Influenza and Asthma: A Review
Posted: December 2010
Robbie D. Pesek, M.D., Fellow
Division of Allergy and Immunology
University of South Florida College of Medicine
James A. Haley Veterans' Hospital
Tampa, Florida USA
Richard F. Lockey, M.D.
Division of Allergy and Immunology
University of South Florida College of Medicine
James A. Haley Veterans" Hospital
Tampa, Florida USA
Viruses commonly cause a variety of different illnesses in humans, ranging from mild upper respiratory tract to life-threatening pulmonary infections. They are associated with significant morbidity and mortality with billions of dollars spent annually in both direct and indirect health care costs. Rhinovirus, respiratory syncytial virus (RSV), and influenza cause wheezing and in some cases lead to the development of asthma. Up to 80% of acute exacerbations of asthma are caused by viral respiratory tract infections, influenza being a particularly important cause. Patients with asthma are at higher risk of developing influenza and have more severe problems associated with this disease. The classification, pathogenesis, treatment, and prevention of influenza and its role in asthma are reviewed in this article.
The influenza virus is a single stranded RNA virus of the family Orthomyxoviridae, of which humans can be infected by strains A, B, and C. Infections typically occur in the United States between October and November with a peak from January to March. Not only are influenza viruses categorized by strain, but also by two cell surface proteins, hemagglutinin (H), and neuraminidase (N). Each year, the influenza virus undergoes slight changes in these proteins, so called “antigenic drift”, leading to seasonal influenza which can reach epidemic proportions. Significant changes in H and N, or “antigenic shift”, have the potential to cause a pandemic. Influenza A and B are typically associated with seasonal disease but also have been associated with several pandemics during the 20th century. For example, in 1918, “Spanish influenza”, a strain of H1N1 influenza A, caused between 50 and 100 million deaths worldwide with a mortality rate of 2.5 to 3%, significantly higher than the 0.1% associated with previous epidemics. Most of the deaths occurred in adults between ages 20 and 40 years. In 1957, “Asian influenza” (H2N2) caused between 1.5 and 2 million deaths, and in 1968, “Hong Kong influenza” (H3N2) caused over 1 million deaths.
Most human disease can be separated into three influenza A strains known to pass from human to human: H1N1, H2N2, and H3N2. Water birds can be contaminated with other strains of influenza such as H5N1 (avian influenza) and can pass the disease to other animals living in close proximity to humans, such as swine or poultry. Mixing of different influenza viruses can lead to a new strain for which the human population has little or no antibody protection, potentially leading to a worldwide pandemic. Water bird and other animal populations are closely monitored by the World Health Organization (WHO) and Centers for Disease Control (CDC) for development of pathogenic influenza strains; when found, these populations are destroyed to prevent further spread and transmission to humans.
Influenza infection begins with invasion of the respiratory epithelium which serves as a site for both viral replication and host immune response. Destruction of normal airway tissue and a pro-inflammatory immune response are the primary causes of symptoms associated with influenza infection.
Viral replication triggers both an innate and adaptive immune response. Viral particles activate toll-like receptors (TLRs), including TLR-3 and TLR-4, which trigger an innate immune response through production of interferons. An adaptive immune response is also generated through TLR signaling resulting in activation of both T and B cells. Production of double stranded RNA during viral replication activates RIG-1 (retinoic acid inducible gene 1) and MDA-5 (melanoma differentiation associated gene 5) which increases production of both nitric oxide and interferons. Interferons promote a Th1 response through increased mononuclear cell (macrophages and monocytes) activity. These cells secrete pro-inflammatory cytokines as well as additional interferon leading to the recruitment of neutrophils and eosinophils. This host immune response limits viral replication and ultimately infection by decreasing protein synthesis, inhibiting translation of viral messenger RNA, degrading viral proteins, and inducing cellular apoptosis.
The immune response of the host causes many of the symptoms associated with any viral respiratory infection and those associated with exacerbations of underlying asthma. Production of pro-inflammatory cytokines, such as IL-8, leads to rhinorrhea and increased airway hyperresponsiveness. These cytokines are also able to recruit inflammatory cells into the lungs causing increased airway inflammation. Neutrophil activation increases production of elastase with increased secretion of mucin by airway goblet cells. Viral particles also contribute to symptoms by directly increasing airway hyperresponsiveness, although the mechanism is unknown. Viral induced damage to respiratory epithelium causes shedding of these cells into the airways exacerbating obstruction and wheezing.
