Respiratory Disease Update 2004: SARS, Influenza, Community-Acquired Pneumonia—The Emergency Medicine Perspective Part I: SARS and Influenza

Author: Jonathan Glauser, MD, FACEP, Attending Staff Physician, Cleveland Clinic Foundation, Department of Emergency Medicine; Faculty, MetroHealth Medical Center, Cleveland, OH.

Peer Reviewers: Sandra M. Schneider, MD, FACEP, Professor and Chair, Department of Emergency Medicine, University of Rochester, Rochester, NY; and Steven M. Winograd, MD, FACEP, Attending Physician, Emergency Department, St. Joseph Medical Center, Reading, PA.

Diagnosis and management of acute respiratory disease continue to present challenges for emergency physicians. Diagnosis, risk stratification, and outcome-optimizing drug therapy is different depending on the nature of the infection, and frequently, pharmacologic therapy is empiric. From an institutional and community perspective, the challenges are even more complex. The mandate to both cure patients acutely and preserve long-term antimicrobial efficacy represents one of the most important missions that emergency physicians face when developing protocols and pathways for in-hospital and outpatient management of such life-threatening infectious conditions as community-acquired pneumonia (CAP). Other respiratory diseases, including severe acute respiratory syndrome (SARS) and influenza, present different but equally important challenges.

With these issues in mind, this issue reviews the current status of SARS, influenza, and CAP, providing essential information for emergency physicians and recommendations at a time when the therapeutic landscape for management of patients constantly is evolving. —The Editor

Severe Acute Respiratory Syndrome (SARS)

Definition, Epidemiology, and History. SARS is an infectious disease that first manifested itself in humans in the Guangdong province of China in November 2002.1 SARS is a respiratory illness caused by a novel coronavirus, called SARS-associated coronavirus (SARS-CoV). The disease first was recognized in Asia in February 2003, with the first index case in Hong Kong on Feb. 22, 2003.2 During the next several months, it spread to more than two dozen countries in North and South America, Europe, and Asia. On March 12, 2003, the World Health Organization (WHO) issued a global alert describing cases of pneumonia of unknown cause in China, Hong Kong, and Vietnam.1 This was the first global alert issued in more than a decade. As of March 27, 2003, there were 367 reported cases in Hong Kong and slightly more than 1400 cases worldwide. The first probable case of SARS in a health care worker in the United States was reported on April 18, 2003.3 As of April 28, 2003, SARS was described in 28 countries and 5050 individuals, causing 217 deaths.4 Unlike historic epidemics, which spread by surface transportation, SARS spread worldwide via the travel and health care industries.

A noteworthy outbreak occurred in the greater Toronto, Ontario, area between March 7 and April 14, 2003. The initial cases involved a family of Hong Kong descent who lived in Toronto: A 78-year-old woman and her husband traveled to Hong Kong from Feb. 13-23, 2003. The ensuing epidemic involved 144 patients. Of these, 111 were exposed in the hospital setting; 20 required mechanical ventilation; and 8 died.5 Between Feb. 1, 2003, and June 24, 2003, there were 37 Canadian deaths related to SARS.6 Fifty-one percent of SARS cases in Toronto affected nurses and physicians. Publicity from the disease affected travel and local economies, and there were scares that SARS would cause a global epidemic. At Mount Sinai Hospital in Toronto, the amount of time it took to triage patients increased. There was a need for nurses to wear N95 respirator masks throughout their 12-hour shifts.7

In May 2003, it was announced that a novel coronavirus was identified in patients with SARS. On the basis of the obtained sequence of 300 nucleotides, conventional and real-time polymerase chain reaction (PCR) assays were established for the virus.8

In July 2003, cases were no longer being reported, and SARS outbreaks worldwide were considered contained. By that time, the WHO had listed 29 cases from the United States, none of them fatal, 8 of whom had serologic evidence of SARS-CoV infection. There were 8098 probable cases of SARS worldwide, with 774 deaths (case fatality rate 9.6%). On July 5, 2003, Taiwan, the last area of the world at that time to have experienced local transmission of SARS, was declared to have broken the chain of person-to-person transmission.9 However, as of Jan. 31, 2004, a new case of infection with SARS-CoV was reported in a practicing physician from Guangzhou, the fourth case detected in China since Dec. 16, 2003.10

