Chapter 130: Influenza and Respiratory Syncytial Virus

Viruses are an important threat to the health of older adults. Each year, it is estimated that influenza alone is associated with the death of 36,000 older adults in the United States. Despite immunization, outbreaks of influenza occur regularly in nursing homes and other long-term care facilities. This section of the chapter summarizes the biological, epidemiological, and clinical features of influenza that are relevant to older adults, with a particular emphasis on prevention.

Clinically Relevant Biologic Characteristics of Influenza Virus

To properly understand the impact of influenza in older adults, it is important to be familiar with several key characteristics of the virus. The structure of influenza consists of an envelope with a central nucleic acid core comprised of single-stranded RNA that encodes key structural proteins of the virus including hemagglutinin and neuraminidase on the envelope. There are three types of influenza viruses A, B, and C. However only A and B are clinically relevant. Influenza A viruses are characterized by the structure of the hemagglutinin, a surface protein that binds glycoprotein on the surface of respiratory epithelial cells, allowing the virus to enter by forming an endosome and then using the protein making machinery of the cell to replicate itself. Annually new mutations occur resulting in small changes in the hemagglutinin (“antigenic drift”) hence the reason why influenza vaccine needs to be reformulated and given annually. The other surface projection, neuraminidase, cleaves terminal sialic acid residues from carbohydrate moieties on surfaces of infected cells, promoting the release of virions that go on to infect other cells. As discussed below, this is a key target for neuraminidase inhibitors (eg, oseltamivir, zanamivir), thus preventing the influenza virus from replicating.

An important feature of influenza is the segmented structure of the RNA at the core of the virus, with each of eight segments coding for a structural or enzymatic component of the virus. This gives the virus the potential to recombine with influenza viruses of animal origin, forming a virus with a novel genotype and hemaglutinnin to which there is no preexisting immunity. This is known as “antigenic shift” and was responsible for pandemics in 1957–1958, 1968–1969, and 2009. Of note, the highest mortality rates occurring in the 1918–1919 and the 2009 pandemics were not in older adults, but in younger adults, perhaps due to cross protection from the many influenza strains to which older adults were exposed over a lifetime. However, mortality in interpandemic periods is highest in those at the extremes of age. At present, there are only three hemaglutinins (H1, H2, H3) and two neuraminidases (N1, N2) that have developed a stable lineage in humans.

General Epidemiology of Influenza

Epidemics of influenza occur annually between November and April in the Northern Hemisphere. In any given season, there may be several strains circulating, hence the annual influenza vaccine contains multiple influenza strains.

Important Host Considerations in Older Adults

During the interpandemic period, older adults and particularly residents of long-term care facilities are equally likely to contract influenza as young, healthy adults, but are among those at highest risk for complications of influenza. Rates of hospitalization for influenza in older persons range from 136 to 508 per 100,000 persons versus 10 to 25 for those 5 to 49 years of age. The presence of chronic conditions, such as chronic lung disease, congestive heart failure, conditions that predispose to aspiration (eg, stroke), and metabolic disease, increase the risk for complications following infection with influenza. Many of these conditions occur predominately in older age groups. Moreover, studies that have assessed complications have found that age older than 65 years alone is independently associated with increased risk for influenza complications.

Based on our current understanding, the cause of death as a result of influenza in older adults in the interpandemic period includes viral pneumonia, a bacterial infection complicating the influenza infection, myocardial infarction, stroke and exacerbation of underlying comorbid conditions. Infection with influenza virus predisposes to Streptococcus pneumoniae or Staphylococcus aureus infection, which most often results in bacterial pneumonia. Deficits in innate immunity (phagocytes, natural killer cells) and acquired immunity (T-cell function, cytokine activity, antibody response) are all felt to play a role, as discussed in Chapter 3.

Clinical Presentation

Young, healthy individuals with influenza characteristically present with a sudden onset of fever, cough, myalgia, sore throat, and headache. Fever and cough have been shown in a systematic review to be the best predictors of influenza in the general population. In older adults, the presentation maybe more subtle with cough and change in baseline temperature predominating. Often times, older adults present with worsening of comorbid conditions such as a chronic obstructive pulmonary disease or congestive heart failure exacerbation. One of the most important factors in making the diagnosis of influenza, whether on clinical grounds or through diagnostic testing, is the local influenza activity. That is, if a community is experiencing an outbreak of influenza, particularly if the incidence of influenza is at its peak, fever and cough in an older person increase the likelihood of infection with influenza. In the nursing home setting, it is essential to obtain prompt diagnostic testing, because, as consistently demonstrated in longitudinal studies that have tied symptoms with specific etiologic agents, the clinical presentation is nonspecific. Even when there are peaks of influenza in the community, respiratory syncytial virus (RSV) or other respiratory viruses can circulate. It is essential to obtain testing, because it can lead to a change in management: an outbreak of influenza in nursing home warrants chemoprophylaxis (see further) as well as immunization of nonimmunized residents in whom it is safe to do so.

