverty

Influenza hospitalization rates increase with increasing census tract poverty across all ages and racial/ethnic groups. In a FluSurv-NET analysis, hospitalization rates in high-poverty census tracts were nearly 2-fold the rates in low-poverty census tracts.[30]

Behavioral and Environmental Risk Factors

Smoking

Smoking is associated with increased risk of influenza acquisition and severity. A meta-analysis of 12 studies found that ever-active smokers had higher odds of influenza-associated hospital admission (OR 1.5; 95% CI 1.3–1.7) and ICU admission (OR 2.2; 95% CI 1.4–3.4) compared with never smokers.[31]

Congregate Settings and Occupational Exposure

  • Healthcare workers are at increased risk of influenza exposure through daily patient contact. ACIP recommends annual vaccination for all healthcare personnel.[1]
  • Household contacts and caregivers of high-risk persons are explicitly listed by ACIP as a priority group for vaccination to reduce transmission to vulnerable individuals.[1]
  • Nursing home and long-term care facility residents are at high risk for both exposure and severe outcomes due to advanced age, comorbidities, and congregate living. During the 2024–2025 season, influenza vaccination coverage was only 61.3% among nursing home residents and 42.1% among nursing home healthcare personnel.[32]
  • Daycare settings facilitate transmission among young children, who are efficient spreaders of influenza.[18]

Travel

Influenza is among the most prevalent infectious diseases in travelers. Risk is increased during cruise ship travel, mass gatherings, and air travel.[33] Modern aircraft HEPA filtration systems capture 99.97% of particles ≥0.3 µm, but close proximity of passengers still permits person-to-person transmission, particularly during boarding, deplaning, and ground delays when ventilation may be reduced.[34]

Lack of Vaccination as a Risk Factor

Absence of influenza vaccination is a modifiable risk factor for severe disease. Influenza vaccination reduces the risk of hospitalization, ICU admission, and death among individuals who develop influenza.[35][36] During the 2024–2025 high-severity season, 89% of vaccine-eligible children who died from influenza were not fully vaccinated.[5]

Clinically Actionable Recommendations

  1. Identify high-risk patients at every clinical encounter. The ACIP high-risk list should be used to guide vaccination prioritization and early antiviral treatment decisions.[1]
  2. Vaccinate all persons ≥6 months without contraindications annually, with particular emphasis on high-risk groups and their household contacts/caregivers.[1]
  3. Initiate antiviral treatment empirically in high-risk patients with suspected influenza without waiting for confirmatory testing. Treatment should be started "as soon as possible" and is most effective within 48 hours of symptom onset; however, for high-risk patients, treatment should not be withheld even if >48 hours from symptom onset.[4][5][37]
  4. Screen for aspirin/salicylate use in children and adolescents with influenza; consider alternative antipyretics and ensure only inactivated influenza vaccine is administered.[23][24]

High-Yield Clinical Pearls

  • The ACIP high-risk list is the foundation for clinical decision-making regarding vaccination prioritization and empiric antiviral treatment. All persons aged ≥50 years are considered high-risk.
  • Influenza triggers AMI within 7 days (6-fold risk) and stroke within 28 days (4.7-fold risk).
  • Congestive heart failure has the highest adjusted rate ratio for influenza-associated hospitalization among specific conditions (aRR 4.2).
  • Approximately 44% of children who die from influenza have no underlying medical conditions (varies by season; range 39–57%), underscoring the importance of universal pediatric vaccination.
  • Immunocompromised patients may present without fever and shed virus for prolonged periods, facilitating nosocomial transmission.
  • Infants <6 months have the highest hospitalization and mortality rates but are too young for vaccination — cocooning through household vaccination is critical.
  • Extreme obesity (BMI ≥40) independently increases the risk of severe influenza.
  • Racial/ethnic disparities in influenza severity persist even after adjusting for insurance and healthcare access.
  • During the 2024–2025 season, 55% of children with influenza-associated encephalopathy (IAE) were previously healthy, and only 16% had received the influenza vaccine.

