Interim Guidance on Follow-up of Close Contacts of Persons Infected with Novel Influenza A Viruses and Use of Antiviral Medications for Chemoprophylaxis

For information on the most recent avian influenza developments specific to the United States, please visit the Current Situation Summary page.

This document provides guidance for follow-up and antiviral chemoprophylaxis of close contacts of cases of human infection with novel influenza A viruses associated with severe human disease or with the potential to cause severe human disease.

This interim guidance is based on expert opinion and currently available published and unpublished data for antiviral treatment and chemoprophylaxis of seasonal, pandemic, and novel influenza A virus infections. These recommendations are based on the following considerations:

  • Novel influenza A viruses have caused sporadic infections resulting in severe human disease and substantial mortality among detected cases to date.
  • Limited, non-sustained human-to-human transmission of some novel influenza A viruses associated with severe human disease likely occurred or cannot be excluded in some case clusters that have occurred worldwide.
  • Sufficient supplies of antiviral agents that are expected to be effective against novel influenza A viruses are available.

The public health goal of this interim guidance is to prevent further spread of novel influenza A viruses associated with severe human disease if there are infected persons in the United States. It is specific to a scenario where there are sporadic cases associated with infected domestic poultry or wild bird exposures, and there is concern for possible limited, non-sustained human-to-human virus transmission.

Definition of Close Contacts

Close contacts are defined as persons within approximately 6 feet (2 meters) or within the room or care area of a confirmed or probable novel influenza A case-patient for a prolonged period of time, or who had direct contact with infectious secretions while the case-patient was likely to be infectious (beginning 1 day prior to illness onset and continuing until resolution of illness). 2

In general, decisions to initiate antiviral chemoprophylaxis should be guided by the risk stratification described below,3 based on observational data for reported cases of human infections with avian influenza A(H7N9) and A(H5N1) viruses, and on data from seasonal influenza studies. The risk of infection following close contact with a confirmed or probable novel influenza A case-patient is higher for persons with prolonged, unprotected exposures (e.g., without use of respiratory and eye protection) than for close contacts (e.g., health care personnel) who were wearing recommended personal protective equipment. More information: Recommended Personal Protective Equipment (PPE)pdf icon and Interim Guidance for Infection Control Within Healthcare Settings.

    1. Highest-risk exposure groups (recognized risk of transmission)
      • Household or close family member contacts with unprotected, prolonged close contact to a confirmed or probable case.
    2. Moderate-risk exposure groups (unknown risk of transmission)
      • Health care personnel with unprotected close contact with a confirmed or probable case or nonhousehold members with prolonged unprotected close contact with a confirmed or probable case outside of a healthcare facility.
    3. Low-risk exposure groups (transmission unlikely)
      • Others who have had social contact of a short duration with a confirmed or probable case in a non-hospital setting (e.g., in a community or workplace environment)4.

Health care personnel with unprotected close contact to case-patients with novel influenza A virus infection may have higher risk exposures than others through caring for patients of greater illness severity and higher viral levels. Persons with prolonged unprotected exposures outside of a healthcare facility may have a higher risk of exposure than those with short duration of close contact with a mildly ill novel influenza case-patient. Persons with an unprotected exposure to novel influenza A virus associated with severe human disease in a laboratory setting may have a high-risk or moderate-risk exposure, and need to be evaluated case by case.

Follow-up of Close Contacts of a Novel Influenza A Case-Patient

Public health personnel should attempt to identify as soon as possible and monitor all close contacts of confirmed or probable cases of human infection with novel influenza A viruses associated with severe human disease for new illness. (Visit Avian Influenza A Virus Case Definitions.) Available data suggest that the estimated incubation period for human infection with avian influenza A(H5N1) and A(H7N9) viruses is generally 3 to 5 days, but has been reported to be 7-10 days [1-12]. Limited non-sustained person-to-person transmission of A(H7N9) virus could not be excluded in some family clusters [7]. Limited non-sustained person-to-person transmission of A(H5N1) virus has been reported in several countries following close, prolonged unprotected contact with a severely ill A(H5N1) patient, including in household and hospital settings [6, 10, 11].