Specific Diagnostic Tests

The traditional method to detect influenza has been viral culture, which is limited by moderate diagnostic accuracy and delay in obtaining results (Table 130-1). Rapid tests include direct fluorescent antigen (DFA), or direct immunofluoresence, where monoclonal antibodies labeled with fluorescent material are directed to influenza cell coat antigens. A result can be reported within hours. Rapid enzyme-linked immunoassay (ELISA) tests are commercially available, but are very insensitive in older adults with sensitivities as low as 20%. Nucleic acid amplification testing, such as reverse transcription polymerase chain reaction (RT-PCR), is the most promising test since it is over 95% sensitive and specific and the turnaround time can be rapid. The drawback, however, is that not all laboratories are capable of performing PCR daily at this time.

Infection Control Aspects

The incubation period of influenza, the period of time from initial infection to development of symptoms, is typically 2 days, but can range from 1 to 4 days. An infected individual becomes contagious 1 day prior to the onset of symptoms. In adults, viral shedding at levels high enough to cause transmission occurs over 5 or 6 days. Although the extent to which influenza can be transmitted by airborne spread is controversial, the majority of spread of influenza is large droplet caused by coughing and sneezing hence medical workers should wear a mask to prevent infection and spread of infection. In terms of practical implications, use of “respiratory etiquette,” coughing, and sneezing into tissues, for example, may help prevent spread to older adults who are susceptible to complications, although supporting epidemiologic evidence is limited.

Immunization

Many influenza vaccine formulations are now available in the United States. Only three, all inactivated vaccines, are licensed for adults aged 65 years or more. The most well-known influenza vaccine is the trivalent inactivated vaccine, now abbreviated as IIV3, which contains components of an H1N1, an H3N2, and B strains. Due to difficulties anticipating that B viral lineage will circulate, many vaccine manufacturers have added an addition influenza B strain to the influenza vaccine. This quadrivalent vaccine is abbreviated as IIV4. Due to decreased immune responses and poorer clinical responses when IIV3 or IIV4 is administered in seniors (when compared with young adults), a new high dose influenza vaccine has been licensed. This vaccine only contains three influenza strains but has four times the dose of each component versus the regular IIV3 and is abbreviated as IIV3-HD. The IIV3-HD has been shown to generate higher antibody levels in older adults than IIV3, and is 24% more effective for the prevention of illness due to influenza. At this time, the advisory committee on immunization practices recommends use of any of these three vaccines in older adults.

For the same reasons that older adults are more likely to have complications due to influenza infection, older adults respond less well to influenza immunizations. A recent systematic review summarized 35 influenza vaccine effectiveness studies. These studies were performed in 15 countries. Cases were influenza positive; controls were patients who also had an acute respiratory illness but who tested negative for influenza. Vaccine effectiveness for the prevention of medically attended acute respiratory illness was found to be 38% to 70% during seasons of vaccine and circulating strain match and 15% to 59% during seasons of mismatch. These data show that influenza immunization plays an important but modest role in prevention.

Studies using seasonal regression modeling with both United States and Italian data show no reduction in mortality among older adults with increased influenza vaccine coverage. These studies assessed trends in excess mortality after adjusting for age. One possible explanation of the results in these studies is that the influenza vaccine failed to protect older adults against death because of immune senescence (see Chapter 3).

