Chapter 4 Travel-Related Infectious Diseases
Katherine Roguski, Alicia Fry
Influenza is caused by infection of the respiratory tract with influenza viruses, RNA viruses of the Orthomyxovirus genus. Influenza viruses are classified into 4 types: A, B, C, and D. Only virus types A and B commonly cause illness in humans. Influenza A viruses are further classified into subtypes based on 2 surface proteins, hemagglutinin (HA) and neuraminidase (NA). Although 4 types and subtypes of influenza virus cocirculate in humans worldwide (influenza A(H1N1), A(H3N2), and influenza B-Yamagata, B-Victoria viruses), the distribution of these viruses varies from year to year and between geographic areas and time of year. Information about circulating viruses in various regions can be found on the CDC website (www.cdc.gov/flu/weekly) or the World Health Organization website (www.who.int/influenza/surveillance_monitoring/updates/latest_update_GIP_surveillance/en/). Avian and swine influenza viruses can occasionally infect and cause disease in humans, usually associated with close exposure to infected animal populations. Notably, avian influenza A(H5N1) and A(H7N9) viruses, as well as swine-origin A(H1N1), A(H1N2), and A(H3N2) variant viruses, have led to sporadic human infections globally.
Influenza viruses spread from person to person, primarily through respiratory droplet transmission (such as when an infected person coughs or sneezes near a susceptible person). Transmission via large-particle droplets requires close proximity between the source and the recipient, because droplets generally travel only short distances (approximately 6 feet or less) through the air, before settling onto surfaces. Indirect (fomite) transmission can also occur, such as when a person touches a virus-contaminated surface and then touches his or her face. Airborne transmission via small-particle aerosols in the vicinity of the infectious person also occurs.
Most adults who are ill with influenza shed the virus in the upper respiratory tract and are infectious from the day before symptom onset to approximately 5–7 days after symptom onset. Infectiousness is highest within 3 days of illness onset and is correlated with fever. Children and those who are immunocompromised or severely ill may shed influenza virus for 10 days or more after the onset of symptoms. Seasonal influenza viruses have rarely been detected from non-respiratory sources such as stool or blood.
Although human infections due to avian or swine influenza viruses are rare, transmission of these viruses from birds or swine to humans is possible. Infected birds shed avian influenza virus in their saliva, mucus, and droppings, and transmission to humans can occur directly (through touching an infected animal or droplet spread) or indirectly (through inhalation of these viruses in the air or through fomite transmission on infected surfaces). See www.cdc.gov/flu/avianflu/avian-in-humans.htm. Infected swine shed the virus in nasal secretions and can transmit viruses to humans in the same way seasonal influenza viruses spread among people (www.cdc.gov/flu/swineflu/people-raise-pigs-flu.htm). Human-to-human transmission of swine or avian viruses is uncommon.
Influenza circulation varies geographically. The risk of exposure to influenza during travel depends on the time of year and destination. In temperate regions, influenza typically circulates at higher levels during colder winter months: October to May in the Northern Hemisphere and April to September in the Southern Hemisphere. In many tropical or subtropical regions, influenza can occur throughout the year.
Influenza may be more common in children, especially in school-aged children. Rates of severe illness and death are typically highest among people aged ≥65 years, children <2 years, and people of any age who have underlying medical conditions that place them at increased risk for complications of influenza. CDC estimates that from 2010 through 2014, approximately 9.2–35.6 million symptomatic infections, 4.2–16.7 million outpatient visits, 139,000–708,000 hospitalizations, and 12,000–56,000 deaths associated with influenza viruses occurred each year in the United States (www.cdc.gov/flu/about/disease/burden.htm).
Influenza A viruses not only circulate among humans but also among many animal species populations, although influenza B viruses circulate widely only among humans. The primary reservoir for influenza A viruses is wild waterfowl and other wild birds, but viruses are common in domestic poultry and swine populations as well. Influenza A viruses can also infect other animal species, such as cats, dogs, horses, ferrets, sea lions, and bats.
