key: cord-324301-bzrh2fni
authors: Zambon, Maria
title: Influenza, respiratory syncytial virus and SARS
date: 2005-05-01
journal: Medicine
DOI: 10.1383/medc.33.5.130.64960
sha: 
doc_id: 324301
cord_uid: bzrh2fni

Abstract Acute lower respiratory tract infections (LRTIs) are a major worldwide health problem, particularly in childhood, and are ranked first among the conditions contributing to the global burden of disease. About 30–50% of acute LRTIs are viral in origin; of these, influenza and respiratory syncytial virus (RSV) are associated with the greatest disease burden in humans. Vaccination against circulating human influenza strains and the use of neuraminidase inhibitor drugs have improved the options for control of influenza, but as yet there are no successful vaccines or antiviral drugs for use against RSV infection. The recent emergence of the SARS coronavirus in the human population in 2003, with an ensuing global epidemic affecting more than 8000 individuals with a case fatality of about 10%, underlines the fact that respiratory viral infections of humans may originate in animals, and that many different influenza A viruses also occur naturally in animal reservoirs, representing a constant threat of zoonotic infections of humans and ensuing global pandemics. Avian influenza viruses have transmitted directly to humans from domestic poultry on several occasions in the last decade, and the current extensive burden of disease from avian influenza in South East Asia provides a real possibility for the emergence of a novel influenza virus pathogenic in humans.

Acute lower respiratory tract infections (LRTIs) are a major worldwide health problem, particularly in childhood. About 30-50% of acute LRTIs are viral in origin; of these, influenza and respiratory syncytial virus (RSV) are associated with the greatest disease burden in humans. The emergence of the severe acute respiratory syndrome (SARS) coronavirus in 2003, and the ensuing worldwide epidemic, highlights the fact that respiratory viral infections in humans may originate in animals. Many different influenza A viruses occur naturally in animal reservoirs, and present a constant threat of zoonotic infections and global pandemics.

Influenza viruses are small (80-120 nm diameter), contain RNA and are enveloped. There are three types -A, B, and C. Type A is further classified according to the properties of the surface proteins haemagglutinin and neuraminidase. All A subtypes are found in aquatic birds, which are the natural reservoir ( Figure 1) ; only a few subtypes circulate in humans and other mammals. Type B and C influenza have only one subtype and are restricted to humans.

Seasonal illness, epidemics and pandemics -influenza viruses circulating in humans (A H1N1, H3N2, B and C) cause respiratory tract disease. Influenza A is generally considered to be clinically more severe than influenza B; influenza C causes only a mild illness confined to the upper respiratory tract. Circulation of influenza A and B viruses in humans ( Figure 2 ) causes unpredictable seasonal epidemics of disease in temperate climates, with excess population morbidity and mortality, usually occurring between October and March in the northern hemisphere and lasting about 6-8 weeks. 1 In the UK, 5000-10,000 deaths are associated with influenza A and B epidemics every year, and more than 20,000 in severe years. Widespread pandemics of severe disease occur less frequently, occurring on at least three occasions in the last century (1918, 1957, 1965) , and have been associated with high mortality.

Clinical features -influenza A and B illness in humans ranges from subclinical or mild upper respiratory tract symptoms to more severe illness including laryngotracheitis and pneumonia or, less commonly, death from respiratory system failure. The most common presenting symptoms are cough, high temperature, joint pain and general malaise ( Figure 3 ). The rapid onset and short incubation period (about 48 hours) are characteristic, though incubation can last up to 4 days. Individuals at greatest risk of complications are those with pre-existing cardiac and respiratory disease, the elderly, and those with impaired immune systems ( Figure 4 ). The severity of the illness reflects pre-existing host immunity and the prevailing virus strain.

Virus variability -protective immunity to influenza is conferred by antibodies. The ability of influenza to cause re-infections is related to the genetic mutability of the virus. In every replication round, mutant viruses are generated, some of which have a growth advantage because they can partially evade host immune responses. Variants capable of causing epidemics in susceptible populations emerge by a process termed 'antigenic drift'. New influenza A drift variants arise every 2-3 years; influenza B drift variants arise every 4-5 years.