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 Grohskopf LA, Blanton LH, Ferdinands JM; et al. (2022). "Prevention and Control of Seasonal Influenza With Vaccines: Recommendations of the Advisory Committee on Immunization Practices - United States, 2022-23 Influenza Season". MMWR Recomm Rep. 71 (1): 1–28. doi:10.15585/mmwr.rr7101a1.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 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 36001333 Check |pmid= value (help).
  3. ↑ 3.0 3.1 Naquin A, O'Halloran A, Ujamaa D; et al. (2024). "Laboratory-Confirmed Influenza-Associated Hospitalizations Among Children and Adults - Influenza Hospitalization Surveillance Network, United States, 2010-2023". MMWR Surveill Summ. 73 (6): 1–18. doi:10.15585/mmwr.ss7706a1.
  4. ↑ 4.0 4.1 4.2 4.3 Molly Valleau and Christine M. Szablewski. Influenza. CDC Yellow Book.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Committee on Infectious Diseases (2025). "Recommendations for Prevention and Control of Influenza in Children, 2025-2026: Technical Report". Pediatrics. doi:10.1542/peds.2025-073622.
  6. ↑ 6.0 6.1 Zhang X, Balasubramani GK, D'Agostino HEA, Liu H, Rick AM (2026). "The Impact of Maternal Influenza Infection and Vaccination During Pregnancy on Birth Outcomes". Pediatr Infect Dis J. doi:10.1097/INF.0000000000005194.
  7. ↑ Dawood FS, Kittikraisak W, Patel A; et al. (2021). "Incidence of influenza during pregnancy and association with pregnancy and perinatal outcomes in three middle-income countries: a multisite prospective longitudinal cohort study". Lancet Infect Dis. 21 (1): 97–106. doi:10.1016/S1473-3099(20)30592-2.
  8. ↑ 8.0 8.1 8.2 8.3 8.4 Committee on Infectious Diseases (2019). "Recommendations for Prevention and Control of Influenza in Children, 2019-2020". Pediatrics. 144 (4): e20192478. doi:10.1542/peds.2019-2478.
  9. ↑ 9.0 9.1 Frutos AM, O'Halloran A; et al. (2025). "Influenza-Associated Hospitalization Rates by Underlying Medical Conditions, United States, 2010-2023". J Infect Dis. doi:10.1093/infdis/jiafXXX.
  10. ↑ Kwong JC, Schwartz KL, Campitelli MA; et al. (2018). "Acute Myocardial Infarction after Laboratory-Confirmed Influenza Infection". N Engl J Med. 378 (4): 345–353. doi:10.1056/NEJMoa1702090.
  11. ↑ Nguyen TQ, Vlasenko D, Shetty AN; et al. (2025). "Systematic Review and Meta-Analysis of Respiratory Viral Triggers for Acute Myocardial Infarction and Stroke". Cardiovasc Res. doi:10.1093/cvr/cvaf092.
  12. ↑ Dicembrini I, Silverii GA, Clerico A; et al. (2023). "Influenza: diabetes as a risk factor for severe related-outcomes and the effectiveness of vaccination in diabetic population. A meta-analysis of observational studies". Nutr Metab Cardiovasc Dis. 33 (6): 1099–1110. doi:10.1016/j.numecd.2023.03.016.
  13. ↑ Owusu D, Rolfes MA, Arriola CS; et al. (2022). "Rates of Severe Influenza-Associated Outcomes Among Older Adults Living With Diabetes-Influenza Hospitalization Surveillance Network (FluSurv-NET), 2012-2017". Open Forum Infect Dis. 9 (5): ofac131. doi:10.1093/ofid/ofac131.
  14. ↑ Lees JS, Škoberne A, Zhang L; et al. (2026). "Chronic kidney disease, complex conditions, and advancing therapeutics: new hope and challenges". Lancet. 407 (10546): 2444–2460. doi:10.1016/S0140-6736(26)00653-7.
  15. ↑ Bartholdy KV, Johansen ND, Modin D; et al. (2025). "High-Dose vs Standard-Dose Influenza Vaccine in Chronic Kidney Disease: The DANFLU-2 Trial Subgroup Analysis". J Am Coll Cardiol. 86 (25): 2636–2647. doi:10.1016/j.jacc.2025.10.005.
  16. ↑ Stroffolini T, Lombardi A, Ciancio A; et al. (2021). "Low influenza vaccination coverage in subjects with liver cirrhosis. An alert waiting for winter season 2020-2021 during the COVID-19 pandemic". J Med Virol. 93 (4): 2446–2452. doi:10.1002/jmv.26763.
  17. ↑ Antoon JW, Hall M, Herndon A; et al. (2021). "Prevalence, Risk Factors, and Outcomes of Influenza-Associated Neurologic Complications in Children". J Pediatr. 239: 32–38.e5. doi:10.1016/j.jpeds.2021.06.075.
  18. ↑ 18.0 18.1 Paules C, Subbarao K (2017). "Influenza". Lancet. 390 (10095): 697–708. doi:10.1016/S0140-6736(17)30129-0.
