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.

Exacerbation of Chronic Obstructive Pulmonary Disease

In adults with chronic obstructive pulmonary disease, influenza A or B virus infection may lead not only to pneumonia but also to acute exacerbation of chronic bronchitis, a syndrome that is associ-ated with other respiratory viruses and bacteria as well.

Nonpulmonic Complications

Reye's Syndrome Reye's syndrome is a frequently rec-ognized hepatic and central nervous system complication of in-fluenza A and B infection.

Other Complications Myositis and myoglobinuria with tender leg muscles and elevated serum creatine kinase (CK) levels have been reported, mostly occurring in children. My-0carditis, pericarditis, and myocardial infarction rarely have been associated with influenza A and B virus infection Gullain-Barre syndrome has been reported to occur after influenza A, but no definite causal relationship has been established. Trans-verse myelitis and encephalitis have also been reported rarely. Toxic shock syndrome due to infection of the respiratory tract with toxin-bearing S. aureus has been reported.

Diagnosis In an individual case, influenza often cannot be distinguished from infection with a number of other viruses and bacteria that produce headache, muscle aches, fever, and cough. On occasion, other respiratory viruses can produce an influenza-like illness, as can streptococcal pharyngitis. In the summer months, enteroviruses produce a clinically indistin-guishable picture, and the acute manifestations of many other infections, such as dengue, may mimic influenza. On the oth-er hand, in the context of an epidemic, influenza may be read-ily distinguished from other acute infections. When local, state, or national health authorities report an epidemic of in-fluenza A or B virus infection in a given community, and a pa-tient is seen with the acute onset of fever, headache, muscle aches, and cough, it is highly likely that these symptoms are caused by an influenza virus infection.

Definitive diagnosis depends on detection of infectious virus or viral antigen in secretions from patients or the detec-tion of a serum antibody response. Influenza virus is readily isolated from throat or nasal specimens, sputum, or tracheal secretion speci-mens in the first 2 or 3 days of illness. Usually infectivity is detected within 48 to 72 hours in cell cultures. Viral antigen may be detected more rapidly in such specimens by use of immunofluorescence or ELISA. Serologic methods are less useful clinically because they require a convalescent serum obtained 10 to 14 days after the onset of infection. However, they are of great use in epidemiologic studies and to document the occurrence of an outbreak. A fourfold increase in antibody titer comparing an acute with a convalescent phase, is diagnostic. The complement fixation antibody test is most use-ful for diagnosis because it is not dependent on strain or sub-type variation, as is hemagglutination inhibition.

Treatment Amantadine shortens the duration of fever and of systemic and respiratory symptoms by about 50 per cent. The dose is 100 to 200 mg per day orally for 3 to 5 days. Rimantadine, although not yet licensed, has a similar effect and reduces the likelihood of the mild, transient central ner-vous system side effects that occur with amantadine. Other symptomatic measures include antipyretics and cough suppres-sants. Many authorities consider that aspirin should not be used, especially for persons under 16 years of age, because of its association with the occurrence of Reye's syndrome. There is no evidence that amantadine or rimantadine is effective in treatment of pulmonary complications of influenza.

Currently, primary influenza viral pneumonia in its severe stages is best managed in an intensive care unit with supportive measures such as respiratory therapy, supplemental oxygen, and fluids. Secondary bacterial pneumonia should be treated with appropriate antibiotics. When studies of the sputum do not clearly indicate which bacterium may be infecting the pa-tient, coverage should include antibiotics that are effective against S. aureus, S. pneumoniae, and H. influenzae.

Prevention The mainstay of prevention is the use of in-activated influenza virus vaccines. These vaccines provide about 80 per cent protective efficacy. The antigenic composi-tion is reviewed annually so that the vaccine contains the most recently circulating strains. Usually the vaccine is a trivalent product containing one or more subtypes of influenza A and in-fluenza B virus. The recent vaccines have been purified by density gradient centrifugation or chromatography and have very low reaction rates. One to two per cent of persons vacci-nated have fever and systemic symptoms peaking at 8 to 12 hours after vaccination and up to 25 per cent may have mild lo-cal reactions at the site of vaccination. "Split" virus (subviri-on) vaccines, contain antigens with disrupted virus and may be less reactigenic than "whole" virus vaccines. The highest pri-ority for vaccination should be given to persons with cardiac or pulmonary conditions requiring ongoing medical care and to residents of nursing homes and other chronic care facilities. Physicians, nurses, and other personnel including home health-care providers who have extensive contact with high-risk patients constitute the next priority for vaccination. Final-ly, persons over age 65 and persons with other chronic disease of any age should be vaccinated. Vaccine may also be given to well persons under age 65 who wish to reduce the likelihood of acquiring influenza. Vaccine should be administered each year in the fall prior to the influenza season.

Amantadine and rimantadine are also effective in prevent-ing influenza A and should be used to supplement vaccine pro-grams. Persons who are not vaccinated in the fall should be placed on amantadine when an outbreak occurs or throughout the influenza season for the highest risk group. If vaccine is available, persons may be vaccinated simultaneously, and amantadine therapy should be stopped after 14 days. Alterna-tively, if vaccine is not available, amantadine administration may be continued for the duration of the outbreak, the dose being 100 to 200 mg per day orally, In the family setting, prophylaxis may fail owing to emergence of resistant viruses. Amantadine, administered to patients and staff alike, is very helpful in managing nosocomial outbreaks.

