Complications of influenza.

The clinical course of influenza may be characterized by complications that include not only lower respiratory tract infections but also nonrespiratory manifestations. The mechanisms by which influenza induces many of these complications remain for the most part unclear. The most frequent complications are shown in Table 1.

Primary Viral Pneumonia

Primary viral pneumonia occurs as a complication of influenza most frequently in the elderly or in patients with cardiopulmonary disease, but it has been documented in pregnant women and in healthy, immunocompetent individuals. (1) Such cases develop within 1 day after the onset of influenza illness and are characterized by the rapid progression of fever, tachypnea, tachycardia, cyanosis, and hypotension. Physical examination of the chest reveals bilateral crepitant rales and chest films reveal nonconsolidating pulmonary infltrates or, less often, areas of consolidation. (2) Blood gas studies demonstrate hypoxemia, and blood counts reveal leukocytosis with a left shift. If cavitation or pleural effusion is seen, bacterial superinfection should be suspected.

Gram stain of the sputum in patients with primary influenza pneumonia fails to reveal significant bacteria, and bacterial cultures yield sparse growth of normal oropharyngeal flora. The diagnosis can be confirmed with the use of antigen detection methods or by viral isolation from respiratory secretions, which have yielded high viral titers of influenza A in patients with primary influenza pneumonia. Mortality as a result of this complication is high and is associated with the development of extensive fibrosis and interstitial inflammation. (1,2) Patients with these findings seem to respond poorly to antibacterial agents.

No controlled studies of amantadine or rimantadine for the treatment of primary viral influenza pneumonia have been conducted, and as such the use of these medications is based on data extrapolated from anecdotal reports. Limited studies of patients with primary influenza pneumonia have demonstrated the resolution of small-airway functional abnormalities with amantadine therapy, and treatment of acute infection with established, effective modalities is appropriate. (3) Further studies are needed to assess the use of amantadine or rimantadine alone or in combination with M2 inhibitors (zanamivir and oseltamivir) or ribavirin in the management of severe infection.

Supportive treatment is important and includes fluid and electrolyte management, oxygenation, intubation, assisted ventilation, and positive end-expiratory pressure. (4) If bacterial superinfection is suspected, appropriate antibiotic agents for the specific organism should be administered. Clinical improvement begins 5 to 16 days after the onset of the pneumonia, with radiographic findings requiring as long as 4 months to resolve. (4) Survivors often develop diffuse pulmonary fibrosis. (5)

Secondary Bacterial Pneumonia

Secondary bacterial pneumonia in the setting of influenza infection is observed more frequently and is more severe in the elderly and in patients with chronic pulmonary disease. Patients develop a typical influenza illness that seems to be improving but is complicated by recrudescence of fever along with shaking chills, pleuritic chest pain, and cough productive of bloody or purulent sputum. (6) There seems to be less cyanosis and tachypnea than observed in patients with primary viral pneumonia. Chest x-rays reveal local areas of lung consolidation, and Gram staining and culture of sputum reveals a predominance of a bacterial pathogen. The most common organisms isolated are Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Moraxella catarrhalis.

This form of pneumonia is milder than primary influenza pneumonia, although fatality rates as high as 7% were described in the influenza pandemic of 1957 and 1958. (1) Options for antimicrobial therapy in the setting of community-acquired pneumonia are continually evolving but should target the pathogen isolated. The Infectious Diseases Society of America has developed guidelines for empiric therapy administered in patients with community-acquired pneumonia before the identification of an outbreak. (7)

Combined Bacterial-Viral Pneumonia

Combined bacterial-viral pneumonia is perhaps more common than primary influenza pneumonia, and the bacteria involved are identical to those observed in secondary bacterial pneumonias. This syndrome may be difficult to differentiate from primary viral pneumonia, with patients presenting with early-onset bacterial infection while sputum cultures still yield influenza virus. These patients respond well to antibiotics, although the mortality rate is still approximately 10%. (1) The mortality rate of S. aureus coinfection in this setting, however, has been reported to be as high as 42%. (8) Studies of infection in murine models have suggested that some strains of S. aureus can secrete a protease that increases the infectivity of influenza virus by cleaving hemagglutinin. (9,10)

Complications in Immunosuppressed Patients

Although influenza infection in the immunocompromised host usually presents similarly to disease in the immunoeompetent patient, severe infections have been described. (11,12) An influenzal disease of greater severity has been noted in patients with acquired immunodeficiency syndrome. It is characterized by high prevalence of hypoxemia and a trend toward longer duration of the illness. (13) In immunocompromised children, viral shedding can be quite prolonged, (14) especially in patients with human immunodeficiency virus infection and low CD4 counts. The treatment of such children with amantadine can lead to a drug-resistant virus that can be shed for an extended duration. (14) One report demonstrated resistance to zanamivir in an immunocompromised child infected with influenza B virus who had been treated with an extended course of zanamivir. (15) The prolonged shedding of influenza virus seen in these settings thus may lead to the dissemination of resistant viruses.