Of the 144 patients described in the Toronto series, 111 (77%) were exposed in the hospital setting.5 Concurrent to the Toronto epidemic, an emergency department (ED) in Singapore implemented protection for staff, patients, and the entire facility utilizing a decontamination chamber completed in 2002. This was in response to a scare that forced ambulance diversion away from the ED serving the busiest hospital in Singapore. The public actually was advised not to present to that ED with non-SARS-related problems. The total ED attendance for the 80-day period until Singapore was removed from the WHO’s list of SARS-affected areas on May 31, 2003 was 16,600, of whom 69% were screened for SARS. No SARS case was traced to a visit to the study ED.11

The causative agent was unknown at the time of the above outbreaks, although it has since been discovered to be a coronavirus. From the outset, the definition of SARS, therefore, included fever and history of travel from areas with documented or suspected community transmission, since lower respiratory symptoms of cough and dyspnea alone were non-specific.12-14 Evidence of pneumonia may require computed tomography (CT) testing, as chest x-rays often initially are normal. In an earlier report from Hong Kong, 18 of 27 scans were positive when chest x-ray was normal.15 The case definition for SARS as revised in December 2003 is listed. (See Table 1.)1,16

For purposes of clarification, the revised SARS case definition modifies the clinical, epidemiologic, laboratory, and case-exclusion criteria used during the 2003 epidemic. Exclusion is now allowed when a serum sample collected more than 28 days of onset of symptoms is negative for antibody to SARS-CoV. SARS report under investigation (RUI) is a nonspecific classification based on clinical or epidemiologic criteria and includes cases classified previously as probable. SARS-CoV disease is based on results from laboratory testing.16

Incubation Period, Clinical Diagnosis, Signs, and Symptoms. The incubation period for SARS is typically 2-7 days; however, isolated reports have suggested an incubation period as long as 10 days.

The illness begins generally with a prodrome of fever (> 100.4° F [> 38.0° C]). Fever often is high, sometimes is associated with chills and rigors, and might be accompanied by other symptoms, including headache, malaise, and myalgia. Cough is typically nonproductive. At the onset of illness, some persons have mild respiratory symptoms. Typically rash and neurologic or gastrointestinal findings are absent; however, some patients have reported diarrhea during the febrile prodrome, with up to 50% overall experiencing diarrhea at some time during the illness.17

After 3-7 days, a lower respiratory phase begins with the onset of a dry, nonproductive cough or dyspnea, which might be accompanied by or progress to hypoxemia. In 10-20% of cases, the respiratory illness is severe enough to require intubation and mechanical ventilation. The case fatality rate among persons with illness meeting the current WHO case definition of SARS is approximately 3%.

Cough has been reported to follow onset of fever, giving a rationalization to a SARS diagnostic score based upon clinical findings in the ED. The score gives one point for each of the following symptoms: myalgias, diarrhea, lymphopenia, and thrombocytopenia. One point is subtracted if rhinorrhea or sore throat is present, and 2 points are subtracted if cough occurred before or concomitant with fever. The score was developed in Singapore, and a score of zero or below was deemed to make SARS less likely.17

Since enzyme immunoassay (EIA) and reverse transcription polymerase chain reaction (RT-PCR) for detecting SARS viral RNA in patients with respiratory symptoms generally are not available acutely, another clinical decision rule for the ED recently has been published. This allows 3 points for bilateral or multilobar infiltrates, 3 points for monocyte predominance in the sputum, 2 points for lymphocytopenia, and 1 point each for the following: history of exposure, elevation of lactate dehydrogenase (LDH) over 450 U/L, C-reactive protein greater than 5 mg/dL, and activated partial thromboplastin time greater than 40 seconds. The point system was significantly higher in the SARS group (6-11, median 9) than in the non-SARS group (3-7, median 4). A cut-off score of 6 was suggested based on cases from Taipei, Taiwan.18