  19. ↑ McGovern I; et al. (2024). "Number of CDC-Defined High-Risk Conditions and Influenza-Related Outcomes". Open Forum Infect Dis. doi:10.1093/ofid/ofadXXX.
  20. ↑ Karki S, Muscatello DJ, Banks E; et al. (2018). "Association Between Body Mass Index and Laboratory-Confirmed Influenza in Middle Aged and Older Adults: A Prospective Cohort Study". Int J Obes (Lond). 42 (8): 1480–1488. doi:10.1038/s41366-018-0029-x.
  21. ↑ 21.0 21.1 Collins JP, Campbell AP, Openo K; et al. (2020). "Outcomes of Immunocompromised Adults Hospitalized With Laboratory-Confirmed Influenza in the United States, 2011-2015". Clin Infect Dis. 70 (10): 2121–2130. doi:10.1093/cid/ciz638.
  22. ↑ Liu Y, Wang Y, Mai H; et al. (2022). "Clinical characteristics, risk factors and antiviral treatments of influenza in immunosuppressed inpatients in Beijing during the 2015-2020 influenza seasons". Virol J. 19 (1): 11. doi:10.1186/s12985-021-01739-1.
  23. ↑ 23.0 23.1 Belay ED, Bresee JS, Holman RC; et al. (1999). "Reye's Syndrome in the United States from 1981 through 1997". N Engl J Med. 340 (18): 1377–82. doi:10.1056/NEJM199905063401801.
  24. ↑ 24.0 24.1 McCrindle BW, Rowley AH, Newburger JW; et al. (2017). "Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association". Circulation. 135 (17): e927–e999. doi:10.1161/CIR.0000000000000484.
  25. ↑ Van Goethem N, Danwang C, Bossuyt N; et al. (2021). "A systematic review and meta-analysis of host genetic factors associated with influenza severity". BMC Genomics. 22 (1): 912. doi:10.1186/s12864-021-08240-7.
  26. ↑ Prabhu SS, Chakraborty TT, Kumar N, Banerjee I (2018). "Association between IFITM3 rs12252 polymorphism and influenza susceptibility and severity: A meta-analysis". Gene. 674: 70–79. doi:10.1016/j.gene.2018.06.070.
  27. ↑ Clohisey S, Baillie JK (2019). "Host susceptibility to severe influenza A virus infection". Crit Care. 23 (1): 303. doi:10.1186/s13054-019-2566-7.
  28. ↑ CDC (2025). "Influenza-Associated Encephalopathy in Children — United States, 2024–2025". MMWR Morb Mortal Wkly Rep. doi:10.15585/mmwr.mm74XX.
  29. ↑ Black CL, O'Halloran A, Hung MC; et al. (2022). "Vital Signs: Influenza Hospitalizations and Vaccination Coverage by Race and Ethnicity-United States, 2009-10 Through 2021-22 Influenza Seasons". MMWR Morb Mortal Wkly Rep. 71 (43): 1366–1373. doi:10.15585/mmwr.mm7143e1.
  30. ↑ 30.0 30.1 30.2 30.3 O'Halloran AC, Holstein R, Cummings C; et al. (2021). "Rates of Influenza-Associated Hospitalization, Intensive Care Unit Admission, and In-Hospital Death by Race and Ethnicity in the United States From 2009 to 2019". JAMA Netw Open. 4 (8): e2121880. doi:10.1001/jamanetworkopen.2021.21880.
  31. ↑ Han L, Ran J, Mak YW; et al. (2019). "Smoking and Influenza-Associated Morbidity and Mortality: A Systematic Review and Meta-Analysis". Epidemiology. 30 (3): 405–417. doi:10.1097/EDE.0000000000000984.
  32. ↑ Bell JM, Barbre K, Meng L; et al. (2026). "Influenza Vaccination Coverage Among Nursing Home Residents and Health Care Personnel - United States, 2024-25 Influenza Season". MMWR Morb Mortal Wkly Rep. 75 (15): 195–201. doi:10.15585/mmwr.mm7515a1.
  33. ↑ Goeijenbier M, van Genderen P, Ward BJ; et al. (2017). "Travellers and influenza: risks and prevention". J Travel Med. 24 (1): taw078. doi:10.1093/jtm/taw078.
  34. ↑ Sundari R Mase, Shannon L. Gearhart, Edward A. Nardell, and Clive M. Brown. Air Travel. CDC Yellow Book.
  35. ↑ Yegorov S, Patel OD, Sharma H; et al. (2025). "Effectiveness of influenza vaccination to prevent severe disease: a systematic review and meta-analysis of test-negative design studies". Clin Microbiol Infect. doi:10.1016/j.cmi.2025.09.023.
  36. ↑ Ferdinands JM, Thompson MG, Blanton L; et al. (2021). "Does influenza vaccination attenuate the severity of breakthrough infections? A narrative review and recommendations for further research". Vaccine. 39 (28): 3678–3695. doi:10.1016/j.vaccine.2021.05.011.
  37. ↑ Uyeki TM; et al. (2020). "Influenza". JAMA. doi:10.1001/jama.2020.14772.
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