Respiratory Viruses 11 Influenza

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Of the viral infections that cause disease in older adults, influenza is recognized as one of the greatest causes of morbidity and mortality. Pneumonia and influenza together comprise the fifth leading causes of death in persons aged 65 yr and older. Influenza viruses are enveloped ribonucleic acid (RNA) viruses that are classified as A, B, or C, based on stable internal proteins (1). The virus contains two major surface proteins, hemagglutinin (H) and neuraminidase (N), which can undergo minor antigenic changes leading to yearly epidemics or major changes resulting in influenza pandemics. Currently, there are two circulating influenza A viruses, H1N1 and H3N2, in addition to influenza B, present in the United States. H1N1 viruses do not appear to cause serious problems in older persons, possibly due to previous immunity (2).

1.1.1. Epidemiology and Clinical Relevance

Peak influenza activity typically lasts 6-8 wk in a community with attack rates highest in preschool and school-aged children and lowest in older persons. During non-pandemic influenza, attack rates are approx 10% in the elderly (3). Despite lower attack rates, hospitalization rates and complications are highest in this age group (4). Mortality from influenza rises dramatically with age and the presence of underlying medical conditions contribute significantly to influenza-related mortality (5). The presence of one high-risk medical condition (cardiovascular, pulmonary, renal, metabolic, neurologic, or malignant disease) increases the risk of death from influenza 39-fold. The devastating impact of influenza is most dramatically seen in long-term care facilities where explosive epidemics may occur. During outbreaks, rates of pneumonia and hospitalization are as high as 52% and 29%, respectively, with case fatality rates of 30% (6). In addition to the suffering caused by influenza, the economic burden is enormous, resulting in more than one billion dollars spent by Medicare in 1989-1990 alone for excess hospitalizations (7).

From: Infectious Disease in the Aging Edited by: Thomas T. Yoshikawa and Dean C. Norman © Humana Press Inc., Totowa, NJ

Table 1

Respiratory Viral Infections

Table 1

Respiratory Viral Infections

Peak season

Incubation (d)

Clinical clues

Antiviral therapy

Influenza A

Winter

1-3

High fever, headache,

Amantadine

myalgias

Zanamivir, Oseltamivir

Rimantadine

Zanamivir, Oseltamivir

Influenza B

Winter

1-3

High fever, headache,

Zanamivir, Oseltamivir

myalgias

RSV

Winter

3-5

Rhinorrhea, wheezing

Ribavirin

Parainfluenza

Fall-spring

1-2

Pharyngitis, hoarseness

None

Rhinovirus

All

1-2

Rhinorrhea

None

Coronavirus

Winter-spring

1-2

Non-specific

None

RSV, respiratory syncytial virus.

RSV, respiratory syncytial virus.

1.1.2. Clinical Manifestations

The classic presentation of influenza is that of the abrupt onset of fever, chills, headache, and myalgias (see Table 1). Dry cough, sore throat, and ocular pain are also common (1). Although nasal congestion and discharge occur with influenza, rhinor-rhea is usually not as profuse as with other respiratory viruses. Fever remains a common finding in the elderly, although the height of the fever may be lower compared with young persons. Although many elderly adults have classic influenza symptoms, a substantial number may have more subtle presentations such as fever and confusion or worsening of chronic cardiopulmonary disease. Thus, it is important to consider the possibility of influenza in the ill elderly adult during the winter months.

Lower respiratory tract involvement increases steadily with advancing age with the rates of pneumonia 4-8% in persons aged 5-50 yr and rising to 73% in persons over age 70 (1). Secondary bacterial pneumonia following acute influenza also occurs more frequently in older persons. In addition to the immediate complications of influenza, residents of nursing homes who survive influenza experience a significant functional decline in activities of daily living (8).

1.1.3. Diagnostic Tests

The diagnosis of influenza can be made in a variety of ways including viral culture, rapid antigen testing, and serology. Although many physicians use clinical features to make a diagnosis of "the flu," laboratory confirmation is best if therapeutic decisions are needed, as influenza may be difficult to distinguish from other respiratory viruses. Virus can be detected in nasopharyngeal secretions or sputum. Older persons typically shed less virus than young persons but will have culturable virus for 3-4 d into the illness (9). Rapid antigen testing may be done directly on nasopharyngeal specimens using an enzyme immunoassay (EIA) (10). Although not as sensitive as viral culture, rapid tests offer several hour turnaround times and may be useful for infection control and treatment decisions (11). Influenza infection can also be confirmed retrospectively by demonstrating a greater than fourfold rise in antibody by hemagglutination inhibi tion assay or enzyme immunoassay (EIA). A single acute titer is not useful for diagnosis of influenza, as all persons have preexisting antibodies.

