Viral infections of the lower respiratory tract are less common but generally more serious and, in some cases, may be life-threatening.

 Infections occur more frequently in the respiratory tract than in any other organ.1 The lung is normally a sterile environment, but infection may result from an alteration of normal host defense mechanisms, deterioration in general immune status, or, perhaps most common, exposure of an immunocompetent individual to a virulent organism that overwhelms host defenses.

Viral infections of the lower respiratory tract are less common than those of the upper system,2 largely because they are prevented by body defenses at the portal of entry. Lower respiratory-tract infections (LRTIs) are generally more serious and, in some cases, may be life-threatening. The four principal viruses that cause lower respiratory diseases in humans are influenza virus, respiratory syncytial virus (RSV), hantavirus, and the virus that causes severe acute respiratory syndrome (SARS), which has been provisionally named Urbani SARS-associated coronavirus.3

Typical influenza includes fever (usually 37.8°C to 39.4°C in adults and often even higher in children); respiratory symptoms such as cough, sore throat, and nasal congestion or rhinorrhea; headache and muscle aches; and, often, extreme fatigue. Most influenza patients recover completely in 1 to 2 weeks, but some develop serious, potentially life-threatening complications such as pneumonia.

Influenza is the sixth leading cause of death in the United States,4 and it has direct and indirect costs of more than $12 billion per year.5-7 Each year, 75 million work days and 53 million school days are lost as a direct result of influenza,5 and it accounts for 12% of medically attended illnesses.8 Influenza vaccine was one of several vaccines deemed most important in a 1999 report by the US Institute of Medicine.9 In this report, potential vaccines were evaluated in terms of their projected impact on morbidity and mortality, effects on health care costs, and estimated cost of development and administration.9

Influenza is an excellent example of the variable interactions that can occur between host and virus. Antigenic changes in influenza viruses are responsible for serious epidemics of the disease in human populations, and are likely to be responsible for the widespread influenza of the current season. Epidemics of influenza also occur in animals such as birds, seals, and pigs, and it is likely that antigenic variation of the virus is partly due to movement of viral genes from one animal species to another.

Influenza virus belongs to the orthomyxovirus family. Its nucleic acid consists of eight segments of single-stranded, negative-sense RNA. The envelope of the virus is derived from the host cell membrane, and projecting from each virion’s envelope are two types of glycoproteins, hemagglutinin (H) and neuraminidase (N). Hemagglutinin allows the virus to attach to specific receptors on ciliated epithelial cells of the host and initiate infection. Neuraminidase, on the other hand, is an enzyme that destroys the viral-specific cell receptor. This aids in the release of a newly formed virion from the infected host cell and allows the spread of the virus to uninfected cells.

Influenza viruses are divided into three types, designated A, B, and C. Influenza types A and B are responsible for epidemics of respiratory illness that occur almost every winter and are often associated with increased rates of hospitalization and death.10 Type C infection usually causes a very mild respiratory illness or no symptoms at all; it does not cause epidemics and does not have the severe public health impact of types A and B.

Influenza type A viruses are divided into subtypes based on differences in H and N. The currently seen subtypes of influenza A are designated A(H1N1) and A(H3N2). Influenza A(H1N1), A(H3N2), and influenza B strains are included in each year’s influenza vaccine. In the years since its emergence, influenza A(H3N2) epidemics have caused more than 400,000 deaths in the United States alone, and more than 90% of these deaths have occurred among people aged 65 years and older.10,11 Of the influenza viruses currently in worldwide circulation, A(H3N2) still has the most severe overall impact.

Influenza type A viruses undergo two kinds of changes. One is a series of mutations that occur over time and cause a gradual change (antigenic drift). This constant changing enables the virus to evade the immune system of its host so that people remain susceptible to influenza infection throughout life. A person infected by influenza develops antibodies against that virus; as the virus changes, the older antibody no longer recognizes the newer virus, and reinfection can occur. The older antibody can, however, provide partial protection against reinfection. The other kind of change is an abrupt change in the H and/or N proteins (antigenic shift). In this case, a new subtype of the virus suddenly emerges. Type A viruses undergo both antigenic shift and antigenic drift; type B viruses change only through antigenic drift.