Human infections with influenza A viruses from infected swine are uncommon and have been sporadically identified in the United States and other countries (www.cdc.gov/flu/swineflu/index.htm). When an influenza virus that normally circulates in swine (but not people) is detected in a person, it is called a “variant” influenza virus and denoted with the letter “v.” Human infections with influenza A(H1N1)v, A(H1N2)v, and A(H3N2)v have been identified. The largest outbreak in the United States occurred in 2012 when a total of 309 cases of human illnesses (1 of whom died) caused by A(H3N2)v viruses were identified. From 2013 through 2017, 119 human infections with variant viruses were identified in 16 states. Infrequent variant virus infections have also been identified and reported in other countries in Europe, the Americas, and Asia. Most people identified with variant influenza virus infections report contact with swine preceding their illness, suggesting swine-to-human spread. There have also been limited reports of human-to-human transmission of variant viruses. Seasonal human influenza viruses have also been known to infect swine, suggesting person-to-swine transmission. Agricultural fairs are a setting that can result in many human exposures to swine. Illnesses associated with variant virus infections have been mostly mild with symptoms similar to those of seasonal influenza; however, variant virus infections can also result in serious illness, causing hospitalization and death.
Avian influenza viruses do not commonly infect humans, although there have also been reports of sporadic disease resulting from these viruses (www.cdc.gov/flu/avianflu/index.htm). From 1997 through January 2018, 860 human illnesses caused by avian influenza A(H5N1) virus were reported globally, approximately 53% of which were fatal. Most disease from A(H5N1) has occurred after direct or close contact with sick or dead infected poultry. A(H5N1) virus is widespread among poultry in some countries in Asia and the Middle East (Map 4-06). Egypt and Indonesia have accounted for 65% of reported infections in humans globally. Instances of limited, nonsustained, human-to-human transmission of A(H5N1) virus have been reported. Since 2012, an increasing number of countries have reported detection of additional influenza H5 virus subtypes different from A(H5N1) among poultry and wild birds: A(H5N2), A(H5N3), A(H5N5), A(H5N6), A(H5N8), and A(H5N9) viruses. Of these virus subtypes, only A(H5N6) has been reported to cause illness in humans.
Avian influenza A(H7N9) virus emerged in China in 2013, and, as of January 2018, has caused 1,566 confirmed human illnesses. Most cases have been identified in mainland China, but several infections in people who reported exposure in mainland China and subsequent travel have been identified in Malaysia, Taiwan, Macao, and Hong Kong. In 2014, Canada reported the first imported A(H7N9) virus infection in North America in a traveler returning from China. Most of the people with infection caused by A(H7N9) had exposure to infected poultry or contaminated environments, such as live bird markets, and the virus has been found in poultry and environmental samples collected in China. A small proportion of human illnesses from A(H7N9) virus has been mild, but most patients have developed severe respiratory illness, and at least 39% have died.
In the United States, North American lineage avian influenza viruses are occasionally detected in wild, domestic, and commercial birds; these viruses are genetically different from those circulating in other regions of the world (www.aphis.usda.gov/aphis/ourfocus/animalhealth/animal-disease-information/avian-influenza-disease/defend-the-flock/defend-the-flock-ai-overview). From 2015 through 2017, H5 virus infections were identified in backyard and commercial poultry in 21 states. In 2016 and 2017, A(H7N8) and A(H7N9) viruses were identified in poultry flocks in 2 states. Although no human infections with H5, A(H7N8), or A(H7N9) viruses have been reported in the United States, surveillance in domestic birds and people exposed to infected birds is ongoing given the low but continued risk of transmission to humans.
Although rare, human infections with other avian influenza viruses, including A(H7N2) and A(H9N2), have been reported globally in recent years. In the United States, 3 infections with A(H7N2) virus were reported in humans in 2002, 2003, and 2016, all of whom recovered.
Map 4-06. Distribution of highly pathogenic avian influenza A(H5N1) virus
Uncomplicated influenza illness is the most common presentation of influenza and is characterized by the abrupt onset of signs and symptoms that include fever, muscle aches, headache, malaise, nonproductive cough, sore throat, vomiting, and rhinitis. Less commonly, rashes have been associated with influenza infection. Illness without fever can occur, especially in the elderly and infants. Children are more likely than adults to also experience nausea, vomiting, or diarrhea when ill with influenza. Physical findings are predominantly localized to the respiratory tract and include nasal discharge, pharyngeal inflammation without exudates, and occasionally rales on chest auscultation. The incubation period is usually 1–4 days after exposure. Influenza illness typically resolves within 1 week for most previously healthy children and adults who do not receive antiviral medication, although cough and malaise can persist for >2 weeks, especially in the elderly. Complications of influenza virus infection include primary influenza viral pneumonia, secondary bacterial pneumonia, parotitis, exacerbation of underlying medical conditions (such as pulmonary and cardiac disease), encephalopathy, myocarditis, myositis, coinfections with other viral or bacterial pathogens, and rarely, death.
