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CDC: Human Case of Swine Influenza A (H1N1) 2005
On December 7, 2005, a previously healthy 17-year-old boy with no history of ...
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Wilderness and Environmental Medicine,
17,
276 281 (2006)
REVIEW ARTICLE
Human Influenza A (H5N1): A Brief Review andRecommendations for Travelers
Timothy R. Hurtado, DO
From the 121st General Hospital, Seoul, South Korea.
Although avian influenza A (H5N1) is common in birds worldwide, it has only recently led to diseasein humans. Humans who are infected with the disease (referred to as human influenza A [H5N1])have a greater than 50% mortality rate. Currently there has not been documented sustained human-to-human transmission; however, should the virus mutate and make this possible, the world couldexperience an influenza pandemic. Probable risk factors for infection include slaughtering, defeath-ering, and butchering fowl; close contact with wild birds or caged poultry; ingestion of undercookedpoultry products; direct contact with surfaces contaminated with poultry feces; and close contact withinfected humans. Possible risk factors include swimming in or ingesting water contaminated with birdfeces or dead birds and the use of unprocessed poultry feces as fertilizer. Clinically, early humaninfluenzaA (H5N1) resembles typical influenza illnesses, with fever and a preponderance of lower respiratorytract symptoms. Often, patients develop rapidly progressive respiratory failure and require ventilatorysupport. Treatment is primarily supportive care with the addition of antiviral medications. Currently,travelers to countries with both human and avian influenza A (H5N1) have a low risk of developing thedisease. There are no current recommended travel restrictions. Travelers are advised to avoid contactwith all birds, especially poultry; avoid surfaces contaminated with poultry feces; and avoid undercookedpoultry products. The use of prophylactic antiviral medications is not recommended.
Key words:
human influenza A (H5N1), avian influenza A (H5N1), bird flu, travelers
Introduction
Avian influenza A is an endemic disease in birds world-wide. In recent years, one strain has leapt to the forefrontof media attention as avian influenza A (H5N1), withthe infection and death of human patients in Asia andnow deaths in the Middle East and eastern Europe.When avian influenza A (H5N1) infects humans, it isreferred to as human influenza A (H5N1). This articlewill review the etiology, incidence, presentation, diag-nosis, and treatment of human influenza A (H5N1) andits implications for travelers. It summarizes the currentbody of knowledge for clinicians advising travelers to
The views, opinions, and findings contained in this report are thoseof the authors and should not be construed as official Department of the Army position, policy, or decision unless so designated by otherofficial documentation. Citations of commercial organizations andtrade names in reports do not constitute an official Department of theArmy endorsement or approval of the products or services of theseorganizations.Corresponding author: MAJ Timothy Hurtado, 121st General Hos-pital, Box 662, APO AP 96205 (e-mail Timothy.Hurtado@us.army.mil).
countries with avian and human influenza A (H5N1)outbreaks.
Background
Avian influenza A (H5N1), a member of the orthomyx-oviridae family, is a common organism found in the di-gestive tracts of mainly aquatic wild birds worldwide. Ithas been described in chickens, ducks, turkeys, guineafowl, geese, quails, pheasants, partridges, mynahs, pas-serine birds, psittacine birds, budgerigars, galls, shore-birds, seabirds, and emus.
1
It typically causes few, if any, symptoms in wild birds, as it preferentially repli-cates in their digestive tracts and is excreted in theirfeces. Conversely, it can cause severe disease and often-times death in domesticated fowl.
1
There have been atleast 17 major outbreaks of avian influenza A (H5) or(H7) subtypes in the past 30 years, resulting in the deathsof millions of birds. For example, in 1983 an outbreak of avian influenza A (H5N2) in Pennsylvania lead to thedeath or culling of 17 million birds at the cost of US$61
277
Human Influenza A (H5N1): A Brief Review
million.
1
After the identification of avian influenza A(H5N1) as the culprit in the initial 1997 Hong Konghuman outbreak, 1.5 million birds were destroyed in 3days—the entire country’s poultry population.
2
This initial outbreak of disease in humans was thefirst documented set of illnesses attributed to humaninfluenza A (H5N1). Eighteen people who had closecontact with poultry were hospitalized, and 6 laterdied.
3
Before these cases, it was thought that avian in-fluenza A (H5N1) had limited ability to directly infectand propagate in humans.
1,4
Because both humans andbirds possess unique receptors for their distinct viruses,and because pigs possess receptors for both avian in-fluenza and human influenza, pigs were thought to bea necessary intermediate host.