Influenza as a zoonosis -the segmented nature of the influenza genome allows reassortment of segments when a single host is infected with more than one virus. This occurs regularly in aquatic birds, in which almost all combinations of influenza A virus segments can be detected, but is less common in mammals. It was previously thought that, for a novel subtype of influenza to arise in humans, reassortment of two virus subtypes had to occur in a mammal that could then transmit to humans. The pig was considered a suitable 'intermediate host', because both avian and human viruses, which differ slightly in their surface receptor requirements, can replicate in pigs. However, following transmission of H5N1 directly from birds to humans on 18 occasions Figure 5 ), it is evident that cross-species barriers to transmission may be less stringent than was thought. Nevertheless, the requirements for adaptation of avian viruses to mammals are poorly understood. Cross-species transmission of novel subtypes into susceptible human populations (antigenic shift) are thought to be the source of pandemics of influenza. Zoonotic infections involving several different subtypes of influenza have occurred in the last few years, indicating the pandemic potential of influenza viruses circulating in domestic poultry.

Control -the presence of a large, mobile animal reservoir of influenza A virus suggests that eradication of this agent will be impossible. Control strategies focus on limiting the opportunities for cross-species transmission of novel subtypes; for example: • housing domestic poultry in shelters to avoid contact with overflying migratory birds • eliminating/reducing live bird markets • housing aquatic birds and domestic poultry separately • slaughtering domestic flocks infected with highly pathogenic influenza A viruses. These measures may achieve some success in preventing zoonotic transmission of influenza A to humans, but have little impact on its annual cycle. Unprecedented levels of H5 circulating in domestic poultry in South East Asia present a particularly high risk for emergence of a novel pandemic influenza A strain.

Immunization -antibodies against haemagglutinin (and, to a limited extent, neuraminidase) can prevent disease caused by the same strain of virus. This is the basis of vaccination for influenza. Currently, most vaccines used worldwide are subunit vaccines. However, the high variability of influenza virus means that antibodies to one strain confer only limited protection against drift variants. Thus, influenza vaccines are given annually before the influenza season to boost pre-existing immunity, and the composition of the vaccine is updated regularly. In developed countries, the benefit of immunization has led to expansion of age-related vaccination policies. In the UK in 2000, vaccination was introduced for all individuals over 65 years of age, irrespective of pre-existing illness. Vaccination rates vary considerably between countries.

There is increasing interest in vaccination of children. 2 they induce broader, long-lasting immunity. Child vaccination may also help to prevent transmission in the community in general. Antiviral drugs -despite the preventive efficacy of vaccination, the need for treatment of severe influenza remains.

Amantadine (or the related compound rimantadine) was, until recently, the only anti-influenza drug available. It selectively targets a viral protein (M2) and inhibits viral replication, but its use has been limited in the last 30 years, partly because of side-effects (dizziness, confusion) that particularly affect the elderly, and also because drug-resistant mutants arise frequently and can be readily transmitted.

Neuraminidase inhibitors are a more recently developed, novel class of anti-influenza compounds ( Figure 6 ). 3 They act on viral neuraminidase, prevent release of virus particles from infected cells, and are likely to be most efficacious when given early in illness. Since 2000, the UK National Institute for Clinical Excellence has recommended that neuraminidase inhibitors may be used for treatment and prophylaxis, with certain restrictions. Mutations conferring resistance to neuraminidase inhibitors do not arise very frequently in vivo, and viruses containing them generally lose reproductive fitness and are at a disadvantage in transmission. This suggests that widespread resistance to antiviral drugs is unlikely to emerge and is most likely in treated children, probably because the viral load is highest and therefore the capacity for viral replication in the presence of drugs is greatest.

RSV (Figure 7) is a negative-sense, non-segmented, enveloped RNA virus of 100-300 nm diameter. It is best known as a cause of bronchiolitis in infants, but can cause respiratory tract infection in all age groups. Upper respiratory tract infections (URTIs) and LRTIs range in severity from subclinical infection to pneumonia and death. More than 60% of children have been infected with RSV by their first birthday and more than 80% by 2 years of age; thereafter, individuals are infected approximately every 3 years. RSV infections in adults are probably under-recognized, and the severity of RSV infection in the elderly may be much underestimated as a cause of pneumonia. About 5% of elderly individuals are thought to become infected with RSV every year.