Influenza is acquired by inhaling aerosolized respiratory secretions from a person with the disease. When a virion attaches to the host cell, the viral envelope fuses with the host cell membrane, and the virus enters the cell. Host-cell protein synthesis and nucleic acid synthesis stop, and rapid synthesis of viral nucleoproteins begins. Regions of the cell membrane become embedded with H and N. Within 6 hours, the mature virion buds from the host cell, receiving an envelope of cell membrane containing the viral glycoproteins H and N as they are released. The virus rapidly spreads to nearby cells. Infected cells ultimately die, destroying the mucociliary apparatus and severely impairing the body’s defense against infection. Immunocompetent individuals control the infection in the majority of cases, although complete recovery of the respiratory epithelium may take 2 months or longer.

Although influenza virus infection alone can kill apparently normal, healthy people, more often, death occurs because of secondary bacterial infections. The most common culprits are Staphylococcus aureus, Streptococcus pyogenes, or Haemophilus influenzae. Individuals whose hearts or lungs are weakened are particularly susceptible to infection.

Influenza Vaccine
Much of the illness and death caused by influenza can be prevented by annual influenza vaccination. Influenza vaccine is specifically recommended for people who are at high risk for developing serious complications of influenza infection.

Other groups for whom vaccine is specifically recommended are residents of nursing homes and other chronic care facilities housing patients of any age with chronic medical conditions, women who will be more than 3 months pregnant during the influenza season, and children and teenagers who are receiving long-term aspirin therapy and who may therefore be at risk for Reye syndrome after influenza. Influenza vaccine is also recommended for people who are in close or frequent contact with anyone in the high-risk groups.

Although annual influenza vaccination has long been recommended for people in high-risk groups, many still do not receive the vaccine. Some do not receive vaccine because they believe that it is not very effective. Overall vaccine effectiveness varies from year to year, depending on the degree of similarity between the virus strains included in the vaccine and the strain or strains that circulate during the influenza season. Because the vaccine strains must be chosen 9 to 10 months before the influenza season, and because influenza viruses mutate over time, sometimes mutations occur in the circulating strains between the time when vaccine strains are chosen and the end of the next influenza season. These mutations sometimes reduce the ability of the vaccine-induced antibody to inhibit the newly mutated virus, thereby reducing vaccine efficacy.

Efficacy also varies from one person to another. Studies12,13 of healthy young adults have shown influenza vaccine to be 70% to 90% effective in preventing illness during previous influenza seasons. In the elderly and those with certain chronic medical conditions, the vaccine is often less effective in preventing illness than in reducing the severity of illness and the risk of serious complications and death. Studies have shown the vaccine to reduce hospitalization by about 25% and death by about 60% among the elderly who are not in nursing homes.14 When antigenic drift results in the circulating virus becoming different from the vaccine strain, overall efficacy may be reduced, especially in preventing illness, but the vaccine is still likely to lessen the severity of the illness.

Beginning each September, influenza vaccine should be offered to people at high risk when they are seen by health care providers for routine care or as a result of hospitalization. The optimal time to vaccinate those in high-risk groups is usually October through mid November, since influenza activity in the United States generally peaks between late December and early March.

Although vaccine generally becomes available in August or September, vaccine availability in any location cannot be ensured consistently in the early fall. Therefore, the planners of large vaccination campaigns may consider scheduling these events for after mid October. Administering vaccine too far in advance of the influenza season should be avoided in facilities such as nursing homes because antibody levels can begin to decline within a few months of vaccination. If regional influenza activity is expected to begin earlier than December, vaccination programs can be undertaken as soon as the season’s vaccine is available.