The Viral Category. Coronaviruses were discovered in the early 1960s. Electron microscopy revealed round particles with knoblike protrusions around the rim, and the viruses were named for their crown-like appearance. These viruses have been found to infect rodents, chickens, turkeys, pigs, dogs, and cats. They may cause the common cold, or more serious respiratory disease in the frail elderly.19

Radiographic Findings. Chest radiographs might be normal during the febrile prodrome and throughout the course of illness. However, in a substantial proportion of patients, the respiratory phase is characterized by early focal interstitial infiltrates progressing to more generalized, patchy, interstitial infiltrates. Some chest radiographs from patients in the late stages of SARS also have shown areas of consolidation. Infiltrates may be unilateral or bilateral, and resemble bronchopneumonia from other causes. In suspicious cases with normal plain chest films, CT scan of the chest may reveal a characteristic subpleural ground glass appearance with air space consolidation. The appearance is similar to acute respiratory distress syndrome and to bronchiolitis obliterans with organizing pneumonia (BOOP), providing a rationale for some of the early therapies attempted.

Characteristically, the following have not been present: lymphadenopathy, pleural effusions, and cavitation.20

Laboratory Findings. Early in the course of disease, the absolute lymphocyte count often is decreased. Overall, white blood cell counts generally have been normal or decreased. At the peak of the respiratory illness, approximately 50% of patients have leukopenia and thrombocytopenia or low-normal platelet counts (50,000-150,000/microliter). Lymphopenia (< 1000/microliter) occurred in 70% of the cases reported from Hong Kong,20 in 89% of cases from Toronto,12 and in 54% of cases reported from the Toronto outbreak.5 Early in the respiratory phase, elevated creatine phosphokinase levels (as high as 3,000 IU/L) and hepatic transaminases (AST two to six times the upper limits of normal) have been noted.12,20 Initial reports described elevated LDH in 87%, hypocalcemia in 70% of cases, hypomagnesemia in 57%, and hypophosphatemia in 53%.5 The elevated AST and LDH suggest that the SARS agent replicates outside of the respiratory tract. In the majority of patients, renal function has remained normal. The severity of illness might be highly variable, ranging from mild illness to death. Although a few close contacts of patients with SARS have developed a similar illness, the majority have remained well. Some close contacts have reported a mild, febrile illness without respiratory signs or symptoms, suggesting the illness may not always progress to the respiratory phase. Respiratory secretions should test negative for common bacterial and viral pathogens for a diagnosis of SARS to be entertained.

Definitive diagnosis depends upon specific diagnostic tools, such as RT-PCR, indirect fluorescent antibody, or enzyme-linked immunoabsorbent assay antibody. Antibody may be detectable after the 10th-21st day after onset of SARS.21 Without a rapid diagnostic tool, and often without a reliable history of exposure, emergency physicians may need to use their best clinical judgment, as well as a combination of laboratory and imaging findings.

Tests to detect SARS-CoV have been refined, and criteria for laboratory diagnosis of SARS-CoV have been evolving. In general, they require:

a) detection of serum antibody to SARS-CoV by a test validated by the CDC, such as enzyme immunoassay;

b) isolation in cell culture of SARS-CoV from a clinical specimen; or

c) detection of SARS-CoV RNA by a RT-PCR validated by the CDC, with subsequent confirmation in a reference laboratory.

A case may be excluded as a SARS report if:

a) an alternative diagnosis can explain the illness in full;

b) antibody to SARS-CoV is undetectable in a serum specimen obtained more than 28 days after onset of illness; or

c) the case report depended contact with a person who subsequently proved not to have SARS-CoV.

SARS-CoV antibody tests may be positive as early as 8-10 days after onset of illness. After appropriate testing for other respiratory pathogens, suitable specimens to collect may include respiratory, blood, and serum samples. Acute and convalescent (greater than 28 days from symptom onset) serum samples should be collected from each patient who meets the SARS case definition. Respiratory specimens for RT-PCR testing may include: nasopharyngeal wash/aspirates, nasopharyngeal swabs, oropharyngeal swabs, bronchoalveolar lavage, tracheal aspirate, pleural fluid tap, sputum, or postmortem tissue. In general, sputum contains more viral RNA than do nasal or throat swabs, making the latter less suitable for testing than sputum.8

Mode of Transmission. The principal way SARS appears to be spread is through droplet transmission; namely, when someone sick with SARS coughs or sneezes droplets into the air and someone else breathes them. It is possible that SARS may be transmitted more broadly through the air or from objects that have become contaminated.

