AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• FURTHER READING
• ACKNOWLEDGMENTS
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• FURTHER READING
• ACKNOWLEDGMENTS
• References

Background

Influenza is a respiratory illness caused by orthomyxoviruses. Both low pathogen (LP) and high pathogen (HP) avian influenza viruses are normally found in species such as wild birds and animals. The word influenza may have been derived from the Latin word influo, which means "to flow in," indicating airborne transmission, or from the Italian word influence, which indicates influence of weather or an astrological influence.¹ Seasonal human influenza causes about 36,000 deaths and 226,000 hospitalizations in the United States annually.^{2, 3} 

Minor or major antigenic changes occur in influenza virus type A; these changes can result in either an epidemic or a pandemic because overall immunity in the population is lower or nonexistent.⁴ When a minor antigenic change occurs in the genetic elements of the influenza virus, the surface hemagglutinins are slightly altered by accumulated point mutations and nucleotide substitutions, insertions, or deletions. Because the antigens are only slightly altered, the patient’s immune system still recognizes the virus to some extent, and the infection is usually less severe. An antigenic shift refers to a major change in the viral RNA due to replacement of H or N caused by gene reassortment.

Because birds have receptors for avian influenza viruses, whereas humans have receptors for human influenza viruses, transmission from birds to humans is rare. However, when an intermediate host that has receptors for both viruses, such as pigs, horses, and birds, are infected with both avian and human influenza viruses, reassortment may produce major changes in the genetic component of surface proteins; this may then allow relatively easier transmission. This antigenic reassortment or shift can result in a pandemic because of a naïve population and a lack of immunity to the newly reassorted viruses. Although the strain that is already in existence causes seasonal influenza, pandemic influenza is due to a new subtype of the virus.

Pathophysiology

Influenza viruses are orthomyxoviruses, which are negative-sense, single-strand RNA viruses.⁵ Human influenza viruses are divided into 3 major types: A, B, and C. Influenza type A viruses cause disease in humans and animals; birds are the natural reservoir for type A. Influenza type B viruses primarily cause disease in humans, particularly children. Infections with influenza type C viruses are rare. 

Influenza viral RNA has 8 genetic elements. The RNA has a lipid envelope with 2 major antigenic components on its surface; these components enable the replication and subsequent release of the virus, leading to its spread. The 2 protein components are hemagglutinins (HA) and neuraminidases (NA). Ionic channel proteins, termed M2 proteins, are also present. These M2 proteins are found only in influenza type A viruses.⁵

The HA antigen is the major virulence determinant because these antigens help viral attachment to the cell. HA proteins are divided into 16 types, whereas NA proteins are divided into 9 types. NA act on the sialic acid component of the cell, which enables viral detachment.^{6, 7} Different subtypes of influenza viruses are identified based on the combinations of these antigenic structures, with 144 combinations possible.

Currently, influenza A/H1N1, A/H3N2, and influenza type B viruses are the circulating influenza strains that cause seasonal human infections. The influenza vaccine components for the current year are intended to provide protection from these strains.⁸ In contrast with the typical course of disease caused by seasonal influenza, a higher viral load and prolonged viral replication are observed in infections caused by HP avian influenza virus A/H5N1. ^{9, 10}

An enormous release of cytokines is probably responsible for the severity of the illness, resulting in rapid progression.¹¹ The major entry site seems to be conjunctiva and oropharynx. 

Hyperinduction of cytokine storm with elevated interferon in serum samples is observed.^{12, 13}  Increased cytokines and chemokines with high levels of tumor necrosis factor alpha, interleukin-6, and interferon gamma lead to tissue destruction.¹³ Pulmonary and intestinal involvement with isolation of viral messenger RNA (mRNA) in these tissues is reported.

Prolonged viral RNA detection in the respiratory tracts results in systemic dissemination in fatal cases of avian influenza.¹³ Lung changes include diffuse alveolar damage, interstitial pneumonia, bronchiolitis, and hemorrhages. The type II pneumocytes showed reactive hyperplasia without cytopathic changes. Predominant macrophage infiltrates in the lung are reported. 