Humans infected with variant influenza viruses have a clinical presentation similar to human influenza virus infections. Reported human infections with avian influenza A(H5N1) or A(H7N9) viruses often have severe pneumonia or respiratory failure and a high case-fatality ratio. However, it is uncommon for people with less severe illness to be tested for A(H5N1) or A(H7N9) viruses.
Influenza can be difficult to distinguish from respiratory illnesses caused by other pathogens on the basis of signs and symptoms alone. The positive predictive value of clinical signs and symptoms for influenzalike illness (fever with either cough or sore throat) for laboratory-confirmed influenza virus infection is 30%–88%, depending on the level of influenza activity.
Diagnostic tests available for influenza include viral culture, rapid influenza diagnostic tests (RIDTs), immunofluorescence assays, and nucleic acid–based assays, such as RT-PCR (www.cdc.gov/flu/professionals/diagnosis/overview-testing-methods.htm). Most patients with clinical illness consistent with uncomplicated influenza in an area where influenza viruses are circulating do not require diagnostic testing for clinical management. Patients who should be considered for influenza diagnostic testing include the following:
- Hospitalized patients with suspected influenza
- Patients for whom a diagnosis of influenza will inform clinical care decisions, including patients who do not improve on antiviral therapy and those with medical conditions that place them at high risk of complications
- Patients for whom results of influenza testing would affect infection control or management of close contacts, including other patients, such as in institutional outbreaks or other settings (cruise ships or tour groups, for example)
The sensitivity of RIDTs varies but is substantially lower than for RT-PCR or viral culture. RIDTs cannot distinguish between seasonal influenza A virus infections and animal-origin influenza A virus infections, and their sensitivity to detect these animal-origin influenza viruses, including avian or variant influenza viruses, can vary by test type and virus subtype. Therefore, a negative RIDT result does not rule out influenza virus infection, and health care providers should not rely on a negative RIDT result to make decisions about treatment. Nucleic acid assays are the most sensitive diagnostic assays. However, no commercially available influenza diagnostic assay can specifically diagnose influenza variant virus or avian virus infection. Thus, if infection with these viruses is suspected, the state health department or CDC should be contacted. The decision to start antiviral treatment should not be delayed while waiting for results of confirmatory laboratory testing.
Use of Antiviral Drugs
Early antiviral treatment can shorten the duration of fever and other symptoms and reduce the risk of complications from influenza. Antiviral treatment is recommended as early as possible for any patient with confirmed or suspected influenza who is hospitalized; has severe, complicated, or progressive illness; or is at a higher risk for influenza-associated complications (www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm). Antiviral treatment can also be considered for any previously healthy patient with confirmed or suspected influenza not at high risk of complications.
Treatment is most effective if it can be initiated within 48 hours of illness onset. For hospitalized patients, those with severe illness, or those at higher risk of complications, antiviral therapy may still be beneficial if started >48 hours after illness onset. Four FDA-approved antiviral agents are recommended for the treatment and prophylaxis of influenza: oral oseltamivir (available as generic or Tamiflu, Genentech), inhaled zanamivir (Relenza, GlaxoSmithKline), intravenous (IV) peramivir (Rapivab, BioCryst Pharmaceuticals), and oral baloxavir (Xofluza, Genentech).
Three of the antiviral medications are neuraminidase inhibitors that have activity against both influenza A and B viruses; baloxavir is an endonuclease inhibitor that also has activity against both influenza A and B viruses. Oseltamivir is recommended for treatment for all ages and is the preferred agent to treat patients with severe or complicated influenza illness who are able to tolerate oral medications. Zanamivir is approved and recommended to treat those aged ≥7 years and for prophylaxis in those aged ≥5 years. Inhaled zanamivir is not recommended for use in people with underlying chronic respiratory disease. Peramivir is approved and recommended to treat those aged ≥2 years and may be useful in patients unable to tolerate or absorb oral antiviral therapy. Baloxavir is indicated to treat acute uncomplicated influenza in patients 12 years of age or older who have been symptomatic for no more than 48 hours (Table 4-05). Two other FDA-approved anti-influenza medications, amantadine and rimantadine, are not recommended for treatment or prophylaxis of influenza because of widespread viral resistance among circulating influenza A viruses. Amantadine and rimantadine are not active against influenza B viruses.