Influenza and Long-Term Care

Residents of nursing homes and other long-term care facilities are at high risk for complications of influenza, including pneumonia, death, and hospitalization. This is likely because there is close contact between residents and staff in these facilities, increasing the exposure to and transmission of influenza, and because the majority of residents have comorbidities, including cognitive impairment, chronic lung diseases, and strokes. Outbreaks of influenza are well characterized in nursing homes, often described as “explosive” in that the onset is relatively abrupt. Such outbreaks are usually first detected by nursing home staff who notice a higher incidence of respiratory symptoms than usual on specific long-term units, although at least one surveillance study has shown that such outbreaks are commonly missed even when active surveillance by trained nurses is performed. Such outbreaks are best managed using a multifaceted approach that includes the following: cohorting residents, increasing adherence to hand hygiene, chemoprophylaxis with antiviral agents, and immunization of those not previously vaccinated. It should be noted that because of space limitations, it is usually not feasible to cohort ill residents together as a means of separating them from noninfected residents in long-term care facilities. Administering neuramindase inhibitors, such as oseltamivir or zanamavir, as chemoprophylaxis to noninfected residents helps to reduce further spread. In one randomized controlled trial where long-term units were randomized to zanamivir or to rimantidine, the risk of influenza was 3% in the zanamivir arm versus 8% in the rimantidine arm (P = 0.038). More recent data suggest that immunizing staff in nursing homes against influenza benefits residents. There have been four cluster-randomized controlled trials showing that immunizing health care workers against influenza reduces mortality in residents of long-term care facilities. Vaccinating nursing home staff against influenza may prevent deaths, use of health services, and influenza-like illness in nursing home residents.

Use of Antivirals to Prevent and Treat Influenza in Older Adults in the Community

There are five antivirals that are approved for treating influenza: amantadine (oral), rimantadine (oral), zanamivir (inhaled), oseltamivir (oral), and peramivir (IV). Amantadine and rimantadine are only active against influenza A and currently circulating influenza A strains are predominantly resistant to both amantadine and rimantadine. The neuraminidase inhibitors zanamivir and oseltamivir are active against influenza A and B are 70% to 90% effective for prophylaxis in preventing influenza and when used as treatment to reduce clinical severity when given within 48 hours of symptom onset. However, the feasibility of using these agents for treatment is reduced since the majority of patients in the community present over 48 hours following symptom onset. It is important to note that the doses of treatment and prophylaxis are different. Hence it is important, to use treatment doses if a patient is symptomatic. Zanamivir and oseltamivir are associated with few adverse effects. Zanamivir may worsen or provoke respiratory distress in those with underlying obstructive disease. Oseltamivir should be dosed based on renal function. In early 2015, the FDA approved a third neuraminidase inhibitor, peramivir, for the treatment of influenza which is only available in an IV formulation.

Indirect Benefit of Immunization in Children to Protect Older Adults

There is observational data to suggest that children play an important role in the spread of influenza in the community. For example, data from a 3-year longitudinal surveillance study of children and adults in New York State demonstrated that children were about twice as likely to acquire and shed influenza as compared to adults. In a longitudinal study conducted in Seattle from 1968 to 1974, elementary and junior high school students had the highest rates of influenza during epidemics, reaching 54%. In the Tecumseh, Michigan, studies from 1976 to 1981, over one-third of children between the ages of 5 and 14 years had influenza virus isolated from specimens, and the highest rate was among persons with febrile respiratory illness. Serological data revealed similar results; from 1977 to 1978, children in 5 to 9, 10 to 14, and 15 to 19 age groups had approximately a 30% infection rate with H3N2. This was over twice the rate seen in adults. There were similar infection rates with influenza B in children aged 5 to 14 years, rates 14-fold higher than those in adults older than 20 years of age.

Given that school-aged children appear to play an important role in introducing and transmitting influenza into households, and hence into the community, immunizing these children may interrupt spread to older adults who are at high risk for complications. In the Tecumseh studies, Monto and colleagues demonstrated that selectively immunizing 86% of children in this 7500-person community with inactivated influenza vaccine reduced influenza in adults by a third when compared to an adjacent community, where children were not immunized. More evidence for the potential benefit of immunizing children with inactivated vaccine has been derived from an analysis of the effect of influenza vaccination in Japan. Japan began a program of immunizing school-aged children in 1962 and continued this policy until 1994. The effect of this policy was to dramatically reduce excess mortality rates to values similar to those in the United States. The fact that there was a rapid increase in excess deaths after 1994, the year in which mass immunization formally ended, supports the conclusion that the effects observed in earlier years were because of vaccine-induced herd immunity, although it is possible that social factors may have amplified the effects of this program. The authors explain their findings by hypothesizing that the high levels of vaccination in school children protected transmission of influenza to their grandparents. There have been several more recent observational studies where children have been immunized showing a reduced attack rate of influenza in adults. However, randomized clinical trial evidence of immunizing children to prevent influenza in older adults is limited.

RSV has been long recognized as the major cause of bronchiolitis in children. Since the 1970s, there have been numerous reports about the burden of RSV in older adults, particularly those residing in nursing homes. RSV is now recognized as an important contributor to morbidity in both community-dwelling older adults as well as in residents of long-term care facilities. This section will describe the epidemiology of RSV in both settings including clinical, diagnostic, and management issues.