The amount of contact that humans have with the original host species may increase the chances of a new virus "jumping species," and veterinary epidemics of SARS are conceivable.

Since the disease spread between continents, the question of spread within aircraft has arisen. It had been reported that one infected passenger on a flight from Hong Kong to Beijing may have infected 22 other passengers and two flight attendants.9 The risk of contagion within aircraft is related to the replacement rate of air and the path of air flow relative to passengers in the aircraft. A study from 1995 indicated that microbial levels in jets were well below those in airport terminals or in other common urban settings.22 As well, the laminar airflow within the cabin yields 20 air exchanges per hour, with sterile air drawn from outside. This is well in excess of the six exchanges per hour recommended for tuberculosis isolation rooms.23

Infection Control. Airborne precautions include use of a fit-tested N-95 respirator.24 The N95 masks are effective to filter 99.5% of particles larger than 0.75 m.25 They allow air to pass, and the mask material is designed to block 95% of particles 0.3 microns in diameter under specified test conditions. The respirator is a mask held in place by elastic bands. If greater protection is desired, a loose-fitting powered air-purifying respirator (PAPR) can be used. This device consists of a Tyvek headcover/hood and a face shield that fits over the head. A blower unit blows filtered air into a mask worn by the user. Protection, unlike the N95 respirator, does not depend upon a tight seal to the face. While more expensive than a N95 respirator, the PAPR devices are reusable and more comfortable to wear for a longer time.26

British Columbia guidelines included protective eyewear until risk assessment was completed and reasons for admission were ascertained. In high-risk cases, this could include goggles, safety glasses, or a face shield.27 Eyeglasses are not considered adequate protection. Contact precautions include use of gown and gloves. Hand washing between patients, and cleaning instruments such as stethoscopes with alcohol swabs should be observed. Personnel should not rub their eyes or touch their mouths, noses, or other mucous membranes while working on exposed equipment. Disinfectants are thought to be very effective against the SARS virus.28 Emergency and elective tracheostomies have been performed without causing infection in any medical or nursing staff utilizing an N95 mask, goggles, and transparent plastic facial shield. Disposable waterproof surgical apron, double surgical gloves, and plastic shoe covers also were utilized.29

Bacterial/viral filters have been used on exhalation valves of mechanical ventilators to prevent contaminated aerosols from entering the environment. Using breathing-circuit filters on the exhalation limb whenever SARS patients are ventilated eliminates the need for cleaning and sterilizing any reusable components downstream of the filter.26

The Singapore response, as noted above, was initiated March 13, 2003, and included giving all ED at-risk patients surgical masks. At-risk patients bypassed the rest of the ED and were placed in a decontamination chamber. None passed into the air-conditioned interior of the ED. An inverted tent was erected outside the ED entrance, with facilities for a second satellite radiology service. A waiting area in front of the tent in the ED shelter could hold up to 50 persons.11 Large numbers of patients could be screened, utilizing the presence of fever, respiratory complaints, chest x-rays, and occasional complete blood count (CBC) results. A rapid turnover of patients helped ED staff to minimize the stress of working in a hot and humid outdoor environment while wearing protective gear.

The SARS coronavirus has been transmitted through a laboratory accident to a health care worker while working with the West Nile virus. This case makes it imperative that biosafety level 3 guidelines be observed among lab workers.30

Period of Communicability. Information to date suggests that people are most likely to be infectious when they have symptoms, such as fever or cough. However, it is not known how long before or after their symptoms begin that patients with SARS might be able to transmit the disease to others.

Case Definitions of SARS. The case definition of SARS was inconsistent among countries for the first months of its discovery. Before the isolation of the SARS virus, the Centers for Disease Control, the WHO, and Health Canada had slightly differing definitions, all based on fever, significant travel or contact history, and respiratory signs and symptoms.21,31 (See Table 1 for SARS case definition information.)