People at increased risk for complications of influenza should discuss antiviral treatment with their health care provider before travel to areas where influenza activity is occurring.
Antiviral drugs can also be used for prophylaxis, to prevent infection after close contact with a confirmed case; however, CDC does not recommend routine use of antiviral medications for prophylaxis except as one of multiple interventions to control institutional influenza outbreaks. Postexposure prophylaxis should be initiated within 48 hours of exposure and never later than 48 hours, because of the risk of treating infection with a subtherapeutic dose. Alternatively, exposed people can monitor for symptoms and initiate antiviral treatment early after symptoms begin.
CDC recommendations for antiviral use for variant virus infections are similar to seasonal influenza virus infection (www.cdc.gov/flu/professionals/antivirals/index.htm); however, CDC recommends antiviral treatment for all suspected cases of human infection with avian influenza viruses (www.cdc.gov/flu/avianflu/severe-potential.htm). Recommendations for exposure prophylaxis of close contacts of confirmed human infections of avian influenza A(H5N1) and A(H7N9) viruses are available at www.cdc.gov/flu/avianflu/novel-av-chemoprophylaxis-guidance.htm. Postexposure prophylaxis is not routinely recommended for people exposed to birds infected with A(H5N1) or A(H7N9). However, prophylaxis can be considered based on clinical judgment, with consideration given to the type of exposure and to whether the exposed person is at high risk for complications from influenza. If antiviral prophylaxis is initiated, twice daily treatment dosing for oseltamivir or zanamivir is recommended instead of once daily prophylaxis dosing (www.cdc.gov/flu/avianflu/guidance-exposed-persons.htm).
Available Vaccine Products and Indications for Use
In the United States, annual vaccination for seasonal influenza is recommended for those aged ≥6 months and is the most effective way to prevent influenza and its complications. Several influenza vaccines are approved for use in the United States (www.cdc.gov/flu/protect/vaccine/vaccines.htm) and can be grouped into categories: inactivated influenza vaccine (IIV), live attenuated influenza vaccine (LAIV), and recombinant influenza vaccine (RIV). For updates and the following season recommendations, providers should access www.cdc.gov/flu/professionals/acip/index.htm. For people for whom more than one type of vaccine is indicated, there is no preference for any particular category. During their first influenza season, children aged 6 months through 8 years require 2 doses of age-appropriate influenza vaccine (given ≥4 weeks apart) to induce sufficient immune response.
IIV can be administered by intramuscular injection, transdermally via needle-free jet injector, or intradermal injection depending on the product. IIVs are labeled for use in people aged ≥6 months, but specific age indications vary by manufacturer and product; label instructions should be followed. High-dose IIV and adjuvanted IIV vaccines, which may elicit higher levels of antibodies than standard-dose vaccines, are available for people aged ≥65 years. RIV is labeled for use in people aged ≥18 years. Cell-based inactivated vaccines are licensed for people aged ≥4 years. LAIV is administered as a nasal spray and is labeled for use in people aged 2–49 years.
Influenza vaccine composition can be trivalent, protecting against 3 different influenza viruses (2 influenza subtype A and 1 type influenza B), or quadrivalent, with protection against 4 different influenza viruses (2 influenza A subtypes and 2 influenza type B lineages). Quadrivalent vaccine includes a representative strain from 2 antigenically distinct influenza B lineages, B-Yamagata and B-Victoria.
CDC recommends that everyone aged ≥6 months get vaccinated yearly. Any traveler, including people at high risk for complications of influenza who did not receive the current seasonal influenza vaccine and who are traveling to parts of the world where influenza activity is ongoing, should consider influenza vaccination ≥2 weeks before departure.
No information is available about the benefits of revaccinating people before summer travel who were vaccinated during the preceding fall, and revaccination is not recommended. People at higher risk for influenza complications should consult with their health care provider to discuss the risk for influenza or other travel-related diseases before traveling during the summer.