1,4
Recent outbreaks inhumans who had close contact with infected poultryand not swine have challenged this notion. Per theWorld Health Organization, as of May 23, 2006, therehave been 218 reported cases of human influenza A(H5N1) resulting in 124 deaths since 1997.
5
Althoughthe majority of deaths have been reported in Asia, sev-eral patients in Turkey, Iraq, and Egypt recently diedfrom the disease, indicating that it has spread to theMiddle East and eastern Europe.
5
A current list of countries with documented avian and human influenzaA (H5N1) infections can be found at the World HealthOrganization website (http://www.who.int/csr/disease/ avian
influenza/country/en/index.html).
Transmission
The primary mode of transmission of avian influenza A(H5N1) to humans has been animal to human.
6–8
Activ-ities that put people at in increased risk of contractingthe disease include playing with poultry; slaughteringdiseased birds; handling fighting cocks; and consumingduck blood and, possibly, undercooked poultry.
6,9,10
In-terestingly, workers responsible for mass culling of poul-try in an attempt to stem the spread of the disease appearto be at low risk, even in instances when they did notwear personal protective equipment.
2,11
There have been rare cases of suggested human-to-human transmission in several household clusters. Thefirst case involved a child who was exposed to dyinghousehold chickens 4 days before becoming ill. Her auntattended to her until the girl’s mother arrived from adistant city to assume care. The mother had no contactwith poultry, poultry feces, or poultry secretions. Shedid not ingest undercooked poultry products. The aunt,who initially provided bedside care for the sick child,did assist with burying the dead chickens during the ini-tial poultry outbreak by using plastic bags to cover herhands but otherwise had no contact with infected fowl.Both women had extensive, close contact with the sick child, which included hugging, kissing, and wiping se-cretions from her mouth. The child died of respiratoryfailure secondary to pneumonia 6 days after she devel-oped symptoms. Three days after the child’s death, themother developed a fever and rapidly progressive respi-ratory failure secondary to pneumonia. She died 10 dayslater. The aunt also developed a fever 9 days after caringfor the child. She was admitted to the hospital for pro-gressive dyspnea secondary to pneumonia. The admit-ting physicians, suspecting influenza, initiated treatmentwith oseltamivir. Her condition gradually improved andshe was discharged from the hospital 2 weeks later.Specimens from the aunt and mother were positive forinfluenza A (H5N1) by reverse-transcriptase polymerasechain reaction. The child’s body had been cremated;therefore, no postmortem specimens for influenza A(H5N1) were obtained. After a thorough epidemiologicinvestigation, it was believed that the most likely expla-nation for the family cluster of this disease was directhuman-to-human transmission.
12
Recently, there have been reports of probable human-to-human transmission in Indonesia as well. The indexcase was a woman suspected of being infected with in-fluenza A (H5N1) from chickens she kept in and aroundher house. Three chickens became ill and died, and shewas known to have used chicken feces as fertilizer inher garden as well. She developed symptoms of an in-fluenza-like illness and later died. No antemortem sam-ples were taken for influenza A (H5N1) before her buri-al; however, her clinical course was consistent with thedisease. During the time when the patient was severelyill and coughing heavily, 9 of her family members spentthe night in a small room with her. Three of these familymembers became ill. In addition, 4 other family mem-bers who had close contact with the patient became ill.All 7 of these family members had laboratory-confirmedinfluenza A (H5N1). Six of the 7 cases were fatal. Noadditional cases of influenza A (H5N1) have been iden-tified beyond the single extended family. No health careworkers became ill either, even in the absence of ade-quate personal protective equipment.
13
Significantly, ge-netic sequencing of the virus responsible for this out-break has demonstrated no evidence of reassortment be-tween human and pig viruses as well as no evidence of genetic mutations to include mutations associated withresistance to neuraminidase inhibitors.
14
Aerosolized particle transmission is not thought to beresponsible for the above instances of probable human-to-human transmission. Rather, intimate person-to-per-son contact is hypothesized to be the cause.
6,12,13
For-tunately, the risk of transmission from patients to healthcare workers also seems to be low.
2,6,13,14
Of 449 health
278
Hurtado
care providers studied, there were 2 reported cases of suspected illness that had not been confirmed serologi-cally and 8 cases of seroconversion that, by in large,remained asymptomatic.