Transmission of RSV is primarily through large aerosol droplet or secretions, causing widespread nosocomial infection. Outbreaks in adult and paediatric facilities are difficult to control. RSV infection in immunocompromised individuals is severe and lifethreatening; mortality may be 50-70% in adult bone marrow transplant recipients, in whom viral shedding may be prolonged.

Pathophysiology -RSV infects the respiratory epithelium, leading to increased goblet cell production of mucus. Dying infected ciliated epithelial cells combine with mucus to form plugs that block the airways; the consequences are most severe in very small babies with narrow airways. This leads to the characteristic signs and symptoms of atelectasis and the clinical syndrome of bronchiolitis. In RSV bronchitis and pneumonia, the peribronchiolar and interstitial infiltrate is characteristically lymphocytic.

Clinical features -the severity of RSV infection is related to age. In young infants, the illness is seldom asymptomatic and lasts for 1-3 weeks. Early signs of infection may include difficulty in feeding, nasal congestion, cough and otitis media compatible with URTI. Fever is often but not invariably present in RSV infection.

Abnormal breath sounds, tachypnoea and hypoxaemia suggest lower respiratory tract involvement. Bronchiolitis and pneumonia are the two primary manifestations of progression to LRTI; they may be difficult to distinguish and can occur simultaneously. The clinical features of bronchiolitis are wheezing and hyperaeration, and these are characteristic of infants with RSV infection.

In the USA, RSV is estimated to cause 4500 deaths per year in children under 2 years of age. The risk of hospitalization in otherwise healthy under-2s is 0.5-2%, and 10-20% of children admitted to hospital require mechanical ventilation. These rates are higher in the first 6 months, and may be higher still in children with underlying acquired or congenital cardiopulmonary disease.

Older children and adults with RSV infection or re-infection usually have a milder or asymptomatic respiratory infection with a lower likelihood of LRTI. Adults with RSV-associated respiratory tract infections may experience prolonged symptoms. Disease in the elderly may be particularly severe; up to 50% develop pneumonia. Investigations -RSV infection is often diagnosed on the basis of the clinical features. The certainty of the diagnosis is increased when RSV is known to be circulating in a seasonal epidemic. Chest radiography findings are nonspecific and commonly include hyperaeration and peribronchial thickening, with areas of consolidation and interstitial infiltrates in patients with RSV pneumonia. There is a range of respiratory findings in immunocompromised adults, including pleural effusions. Laboratory diagnosis depends on detection of viral antigen in respiratory secretions by immunofluorescence, rapid antigen tests or culture of the virus. Serological tests are of little help in diagnosis of RSV infection, because they rely on the use of paired acute and convalescent sera.

Complications -premature and very young infants are more likely to suffer acute apnoeic episodes and require assisted ventilation. Bronchiolitis and pneumonia are the major complications of RSV disease in young children. Children with congenital heart disease or chronic lung disease, and immunocompromised children and adults, are also at risk of severe disease.

Pneumonia is the major complication in adults and the elderly. Estimates of the incidence range from 10% in nursing homes to 55% in a hospital in-patient population; estimated mortalities in the elderly are 3-5% in the former and 10-20% in the latter.

RSV infection has very high mortality (50-70%) in severely immunocompromised individuals. Management -supportive care is the mainstay of management of RSV disease in infancy. Maintenance of oxygenation, hydration and nutrition is essential in hospitalized patients, and ventilatory support may be necessary in severe cases. A trial of bronchodilators may be beneficial. Controlled trials of corticosteroids and vitamin A supplementation have not proved efficacy in infant RSV disease.

Immunization -there are two subtypes of RSV -A and B. The surface glycoproteins F and G are the major antigens of the virus to which neutralizing antibodies are directed. Protective immunity to RSV is complex. Antibodies generated during natural infection are not necessarily protective. A high proportion of primary RSV infections occur before 6 months of age, when maternal antibody levels are highest. Overall, current (controversial) data suggest that neutralizing antibody to RSV is beneficial. Neutralizing antibody titres in human sera correlate inversely with the likelihood of hospitalization as a result of RSV infection, and neutralizing antibody titre correlates with a reduced risk of re-infection.