Seasonal influenza vaccines are not expected to provide protection against human infection with animal-origin influenza viruses, including avian influenza A(H5N1 and H7N9) viruses. No commercially available influenza vaccines are available to protect against avian or swine influenza viruses.
Vaccine Safety and Adverse Reactions
INACTIVATED INFLUENZA VACCINE (IIV)
The most frequent side effects of vaccination with intramuscular and intradermal IIV in adults are soreness and redness at the vaccination site. These local injection-site reactions are slightly more common with vaccine administered intradermally, with needle-free jet injection and with high-dose IIV. They generally are mild and rarely interfere with the ability to conduct usual activities. Fever, malaise, myalgia, headache, and other systemic symptoms sometimes occur after vaccination; these may be more frequent in people with no previous exposure to the influenza virus antigens in the vaccine (such as young children) and are generally short-lived.
Guillain-Barré syndrome (GBS) was associated with the 1976 swine influenza vaccine, with an increased risk of 1 additional case of GBS per 100,000 people vaccinated. None of the studies of influenza vaccines other than the 1976 influenza vaccine has demonstrated a risk of GBS of similar magnitude. If there is an increased risk of GBS after seasonal influenza vaccines, it is small, approximately 1–2 additional cases per 1 million people vaccinated.
Live Attenuated Influenza Vaccine (Laiv)
The most frequent side effects of LAIV reported in healthy adults include minor upper respiratory symptoms, runny nose, and sore throat, which are generally well tolerated. Some children and adolescents have reported fever, vomiting, myalgia, and wheezing. These symptoms, particularly fever, are more often associated with the first administered LAIV dose and are self-limited.
Children aged 2–4 years who have a history of wheezing in the past year or who have a diagnosis of asthma should not receive LAIV. Children and adults aged 2–49 years who have conditions that increase the risk of severe influenza, including pregnancy and immunocompromising conditions, should receive IIV or RIV and not LAIV. Caretakers of severely immunocompromised people should also not receive LAIV or should avoid contact with such people for 7 days after receipt of LAIV to decrease the risk of live virus transmission.
Recombinant Influenza Vaccine (Riv)
The first RIV was licensed in the United States in January 2013. Limited postmarketing safety data are available, but prelicensure safety data indicate that the most common reactions were headache, fatigue, and myalgia. RIV is not indicated for people <18 years.
Precautions and Contraindications
Influenza vaccine is contraindicated in people who have had a previous severe allergic reaction to influenza vaccine, regardless of which vaccine component was responsible for the reaction. Immediate hypersensitivity reactions (such as hives, angioedema, allergic asthma, and systemic anaphylaxis) rarely occur after influenza vaccination. These reactions likely result from hypersensitivity to vaccine components, one of which is residual egg protein. People with a history of egg allergy who have experienced only hives after exposure to eggs can receive any licensed and recommended influenza vaccine for their age and health status. Vaccine options are also available for people with a history of egg allergy with a history of severe reaction to egg; these are outlined at www.cdc.gov/flu/professionals/vaccination/vax-summary.htm#egg-allergy.
PERSONAL PROTECTION MEASURES
Measures that may help prevent influenza virus infection and other infections during travel include avoiding close contact with sick people and washing hands often with soap and water (where soap and a safe source of water are not available, use of an alcohol-based hand sanitizer containing ≥60% alcohol is recommended). No recommendation can be made at this time for mask use by people without influenza illness symptoms outside the health care setting. If people are ill, they can help prevent the spread of illness to others by covering their nose and mouth when coughing and sneezing and avoiding close contact with others. If symptomatic people cannot avoid contact with others, consideration should be given to having them wear a mask when they are in close contact with others (www.cdc.gov/flu/professionals/infectioncontrol/maskguidance.htm).
The best way to prevent infection with animal-origin influenza viruses, including A(H5N1) and A(H7N9), is to follow standard travel safety precautions: follow good hand hygiene and food safety practices and avoid contact with sources of exposure. Most human infections with animal-origin influenza viruses have occurred after direct or close contact with infected poultry or swine. In countries where avian influenza virus outbreaks are occurring, travelers or those living abroad should avoid markets and farms where live animals are sold or raised, avoid contact with sick or dead animals, not eat undercooked or raw animal products (including eggs), and not eat or drink foods or beverages that contain animal blood.
