Influenza: diagnosis, management, and prophylaxis

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Abstract
Key messages Influenza causes enormous morbidity, death, and economic loss Annual vaccination is strongly recommended for groups at high risk Amantadine is effective treatment for and prophylaxis against influenza A during epidemics New developments include rapid laboratory diagnosis, live attenuated vaccines, and antiviral drugs Outbreaks of influenza have been recognised since ancient times and are responsible for devastating global morbidity and mortality. The characteristic epidemiological features of influenza include the occurrence of frequent, but unpredictable epidemics and periodic worldwide pandemics. Four pandemics have been recorded this century (table I). The potential consequences of a future pandemic can be judged by the impact of the 1918-19 pandemic, which was known as Spanish flu. Over a period of months influenza caused more deaths than the first world war. An estimated 200000 people died as a result of influenza in England and Wales alone, with over 20 million deaths worldwide. Influenza remains a great challenge to modern medicine. In this review I will discuss the epidemiology and surveillance of influenza outbreaks and recent advances in the diagnosis and management of infection. View this table: In this window In a new window TABLE I Recent global pandemics of influenza Pandemics are caused by antigenic shift of influenza A resulting in the appearance of an influenza virus with a novel haemagglutinin (H antigen) or neuraminidase (N antigen) subtype. Influenza pandemics usually arise in China and spread westward to the rest of Asia, Europe, and America. Influenza viruses have been isolated from many different animal species, and recent evidence suggests that antigenic shift results from genetic reassortment of virus between humans and the animal reservoir. This process is facilitated by farming practices in south east Asia, which allow close proximity between humans, ducks, and domestic pigs.1 During interpandemic periods outbreaks of influenza A or B infection are reported nearly every winter and vary in severity. Antigenic variability during interpandemic periods is less marked and is caused by antigenic drift. This describes a process of minor antigenic changes resulting from the accumulation of random point mutations. These mutations lead to alterations in the amino acid composition of haemagglutinin and neuraminidase. New strains of influenza A and B are constantly being generated by antigenic drift, and epidemics arise if circulating strains are significantly different from previous strains encountered by the population. The last major epidemic in England and Wales occurred during 1989-90. Laboratory diagnosis of influenza * Virus isolation Amniotic cavity of chicken embryos Tissue culture * Serological tests Complement ixation Haemagglutination inhibition * Antigen detection Immunofluorescence Enzyme linked immunosorbent assay (ELISA) * Gene amplification Polymerase chain reaction Diagnosis of influenza Influenza causes an acute febrile illness associated with myalgia, headache, and cough. The median duration of fever is three days, but cough and malaise often persist for 1-2 weeks.2 The clinical features of influenza are often indistinguishable from those caused by other respiratory viruses that may be circulating in the community at the same time. Laboratory confirmation of influenza infection therefore has a vital role in surveying influenza outbreaks and is essential for assessing the efficacy of vaccines and antiviral agents. The first box summarises the laboratory diagnosis of influenza. The diagnosis of influenza is usually confirmed by isolation of virus or from serological results. Influenza is transmitted by spread of airborne droplets, high titres of virus being shed by patients with symptoms. Influenza A and B replicate in several primary kidney cell lines, and influenza may be shown in tissue culture by adsorption of guinea pig erythrocytes, even if there is no obvious cytopathic effect. Isolation of the virus is labour intensive and takes several days. Serological tests include complement fixation and haemagglutination inhibition. These tests provide useful epidemiological information but will only confirm a diagnosis after the patient has recovered from the acute illness. Diagnosis needs to be more rapid, particularly in severely ill patients who might benefit most from prompt antiviral treatment. Techniques for the rapid diagnosis of influenza include gene amplification and antigen detection by immunofluorescence or enzyme linked immunosorbent assay (ELISA).3 Immunofluorescence is comparatively inexpensive and straightforward; sensitivity is poor compared with standard tissue culture. A capture ELISA has been described for the detection of influenza antigen in clinical specimens. The test uses a monoclonal antibody to nucleoprotein and has a high sensitivity and specificity.4 The polymerase chain reaction has recently been used to identify influenza virus genome in clinical material, and several methods have been described. The procedure uses reverse transcriptase (to convert viral RNA to DNA) and type specific primers based on highly conserved sequences. The technique offers greatly enhanced sensitivity and gives a result within 24 hours. Influenza primers may be combined with specific primers for a range of other respiratory viruses in a more comprehensive assay known as a multiplex polymerase chain reaction. INFLUENZA SURVEILLANCE Influenza surveillance provides important information on the timing and potential impact of an influenza outbreak. This information is used to coodinate an appropriate public health response, including issuing guidelines on vaccination and antiviral treatment and assessing the need for additional medical resources. Influenza epidemics usually follow a characteristic pattern. Small, isolated outbreaks are followed by a steep rise in the number of reported cases, which reach a peak after 3-4 weeks and decline...