Exacerbation of Chronic Pulmonary Disease

Approximately 20 to 30% of exacerbations of chronic obstructive pulmonary disease are associated with respiratory tract viral infections. (16,17) Influenza may lead to such exacerbations and deteriorate a previous asthmatic status. Several randomized, controlled trials have shown the benefit of corticosteroids, bronchodilators, antibiotics, and noninvasive positive pressure ventilation for the treatment of severe exacerbations. Annual influenza vaccination and smoking cessation are the most important factors in the prevention of exacerbation. In patients with cystic fibrosis, influenza virus may produce deterioration of pulmonary function and disease progression. (18)

Croup 

Croup in children is manifested by a dry, barking cough and inspiratory stridor with respiratory distress. Significant numbers of croup cases occur during influenza A and B outbreaks, although croup associated with influenza A virus seems to be more severe and less frequent than that associated with parainfluenza virus Type 1 or 3 or respiratory syncytial virus infections. The main treatment for children who develop croup is mist therapy to moisten airway secretions. (19)

Cardiac Complications

Patients with previous cardiac disease are predisposed to cardiac complications during influenza seasons, most notably heart failure. Influenza immunization has been shown to prevent the number of hospitalizations because of congestive heart failure. (20) Electrocardiographic abnormalities have been found in as many as 81% of hospitalized patients with influenza, and myocardial infarction has been described more frequently in patients with a history of coronary artery disease in association with influenza viral pneumonia. Myocarditis and pericarditis are uncommon complications of influenza A and B. (21) One report suggested that myocarditis can lead to the rare sudden death complication of influenza, but attempts to isolate the virus from myocardial and lung tissue have been unsuccessful in such patients. Myocardial dysfunction does not seem to be a direct result of influenza A infection, as demonstrated by cardiac function studies performed in patients with primary influenza pneumonia, (1,22,23) There is no specific treatment for influenza myocarditis other than supportive care.

Central Nervous System Complications

Central nervous system complications have been observed during influenza A and B virus infections and include seizures, acute encephalitis, and postinfectious encephalopathy. Seizures are observed most frequently in febrile young children during the acute phase of the illness and have been described in as many as 20% of hospitalized children. (24,25) Seizures are more rarely described in adults. Acute encephalitis (ie, encephalitis lethargica) may be difficult to diagnose and may occur more frequently than suspected. (26) Encephalitis occurs during the acute phase of the influenza illness, with symptoms ranging from irritability and drowsiness to confusion, psychosis, delirium, coma, and death. (6) Cerebrospinal fluid (CSF) analysis is normal, although one report demonstrated the isolation of influenza B virus from CSF on the basis of reverse transcription polymerase chain reaction. (26) Severe, periodic, lateralized epileptiform discharges have been noted on electroencephalograms of patients with influenza B-associated encephalopathy. (27) Postinfectious encephalitic syndrome usually occurs 2 to 3 weeks after recovery from influenza and is rare. The CSF shows inflammatory changes, but virus is not usually recovered, and most patients recover from this syndrome. There are no specific treatments that have been shown to be effective for this syndrome.

Reye's Syndrome

Reye's syndrome is a neurologic and metabolic disease that occurs primarily in children aged 2 to 16 years. Classically, Reye's syndrome is seen after gastrointestinal infections, respiratory viruses, and varicella, (28) but it also has been described in adults several days after influenza. The pathophysiology is not clearly understood, but children who are administered aspirin have an excess frequency of this syndrome. (29) Reye's syndrome is more frequently associated with influenza B than with influenza A and has a high mortality rate (10-40%). (28) The clinical presentation is that of rapidly progressing, noninflammatory encephalopathy with fatty infiltration of the liver, resulting in hepatic failure and elevated serum transaminase and ammonia levels. This presentation occurs as respiratory tract symptoms resolve.

General supportive measures include hemodynamic monitoring with careful attention to fluid and electrolyte balance and assistance with ventilation when needed. Modalities such as dialysis and amino acid, phosphate, and insulin infusions to correct specific metabolic abnormalities have not altered patient outcome. (30) Because the major cause of death is cerebral edema, monitoring of intracranial pressure (31) with therapy directed at decreasing intracranial pressure (eg, mannitol, glycerol) constitutes a reasonable approach. The recognition of the connection between administration of aspirin and Reye's syndrome led to recommendations to avoid prescribing aspirin for patients with viral infections. This has resulted in a dramatic decrease in the incidence of Reye's syndrome in the United States. (32,33)

Myositis 

Myositis and myoglobinuria with tender leg muscles and elevated serum creatine kinase levels have been reported during influenza infection, primarily in children after influenza A or, more commonly, influenza B infection. This may occur in adults as well and is characterized by generalized pain, tenderness, and weakness of muscles, high serum levels of muscle enzymes, myoglobinemia, and myoglobinuria. (34) Rhabdomyolysis can lead to acute renal failure that may be fatal. (35) The relationship between influenza virus and myositis is unclear. Although the virus has been recovered from muscle cells, muscle cell necrosis with and without inflammation may be seen. (34,36) There is no specific therapy for myositis associated with influenza infection other than general measures such as hydration, correction of electrolyte abnormalities, and alkalinization of the urine to prevent acute renal failure.

Toxic Shock Syndrome 

In recent outbreaks of influenza A or B, a toxic shock-like syndrome has occurred in previously healthy children and adults. The presumed pathogenic mechanism was a virus-effected change in bacterial colonization and replication mediated by the exotoxin toxic shock syndrome toxin-1 produced by S. aureus. (37,38)

Table 1. Most common complications of influenza

Respiratory                               Nonrespiratory

Primary viral pneumonia              Electrocardiographic
                                       abnormalities
Secondary bacterial pneumonia        Heart failure
Combined viral-bacterial pneumonia   Myocarditis
Exacerbation of chronic              Encephalitis
  obstructive airway disease         Reye's syndrome
Exacerbation of asthma               Poor diabetes control

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From the James H. Quillen VA Medical Center and the Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN.

No financial support was obtained for this manuscript. The authors of this manuscript do not have any financial, commercial or proprietary interest in any drug, device, or equipment mentioned in this article. The views contained in this article do not necessarily reflect those of the Department of Veterans Affairs of the United States.

Reprint requests to Felix A. Sarubbi, MD, Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Box 70622, Johnson City, TN 37614. Email: [e-mail]

Accepted June 19, 2003.