Superimposed opportunistic infection by fungus and aspergillosis has been reported. Histiocytic hyperplasias have been noted in the spleen, bone marrow, and lymph nodes. Hemophagocytic syndrome with multisystem involvement is also reported.¹⁴ Minimal fatty changes in liver with portal infiltrates with lymphocytes were reported. Edema and focal areas of necrosis in the brain have been reported. The intestines, heart, kidneys, and other organs are unremarkable.

Frequency

United States

A potential influenza pandemic could have a major impact both economically and in health care. In the United States, a medium-level pandemic could lead to approximately 89,000-207,000 deaths, 314,000-734,000 hospitalizations, 20-47 million people with infection, and probably 18-42 million outpatient visits.¹⁵

Previous pandemics have occurred in waves, with new waves occurring in intervals of 3-7 months. Approximately 15-35% of the US population may be involved by an influenza pandemic, and the economic loss could be between $71.3 and $166.5 billion.¹⁵

International

The main reservoir for influenza A viruses are migratory birds, especially waterfowl. Birds with LP influenza A virus infection can be asymptomatic and can be a source of infection for domestic poultry. The influenza A viruses are shed in oral secretions and feces. Domesticated birds are infected via secretions and excretions and via contaminated utensils. HP avian influenza A viruses can kill domesticated birds in 48 hours. These HP avian influenza viruses have crossed the species barrier in Asia, resulting in several human cases.¹⁶ This poses a potential pandemic threat. 
 
In 1997, the first report of human cases infected with HP avian influenza A/H5N1 documented 6 deaths among 18 hospitalized patients in Hong Kong.¹⁷ In 1999, HP avian influenza A/H9N2 infection was reported in 2 girls with fever and rhinorrhea; they recovered and no human-to-human transmission was noted.¹⁸  

Between January-March of 2004, 34 human cases of HP avian influenza A/H5N1 virus infections were confirmed from Vietnam and Thailand. Significant respiratory illness that required hospitalization resulted in a 68% fatality rate. In Vietnam, 15 deaths were reported among 22 cases; in Thailand, 8 deaths were reported among 12 cases.¹⁸ Children and young adults were predominantly involved, and all human cases were associated with outbreaks of HP avian influenza A/H5N1 among domestic poultry in the back yard and in the farms. More than 100 million domestic poultry have been culled.¹⁹

Migratory birds are presumed to be responsible for the recent spread of HP avian influenza virus A/H5N1 from Southeast Asia, where the poultry outbreak has been reported, to other regions across the globe. The HP avian influenza virus A/H5N1 was confirmed in ducks, chicken, turkey, and geese in Russia and Kazakhstan in July 2005, resulting in an implementation of restrictions on importation of birds from these areas.⁴ In January 2006, 2 cases of HP avian influenza virus A/H5N1 infection were reported in humans in Turkey. By August 2007, a total of 12 cases and 4 deaths were reported.²⁰ Iraq, the seventh country to have reported human cases, has reported 3 HP avian influenza A/H5N1–related human cases. Laboratory confirmation is performed by the US Naval Medical Research Unit, located in Cairo, Egypt.²¹ In Egypt, from 2006-2007, 38 human cases were reported, with 15 deaths due to severe respiratory illness.²⁰ Although poultry deaths are noted, HP avian influenza A/H5N1 viruses have not been isolated from poultry in these areas.

Mortality/Morbidity

These highly pathogenic avian influenza viruses have crossed the species barrier in Asia, resulting in several human cases.¹⁶ This poses a potential pandemic threat. From January to March 2004, 34 human cases of HP avian influenza virus A/H5N1 infection were confirmed in Vietnam and Thailand. Significant respiratory illness that required hospitalization resulted in a 68% fatality rate; 15 deaths were reported among 22 cases in Vietnam, and 8 deaths were reported among 12 cases in Thailand.¹⁸ Children and young adults were predominantly involved, and all human cases were associated with outbreaks of the HP avian influenza virus A/H5N1 among domestic poultry in backyards and farms. More than 100 million domestic birds have been culled.¹⁹ Through August 2007, 327 cases of HP avian influenza A virus have been reported worldwide, with 199 (60%) fatalities.²¹ The average duration from onset of illness to death varied from 1-3 weeks.²¹

Race

Most outbreaks have been noted in east Asian countries. No other racial predilection has been noted.