Certain individuals seem to be at higher risk for developing infection in the lower airway. For example, age less than 6 months, second hand smoke exposure, and genetic factors all play a role in increasing the risk of infection. Allergic subjects are also more susceptible due to an impaired immune response with decreased production of interferons. Subjects with asthma have a similar incidence of viral respiratory tract infections as does the general population but the risk of developing lower respiratory tract disease is two-fold higher, believed to be due to poor airway clearance of viral particles. Asthmatics with repeated exacerbations have chronic damage to the airway epithelium resulting in lower airway function, likely contributing to poor airway clearance. Subjects with asthma also have higher levels of IL-13 which promotes goblet cell formation, increased mucin secretion, profibrotic repair of airway epithelium, and decreased production of interferon-gamma.
Uncomplicated influenza infection can present with symptoms including fever, myalgias, headaches, photophobia, cough, and rhinorrhea, while pandemic H1N1 infection also has been associated with vomiting and diarrhea. Influenza infection can be associated with a variety of complications, particularly in those with underlying lung and cardiovascular diseases. Pulmonary complications include croup (laryngotracheobronchitis), influenza pneumonia, and exacerbation of asthma with wheezing and respiratory distress. Such subjects are also at risk for secondary bacterial infection with organisms such as Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae. Other complications include myositis, carditis, encephalopathy, and Guillain-Barre syndrome. Children are at risk of Reye’s syndrome which can follow influenza infection in those treated with aspirin. Symptoms include fever, vomiting, lethargy, seizure, and coma with a mortality rate of 40%. Death associated with influenza occurs most commonly in patients over the age of 65 and is secondary to bacterial pneumonia or cardiac related death.
Asthma represents the most common chronic disease of childhood. It is the third leading cause of hospitalization in children less than 15 years of age. In the USA, $3.2 billion is spent annually in health care costs, and it is associated with 14 million missed school days per year. There are approximately 5 new cases of asthma per 1000 population per year. Respiratory tract infections represent the most common trigger for acute asthma exacerbations, accounting for 60% of exacerbations in adults and up to 80% in children. In spite of this, only 29% of asthmatic and 10.3% of non-asthmatic children were vaccinated against influenza in 2007.
Two classes of antivirals are available to treat influenza infection, adamantanes and neuraminidase inhibitors. The adamantanes, amantidine and rimantidine, are effective in treating influenza A; however, neuraminidase inhibitors, oseltamivir and zanamivir, are effective to treat both influenza A and B. Both classes reduce the duration of influenza by 1 to 3 days, especially when given during the first 24 hours of symptoms. There is little or no benefit if therapy is started two days after symptoms begin. The most common adverse effect is gastrointestinal upset. Zanamivir can cause bronchospasm in subjects with asthma and oseltamivir has been linked to development of neuropsychiatric side effects in Japanese teenagers. Although these medications improve symptoms there is no firm benefit in preventing influenza-related complications such as pneumonia or secondary bacterial infection. However, oseltamivir does reduce mortality and length of hospitalization associated with influenza infection.
Resistance has become a significant problem for both classes of drugs, e.g., amantidine resistance by influenza develops within several days of use and is no longer recommended in the United States. Neuraminidase resistance is prevalent in many seasonal influenza strains, e.g. in 2008-2009, 91% of Philippino, 93% of Australian, and 100% of South African seasonal H1N1 influenza were resistant. Pandemic H1N1 is slightly resistant to neuraminidase inhibitors and resistance to oseltamivir is documented in influenza B.
Indications for antiviral use include patients that are at high risk of influenza-related complications including pregnant women, adults over 65, immunosuppresed subjects, and those with chronic medical conditions such as asthma and COPD. Antivirals should be used if a subject requires hospitalization, during severe or complicated infection, and during pregnancy or the two week postpartum period, even in mild disease.
Oseltamivir is the first line choice for seasonal H1N1 strains, but if regional resistance is high, zanamivir can be substituted. Zanamivir, however, is contraindicated in subjects with asthma and COPD because of its potential to cause bronchospasm. Oseltamivir can be combined with rimantidine or amantidine for those in whom zanamivir is contraindicated. All subjects should be treated for a total of five days.
Short-acting bronchodilators are indicated for short-term relief of symptoms such as cough and wheeze. Increased doses of inhalational corticosteroids or initiation of systemic corticosteroids may be indicated for more severe subjects who should also be closely monitored for complications such as viral pneumonia or secondary bacterial infection.