Identified close contacts should be monitored daily for 10 days after the last known exposure to a confirmed or probable case. Measured temperature and presence of respiratory symptoms should be assessed daily during this period. Any close contacts of a confirmed or probable case with a measured temperature of ≥38.0°C (≥100.4°F) or any new respiratory symptoms (e.g., cough, sore throat, shortness of breath, difficulty breathing) should be referred for prompt medical evaluation and testing for novel influenza A virus infection. To facilitate investigation, and if resources are available, close contacts of cases under investigation (especially those with a high index of suspicion) also may be identified and monitored for fever and respiratory symptoms while the results of laboratory testing are pending.

Post-exposure Antiviral Chemoprophylaxis of Asymptomatic Close Contacts

  • Oral oseltamivir or inhaled zanamivir chemoprophylaxis should be provided to close contacts of a confirmed or probable novel influenza A case-patient according to risk of exposure.
    1. In highest-risk exposure groups, chemoprophylaxis should be administered.
    2. In moderate-risk exposure groups, chemoprophylaxis could be considered.
    3. In low-risk exposure groups, chemoprophylaxis is not routinely recommended.
  • Decisions to initiate antiviral chemoprophylaxis for persons in moderate- and low-risk exposure groups should be based on clinical judgment, with consideration given to the type of exposure and to whether the close contact is at higher risk for complications from influenza (visit Influenza Antiviral Medications: Summary for Clinicians).
  • Administration of antiviral chemoprophylaxis should begin as soon as possible (within 48 hours) after the first exposure to the confirmed or probable case.
  • The treatment frequency dosing for oral oseltamivir or inhaled zanamivir (one dose twice daily) is recommended instead of the typical antiviral chemoprophylaxis regimen (once daily). For specific dosage recommendations for treatment by age group, please visit Recommended Dosage and Duration of Influenza Antiviral Medications for Treatment or Chemoprophylaxis and refer to the treatment dosing (twice daily) as provided for seasonal influenza.
    • This recommendation for twice daily antiviral chemoprophylaxis dosing frequency is based on limited data that support higher chemoprophylaxis dosing in animals for avian influenza A(H5N1) virus infection [13], and on the desire to reduce the potential for development of antiviral resistance while receiving once daily chemoprophylaxis [14-16].
  • Antiviral chemoprophylaxis with treatment frequency dosing (twice daily) of oral oseltamivir or inhaled zanamivir should be continued for 5 or 10 days. If the exposure was time-limited and not ongoing, the recommended duration is 5 days from the last known exposure. If the exposure is likely to be ongoing (e.g., household setting), a duration of 10 days is recommended because of the potential for prolonged infectiousness from the novel influenza A case-patient.
  • Oral oseltamivir is recommended for persons of any age including newborn infants; inhaled zanamivir for persons aged 7 years and older.5 Inhaled zanamivir is not recommended for persons with underlying airway disease (e.g., asthma or chronic obstructive pulmonary disease). Physicians should consult the manufacturer’s package insert for dosing, limitations of populations studied, contraindications, and adverse effects.

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Antiviral Treatment of Symptomatic Close Contacts (Cases under Investigation)

New Symptoms after Use of an Antiviral Agent

CDC will provide updated information as it becomes available on the CDC website at the Avian Influenza Current Situation Summary and Avian Influenza: Information for Health Professionals and Laboratorians.

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1 This guidance is intended to address human infections with novel influenza A viruses that cause severe or progressive disease in otherwise healthy persons resulting in hospitalization and/or death. A number of different subtypes of novel influenza A viruses have been reported to cause severe pneumonia and death, including A(H5N1), A(H5N6), A(H7N7), A(H7N9), A(H9N2), A(H10N3), A(H10N8), and A(H1N1v) and A(H3N2v) viruses; however, in recent years avian influenza A(H5N1), A(H5N6) and A(H7N9) virus infections have caused severe illness in a high proportion of cases and have been reported in substantial numbers.