Diagnosis in Traditional Chinese Medicine

This disease is called "Liu Xing Xing Gan Mao" in tradi-tional Chinese medicine.

1. A large number of patients are affected within a short period with clinical features of fever, headache and myalgia.

2. Clinical features.

(1) The onset of the disease is abrupt, with marked gen-eral toxemic symptoms such as chill, fever, headache, myal-gia, weakness, etc.

(2) Symptoms referable to the respiratory tract such as stuffy nose, rhinorrhea, sore throat and dry cough are usually mild. In some cases, symptoms of the digestive tract such as loss of appetite, nausea, vomiting, abdominal pain and diar-rhea may be present.

(3) High fever, chest pain, cough, bloody sputum, dys-pnea and even coma may occur in severe cases.

(4) Physical examination reveals acutely ill complexion and malar flush with congestion of conjunctival and nasopha-ryngeal mucosa. In patients with influenzal pneumonia or sec-ondary bacterial pneumonia, the respiratory sounds are dimin-ished. Diffuse moist rales may be heard over the lung fields.

3. Laboratory tests show a decreased leukocyte count and the ratio of neutrophils to leukocytes, while the lymphocytes count may be relatively elevated. Mucosal imprint from inferi-or nasal conchae may show inclusions of influenza virus. This is valuable for the early diagnosis. In serological examinations, hemagglutination inhibition test or complement fixation test can be used for the diagnosis. Viral isolation is helpful in con-firming the type of pathogen.

Differentiation and Treatment of Common Syndromes in Traditional Chinese Medicine

1. Wind-cold Syndrome:

Clinical manifestations: Severe aversion .to cold, slight fever, absence of sweat, headache, aching pain of extremities, stuffy nose with nasal discharge, cough with thin sputum, thin and whitish coating of tongue, floating and tight pulse.

Therapeutic method: Relieving exterior syndrome with the drugs pungent in flavor and warm in property, ventilating the lung and expelling pathogenic cold.

Recipe: Modified Antiphlogistic Powder of Schizonepeta and Ledebouriella.

Ingredients:

Herba Schizonepetae 10g

Radix Ledebouriellae 10g

Rhizoma Seu Radix Notopterygii 10g

Radix Bupleuri 10g

Radix Peucedani 10g

Folium Perillae 10g

Radix Platycodi 10g

Rhizoma Zingiberis Recens 3 pieces

Administration: All the above drugs are to be decocted in water for oral administration.

Modification: Supplementary drugs should be added with emphasis on certain symptoms, Radix Angelicae Dahuricae 10g, and Rhizoma Ligustici Chuanxiong 10g, are used to treat severe headache; add Radix Bupleuri 12g and Herba Menthae 6g for the case with high fever; Rhizoma seu Radix Noteptery-gii 12g and Radix Angelicae Pubescentis 9g is used instead for exhibiting of more symptoms and signs of exterior dampness; If the case is complicated with exterior syndrome of excess characterized by no sweating, headache and pantalgia, severe aversion to cold, Ephedra Decoction is preferred; If the case is manifested as exterior deficiency with sweating, aversion to wind, slight fever, stuffy nose and retching, Cinnamon Twig Decoction is recommended.

2. Wind-heat Syndrome

Clinical manifestations: Higher fever, slight aversion to co1d, headache, sore throat with congestion, expectoration of yellowish sputum, thirst or with epistaxis, reddened tongue with thin and yellowish fur, floating and rapid pulse.

Therapeutic method: Relieving exterior syndrome with the drugs pungent in flavor and cool in property, promoting the dispersing function of the lung and clearing up pathogenic heat.

Recipe: Modified Powder or Lonicera and Forsythia.

Ingredients:

Flos Lonicerae 30g

Fructus Forsythiae 15g

Radix Isatidis 30g

Radix Puerariae 20g

Folium Mori 10g

Flos Chrysanthemi 10g

Fructus Arctii 12g

Herba Lophatheri 10g

Radix Platycodi 10g

Administration: Decoct the above drugs in an adequate amount of water to get 200-300ml of decoction. Divide it in-to two equal portions. Take one half in the morning and the other half in the evening.

Modification: In case of high fever, add

Gypsum Fibrosum 30g

In case of severe cough, add

Semen Armeniacae Amarum 10g

Bulbus Fritillariae Cirrhosae 10g

In case of severe throat, add

Radix Sophorae Subprostratae 10g

Radix Scorophulariae 10g

In case of epistaxis,add

Rhizoma Imperatae 30g

In case of patients with alternate spells of fever and chill, nausea and vomiting, add

Radix Scutellariae 12g

Rhizoma Pinelliae 10g

In case of the patients with weak constitution and profuse sweat, add

Radix Astragali seu Hedysari 15g

In cases of complicated with summer-damp, add

Herba Elscholtziae seu Moslae 10g

Six to One Power 20g (wrapped with cloth in decocting)

In cases of gastro-intestinal influenza pertaining to the syndrom of exterior cold and interior dampness, marked by fever, aversion to cold, vomiting, diarrhea, feeling of fullness and stuffiness in the chest and hypochondrium, thick and greasy fur of the tongue, Powder of Agastachis for Restoring Health is preferred.