1.1.4. Treatment

At the present time, four antiviral agents, amantadine, rimantadine, zanamivir, and oseltamavir are approved for the treatment of influenza A. These agents are 70-90% effective as prophylactic agents and also reduce illness severity, duration of symptoms, and viral shedding when given within 48 h of symptom onset (12). Central nervous symptoms are a problem in older persons given amantadine. Rimantadine is more costly but appears to be better tolerated. Although resistance develops rapidly on therapy with either agent, a net therapeutic benefit is preserved (13). The appropriate dose of amantadine or rimantadine for most elderly persons is 100 mg/day taken orally with further dose adjustments necessary for amantadine based on renal function. Zanamivir and oseltamavir are new agents that inhibit the action of viral neuraminidase and show promise for prophylaxis and treatment of influenza A or B (14-16). Resistance and central nervous system side effects do not appear to be a problem.

1.1.5. Prevention

The cornerstone of infection control in long-term care facilities is yearly vaccination of residents and staff. (See also Chapter 23.) In addition, the Centers for Disease Control and Prevention (CDC) recommends that antiviral prophylaxis be given to all residents once influenza A has been documented in the institution (17). Chemoprophylaxis is given regardless of vaccination status and is continued until 1 wk after the onset of the last influenza case. Because some authorities remain concerned about adverse side effects of amantadine, more conservative approaches have been put forward that recommend antivirals to those ill less than 48 h and to their roommates and reserve institutionwide prophylaxis only when more than 10% of residents are ill (18).

Influenza vaccination has been clearly shown to be efficacious and cost effective in older persons and is recommended for all persons aged 65 and older (17,19). Although serologic response is diminished in residents of nursing homes, vaccination reduces the severity of disease and prevents hospitalization and death (17). The current vaccine contains antigens from two type A and one type B viruses. Mild acute local reactions occur in approx one third of vaccinees and systemic reactions, such as fever and myalgias are uncommon in older persons. Influenza vaccine may be safely given simultaneously with pneumococcal vaccine, and the only contraindication to vaccination is anaphylactic hypersensitivity to eggs or other components of the vaccine (17).

1.2. Respiratory Syncytial Virus 1.2.1. Epidemiology and Clinical Relevance

RSV is an enveloped RNA virus that belongs to the paramyxovirus family and consists of two antigenically distinct groups, designated A and B. RSV has long been recognized as the leading cause of lower respiratory tract disease in children; however, recently, it has been increasingly implicated as a cause of serious disease in elderly persons (20). Although the magnitude of the problem of RSV in the elderly has not been completely defined, it appears to rank second to influenza as a major viral respiratory pathogen in this group (21,22).

RSV was initially recognized as a pathogen in older persons when several outbreaks were described in long-term care facilities (23,24). Since 1977, there have been 20 studies published that have identified RSV infections in nursing homes (25-29). Attack rates are variable and may be as high as 90% during outbreaks, but are more commonly range from 1-7% when residents are followed prospectively (28,30). Rates of pneumonia range from 0-53% and death from 0-55% in published reports (28,31,32). The variable severity may be in part due to case selection bias in some studies, but also may reflect differences in strain virulence. In addition to long-term care facilities, RSV has also been found to be a frequent problem in senior daycare centers (33).

Although less data are available, RSV appears to cause serious disease in community-dwelling older persons as well (21,22). Similar to influenza, when peaks of RSV activity occurred among children in the United Kingdom, a peak in excess acute respiratory infection and mortality occurred in persons aged 65 and older (22). In a 3-yr study examining persons aged 65 and older admitted to the hospital with acute cardiopulmonary conditions, RSV accounted for 10% of cases compared with 13% due to influenza A or B (21). The impact of RSV illness was significant; 18% required intensive care, 10% needed ventilatory support, and 10% died. Finally, a large study of community-acquired pneumonia in adults found RSV to be the third most commonly identified pathogen at 4.4% compared to 6.2% due to Streptococcus pneumoniae and 5.4% due to influenza (34). A recent analysis of the economic burden of RSV in adults concluded that 0.04-0.2% of the population 65 yr of age and older are hospitalized yearly with RSV pneumonia with estimated annual health-care costs of $150-680 million (35).