2 Limited data are available regarding the risk of transmission for novel influenza A viruses; however, limited non-sustained person-to-person transmission of A(H5N1) virus has been demonstrated only with close, prolonged, unprotected exposure to a symptomatic A(H5N1) patient either at home or in a hospital [61011], and limited non-sustained person-to-person transmission of A(H7N9) virus could not be excluded in some family clusters [7]. To define a close contact, this document uses “within approximately 6 feet of an ill person” to include the potential for transmission by large droplets or small particle droplet nuclei within the vicinity of the patient. Three feet has often been used by infection control professionals to define close contact and is based on studies of respiratory virus infections; however, for practical purposes, this distance may range up to 6 feet or more. The World Health Organization defines close contact as “approximately 1 meter;” the U.S. Occupational Safety and Health Administration uses “within 6 feet.” For consistency with infection control recommendations for healthcare settings, this document also defines “within the room or care area of a novel influenza A patient” as close contact for a health care provider or caregiver.

3 Exposure groups adapted from the stratification of risks for human infection with avian influenza A(H5N1) virus from the “World Health Organization Rapid Advice Guidelines on pharmacological management of humans infected with avian influenza A (H5N1) virus, 2006” (https://www.who.int/medicines/publications/WHO_PSM_PAR_2006.6.pdf)

4 Recommendations for special situations (e.g., travelers potentially exposed to novel influenza A viruses during air travel) will be made in the setting of specific contact investigation protocols.

5 Oral oseltamivir is approved by the FDA for treatment of acute uncomplicated influenza with twice-daily dosing for 5 days in persons 14 days old, and for prophylaxis with once-daily dosing in persons 1 year and older. Although use of oral oseltamivir for treatment of influenza in infants less than ≥14 days old, and for chemoprophylaxis in infants less than 1 year of age, are not part of the FDA-approved indications, these uses are recommended by the CDC and the American Academy of Pediatrics. Inhaled zanamivir is approved for treatment of acute uncomplicated influenza with twice-daily dosing in persons aged 7 years and older, and for prophylaxis with once-daily dosing in persons aged 5 years and older. Because this guidance recommends chemoprophylaxis using the twice-daily dosing studied in clinical trials of influenza treatment rather than the once-daily dosing studied in clinical trials supporting approval for influenza prophylaxis, it is recommended that inhaled zanamivir be used only in persons aged 7 years and older. Oral baloxavir (single-dose) is approved by FDA for treatment of acute uncomplicated influenza within 2 days of illness onset in persons aged 12 years and older, and for post-exposure chemoprophylaxis (single-dose) of influenza in persons aged 12 years and older.

Table. Follow-up and chemoprophylaxis recommendations according to the case definition category for human infection with novel influenza A viruses associated with severe disease. (Case Definitions for Investigations of Human Infection with Avian Influenza A Viruses in the United States)

Case category of Exposure

Definition

Management of Close Contacts1

Case category of Exposure

Confirmed Case

Definition

Avian influenza A virus infection in a person that is confirmed by CDC’s Influenza Division Laboratory or a CDC designated laboratory using methods mutually agreed upon by CDC and the Council of State and Territorial Epidemiologists (CSTE).

Management of Close Contacts1

Monitor for fever and respiratory symptoms for 10 days after the last exposure to the confirmed case; Consider antiviral chemoprophylaxis based on risk of exposure2

Case category of Exposure

Suspected Case (also called Case under investigation)

Definition

A person meeting criteria for avian influenza A virus infection below and for whom confirmatory laboratory test results are unknown or pending.

Management of Close Contacts1

Case category of Exposure

Probable case

Definition

A person meeting criteria for avian influenza A virus infection below and for whom laboratory test results do not provide a sufficient level of detail to confirm HPAI A H5 virus infection.