Age

The case-fatality rate in children younger than 15 years was approximately 89%.¹¹

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• FURTHER READING
• ACKNOWLEDGMENTS
• References

History

• Determine if the patient has a history of travel to countries where epidemics are reported.²¹
• Determine if the patient has a history of exposure to poultry from a region with an outbreak of HP avian influenza A virus. They may be health care workers with exposure to infected patients. Poultry cullers with this infection have been reported. 
• Patients have history of cough, respiratory distress, myalgia, conjunctivitis, diarrhea, and vomiting. 
• Diarrhea can precede respiratory symptoms and is watery without any inflammatory features.  
• Occasionally, signs and/or symptoms of encephalitis may be noted upon presentation. 
• The incubation period of HP avian influenza A virus is typically 2-5 days but can be as long as 8-17 days.¹⁶

Physical

• Patients with influenza can present with myalgia, fever, respiratory symptoms.²²
• Patients with HP influenza A/H5N1 virus infection predominantly present with community-acquired pneumonia, conjunctivitis, and fever.
• Influenza causes complications such as secondary bacterial infection, myocarditis, encephalitis, and Guillain-Barré syndrome.²³
• Compared with patients with seasonal human influenza viruses, patients infected with HP avian influenza A virus tend to have fever more than 90% of the time, vomiting, pleurisy, abdominal pain, myalgia, sore throat, rhinorrhea, lymphadenitis, and nasal and gingival bleeding. 
• Patients can develop dyspnea within approximately 5 days from onset of illness.
• The sputum is occasionally bloody. 
• Leukopenia reportedly is associated with a higher mortality rate. 
• Some patients infected with HP avian influenza A/H5N1 viruses reportedly had watery, nonbloody diarrhea that preceded respiratory symptoms.²¹
• Respiratory failure due to acute respiratory distress syndrome (ARDS)-like picture reportedly occurs 4-13 days after onset of illness. 
• Septic shock and pulmonary hemorrhage may be observed.
• Arrhythmias can develop as a complication. 
• Very rarely, CNS involvement is documented by viral isolation from cerebrospinal fluid and blood in patients who present with seizure and coma.²⁴
• Aminotransferase levels have been noted to be elevated.

Causes

• The HP influenza A/H5N1 virus is a recombinant virus. 
• Infection has been associated with exposure to infected poultry and poultry products. See Pathophysiology.

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• FURTHER READING
• ACKNOWLEDGMENTS
• References

Other Problems to Be Considered

Pulmonary embolism
Pulmonary hemorrhage
Pneumocystis jiroveci infection in immunocompromised host

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• FURTHER READING
• ACKNOWLEDGMENTS
• References

Lab Studies

• The US Food and Drug Administration (FDA) has approved the Influenza A/H5 (Asian Lineage) Virus Real-Time Reverse Transcription–Polymerase Chain Reaction (RT-PCR) Primer and Probe Set and inactivated virus to be used as a positive RNA control for the in vitro detection of highly pathogenic influenza virus A/H5 (Asian lineage).²⁵ Testing with the new assay is limited to approximately 140 US laboratories in 50 states designated by the Laboratory Response Network (LRN). 
• These laboratories are mainly city or state public health laboratories. The Centers for Disease Control and Prevention (CDC) recommendation is to test for HP avian influenza A/H5N1 if a patient has severe respiratory symptoms and a risk for exposure (eg, direct contact with ill, dead, or infected poultry in a country with known poultry outbreaks of HP avian influenza A/H5N1), with specific criteria included. Testing must be performed under biosafety level 3.^{26, 27}
• Viral culture should be avoided unless performed under biosafety level 3 with containment.
• Viral culture of human and animal specimens should not be performed in the same laboratory.²⁷ 
• Positive laboratory test findings must be confirmed by the CDC, which is the World Health Organization (WHO) H5 reference laboratory. 
• Immunofluorescence assay (IFA) can be used to identify the virus in culture. 
• If other test findings are negative, paired avian influenza virus serologies can be performed. However, reagents may not be widely available, and acute and convalescent serum analysis requires time to allow a 4-fold increase in antibody.
• Other laboratory tests include:
• • Blood culture
  • CBC count with differential
  • Electrolyte level measurement
  • Liver enzyme assay
  • BUN and creatinine level measurement