1.2.2. Clinical Manifestations

Manifestations of RSV infection can be difficult to distinguish from other viral respiratory infections, particularly influenza. Most individuals with RSV have nasal discharge, cough, sputum production, and constitutional symptoms (21,34). In addition, wheezing is a frequent complaint (30). Fever is present in approx half of the cases but is usually lower than in influenza infection. Although overlap exists, there are some helpful clues to differentiate RSV from influenza. High fever, sore throat, myalgias, and gastrointestinal complaints are more characteristic of influenza, whereas rhinor-rhea and wheezing are more frequently associated with RSV infection (21,27,34).

1.2.3. Diagnostic Tests

The diagnosis of RSV infection can be accomplished by viral culture, rapid antigen tests, or serology. Unfortunately, because of the labile nature of the virus and low titers of virus in nasal secretions in adults, diagnosis of acute RSV infection is very difficult. Under ideal circumstances, viral culture is only 50% sensitive when compared with serology using EIA (30). Both commercial rapid antigen tests and indirect immunofluorescence have poor sensitivity in adults (36). New molecular tests, such as polymerase chain reaction (PCR), may offer a significant advantage for the diagnosis of acute RSV in this population and need further development. Infection can also be demonstrated retrospectively by a >fourfold rise in RSV-specific IgG, either by complement fixation or EIA. Because RSV in adults always represents reinfection, a single elevated titer is not useful for acute diagnosis. RSV-specific IgM has been detected in 11-81% of older subjects with acute RSV, but its clinical utility has yet to be defined (26,37).

1.2.4. Treatment

The treatment of RSV infection in adults is largely supportive. Supplemental oxygen and bronchodilators may be useful and antibiotics should be considered if bacterial super-infection is suspected. Ribavirin is a nucleoside analogue which has broad antiviral activity, including RSV (38). Although inhaled ribavirin is approved in young children with RSV, no controlled data exist in adults. Anecdotal experience suggests it may be beneficial in selected cases; however, general recommendations on its use cannot be made due to lack of data (39). Although relatively nontoxic, the major problems with ribavirin are its high cost and difficulty with administration. The recommended 12-18 h/d of aerosol at 20 mg/mL concentrations may be quite difficult for the elderly adult to tolerate. Recent data indicate that higher concentrations (60 mg/mL) given three times a day may also be effective.

1.2.5. Prevention

Although research is ongoing, an effective RSV vaccine has yet to be developed. Thus, prevention of RSV is limited to good basic infection control policies. RSV is spread primarily by large droplet inoculation and fomites. Therefore, close person-to-person contact or contact with contaminated environmental surfaces is required for transmission to occur. Handwashing is the single most important measure in the control of RSV. Because compliance with hand washing is frequently poor, some authorities advocate the use of gowns and gloves when caring for RSV-infected patients (40).

1.3. Parainfluenza Viruses

1.3.1. Epidemiology and Clinical Relevance

The parainfluenza viruses (PIV) are most commonly thought of as the etiologic agents of croup, bronchiolitis, and pneumonia in young children. Although comprehensive studies are lacking, these common respiratory viruses also affect older adults. The parainfluenza viruses are members of paramyxovirus family with four serotypes and two subgroups recognized (1, 2, 3, 4a, and 4b); PIV-3 is endemic throughout the year, whereas PIV-1 and PIV-2 tend to occur during the fall. Most reinfections in young adults result in mild upper respiratory infections; however, occasional outbreaks of pneumonia have been described (41). Although PIV infections are not commonly documented in older adults, several studies of community-acquired pneumonia implicate PIV as a cause in 2-11% of cases (42,43). The PIV-1 and 3 serotypes account for the majority of isolates in older persons, with PIV-2 being relatively uncommon (44).

1.3.2. Clinical Manifestations

Similar to RSV, outbreaks of PIV infections in nursing homes have been described (44-46). High attack rates and significant morbidity and mortality have been reported. Clinical characteristics of PIV infection are not distinctive and include rhinorrhea, sore throat, hoarseness, and cough with high rates of pneumonia ranging from 20-30%. In a recent institutional outbreak of PIV-3, the attack rates among residents and nursing staff were 31% and 11%, respectively. The epidemic pattern, with a steady number of new cases over a 1-mo period, suggested person-to-person transmission (46).