The WHO Influenza Surveillance Network works in conjunction with the U.S. Centers for Disease Control (CDC) to monitor circulating influenza strains in humans through 122 national monitoring centers in 94 countries. Data are published for the northern hemisphere in February and for the southern hemisphere in September. The WHO and CDC determine which strains pose the greatest risk for humans. Each year the seasonal influenza vaccine contains three strains: H3N2, H1N1, and influenza B. The 2010-2011 vaccine replaces seasonal H1N1 with the 2009 pandemic H1N1 strain.
There are two vaccines available: a trivalent, inactivated vaccine (TIV) and a live, attenuated vaccine (LIAV). The CDC recommends that all subjects over 6 months of age receive the influenza vaccine yearly. Contraindications to its use include a history of hypersensitivity to one of the vaccine components or Guillain-Barre syndrome developing within 6 weeks of a previous influenza vaccination. Specific contraindications to LIAV include uncontrolled asthma, HIV, regardless of CD4 count, and pregnancy.
Certain populations deserve further discussion:
There is a postulated risk of increased asthma exacerbations after influenza vaccination; however, a 2008 Cochrane review and a 2001 study by the American Lung Association Asthma Clinical Research Centers of over 2000 adults and children with asthma and COPD did not find an increased rate of exacerbation for two weeks following vaccination. Data on the effectiveness of the influenza vaccine in asthmatics is conflicting, with some studies demonstrating a decreased rate of exacerbations following vaccination, and some not. A 2003 case control study by Tata, et al. of adults with asthma and COPD found no reduction in severity of disease or fatal complications following influenza vaccination.
Because the live-attenuated vaccine can potentially cause an acute exacerbation, especially in uncontrolled asthmatics, they should receive the inactivated vaccine. Recommended doses of inhaled corticosteroids (ICS) do not decrease responsiveness to influenza A; however, a study by Hanania, et al. found that high dose ICS may decrease responsiveness to influenza B. High dose systemic corticosteroids (prednisone, 2mg/kg/day or equivalent corticosteroid) used to treat acute exacerbations do not reduce the immune response to the influenza vaccine.
Pregnant women are at high risk for complications associated with influenza infection. For example, in 2009, pregnant and postpartum women had more severe disease and accounted for 5% of all deaths following infection with pandemic H1N1 influenza. During the same year, over 20% of pregnant women infected with influenza were admitted to intensive care units. Because of the risk of severe disease, influenza vaccination is recommended for all pregnant women. LIAV should be avoided, but TIV can be given at any time during pregnancy.
Egg allergic subjects are more likely to have asthma and thus are at higher risk of complications associated with influenza infection; however, influenza vaccination is contraindicated because the vaccine is prepared in embryonated hen eggs and contains measureable levels of egg protein.
A study by James, et al. found that patients with a previous convincing history of egg allergy with either a positive egg food challenge or skin test to egg could safely receive the influenza vaccine if he/she had a negative influenza skin test and the vaccine contained less than 1.2mcg/ml of egg protein. Patients received the vaccine in two divided doses: 10% followed by the remaining 90%, thirty minutes later. Chung, et al. found that those without a history of anaphylaxis to egg could tolerate a divided dose influenza vaccine without prior skin testing.
It is important to determine the type of reaction that occurred following egg ingestion before considering influenza vaccination in an egg allergic subject. For example, if the subject is able to eat eggs or is egg-intolerant, i.e., does not have IgE-mediated allergic symptoms, the full dose vaccine can be given without further intervention. If a patient has a convincing history of egg allergy, he/she should first undergo skin testing to the influenza vaccine. If negative, the vaccine should be given in divided doses in a setting where the subject can be monitored for reaction. If the skin test is positive, the subject should proceed with influenza vaccine desensitization as outlined by Rank and Li.
Adults over 65
Adults over the age of 65 are at higher risk of complication associated with influenza infection and have lower antibody responses against hemagglutinin after vaccination. A high dose influenza vaccine is available for this population and contains 180mcg of hemagglutinin per dose compared to 45mcg present in the standard dose. This higher dose generates a better antibody response against hemagglutinin, although the vaccine is associated with a higher incidence of local reactions and fever. There are no studies regarding the efficacy of the high dose vaccine in preventing infection or influenza-related complications.
Influenza is an important respiratory pathogen that causes significant morbidity and mortality, especially in high-risk populations such as those with asthma. These subjects are also at higher risk for complications when influenza infection occurs. Treatment medications are available but a high rate of resistance limits their effectiveness. Therefore, vaccination remains the best strategy to reduce the burden of disease causes by this virus.
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