Management of Close Contacts1

Monitor for fever and respiratory symptoms for 10 days after the last exposure to the probable case;
Consider antiviral chemoprophylaxis based on risk of exposure2

1 For specific dosage recommendations for chemoprophylaxis by age group, please visit https://www.cdc.gov/flu/professionals/antivirals/antiviral-dosage.htm.
2 Among close contacts: (1) Highest-risk exposure groups (recognized risk of transmission): Household or close family member contacts of a confirmed or probable case. (2) Moderate-risk exposure groups (unknown risk of transmission): Health care personnel with unprotected contact with a confirmed or probable case. (3) Low-risk exposure groups (transmission unlikely): Others who have had social contact of a short duration with a confirmed or probable case in a non-hospital setting (e.g., in a community or workplace environment)3

  1. Human cases of avian influenza A (H5N1) in North-West Frontier Province, Pakistan, October-November 2007. Releve epidemiologique hebdomadaire / Section d’hygiene du Secretariat de la Societe des Nations = Weekly epidemiological record / Health Section of the Secretariat of the League of Nations 2008; 83(40): 359-64.
  2. Areechokchai D, Jiraphongsa C, Laosiritaworn Y, et al. Investigation of avian influenza (H5N1) outbreak in humans–Thailand, 2004. MMWR Morbidity and mortality weekly report 2006; 55 Suppl 1: 3-6.
  3. Chen Y, Liang W, Yang S, et al. Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: clinical analysis and characterisation of viral genome. Lancet 2013; 381(9881): 1916-25.
  4. Dinh PN, Long HT, Tien NT, et al. Risk factors for human infection with avian influenza A H5N1, Vietnam, 2004. Emerging infectious diseases 2006; 12(12): 1841-7.
  5. Huai Y, Xiang N, Zhou L, et al. Incubation period for human cases of avian influenza A (H5N1) infection, China. Emerging infectious diseases 2008; 14(11): 1819-21.
  6. Kandun IN, Wibisono H, Sedyaningsih ER, et al. Three Indonesian clusters of H5N1 virus infection in 2005. The New England journal of medicine 2006; 355(21): 2186-94.
  7. Li Q, Zhou L, Zhou M, et al. Epidemiology of human infections with avian influenza A(H7N9) virus in China. The New England journal of medicine 2014; 370(6): 520-32.
  8. Oner AF, Bay A, Arslan S, et al. Avian influenza A (H5N1) infection in eastern Turkey in 2006. The New England journal of medicine 2006; 355(21): 2179-85.
  9. Tran TH, Nguyen TL, Nguyen TD, et al. Avian influenza A (H5N1) in 10 patients in Vietnam. The New England journal of medicine 2004; 350(12): 1179-88.
  10. Ungchusak K, Auewarakul P, Dowell SF, et al. Probable person-to-person transmission of avian influenza A (H5N1). The New England journal of medicine 2005; 352(4): 333-40.
  11. Wang H, Feng Z, Shu Y, et al. Probable limited person-to-person transmission of highly pathogenic avian influenza A (H5N1) virus in China. Lancet 2008; 371(9622): 1427-34.
  12. Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza AV, Abdel-Ghafar AN, Chotpitayasunondh T, et al. Update on avian influenza A (H5N1) virus infection in humans. The New England journal of medicine 2008; 358(3): 261-73.
  13. Boltz DA, Rehg JE, McClaren J, Webster RG, Govorkova EA. Oseltamivir prophylactic regimens prevent H5N1 influenza morbidity and mortality in a ferret model. The Journal of infectious diseases 2008; 197(9): 1315-23.
  14. Centers for Disease C, Prevention. Oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infection in two summer campers receiving prophylaxis–North Carolina, 2009. MMWR Morbidity and mortality weekly report 2009; 58(35): 969-72.
  15. Baz M, Abed Y, Papenburg J, Bouhy X, Hamelin ME, Boivin G. Emergence of oseltamivir-resistant pandemic H1N1 virus during prophylaxis. The New England journal of medicine 2009; 361(23): 2296-7.
  16. Cane A, Casanueva E, Iolster T, et al. First isolation of a oseltamivir-resistant influenza A (H1N1) strain in Argentina. The Pediatric infectious disease journal 2010; 29(4): 384.
  17. Hu Y, Lu S, Song Z, et al. Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance. Lancet 2013; 381(9885): 2273-9.