Imaging Studies

• Chest radiography, both posteroanterior and lateral views, may reveal patchy or diffuse infiltrates, an interstitial pattern, and lobar consolidation revealing air bronchogram or an ARDS-like picture. 

Histologic Findings

• Histologic findings may include pulmonary changes with alveolar damage similar to seasonal influenza.
• Fibrinous exudate membrane formation and lymphocyte infiltrates are noted in postmortem analysis of patients who had avian influenza. 
• Necrosis is noted in organs such as the liver and kidney. The spleen may be depleted of lymphoid cells. 
• Bone marrow demonstrates hemophagocytosis.¹¹

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• FURTHER READING
• ACKNOWLEDGMENTS
• References

Medical Care

• Hospitalization is required if respiratory distress results in subsequent ventilatory support. 
• Oseltamivir is the primary drug of choice.²⁷
• The WHO recommendations for HP Avian influenza (H5N1) are as follows:²⁸
• • Patients with confirmed or suspected H5N1 infection should be treated with oseltamivir as soon as possible. This applies to adults, pregnant women, and children. 
  • Zanamivir might also be considered as an alternative if the patients are capable of using inhalers. 
  • If neuraminidase inhibitors are available, amantadine should not be used as first-line therapy because of the risk of potential resistance.  
  • If neuraminidase inhibitors are not available, amantadine can be used as a first-line therapy, provided the virus is susceptible. 
  • If neuraminidase inhibitors are available, rimantadine should not be used as first-line therapy. 
  • If neuraminidase inhibitors are not available, rimantadines can be used if the virus is known to be susceptible because they have less side effects than amantadines. 
  • If neuraminidase inhibitors are available, and if the virus is susceptible, then a combination of neuraminidase inhibitors and M2 inhibitors can be used in confirmed cases of H5N1 infection. 
  • In regards to prophylaxis, the WHO recommends oseltamivir in high-risk and moderate-risk exposures for 7-10 days from the day of exposure.
  • Prophylaxis is not recommended for low risk groups. 
  • For more information, see World Health Organization Updates Guidelines for Avian Influenza Virus Management. 
• A combination of antiviral therapy (eg, oseltamivir and adamantanes if susceptibility is expected) and antibiotics is recommended if pneumonia and rapid progression is noted. 
• If septic shock is present, corticosteroids and vasopressors may play a role. 
• Patients should be isolated with standard, contact, and airborne precautions, with doors closed and single rooms if possible. 
• The hydration status should be addressed. 
• ARDS should be managed according to guidelines.

Consultations

• Infectious diseases specialist
• Pulmonologist
• Critical care specialist
• Infection control specialist

Diet

• The diet is as tolerated.
• If patient requires ventilation or has respiratory distress, they may not be able to tolerate oral feeding.

Activity

• If the patient is hospitalized, an isolation room is required, with airborne precautions or a negative-pressure room. A particulate mask, such as N95, and goggles are recommended. 
• Patients who are clinically stable and are able to convalesce at home are instructed to stay at home to avoid spread in the community.

MEDICATION

Section 7 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• FURTHER READING
• ACKNOWLEDGMENTS
• References

Current seasonal influenza vaccines provide no protection against human infection with HP avian influenza type A viruses, including H5N1. However, reducing seasonal influenza risk through influenza vaccination of persons who might be exposed to nonhuman influenza viruses (eg, H5N1 viruses) might reduce the theoretical risk for recombination of an avian influenza type A virus and human influenza type A virus by preventing seasonal influenza virus infection within a human host. The CDC has recommended that persons who are charged with responding to avian influenza outbreaks among poultry receive seasonal influenza vaccination.

