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

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, which currently includes avian influenza A (H7N9) virus and highly pathogenic avian influenza A (H5N1) virus.¹ This guidance merges previously posted guidance on the use of antiviral agents for chemoprophylaxis of human infections with avian influenza A (H7N9) and avian influenza A (H5N1).

This interim guidance is based on expert opinion and currently available published and unpublished data for antiviral treatment and chemoprophylaxis of seasonal, pandemic, and novel influenza.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

• Novel influenza A viruses have caused severe human disease and substantial mortality among detected cases to date.
• Limited, non-sustained human-to-human transmission cannot be excluded in some case clusters.
• 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 is introduction/travel of infected persons into the United States. It is specific to a scenario where there are sporadic cases associated with poultry exposure and possible limited, non-sustained human-to-human virus transmission.

This guidance will be updated as additional information on epidemiology and transmissibility becomes available for novel influenza A viruses causing severe human disease.

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 with 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 H7N9 and H5N1 viruses, and on data from seasonal influenza studies.

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 close 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)⁴

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 all confirmed or probable cases of human infection with novel influenza A viruses associated with severe human disease for new illness. (See H7N9 case definitions and H5N1 case definitions.) Available data suggest that the estimated incubation period for human infection with H5N1 and H7N9 viruses is generally 3 to 7 days, but has been reported to be as long as 10 days [1-12].

Therefore, 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 high risk for complications from influenza (See the Influenza Antiviral Medications: Summary for Clinicians).
• Administration of chemoprophylaxis should begin as soon as possible (within 48 hours) after 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 see 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 [13], and on the desire to reduce the potential for development of antiviral resistance while receiving once daily chemoprophylaxis [14-16].
• Chemoprophylaxis with treatment frequency dosing (twice daily) of oseltamivir or inhaled zanamivir should be continued for 5 or 10 days. If exposure was time-limited and not ongoing, 5 days of medication from the last known exposure is recommended. If exposure is likely to be ongoing (e.g., household setting), 10 days is recommended because of the potential for prolonged infectiousness in 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)

• Symptomatic close contacts should be promptly tested for novel influenza A virus infection (see Interim Guidance for Specimen Collection, Processing, and Testing for Patients with Suspected Infection with Novel Influenza A Viruses Associated with Severe Disease in Humans) and simultaneously treated with a neuraminidase inhibitor medication (oseltamivir, inhaled zanamivir, or intravenous (IV) peramivir). (See the Interim Guidance on the Use of Antiviral Medications for Treatment of Human Infections with Novel Influenza A Viruses Associated with Severe Human Disease.)
• Symptomatic persons should be requested to stay home except to seek medical care and limit contact with other persons until their illness is resolved.

New Symptoms after Use of an Antiviral Agent

• If a close contact becomes symptomatic or has worsening of symptoms after or during use of an antiviral agent, contact with other persons should be minimized, appropriate infection prevention and control measures should be used in health care settings (see Interim Guidance for Infection Control Within Healthcare Settings When Caring for Patients with Confirmed Cases, Probable Cases, and Cases Under Investigation for Infection with Novel Influenza A Viruses Associated with Severe Disease, and respiratory specimens should be collected for novel influenza A virus testing at the state health department as soon as possible.
• If a close contact tests positive for H5N1 or H7N9 virus and had taken oseltamivir chemoprophylaxis for 3 or more days before becoming symptomatic [17], oseltamivir should be stopped as soon as treatment with inhaled zanamivir (twice daily) can be initiated. This is because some novel influenza A viruses may rapidly become oseltamivir-resistant (and potentially peramivir-resistant) and remain zanamivir-susceptible. If the patient manifests progressive lower respiratory disease, the patient should be promptly hospitalized for treatment with investigational IV zanamivir. IV zanamivir is an investigational parenterally administered neuraminidase inhibitor product available only either by enrollment in an ongoing phase III clinical trial, or under an emergency investigational new drug (EIND) request to the manufacturer for compassionate use in hospitalized adult and pediatric patients with severe influenza. (See CDC Considerations Related to Investigational Use of Intravenous Zanamivir for 2014-2015 Influenza Season.)
• Investigation for antiviral resistance should be initiated immediately (in conjunction with the CDC Influenza Division), and infection prevention and control measures recommended for patients with novel influenza A virus infection should be implemented. (See Interim Guidance for Infection Control Within Healthcare Settings When Caring for Confirmed Cases, Probable Cases, and Cases Under Investigation for Infection with Novel Influenza A Viruses Associated with Severe Disease)
• Questions regarding arranging testing for antiviral resistance, or regarding appropriate clinical management if antiviral resistance is a concern, should be directed to the CDC Influenza Division via the CDC Emergency Operations Center (770-488-7100).