Immunoglobulin infusions with high neutralizing titres of antibody to RSV (RSVIg, Figure 8 ) have been used to treat RSV illness in normal-risk and high-risk infants. In normal infants, there is little evidence to justify RSVIg for treatment of RSV infection. However, prophylaxis may be useful in high-risk infants (e.g. those with bronchopulmonary dysplasia). Assessment of risk is important, because intravenous RSVIg is contraindicated in congenital cyanotic heart disease. Recombinant humanized RSV monoclonal antibodies are now available for intramuscular treatment and prophylaxis of RSV. Early clinical data suggest that this preparation of passive antibodies may have wider application, with fewer limitations than RSVIg; however, it is extremely expensive.

Few antiviral drugs are available for RSV. Ribavirin is a guanosine analogue that has been used widely, though its precise mode of action is uncertain and many clinical studies show conflicting results. Several studies have raised further doubts about the clinical effectiveness of ribavirin in infants and children at risk of severe RSV disease, and in ventilated children. In most centres, its use is now restricted to the immunocompromised or severely ill.

Several RSV vaccines (live attenuated, subunit and recombinant) are undergoing clinical trials. Development of safe vaccines has been impeded by poor understanding of the factors governing immune protection in different age groups, 4 and early vaccination attempts in which more severe disease was seen in vaccinees. It is likely that there will be significant progress in future and that the types of vaccines suitable for different age groups may differ. Transmission -SARS CoV spread worldwide within weeks in early 2003. The major route of transmission was respiratory, primarily through droplet, secretions and aerosol formation. About 60% of cases resulted from infection in health-care settings, emphasizing the importance of close contact and exposure to bodily secretions. (The syndrome was noticed through unusual clusters of severe respiratory illness in hospital settings.)

Peak virus shedding is 7-12 days after the onset of illness (Figure 9 ). The virus is found in various body fluids. Infectious virus has not been recovered later than 21 days after illness onset. Neutralizing antibody is detected from about 10 days post-onset.

Risk factors for SARS CoV infection are: • close contact with civet cats/racoon dogs • eating/preparing civet meat • laboratory work with SARS CoV • contact with a known case of SARS.

Clinical features -presentation is with fever and respiratory illness with cough and shortness of breath, progressing to acute respiratory distress syndrome and death in 10% of cases. Fatalities increase significantly over the age of 40 years; mortality is up to 40% in the over-50s. Onset of illness is 2-10 days post-infection, with a mean of about 5-6 days. About 60% of patients suffer later gastrointestinal symptoms of diarrhoea and vomiting.

Management and control -specific control measures have not yet been developed, though work is in progress on antiviral drugs and suitable vaccines. During the 2003 epidemic, various nonspecific therapeutic measures were used with variable success: • corticosteroids • antimicrobials to prevent secondary bacterial infection • positive-pressure ventilatory support • anti-inflammatory drugs • infusion of antisera from convalescent patients. The epidemic was controlled mainly through public health measures such as contact-tracing and quarantining. This policy was effective because there is little evidence of transmission before symptom onset, so infected individuals are easily identified. 

• Consider for prophylaxis in infants < 2 years receiving oxygen therapy for bronchopulmonary dysplasia • Infants born < 32 weeks with bronchopulmonary dysplasia are likely to benefit from 6-12 months' prophylaxis • Infants born > 32 weeks with bronchopulmonary dysplasia may not benefit • Should not be used in cyanotic congenital heart disease • Not evaluated in paediatric or adult immunocompromised patients • Main emphasis in nosocomial outbreaks should be infection control; efficacy is improved in such settings • Initiate treatment before onset of respiratory syncytial virus season • Defer live virus vaccines (e.g. MMR) until last dose 

The contribution of influenza to acute respiratory infections, hospital admissions and deaths in winter

The Japanese experience with vaccinating school children against influenza

Neuraminidase sequence analysis and susceptibilities of influenza virus clinical isolates to zanamivir and oseltamivir

Age related differences in humoral immune response to respiratory syncytial virus infection in adults

Confirmation of a novel corona virus as the primary cause of severe acute respiratory syndrome