Any suspicious or probable cases of SARS may be reported to the state or local health department. For submission of the enzyme immunoassay, an informed consent form may be obtained from: www.cdc.gov/ncidod/sars/lab/eia/consent.htm. For the RT-PCR test, the consent form may be obtained at: www.cdc.gov/ncidod/sars/lab/rtpcr/consent.htm.32 Testing of clinically well contacts of probable or suspect SARS cases may be done, but only as part of epidemiological studies. Persons who test SARS-CoV positive in these studies will not be notified as SARS cases to the WHO at this time.33

Treatment and Prognosis. No specific therapy has been shown to be effective. Early reports listed anecdotal experience with ribavirin and steroids.21 Ribavirin is a ribonucleoside analogue that induces mutagenesis of RNA viral genomes and has activity against many RNA viruses including respiratory syncytial virus and coronaviruses, justifying empiric therapy against a then-unknown agent. The dose of ribavirin utilized typically was 2 g intravenously, followed by 1 g every 6 hours for 4 days, followed by 500 mg every 8 hours for four to six days. However, use of ribavirin was temporally associated with hemolysis, as well as elevation of transaminases. There was a trend toward poor outcomes in those treated with ribavirin, which did not attain statistical significance. Because of the radiologic similarity to other atypical pneumonias, to respiratory distress syndrome, and to BOOP, empiric treatment has included antibiotics such as cefotaxime, clarithromycin, levofloxacin,21 steroids, or antiviral agents such as oseltamivir and ribavirin.12,34 None of these therapies has proven effective.

Samples of sputum, sera, blood, and urine should be obtained to exclude other causes for pneumonia. Blood samples that may aid in the diagnosis of SARS may include: white blood count and differential, platelet count, creatine phosphokinase, liver function tests, C-reactive protein and paired sera for antibody response. Treatment for community-acquired pneumonia is recommended. Appropriate precautions must be maintained at all times, especially to therapies that may cause aerosolization such as nebulizers with a bronchodilator, bronchoscopy, gastroscopy, chest physiotherapy, or any other intervention which may disrupt the respiratory tract.17

Treatment remains supportive, with intubation and mechanical ventilation if necessary.

Overall mortality during the Toronto outbreak was 6.5%, similar to Hong Kong data,20 with worse prognosis if comorbid disease such as chronic obstructive pulmonary disease, cancer, cardiac disease, or diabetes were present.5 Early reports from Hong Kong indicated that 14-20% of patients required intubation and ventilatory support.

Predictors for ICU admission and death have included low serum sodium levels, advanced age, high lactate dehydrogenase levels, and a high peak creatine kinase level.20

SARS contacts who feel otherwise well should be warned that the earliest reliable symptom if the illness is fever. Close contacts include persons having cared for, having lived with, or having had direct contact with respiratory secretions and body fluids of persons with SARS.2 They may be observed passively for 10 days, but are free to pursue usual activities.17

Criteria for admission have not been defined clearly, apart from those recognized as applicable for community-acquired pneumonia. (For details, see part 2 of this series.) However, in the Singapore study describing the screening of 11,641 persons, the following criteria were used for admission:

1) travel to an affected area;

2) contacts with a SARS patient;

3) health care worker;

4) cluster fever (that is, multiple persons in the same household or workplace all becoming sick within a short interval);

5) person on a home quarantine order;

6) cough with or without shortness of breath;

7) chest radiograph showing changes of pneumonia;

8) clinical features of atypical pneumonia; and

9) clinical features of pneumonia or infective process in an immunocompromised person recently discharged from the hospital.11

Of the 10,075 patients discharged using these criteria,28 re-attended and were diagnosed as SARS or probable SARS. None of these 28 patients caused secondary transmission of the virus.