Currently recommended influenza vaccine components include influenza virus A/H1N1, influenza virus A/H3N2, and influenza type B virus. The vaccine virus strains for the 2007-2008 trivalent vaccine are A/Solomon Islands/3/2006 H1N1–like (new for this season), A/Wisconsin/67/2005 H3N2-like, and B/Malaysia/2506/2004–like antigens.⁸  Prior to each influenza season, strains with the most potential to cause an epidemic or pandemic outbreak are isolated by scientists; the manufacturers then develop the vaccines. Most of the influenza vaccines in the United States and Europe consist of the influenza virus grown in embryonated eggs.

Using reverse-genetics, the influenza virus can be recovered from plasmid DNAs transfected into tissue culture cells. This enables the recovery of the circulating virus and the distribution to vaccine manufacturers within a 2-week period. Neirynck et al have described a vaccine based on the most conserved portion of M2 protein from the extracellular surface of the influenza virus.²⁹ Such an antigen may induce cross-protection. A genetically engineered vaccine is considered to express more variant epitopes, rendering cross-protection. Li et al have described a chimeric HA recombinant virus that can express about 144 additional amino acids and can present many of the conserved antigens; this could lead to a universal influenza vaccine.³⁰

The FDA approved the first vaccine for HP avian influenza virus H5N1 (ie, avian or bird flu) in April 2007. The approval was based on one multicenter, randomized, double-blind, placebo-controlled, dose-ranging study in healthy adults aged 18-64 years.³¹ The trial investigated the safety and immunogenicity of the vaccine. A total of 103 healthy adults received a 90-mcg dose of the vaccine by intramuscular injection, followed by another 90-mcg dose 28 days later. In addition, approximately 300 additional healthy adults received the vaccine at doses lower than 90 mcg, and 48 received placebo injections. The study showed that the 90-mcg 2-dose regimen had an improved immune response and produced antibody levels expected to reduce the risk of HP avian influenza virus H5N1 infection in 45% of those who received it.

The FDA-approved H5N1 vaccine is not commercially available and is stockpiled by the federal government to be distributed when necessary.³² 

Some concern surrounds whether pneumococcal vaccination may be helpful as a prophylaxis option; however, deaths due to HP avian influenza A virus have been reported even without secondary bacterial infection.

Drug Category: Vaccines

These agents elicit active immunization to increase resistance to infection. Vaccines consist of microorganisms or cellular components, which act as antigens. Administration of the vaccine stimulates the production of antibodies with specific protective properties.

Drug Category: Antiviral agents

Zanamivir and oseltamivir are neuraminidase inhibitors that have activity against both influenza type A and type B viruses and are recommended for prophylaxis and treatment of influenza virus infection. Studies are currently underway to determine if the avian influenza A/H5N1 strain is sensitive to these agents.
 
Influenza type A strains (including H5N1) developed resistance to amantadine (Symmetrel) and rimantadine (Flumadine) during the 2005-2006 influenza season; therefore, these antiviral agents are not recommended for prophylaxis or treatment. Similarly, resistance to oseltamivir is reported with increasing frequency.

FOLLOW-UP

Section 8 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• FURTHER READING
• ACKNOWLEDGMENTS
• References

Further Inpatient Care

Oxygen saturation, nutrition, prevention of hospital-acquired infection, and GI bleeding should be monitored.

In/Out Patient Meds

• The following 2 types of antiviral agents are available for influenza:^{6, 33, 34}
• • Adamantanes (amantadine, rimantadine)  
  • • Adamantanes are M2 ion channel inhibitors. 
    • The CDC issued alerts to avoid using the adamantanes for treatment or prophylaxis during the 2005-2006 influenza season because of resistance noted among influenza A viruses secondary to mutation in amino acids.³⁵ 
    • From October 2005 to January 2006, a total of 123 seasonal influenza type A viruses from 23 states were analyzed by the CDC for resistance to adamantanes; among the 120 influenza virus A/H3N2 infections tested, 109 (91%) revealed the S31N substitution in the M2 protein, which leads to resistance against amantadine and rimantadine. The substitution was confirmed by sequencing. None of the 3 influenza A/H1N1 viruses had any mutations.
    • The HP Asian avian influenza virus A/H5N1 has been reported to be resistant to amantadine and rimantadine.³⁶
    • As of January 2006, all US influenza viruses tested for resistance by the CDC are susceptible to NI. 
  • Neuraminidase inhibitors (oseltamivir, zanamivir)
  • • Neuraminidase inhibitors inhibit the release of virus and its spread.
    • Oseltamivir (Tamiflu) is FDA approved for treatment and prophylaxis of influenza types A and B and is effective in treating avian influenza.³⁴
    • Oseltamivir resistance has been rarely reported in patients with avian influenza.¹⁰
• Longer therapy may be needed to treat HP avian influenza than seasonal influenza. 
• Some countries are stockpiling these antiviral agents.