The newly available intranasal vaccine consists of three influenza viruses that have stable cores but changeable coats. Scientists take internal proteins from master strains of influenza A and B viruses that have been adapted to grow at cooler temperatures and combine these with the H and N surface proteins of currently circulating influenza viruses. Each year, as needed, the surface proteins can be changed to match those of viruses expected to circulate during the upcoming flu season. Like the conventional inactive virus (injectable) vaccine, the intranasal live attenuated vaccine contains two different A strains and one B strain. In clinical trials,15,16 it has been shown to be up to 92% protective against culture-confirmed influenza.

Antiviral drugs for influenza are not a substitute for vaccination. Four licensed influenza antiviral agents are available in the United States: amantadine, rimantadine, zanamivir, and oseltamivir. According to the US Centers for Disease Control and Prevention (CDC),17 when antiviral drugs are used for the treatment of influenza within 48 hours of the onset of illness, they can decrease the duration of clinical illness by an average of 1 to 2 days and can reduce virus shedding.

Respiratory illness of unknown etiology with onset since February 1, 2003, and meeting the following criteria:
•     measured temperature of more than 38°C;
•    one or more clinical findings of respiratory illness (cough, shortness of breath, difficulty breathing, hypoxia, or radiographic findings of either pneumonia or acute respiratory distress syndrome);
•     travel within 10 days of onset of symptoms to an area with suspected or documented community transmission of SARS, or close contact* within 10 days of onset of symptoms with either a person with a respiratory illness and travel to a SARS area or a person under investigation or suspected of having SARS.
*Close contact is defined as having cared for, having lived with, or having had direct contact with respiratory secretions and/or body fluids of a patient suspected of having SARS.
Updated interim definition for severe acute respiratory syndrome (SARS). Adapted from MMWR Morb Mortal Wkly Rep.24

RSV Infection
RSV infection ranks first among serious LRTIs of infants and young children, causing an estimated 90,000 hospitalizations and 4,500 deaths in the United States each year.18,19 It is the major life-threatening pathogen in children under 1 year of age. The estimated risk of hospitalization of infants infected with RSV ranges from 1 in 50 to 1 in 200 infants.19 Of infants who contract RSV, 50% will develop LRTIs.20 Children less than 1 year old who develop RSV pneumonia and survive may suffer permanent brain damage. The severity of RSV infection diminishes greatly after 1 year of age; by age 3, RSV infections are usually no more serious than the common cold. RSV also can cause serious illness in the elderly.

RSV is a member of the paramyxovirus family and contains single-stranded, nonsegmented, negative-sense RNA. RSV is an enveloped virus, but does not contain the glycoproteins H and N. Instead, the virus envelope has surface spikes called fusion (F) glycoproteins. The F proteins cause the viral envelope to fuse with the cytoplasmic membrane of the host cell and also cause infected cells to fuse together. The clumps of fused cells are known as syncytia.

RSV enters the body by inhalation and infects the respiratory tract epithelium, causing cellular death and sloughing. Bronchiolitis is a common feature of the disease. The infected bronchioles become partially closed by cellular debris, mucus, and clotted plasma that has leaked from the walls of the bronchi. The initial obstruction causes wheezing when air rushes through the narrowed passageways, often causing the condition to be confused with asthma. The obstruction acts like a one-way valve, allowing air to enter the lungs, but not to leave. In many cases, the inflammation extends into the alveoli, causing pneumonia. There is high risk of secondary infection because of the damaged mucociliary escalator.

Treatment of patients with RSV is necessary to relieve symptoms and reduce the likelihood of long-term illnesses caused by RSV. The treatment of mild cases of RSV usually focuses on relieving the symptoms. Cough and cold medicines and bronchodilators such as metaproterenol or albuterol may help relieve chest congestion and wheezing. Whether epinephrine has a therapeutic role in the management of acute bronchiolitis is controversial.21 For more severe cases of RSV, hospitalization and antiviral therapy may be indicated.