1.3.3. Diagnostic Tests and Treatment

Diagnosis of PIV infection can be made by viral culture or by demonstrating a rise in serum antibody by EIA or complement fixation. Both PIV-1 and 3 infections result in cross-reactive antibody responses and, thus, cannot be distinguished serologically. At present, a rapid antigen test for PIV is not commercially available and no antiviral agents have been approved for the treatment of PIV infection. Therefore, treatment is supportive

1.4. Rhinoviruses

1.4.1. Epidemiology and Clinical Relevance

Rhinoviruses are the most commonly identified cause of the "common cold," accounting for approx 25-50% of upper respiratory infections (47). These ubiquitous viruses are members of the picornavirus family with over 100 antigenic types. Rhinoviruses circulate at all times of the year, but peak activity tends to be during the spring and fall. Infections with rhinoviruses are common throughout life and, although a major cause of school and work absenteeism, illnesses are generally mild in young persons (48). Pneumonia due to rhinovirus is very uncommon, even in immunocompromised persons and is likely because the virus does not replicate well at the lower airway temperature of 37°C (49).

There are little data on the incidence of rhinovirus infections in independent elderly persons living in the community. However, a recent prospective study from the United Kingdom indicates that rhinoviruses are an important cause of debility and lower respiratory disease in elderly people in the community (50). Rhinoviruses accounted for 121 of 497 (24%) respiratory illnesses that occurred in a cohort of 533 persons over a 2-yr period. Seminested reverse transcriptase (RT)-PCR was used to identify rhinovirus infection and the increased sensitivity of this technique was likely responsible for the high infection rates. Although death and hospitalization rates were low, the mean length of illness was 16 d and 26% were unable to perform their normal household activities. Fifty-six percent had evidence of lower respiratory tract involvement such as productive cough or wheezing. The presence of chronic medical conditions and smoking increased the likelihood of lower respiratory tract complications. Because of the frequency of rhinovirus infection, the overall burden of disease in the elderly may approach influenza (50).

1.4.2. Clinical Manifestations

Rhinovirus infections are also common in senior daycare settings and long-term care facilities (30,51,52). In frail elderly persons, nasal congestion (79-89%), cough (71-94%), constitutional symptoms (43-91%) and sore throat (21-51%) characterize illnesses. Similar to independent seniors, illnesses were prolonged, lasting approx 2 wk and approx 50% had lower respiratory involvement.

1.4.3. Diagnostic Tests and Treatment

The diagnosis of rhinovirus is usually made by viral culture of nasopharyngeal secretions. Although the use of RT-PCR greatly increases detection rates, this technique is currently only available in research settings (50). Treatment is supportive and care should be exercised when prescribing "cold" medications to elderly persons as many contain combinations of sympathomimetics and antihistamines. At the present time, specific antiviral therapy of rhinoviruses is not available. Recently, a new compound, tremacamra, which blocks the cellular receptor for rhinovirus, intercellular adhesion molecule 1 (ICAM), shows promise for the treatment of rhinovirus infections (53).

1.5. Coronaviruses

Coronaviruses are RNA viruses of which two major serotypes, 229E and OC43, cause respiratory disease in humans (54). Peak viral activity occurs in the winter and spring (55). Reinfections with coronaviruses are common throughout life, and similar to rhinoviruses; illnesses are generally mild upper respiratory infections in healthy adults. Symptoms include malaise, headache, sore throat, and nasal congestion (54). Exacerbations of chronic obstructive pulmonary disease have been linked to coronavirus infections in several studies (56).

Coronavirus infections have been evaluated in the community-dwelling elderly in one prospective study from the U.K. and accounted for 9.5% of the respiratory illnesses (57). They were associated with lower respiratory tract symptoms in more than 40% of cases. Coronavirus infections have been documented in long-term care facilities and in frail elderly people attending daycare centers (52,58). The most common symptoms were cough (94%), constitutional symptoms (88%), and nasal congestion (84%). Significantly, 66% had a productive cough, 34% experienced shortness of breath, and 22% developed wheezing. Illnesses lasted approx 2 wk and almost half of the patients required antibiotics. Although many of the subjects were very frail, all recovered without sequelae. Unfortunately, diagnosis of coronavirus infections is not generally available outside of research facilities due to the fastidious nature of the virus and the lack of commercial reagents for serologic diagnosis. No antiviral agents are available and treatment is supportive.

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