CDC will provide updated information as it becomes available on the CDC website at the avian influenza home page for health professionals and laboratorians.

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 H5N1, H7N9, H7N2, H7N7, H9N2, H10N8, and H3N2v viruses; however, currently only H5N1 and H7N9 cause 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 H5N1 virus has been demonstrated only with close, prolonged, unprotected exposure to a symptomatic H5N1 patient either at home or in a hospital [6, 10, 11], and limited non-sustained person-to-person transmission of H7N9 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 H5N1 virus infection from the “World Health Organization Rapid Advice Guidelines on pharmacological management of humans infected with avian influenza A (H5N1) virus, 2006” (http://www.who.int/influenza/resources/documents/pharmacological_management_h5n1_05_2006/en)

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 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 prophylaxis 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.

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Table. Follow-up and chemoprophylaxis recommendations according to the case definition category for human infection with novel influenza A viruses associated with severe disease. (See H7N9 case definitions and H5N1 case definitions.)

Case category of Exposure	Definition	Management of Close Contacts 1
Confirmed case	Novel influenza A virus infection in a patient that is confirmed by CDC’s Influenza Laboratory or a CDC certified public health laboratory using methods agreed upon by the CDC and the Council of State and Territorial Epidemiologists. Confirmation of novel influenza A viruses may be made by public health laboratories following CDC-approved protocols for detection of novel influenza A viruses, or by laboratories using an FDA-authorized test specific for detection of novel influenza A viruses.	Monitor for fever and respiratory symptoms; Consider antiviral chemoprophylaxis based on risk of exposure 2
Probable case	Illness compatible with influenza in a patient meeting any of the exposure criteria below and for whom laboratory diagnostic testing is positive for influenza A, negative for H1, negative for H1pdm09, and negative for H3 by real-time reverse transcription polymerase chain reaction (RT-PCR) and therefore unsubtypeable.	Monitor for fever and respiratory symptoms; Consider antiviral chemoprophylaxis based on risk of exposure 2
Case under investigation	Illness compatible with influenza in a patient meeting any of the exposure criteria below and for whom laboratory confirmation is not known or pending or for whom test results do not provide a sufficient level of detail to confirm novel influenza A virus infection.
Exposed during travel	Patients with recent travel (within <10 days of illness onset) to areas where human cases of novel influenza A virus infection have become infected or to areas where novel influenza A viruses are known to be circulating in animals.3	Monitor for fever and respiratory symptoms
Exposed to confirmed or probable case	Patients who have had recent close contact (within <10 days of illness onset) with confirmed or suspected4 cases of human infection with novel influenza A virus. Close contact may be regarded as coming within about 6 feet (2 meters) of a confirmed case while the case was ill (beginning 1 day prior to illness onset and continuing until resolution of illness). This includes healthcare personnel providing care for a confirmed case, family members of a confirmed case, persons who lived with or stayed overnight with a confirmed case, and others who have had similar close physical contact.5	Monitor for fever and respiratory symptoms
1 For specific dosage recommendations for chemoprophylaxis by age group, please see 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 As of March 19, 2015, China was the only country where avian influenza A (H7N9) viruses were known to be circulating in animals (poultry) or where human cases have become infected. For avian influenza A (H5N1) virus, please see WHO website. http://www.who.int/influenza/human_animal_interface/EN_GIP_20131210CumulativeNumberH5N1cases.pdf [39 KB, 2 pages] and link to countries with animal cases. For more information, including updates on countries affected, please see the CDC Novel/Avian Influenza A Virus Home Page. 4 Patients suspected of having infection with a novel influenza A virus can include probable cases, cases under investigation for infection with novel influenza A virus, and other patients for whom available clinical and epidemiologic information support a diagnosis of infection with novel influenza A virus. 5 Limited non-sustained person-to-person transmission of H7N9 virus could not be excluded in some family clusters [7] . Limited non-sustained person-to-person transmission of H5N1 virus has been reported in several countries following close, prolonged unprotectedcontact with a severely ill H5N1 patient, including in household and hospital settings [6, 10, 11] .

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References

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.

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