Transfer

Consider transfer to another facility if required personnel or measures are not locally available.

Deterrence/Prevention

• Preparedness
• • To curtail a potential pandemic situation, the major goals are early identification of sources of HP avian influenza virus A/H5N1 infection and limiting spread of the virus. 
  • Both the WHO and the CDC recommend a high degree of surveillance worldwide to identify outbreaks in poultry and death of migratory birds.³⁷ 
  • Rapid containment processes, such as culling of infected birds, vaccinating nearby at-risk poultry, and vigilance for respiratory illness among personnel in contact with the affected poultry, are also needed. 
  • Simple measures (eg, strict hand hygiene; standard, contact, droplet, and airborne precautions for 21 d) might reduce the spread of the virus.
  • An alert system has been developed for avian influenza depending on the incidence of human cases due to HP avian influenza virus A/H5N1. It ranges from level I-VI.³⁷ Currently, the alert is set at level III because of a few cases of human-to-human transmission.  
  • The United States and several other countries have developed a preparedness plan for a potential influenza pandemic.⁹  
  • The US Secretary of Health and Human Services has developed a multiagency National Influenza Pandemic Preparedness and Response Task Group. This initiative jointly involves the CDC and several other agencies (international, national, state, local, and private) in preparing for a potential pandemic.³⁸ 
• Travel recommendations
• • No recommendations have advocated carrying oseltamivir or zanamivir when traveling to countries where human avian influenza has been reported. However, consulting a local physician if illness develops has been recommended.³⁸
  • Avoiding undercooked poultry and areas where the poultry is sold in the market is prudent. 
  • Avoid raw or undercooked eggs. 
  • After exposure to poultry or eggs, wash hands, utensils, and exposed surfaces with soap and water. 
  • If an illness develops with fever, cough, sore throat, or respiratory distress after exposure to poultry in areas where avian influenza has been identified, individuals must contact medical personnel.  
  • The history of travel and exposure to poultry must be disclosed prior to contact with the physician. 
  • Avoiding contact with health care workers can reduce the spread. Sick or dying poultry should not be consumed because doing so increases the risk of acquiring the virus.
• Prevention
• • The Society of Hospital Epidemiology of America has published a document recommending universal vaccination of health care workers as a preparedness plan.³⁹ By enhancing the vaccination rate, viral shedding and transmission can be reduced. This eventually decreases the risk of reassortment.  
  • The challenges faced include manufacturing vaccines in a timely manner, finding appropriate substrates from which to isolate the virus, product safety, efficacy, and acceptance by the approving agency and the public. 
  • The HP avian influenza A virus vaccine poses a challenge because the contemporary method of growing the vaccine in the egg may not work because the HP avian influenza A virus can kill the embryonated egg.  
  • Once an outbreak occurs, both the infected individual and contacts require neuraminidase inhibitors. This may necessitate mobilization of neuraminidase inhibitors from nations with stockpiles to regions where an avian outbreak is detected. Although this may not completely inhibit the transmission, the inhibitors may slow it down by decreasing viral shedding. 
  • An effort should be made to enhance seasonal influenza immunization rates.

