Influenza is an acute, usually self-limited febrile illness that occurs in outbreaks of varying severity almost every win-ter. The causative virus is transmitted by the respiratory mute; however, systemic symptoms are out of proportion to those in the respiratory tract. Infection with influenza virus can produce several other clinical syndromes common with in-fection with respiratory viruses, such as common colds, pharyngitis, croup, tracheobronchitis, bronchiolitis, or pneu-monia. Conversely, infections with other respiratory viruses, such as respiratory syncytial virus, rhinovirus, or adenovirus, may produce sporadic cases indistinguishable from those of typ-ical influenza. In addition to enormous morbidity and loss of time from school and work, influenza epidemics are associated with substantial mortality caused in large part by pulmonary complications.

Etiology Influenza viruses belong to the family Ortho-myxoviridae. Influenza A virus constitutes one genus and in-fluenza B virus another. The virion is a medium-sized (80 to 100nm in diameter)enveloped spherical or elongated particle covered with surface projections that are glycoprotein possess. ing either hemagglutinin (H) or neuraminidase (N) activity. The envelope is composed of a lipid bilayer, on the inner sur-face of which is the matrix(M)protein. Within the envelope are eight segmented pieces of nucleocapsid, formed by a single species of protein, the nucleoprotein (NP), and single-strand. ed ribonucleic acid(RNA). Three polymerase (P) proteins and three nonstructural (NS1, NS2, and M2) proteins of unknown function are found within the envelope. The H is responsible for binding of the virus to the cell. Antibody to this protein neutralizes viral infectivity and thus is the major determinant of immunity. The viral N is instrumental in release of virus from cells. Antineuraminidase antibody is not neutralizing but limits viral replication and therefore the severity of infection. The M protein plays a role in stability of the membrane and in organization of the virion during assembly. The three poly-merases are important in viral replication. The internal M, NP, and P proteins are antigenically indistinguishable in all in-fluenza A viruses but vary from those found influenza B and C viruses. Thus. type-specific (A, B, or C) distinction of in-fluenza of influenza viruses depends on serologic reactions me-diated by these internal antigens. However, the surface pro-teins (H and N) do vary, not only among influenza virus types but also among subtypes of influenza A.

The viral genome comprises eight segmentsof RNA, each 0f which codes for one or two viral proteins. Reassortment of gene segments occurs frequently during coinfection of cells with two influenza A viruses. Influenza B and C viruses have been studied much less but appear to be structurally similar to influenza A virus. Antigenic variation is much less frequent with influenza B, and it may not occur with influenza C.

Pathogenesis and Pathology Influenza virus infection is acquired by transfer of virus-containing respiratory secretions from an infected to a susceptible person. Small-particle aerosols (less than 10 mass medium diameter)may be most significant in such person-to-person transmission. Once the virus has been deposited in the respiratory tract epithelium, unless it is pre-vented by specific secretory antibody, nonspecific muco-pro-teins, or mechanical actions of the mucociliary blanket, it at-taches to and penetrates columnar epithelial cells by pinocyTo-sis. Viral replication lasts 4 to 6 hours, and virus release con-tinues for several hours before cell death ensues. Infection of adjacent and nearby cells follows, so that within a few replica-tion cycles large numbers of cells in the respiratory tract are in-fected. The duration of the incubation period until onset of ill-ness and virus shedding, which occur in close proximity, varies from 18 to 72 hours, depending in part on the inoculum size. Quantitation of virus in respiratory tract specimens re-veals a characteristic pattern that correlates with severity of ill-ness, suggesting that a major mechanism in the production of illness is cell death resulting from viral replication. Serum or secretory antibody or cell-mediated immune mechanisms are not detectable at the time indicating that immunologic mecha-nisms are probably not involved in production of illness, with the exception of circulating interferon, which may contribute to systemic symptoms and fever. Viremia is rare.

Interferon is frequently detected in respiratory tract and serum specimens. Shedding of virus precedes by 1 to 2 days the appearance of interferon, which is correlated with im-provements of signs and symptoms and decrease of virus titer, suggesting that interferon is active in the recovery process.

Neutralizing, hemagglutination-inhibiting (HAI), an-tineura-minidase, complement-fixing, enzyme-linked im-munosorbent as-say (ELISA), and immunofluorescent anti-bodies begin to develop in the sera of persons with primary in-fluenza virus infection during the second week after exposure to antigen and reach a peak by 4 weeks. Secretory antibodies develop in the respiratory tract after influenza infection and consist predominantly of immunoglobulin A (IgA) antibodies that reach peak titers in 14 days. Protection against infection is afforded by serum HAI titers of 1:40 or greater, serum-neu-tralizing titers of 1:8 or greater, or nasal-neutralizing antibody titers of 1:4 or greater.

Nasal and bronchial biopsy specimens from persons with un-complicated influenza reveal desquamation of the ciliated columnar epithelium. Individual cells show shrinkage, pyknot-ic nuclei and loss of cilia. In addition, the lungs in fatal in-fluenza show extensive hemorrhage, hyaline membrane forma-tion, and paucity of polymorphonuclear cell infiltration. Pa-tients with secondary bacterial pneumonia have the changes characteristic of bacterial pneumonia in addition to the tracheo-bronchial findings of influenza in the tracheobronchial tree.