Another report generated a SARS score based upon the following scoring system among febrile patients presenting to the ED in Taiwan during the 2003 epidemic. One point each was given for myalgia, diarrhea, lymphopenia, or thrombocytopenia, respectively. One point was subtracted for rhinorrhea or sore throat, and 2 points were subtracted for cough onset before or during fever.35 Admission for isolation was indicated for patients with at least one of the following:

1. Infiltrate on chest radiograph;

2. Clinical score of 1 or greater;

3. Significantly abnormal laboratory data, such as severe leukopenia.

Conclusions. Hospitals and EDs in particular must be prepared to institute respiratory precautions in the face of potential worldwide epidemics. Patients with undifferentiated respiratory conditions and their family members represent a potential threat to the spread of illness in the hospital setting. Health care workers and individual contacts, especially those with early symptoms, must be placed in isolation with appropriate follow-up. Any new disease may strike with particular force at "first contact" health care workers, including EMS and ED staff. Although the SARS outbreak was not a bioterrorism event, and no fatalities have ensued so far from SARS in the United States, there are lessons to be learned regarding future infection control measures, disaster response, and protection for patients. SARS was spread from only a handful of countries in Asia and from Toronto, and therefore may have been easier to contain.

Influenza

Overview. Epidemics of influenza generally occur in the winter months, and are responsible for approximately 36,000 deaths annually in the United States, and approximately 200,000 hospitalizations.36,37 Each year in Canada, up to 75,000 people are admitted to the hospital, and 6700 die with influenza.38 It was the first human virus to be isolated and characterized. Influenza viruses are negative stranded RNA viruses, categorized as orthomyxoviruses.39 Two surface glycoproteins are seen on the surface as projections, and are used to categorize influenza: hemagglutinin and neuraminidase. For example, A/Hong Kong/1/68 (H3N2) represents an influenza A virus isolated from a patient in 1968, with specific hemagglutinin and neuraminidase antigens.

Rates of serious illness and death are highest in persons aged 65 years and older. There have been pandemics in 1889, 1918-1919, 1957, 1968-1969, and 1977. Approximately 21 million people died worldwide in the 1918-1919 pandemic, with 549,000 deaths in the United States. The next pandemic is thought to be overdue.40 Pandemics are associated with antigenic shift when new antigenic subtypes appear, against which the population has no immunity. The hemagglutination antigen always is involved in antigenic shift, as it is responsible for eliciting virus-neutralizing antibodies. Lesser antigenic changes are known as antigenic drift. Epidemics due to new strains arising from antigenic drift tend not to be as lethal, as the population has some underlying immunity. An avian influenza virus was shown to infect humans directly when 18 people in Hong Kong were infected in 1997; of these 6 died.41 The source of the outbreak was infected chickens, and the outbreak was stopped after all of the chickens in the territory were slaughtered. Some experts felt that another pandemic was likely, if not inevitable.42

Influenza is an acute infection of the respiratory tract. The virus is shed in respiratory secretions for 5-10 days, and viremia does not occur.37 Typical symptoms begin 2-3 days after exposure to the virus. There are three types of viruses: A, B, and C. The latter tends not to cause significant disease. Treatment is geared to management and prevention of influenza A and B. The virus is highly contagious, and generally spread via inhalation of airborne droplets or by direct contact with an infected person’s secretions. In the United States, influenza season is from November through April, peaking typically from December through March. Airborne/TB precautions are unnecessary, as the influenza virus is heavier than tuberculosis and does not stay airborne for prolonged periods.

Symptoms. Patients may present with high fever, chills, malaise, myalgia, and headache. Respiratory symptoms typically predominate, with nasal congestion, rhinitis, sore throat, conjunctivitis, and nonproductive cough. Photophobia and shivering may be present. While the term "intestinal flu" frequently is employed, gastrointestinal symptoms generally do not predominate in adults, and are reported more frequently in children. Cervical adenopathy may be present.

Complications. In young infants, influenza may cause croup or a sepsis picture. Tracheobronchitis is more common in the elderly. Pneumonia may occur, either related primarily to influenza or to a bacterial complication from S. pneumoniae, S. aureus, or H. influenza. Infection of cells by influenza A requires cleavage of the virus hemagglutinin by proteases. Some strains of S. aureus produce such proteases, possibly accounting for the frequency with which S. aureus pneumonia complicates influenza infections.40 Influenza may induce an exacerbation of chronic obstructive pulmonary disease. It has been implicated in myositis and myocarditis, and myoglobinuria can occur. It may be implicated in acute viral encephalitis, Reye’s syndrome, Guillain-Barré syndrome, or toxic shock syndrome. (See Table 2.)