Complications

• Pneumonia
• Respiratory failure
• Congestive heart failure
• Multiorgan failure
• ARDS
• Pulmonary hemorrhage
• Cardiac arrhythmia
• Death

Prognosis

• Prognosis is poor, with a mortality rate of more than 50%.
• Poor prognostic features include a high viral load, leukopenia, lymphopenia, longer duration of illness prior to treatment, and old age.¹²
• Whether pneumococcal vaccination might be helpful as a prophylaxis is a concern, but deaths have been reported even without secondary bacterial infection.

Patient Education

• Follow the travel advisories recommended by the CDC and WHO. 
• People traveling to certain countries should avoid poultry farms and markets or other places where live poultry are present. 
• Education regarding covering the mouth when coughing and strict handwashing is helpful. 
• Household contacts of patients should be instructed to monitor fever, cough, and respiratory distress symptoms. These household contacts should be given prophylactic antiviral therapy with oseltamivir.  If they are symptomatic they must be tested for the virus. 
• Avoiding close contact with the patient is recommended. 

MISCELLANEOUS

Section 9 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• FURTHER READING
• ACKNOWLEDGMENTS
• References

Medical/Legal Pitfalls

• Failure to recognize the etiology with epidemiologic factors
• Failure to adequately isolate infected patients, which can cause a rapid spread in the community

Special Concerns

• Biopreparedness should be applied to all facilities, including schools, churches, transport, hospitals, and the communities. 
• Vaccines, antivirals, and other supplies may be inadequate.
• Major economic impact could occur. 

FURTHER READING

Section 10 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• FURTHER READING
• ACKNOWLEDGMENTS
• References

ACKNOWLEDGMENTS

Section 11 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• FURTHER READING
• ACKNOWLEDGMENTS
• References

The author would like to thank Anthony R Sambol, MA, SM(NRM), SV(ASCP), CBSP, and Mary Windle, PharmD.

REFERENCES

Section 12 of 12

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• MEDICATION
• Follow-up
• Miscellaneous
• FURTHER READING
• ACKNOWLEDGMENTS
• References

1. Glezen WP. Orthomyxoviridae: Influenza viruses. In: Feigen RD. Textbook of Pediatric Infectious Diseases. 5th Ed. Philadelphia, PA: Saunders; 2004.
2. Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in the United States. JAMA. Sep 15 2004;292(11):1333-40. [Medline].
3. Thompson WW, Shay DK, Weintraub E, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. JAMA. Jan 8 2003;289(2):179-86. [Medline].
4. CDC. Embargo of Birds from Specified Countries. Avian Influenza. Available at http://www.cdc.gov/flu/avian/outbreaks/embargo.htm.
5. Horimoto T, Kawaoka Y. Pandemic threat posed by avian influenza A viruses. Clin Microbiol Rev. Jan 2001;14(1):129-49. [Medline]. [Full Text].
6. Hayden FG, Gubareva LV, Monto AS, et al. Inhaled zanamivir for the prevention of influenza in families. Zanamivir Family Study Group. N Engl J Med. Nov 2 2000;343(18):1282-9. [Medline].
7. Gubareva LV, Kaiser L, Hayden FG. Influenza virus neuraminidase inhibitors. Lancet. Mar 4 2000;355(9206):827-35. [Medline].
8. Fiore AE, Shay DK, Haber P, et al. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2007. MMWR Recomm Rep. Jul 13 2007;56(RR-6):1-54. [Medline]. [Full Text].
9. WHO. Responding to the avian influenza pandemic threat. 2005. WHO Recommendations. [Full Text].
10. de Jong MD, Simmons CP, Thanh TT, et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med. Oct 2006;12(10):1203-7. [Medline].
11. Uiprasertkul M, Puthavathana P, Sangsiriwut K, et al. Influenza A H5N1 replication sites in humans. Emerg Infect Dis. Jul 2005;11(7):1036-41. [Medline].
12. Wong SS, Yuen KY. Avian influenza virus infections in humans. Chest. Jan 2006;129(1):156-68. [Medline].
13. Peiris JS, de Jong MD, Guan Y. Avian influenza virus (H5N1): a threat to human health. Clin Microbiol Rev. Apr 2007;20(2):243-67. [Medline].
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Article Last Updated: Apr 29, 2008
Topic originally published: Apr 29, 2008