Characteristics of Respiratory Syncytial Virus

RSV is an enveloped RNA virus that can be classified into two major groups, A and B, based on antigenic and genetic properties. An important feature of RSV is that reinfections occur frequently throughout life and into older age. Because RSV infection does not produce robust immunity, developing a vaccine has been a major challenge. In addition, RSV is a very labile virus meaning it can be difficult to grow if it is not transported very carefully. This makes diagnoses difficult outside of the hospital setting.

General Epidemiology

Like influenza, RSV circulates during winter months in temperate climates roughly beginning in November and lasting until early spring. Often clinical cases precede influenza epidemics. The incubation period of RSV is 3 to 5 days. The majority of those who are infected show respiratory symptoms. In contrast to infants who shed higher titers (10^5–6 plaque forming units/mL of secretion) for longer time periods (10–14 days), adults tend to shed lower titers of the virus (10^2–3 plaque forming units/mL of secretion for 3 to 6 days). RSV is spread primarily by large droplets and fomites.

Community-Dwelling Older Adults and Respiratory Syncytial Virus

The best data about RSV in older persons living in the community are derived from a cohort study conducted in Rochester, New York, from 1999 to 2003. This cohort was comprised of 608 healthy persons aged 65 years and older. Forty-six (8%) of the 608 participants developed RSV, compared to 56 (10%) of high-risk older participants (defined as having congestive heart failure or chronic pulmonary disease). The impact of RSV infection was important in both the healthy older adults group and in the high-risk group: 17% and 23%, respectively, in these groups made physician office visits. Morbidity was greater in the high-risk group, where 16% required hospitalization. The study was also useful because it allowed for a comparison to influenza: 42% of healthy older participants and 60% of high-risk participants required office visits for influenza, rates statistically significantly higher than for RSV. Since then, RSV has been shown in other studies to cause similar if not higher hospitalization rates than influenza in older adults.

Epidemiology of Respiratory Syncytial Virus in Long-Term Care Facilities

Respiratory syncytial virus attack rates during nursing home outbreaks have been reported to be variable, ranging from 2% to 90%. However, most involved relatively small numbers of residents and included the use of diagnostic assays with varying levels of sensitivity. In one prospective study conducted in Rochester, where a sensitive enzyme immunoassay was used, the overall attack rate was 7% and the virus was identified as a cause of 27% of illness. One retrospective cohort study estimated the burden of illness in nursing homes in Tennessee by linking cardiopulmonary hospitalization, medical utilization, and death to viral activity in the general community during a period of 88,581 person-years. According to these data, RSV accounted for 15 hospitalizations and 17 deaths per 1000 residents.

Clinical Features of Respiratory Syncytial Virus in Older Adults

It is important to note that the clinical features of RSV cannot be distinguished from those of other viruses, such as influenza, with the exception that fever is less pronounced than for influenza. The nonspecific nature of the clinical presentation indicates the need for diagnostic testing. Signs and symptoms include rhinorrhea, nasal congestion, sore throat, cough, and dyspnea. Similar to patients infected with influenza, patients with RSV may present with exacerbation of underlying conditions such as chronic obstructive pulmonary disease and congestive heart failure.

Diagnosis

This can be done by viral culture, antigen detection in respiratory secretions, nucleic acid amplification, or serology. For diagnosis in real time, only the first three tests are appropriate. It is important to note that viral culture is only 50% sensitive. Similarly, detection of RSV antigens using immunofluorescence is very insensitive in older adults. In contrast, reverse transcriptase-polymerase chain reaction (RT-PCR) is relatively sensitive and specific. As the use of multiplex PCR systems increases, RSV will likely be recognized more often as the causative agent in the clinical setting.

Therapy

Care is mainly supportive in the older adult with RSV infection, the only licensed antiviral with activity versus RSV is ribavirin, but there are sparse data on which to base treatment recommendations in adults. Practical considerations about ribavirin include that the administration of this aerosolized drug to older adults using face masks may be difficult and ribavirin is teratogenic, which is important for the health care provider who is delivering care and the family that is entering the patient’s room.

Prevention

Transmission of RSV is believed to be caused by large droplets and fomites. Strategies such as increasing hand hygiene, particularly in nursing homes, may help to reduce spread. Isolation practices for RSV include gowning and gloving when taking care of a patient with RSV. At the present time, there are no licensed RSV vaccines.