In the spring of 1993, a brief epidemic of hantavirus pulmonary syndrome (HPS) occurred among Native Americans living in the southwestern United States. It was named the four corners disease for its occurrence where Arizona, Colorado, New Mexico, and Utah meet. The initial outbreak involved fewer than a dozen young, healthy Navajos who presented with influenza-like symptoms, but were dead within a week. The CDC, along with area health officials and epidemiologists, quickly established that airborne viral particles from the dried urine and feces of rodents (especially deer mice) were the vector for the virus. Immunological studies of the victims indicated that the virus was related to a hantavirus that had plagued US troops in Korea during the 1950s. By the end of 1993, 91 cases of HPS had been confirmed in 20 states, resulting in 48 deaths. As of January 2002, 289 cases had been reported from 31 states.

The causative viral agents are the sin nombre virus, Muerto Canyon virus, and various related hantaviruses that exist at different locations in the Western hemisphere. Hantaviruses are enveloped members of the bunyavirus family. Their genome consists of three segments of single-stranded, negative-sense RNA. In nature, these organisms cause lifetime infections in rodents, without any apparent harm to the animals.

Hantavirus enters the body through inhalation of air containing dust contaminated with the urine, feces, or saliva of infected rodents. The virus enters the circulation through a process that is not fully understood and is carried throughout the body, thereby infecting the cells that line tissue capillaries. Massive amounts of the viral antigen appear in lung capillaries (and, to a lesser extent, in heart and other organ capillaries). The inflammatory response to the viral antigen causes the capillaries to leak large amounts of plasma into the lungs, causing acute respiratory failure. Shock and death occur in more than 40% of cases.22,23 Luckily, despite the large amount of viral antigen in the lung capillaries, few mature infectious viral particles enter the bronchi of the lung; thus, person-to-person transmission rarely occurs.

Early symptoms of HPS include fatigue, fever, and muscle aches, particularly in the large muscle groups (thighs, hips, back, and sometimes shoulders). There may also be headaches, dizziness, chills, and abdominal problems such as nausea, vomiting, diarrhea, and abdominal pain. Four to 10 days after the initial phase of illness, the late symptoms of HPS appear. These include coughing, shortness of breath, and tightness around the chest (a hallmark of the disease). There is no specific treatment, cure, or vaccine for hantavirus infection. If infected individuals are identified early and receive medical care in an intensive care unit, they may survive. In intensive care, patients are intubated and given oxygen therapy to help them through the period of severe respiratory distress. The earlier the patient is brought to the intensive care unit, the better. If a patient is experiencing total respiratory distress, it is less likely that the treatment will be effective.

SARS Characteristics
SARS is an acute respiratory syndrome of unknown etiology. To date, more than 4,400 suspected SARS cases have been reported to the World Health Organization (WHO), primarily from locations in Asia, North America, and Europe.24,25 To date, most cases have occurred in China (2,422), Hong Kong (1,488), and Singapore (192).25 There have been 140 cases in Canada and 37 in the United States.25 Clusters of SARS-infected people have been identified, suggesting that SARS is highly contagious. A fatality rate of 3% to 4% has been observed in patients with SARS.24

Coronaviruses are large, enveloped, plus-stranded RNA viruses that cause disease in humans and domestic animals. They were given their name due to the unusual petal-shaped projections that emanate from their envelope, giving the virus the appearance of a solar corona. The virus is roughly spherical, with long, helical nucleocapsids, and can range in size from 60 nm to 220 nm.26 Coronaviruses have the largest genome of all RNA viruses and display a unique replication strategy, genome organization, and mRNA structure that results in a high frequency of genetic recombination.26 The frequency with which genetic recombination between the genomes of different but related coronaviruses produces a virus with new biological properties can be as high as 25%.27 Viral progeny are produced in the cytoplasm and are released by exocytosis, eventually killing the infected cell.