Clinical Findings Many patients can pinpoint the hour

0f onset. Initially, systemic symptoms predominate and in-clude feverishness, chilliness of frank shaking chills, headache, myalgias, malaise, and anorexia, In more severe cases, prostration is observed. Usually myalgias or headaches are the most trouble-some symptoms, and their severity is re-lated to the level of the fever, Arthralgias are commonly ob-served. Ocular symptoms, although less commonly present, are helpful diagnostically and include photophobia, tearing, burning, and pain on moving the eyes. Respiratory symp-toms, particularly dry cough and nasal discharge, are usually also present a the onset but are overshade-owed by the sys-temic symptoms. Nasal obstruction, hoarseness and dry sore throat may also be present.

Fever is the most important physical finding. The tem-perature usually rises rapidly to a peak of 38 to 40¡ãC and occa-sionally to 41¡ãC within 12 hours of onset, concurrently with the development of systemic symptoms. Fever is usually con-tinuous but may be intermittent, especially if antipyretics are administered. On the second and third days of illness, the temperature elevation is usually less than on the first day. As fever subsides, the systemic symptoms diminish. Typically, the duration of fever is 3 days, but it may last from 1 to 5 or more days. In a few cases, a second fluctuation in fever occurs on the third or fourth day, resulting in a biphasic fever curve. Early in the course of illness, the patient appears toxic, the face is flushed, and the skin is hot and moist . The eyes are watery and reddened, Clear nasal discharge is common, but nasal obstruction is uncommon. The mucous membranes of the nose and throat are hyperemic, but exudate is not observed. Small, tender cervical lymph nodes are often present, and transient, scattered rhonchi or localized areas of rales are found in less than 20 per cent of cases.

As systemic signs and symptoms diminish, respiratory com-plaints and findings become more apparent. Cough is the most frequent and troublesome of these symptoms and may be accompanied by substernal discomfort or burning. Nasal ob-struction, discharge, pharyngeal pain, and injection are also common. Such symptoms and signs usually persist 3 to 4 days after fever subsides; however, cough, lassitude, and malaise may persist for 1, 2, or more weeks before full recovery.

This pattern of illness just described occurs with any type or subtype of influenza A or B virus. Attack rates are higher in children than in adults, although the incidence of pulmonary complications is lower in children. Maximum temperatures are higher in children, cervical adenopathy may be more frequent, and croup occurs only among children.

Pulmonary Complications Three kinds of pulmonary complications are well recognized: primary influenza viral pneumonia, secondary bacterial pneumonia, and mixed viral and bacterial pneumonia. In addition, during an outbreak of influenza, less distinct and milder pulmonic syndromes often occur that may represent viral tracheobronchitis, localized viral pneumonia, or possibly mixed viral and bacterial infection.

Primary Influenza Viral Pneumonia This syndrome first became well documented in the pandemic of 1957 to 1958. However. It is clear that many of the deaths in the 1918 to 1919 outbreak were due to this syndrome in healthy young adults. Primary influenza viral pneumonia has occurred predominantly among persons with cardiovascular disease, es-pecially rheumatic heart disease with mitral stenosis. Although this syndrome occurs in healthy young adults in every large outbreak, other chronic disorders and pregnancy have been im-plicated as risk factors in some epidemics. Following a typical onset of influenza, there is rapid progression to fever, cough, dyspnea, and cyanosis. Physical examination and chest roentgenograms reveal bilateral findings consistent with the adult respiratory distress syndrome. Blood gas studies show marked hypoxia. Gram's stain of the sputum fails to reveal significant bacteria, and bacterial culture yields sparse growth of normal flora. Viral cultures of sputum or tracheal aspirates yield high titers of influenza virus. Such patients do not re-spond to antibiotics, and mortality is high.

Secondary Bacterial Pneumonia Bacterial superinfection is often clinically distinguishable from primary viral pneumonia. The patients are most often elderly or have chronic pulmonary, cardiac, metabolic, or other diseases. Following a typical in. fluenza illness, a period of improvement lasting from 1 to 4 days may occur. Recrudescence of fever is associated with symptoms and signs of bacterial pneumonia, such as cough, sputum production, and a localized area of consolidation appar-ent on physical and chest roentgenogram examination. Gram's stain and sputum culture reveal predominance of a bacterial pathogen, most often Streptococcus pneumoniae, Staphylococ-cus aureus, or Haemophilus influenzae. Such patients usually respond to specific antibiotic therapy.

Mixed Viral and Bacterial Pneumonia During an out-break of influenza, many cases are observed that do not clearly fit into either of the categories just described, The disease is not relentlessly progressive, and yet the fever pattern may be persistent and not biphasic. These patients may have a milder form of primary viral, secondary bacterial, or mixed viral and bacterial infection. Many respond to antibiotics. Milder forms of primary viral pneumonia involving only one lobe or segment have been described that do not invariably lead to death. Such cases are more likely to be confused with a pneumonia due to Mycoplasma pneumoniae than to that produced by bacterial in-fection. Pneumonia may occur in children, but it is less com-mon than in adults. In addition, bronchiolitis and croup may be caused by influenza A or B virus infection.

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