6
Other theoretical avenues of human infection include the ingestion of contaminatedwater, mucous membrane exposure (during bathing orswimming), fomite transmission, and the ingestion of food contaminated with unprocessed poultry feces fer-tilizer.
6,12
Clinical course
The clinical course of human influenza A (H5N1) hasbeen extrapolated from hospitalized patients because theincidence of minimally symptomatic infections is notknown. The incubation period for the disease rangesfrom 2 to 17 days, with the average period being 3days.
2,6,8,15,16
The majority of patients presented withfever and influenza-like symptoms with a preponderanceof lower respiratory symptoms to include dyspnea withcough. Sputum production is variable. Upper respiratorysymptoms are less common.
2,6,8,15,16
Atypical initial presentations have been reported toinclude 1 case of fever with diarrhea alone
17
and 2 casesof fever with diarrhea and coma without respiratorysymptoms.
18
Gastrointestinal symptoms (eg, diarrhea,abdominal pain, vomiting) are more commonly seenwith human influenza A (H5N1) compared with othertypical human influenza illnesses.
2
Unlike avian influ-enza A (H7), human influenza A (H5N1) is not usuallyassociated with conjunctivitis.
6,19
Other possible com-plications include multiorgan failure, pulmonary hem-orrhage, pneumothorax, pancytopenia, Reye syndrome,and sepsis syndrome without documented bacteremia.
6
Radiographic findings
Patients with human influenza A (H5N1) usually devel-op lower respiratory symptoms early in the disease pro-cess. Nearly all patients develop pneumonia. Radio-graphic findings include segmental or lobar consolida-tions as well as diffuse, multifocal infiltrates. As patientsprogress toward respiratory failure, the radiograph maydemonstrate diffuse, bilateral ground-glass infiltratesconsistent with acute respiratory distress syndrome. Themean time to onset of acute respiratory distress syn-drome in one study was 6 days.
8,20
Laboratory screening
Both viral cultures and H5-specific RNA antigen studieshave been successfully used to detect human influenzaA (H5N1).
6
Routine viral cultures should not be per-formed unless appropriate Biosafety Level Laboratoryprecautions can be observed at all times.
21
Reverse-tran-scriptase polymerase chain reaction assays are superiorto commercially available rapid antigen studies, whichare not recommended at this time because the clinicalaccuracy of the detection of influenza A (H5N1) in hu-mans is unknown.
22
It appears that pharyngeal samplingyields a higher level of detection than do nasopharyngealswabs.
6,20,22
However, because of limited clinical data,it is currently recommended that nasopharyngeal swabs,nasopharyngeal aspirates, or nasal washing be used inaddition to pharyngeal swabs to collect samples. Nasalswabs and acute and convalescent sera can also be ob-tained.
23
For optimal yield, specimens should be ob-tained within 3 days of onset of symptoms.
23
During routine laboratory screening, common findingsinclude leukopenia (particularly lymphopenia), throm-bocytopenia, and a mild increase in aminotransferas-es.
2,6,8
In one small study, increased mortality was as-sociated with leukopenia, thrombocytopenia, and lym-phocytopenia on presentation for medical care.
20
Finally,bacterial cultures are usually negative, indicating that theillness is primarily related to a viral pneumonia withlimited secondary bacterial infection.
2,6
Treatment
The treatment for human influenza A (H5N1) is primar-ily supportive. The majority of hospitalized patients re-quire early ventilator support (usually within 48 hoursof admission).
2,6,20
They are typically started on bothbroad-spectrum antibiotics and antiviral agents. Corti-costeroids, though widely used, have not shown clearclinical benefit.
6
Similar to other influenza infections,preliminary data indicate that the early administration of antiviral agents offers the greatest advantage, whereasinstituting antiviral therapy late in the illness provideslittle benefit.
2,6,24
The oral neuraminidase inhibitor oseltamivir appearsto be the most useful agent. Although 5 days of therapyis considered adequate for treating mildly symptomaticpatients early in the disease process, higher doses maybe needed for a longer duration in more severe infec-tions. The optimum dose and duration has not been pro-spectively studied, and the dose should be adjusted forrenal disease.
2,6,25–27
The inhaled neuraminidase inhibi-tor zanamivir has been used in animal models with somesuccess; however, it has not been studied in humans.Table 1 summarizes the treatment of human influenza A(H5N1) with the neuraminidase inhibitors.Drug-resistant human influenza A (H5N1) has recent-ly made the news with case reports of oseltamivir-resis-tant infections, primarily in Vietnam.
30
This is signifi-
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