Different members of the coronavirus family display specificity for the respiratory tract, gastrointestinal organs, liver, or brain. Until now, no evidence was obtained to link human coronavirus with any human disease other than the common cold.

The primary mode of spread of SARS is through respiratory secretions. Close person-to-person contact is usually needed. Touching the skin of other people or objects contaminated with the virus and then touching the eyes, nose, or mouth may spread SARS. This can happen when those who are ill with SARS sneeze, cough, or talk respiratory droplets onto themselves, other people, or nearby surfaces.

The majority of patients with SARS have been adults aged 25 to 70 years who were previously healthy. The incubation period for SARS is typically 2 to 7 days; however, some reports have suggested an incubation period as long as 10 days.28

The WHO has provided an updated clinical definition of SARS, which is shown in the table.24 SARS typically begins with a prodrome of high fever that may be accompanied by chills, rigors, headache, malaise, and myalgia. Some patients experience mild respiratory distress at the onset of illness. Rash and gastrointestinal findings are normally absent. The severity of SARS is highly variable, ranging from mild illness to death.

Approximately 3 to 7 days after the onset of symptoms, a lower-respiratory phase begins. This phase is characterized by a dry, nonproductive cough and/or dyspnea, which may progress to hypoxemia. In 10% to 20% of cases, SARS is severe enough to require intubation and mechanical ventilation.25

Chest radiographs may be normal during the prodrome and throughout the course of illness. In many patients, however, the lower-respiratory phase is characterized by early focal interstitial infiltrates that can progress to more generalized patchy interstitial infiltrates. In the late stages of SARS, chest radiographs may show areas of consolidation.

No specific treatment recommendations can be made at this time. Empiric therapy should include coverage for organisms associated with any community-acquired pneumonia of unclear etiology, including agents with activity against both typical and atypical respiratory pathogens.29 Treatment choices may be influenced by severity of the illness. Infectious disease consultation is recommended. The CDC requests that health care personnel who suspect cases of SARS report them to their state health departments immediately. State health departments, international airlines, cruise ships, and cargo carriers are asked to report the cases directly to the SARS Investigative Team at the CDC Emergency Operations Center by telephoning (770) 488-7100.

Influenza, RSV infection, HPS, and SARS represent the major viral LRTIs. Influenza accounts for the vast majority of viral lower respiratory infections. Clinicians should recommend influenza vaccine to appropriate patients. Early postmarketing surveillance of the new intranasal influenza vaccine has been extremely favorable, and practitioners may want to consider this alternative, particularly in children 5 years of age and older.

Phyllis C. Braun, PhD, is professor, Department of Biology, Fairfield University, Fairfield, Conn. John D. Zoidis, MD, is a contributing writer for RT.