CDC website: www.cdc.gov/flu
Table 4-05. Recommended dosage and duration of antiviral medications for treatment and prophylaxis of influenza A and B
|Oral oseltamivir||Treatment (5 days)||If child is <1 year old1:
3 mg/kg/dose twice daily2,3
If ≥1 year old, dose varies by child's weight:
≤15 kg, the dose is 30 mg twice a day.
>15–23 kg, the dose is 45 mg twice a day.
>23–40 kg, the dose is 60 mg twice a day.
>40 kg, the dose is 75 mg twice a day.
|75 mg twice daily|
|Prophylaxis (7 days)||If child is <3 months old: use of oseltamivir for prophylaxis is not recommended unless situation is judged critical because data in this age group are limited.
If child is ≥3 months and <1 year old1:
3 mg/kg/dose once daily.2
If ≥1 year old, dose varies by child's weight:
≤15 kg, the dose is 30 mg once a day.
>15–23 kg, the dose is 45 mg once a day.
>23–40 kg, the dose is 60 mg once a day.
>40 kg, the dose is 75 mg once a day.
|75 mg once daily|
|Inhaled zanamivir4||Treatment (5 days)||10 mg (two 5-mg inhalations) twice daily (FDA approved and recommended for use in children ≥7 years)||10 mg (two 5-mg inhalations) twice daily|
|Prophylaxis (7 days)||10 mg (two 5-mg inhalations) once daily4 (FDA approved and recommended for use in children ≥5 years)||
10 mg (two 5-mg inhalations) once daily
|Intravenous peramivir5||Treatment (1 day)||(2–12 years of age) One 12-mg/kg dose, up to 600 mg maximum, via IV infusion for a minimum of 15 minutes5 (FDA approved and recommended for use in children ≥2 years)||(≥13 years)
600 mg dose via IV infusion for 15–30 minutes5
|Oral baloxavir||Treatment (1 day)||Weight 40 to <80 kg: one 40 mg dose
Weight ≥80 kg: one 80 mg dose
(FDA approved for use in children ≥12 years)
1 Oral oseltamivir is approved by the FDA for treatment of acute uncomplicated influenza within 2 days of illness onset with twicedaily dosing in people aged ≥14 days and for prophylaxis with once-daily dosing in people aged ≥1 year. Although not part of the FDA-approved indications, use of oral oseltamivir for treatment of influenza in infants <14 days old, and for prophylaxis in infants 3 months to 1 year of age, is recommended by CDC and the American Academy of Pediatrics (AAP).
2 This is the FDA-approved oral oseltamivir treatment dose for infants aged ≥14 days and <1 year old and provides oseltamivir exposure in children similar to that achieved by the approved dose of 75 mg orally twice daily for adults, as shown in 2 studies of oseltamivir pharmacokinetics in children. The AAP recommended an oseltamivir treatment dose of 3.5 mg/kg orally twice daily for infants aged 9–11 months, on the basis of data that indicated that a higher dose of 3.5 mg/kg was needed to achieve the protocol-defined targeted exposure for this cohort as defined in the CASG 114 study. It is unknown whether this higher dose will improve efficacy or prevent the development of antiviral resistance. However, there is no evidence that the 3.5 mg/kg dose is harmful or causes more adverse events to infants in this age group.
3 Current weight-based dosing recommendations are not appropriate for premature infants. Premature infants might have slower clearance of oral oseltamivir because of immature renal function, and doses recommended for full-term infants might lead to very high drug concentrations in this age group. CDC recommends dosing as also recommended by the American Academy of Pediatrics: 1.0 mg/kg/dose, orally, twice daily, for those <38 weeks postmenstrual age; 1.5 mg/kg/dose, orally, twice daily, for those 38–40 weeks postmenstrual age; 3.0 mg/kg/dose, orally, twice daily, for those >40 weeks postmenstrual age.
4 Inhaled zanamivir is approved to treat acute uncomplicated influenza within 2 days of illness onset with twice-daily dosing in people aged ≥7 years and for prophylaxis with once-daily dosing in people aged ≥5 years.
5 Intravenous peramivir is approved for treatment of acute uncomplicated influenza within 2 days of illness onset with a single dose in people aged ≥2 years. Daily dosing for a minimum of 5 days was used in clinical trials of hospitalized patients with influenza.
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