1. File TM. Viral respiratory tract infections: increasing importance and a new pathogen. Curr Opin Infect Dis. 2003;16:125-127.
2. Fendrick AM, Saint S, Brook I, Jacobs MR, Pelton S, Sethi S. Diagnosis and treatment of upper respiratory tract infections in the primary care setting. Clin Ther. 2001;23:1683-1706.
3. Ksiazek TG, Erdman D, Goldsmith CS, et al. A novel coronavirus associated with severe acute respiratory syndrome. N Engl J Med. 2003;348:19647-1958.
4. US Department of Health and Human Services, Centers for Disease Control and Prevention. Health, United States, 1998. Atlanta: CDC; 1999.
5. Nichol KL, Mallon KP, Mendelman PM. Cost benefit of influenza vaccination in healthy, working adults: an economic analysis based on the results of a clinical trial of trivalent live attenuated influenza virus vaccine. Vaccine. 2003;21:2207-2217.
6. Neuzil KM, Mellen BG, Wright PF, Mitchel EF Jr, Griffin MR. The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N Engl J Med. 2000;324:225-231.
7. Neuzil KM, Reed GW, Mitchel EF Jr, Griffin MR, et al. Influenza-associated morbidity and mortality in young and middle-aged women. JAMA. 1999;281:901-907.
8. Glezen WP. Emerging infections: pandemic influenza. Epidemiol Rev. 1996;18:64-76.
9. Marwick C. IOM Committee gazes into new vaccine future. JAMA. 1999;281:1367-1372.
10. Izurieta HS, Thompson WW, Kramarz P, et al. Influenza and the rates of hospitalization for respiratory disease among infants and young children. N Engl J Med. 2000;342:232-239.
11. Benson V, Marano MA. Current estimates from the National Health Interview Survey, 1995. Vital Health Stat. 1998;10:1-428.
12. Vu T, Farish S, Jenkins M, Kelly H. A meta-analysis of effectiveness of influenza vaccine in persons aged 65 years and over living in the community. Vaccine. 2002;20:1831-1836.
13. Hurwitz ES, Haber M, Chang A, et al. Studies of the 1996-1997 inactivated influenza vaccine among children attending day care: immunologic response, protection against infection, and clinical effectiveness. J Infect Dis. 2000;182:1218-1221.
14. Nordin J, Mullooly J, Poblete S, et al. Influenza vaccine effectiveness in preventing hospitalizations and deaths in persons 65 years or older in Minnesota, New York, and Oregon: data from 3 health plans. J Infect Dis. 2001;184:665-670.
15. Belshe RB, Gruber WC. Safety, efficacy and effectiveness of cold-adapted, live, attenuated, trivalent, intranasal influenza vaccine in adults and children. Philos Trans R Soc Lond B Biol Sci. 2001;356:1947-1951.
16. Belshe RB, Mendelman PM, Treanor J, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. N Engl J Med. 1998;338:1405-1412.
17. Centers for Disease Control and Prevention. Influenza antiviral medications: interim chemoprophylaxis and treatment guidelines. 2003. Available at: Accessed February 23, 2004.
18. Deshpande SA, Northern V. The clinical and health economic burden of respiratory syncytial virus disease among children under 2 years of age in a defined geographical area. Arch Dis Child. 2003;88:1065-1069.
19. Leader S, Kohlhase K. Recent trends in severe respiratory syncytial virus (RSV) among US infants, 1997 to 2000. J Pediatr. 2003;143:S127-S132.
20. Nielsen HE, Siersma V, Andersen S, et al. Respiratory syncytial virus infection—risk factors for hospital admission: a case-control study. Acta Paediatr. 2003;92:1314-1321.
21. Hartling L, Wiebe N, Russell K, Patel H, Klassen TP. A meta-analysis of randomized controlled trials evaluating the efficacy of epinephrine for the treatment of acute viral bronchiolitis. Arch Pediatr Adolesc Med. 2003;157:957-964.
22. Riquelme R. Hantavirus pulmonary syndrome, southern Chile. Emerg Infect Dis. 2003;9:1438-1443.
23. Simmons JH, Riley LK. Hantaviruses: an overview. Comp Med. 2002;52:97-110.
24. Update: outbreak of severe acute respiratory syndrome—worldwide, 2003. MMWR Morb Mortal Wkly Rep. 2003;52:241-248.
25. World Health Organization. SARS: cumulative number of reported probable cases. Available at: sars/map2003_04_24.gif. Accessed February 23, 2004.
26. Peiris J, Lai S, Poon L, et al. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet. 2003;361:1319-1325.
27. Lai MM. Genetic recombination in RNA viruses. Curr Top Microbiol Immunol. 1992;176:21-32.
28. Preliminary clinical description of severe acute respiratory syndrome. MMWR Morb Mortal Wkly Rep. 2003;52:255-256.
29. Centers for Disease Control and Prevention. Severe acute respiratory syndrome (SARS): treatment. Available at:
sars/treatment.htm. Accessed February 23, 2004.
30. Centers for Disease Control and Prevention. Influenza: the disease. Available at: Accessed February 23, 2004.