Table 2. Influenza Complications

Diagnosis. Early diagnosis of influenza may prevent unnecessary use of bacterial antibiotics, and may afford the opportunity for more directed antiviral therapy. Tests for influenza include viral culture, rapid antigen testing, serology, PCR, and immunofluorescence (IF).45,50,51

Viral cultures should be obtained within three days of symptom onset. Throat swabs, nasopharyngeal washes or sputum collection all may be used to isolate viruses or viral antigen. PCR may be used to detect viral RNA in respiratory secretions. Nasal washings may be the best specimens for virus isolation.40,52

Rapid tests can detect the virus within 30 minutes to 1 hour. However, they tend to have lower sensitivity, and if confirmation is necessary, a viral culture should be sent.53 Viral antigens in respiratory secretions can be detected by IF, time-resolved immunofluorescence assay (TRIFA), radioenzyme immunoassay, or enzyme-linked immunosorbent assay (ELISA).

Immunofluorescence or hemagglutination techniques (HAI) may determine the type of influenza virus (A or B), as well as the hemagglutination subtypes H1, H2, or H3. Complement fixation and hemagglutination inhibition (HI) tests commonly are used to compare acute and convalescent sera. The HI test is considered more specific.40 A rise in immunoglobulin (Ig) titer at least fourfold is considered diagnostic of infection. Rises detected by ELISA are diagnostic of acute infection.37

Influenza Vaccine. The most efficacious means to combat influenza is via prevention. The influenza vaccine generally covers two A strains, and one B strain. The 2003 trivalent vaccine includes the same strains as the 2002 vaccine: A/New Caledonia/20/99 (H1N1) and A/Moscow/10/99 (H3N2)-like, and the B/HongKong/330/01-like.56 Antibodies reach protective levels approximately two weeks after injection. They generally persist for at least six months, although serum antibody levels may fall below protective levels after four months or fewer. For optimal protection during influenza season, vaccination has been recommended in October or November. In years prior to 2002, there has been a shortage of vaccine, although none was forecast for 2003-2004. For travel to the southern hemisphere, it may be advisable to protect patients during April through September.

The United States Public Health Service recommends influenza vaccine for all persons older than 50 years, and healthy children aged 6-23 months. A single intramuscular dose of inactivated vaccine is recommended for adults and for children older than 3 years of age. Children 6-35 months of age should receive 0.25 mL. Children younger than 9 years who have never been immunized should receive two doses at least four weeks apart, optimally timed so that the second dose is administered before December. Hypersensitivity reactions to the egg protein used in the vaccine can occur. Persons with known anaphylactic hypersensitivity to eggs and patients with acute febrile illness should not be vaccinated. The list of people who should receive vaccination includes those with hemoglobinopathies, patients with chronic diseases, nursing home residents, patients older than 50 years, health care workers, and household members of persons at high risk. Women who expect to be in their second to third month of pregnancy during influenza season, as well as some international travelers, should be vaccinated as well. (See Table 3.)

Table 3. People Who Should Receive Influenza Vaccine

A new intranasal vaccine, influenza virus vaccine live (Flumist), was released in 2003 for use in healthy people between the ages of 5 and 49 years.59 Since it is an attenuated live virus, it should not be given to health care workers and others who might come in contact with immunosuppressed patients because of the risk for transmission of the vaccine-strain virus. Each syringe-like sprayer contains a 0.5 mL dose; 0.25 mL to be sprayed into each nostril. Previously unimmunized children should receive two doses at least six weeks apart. Children who take aspirin should not receive this vaccine.

The efficacy of vaccination has been well established, in generating lower rates of influenza outbreaks. It has been recommended that at least 80% of residents of long-term care facilities be vaccinated to achieve herd immunity.38 As well, two randomized controlled studies have shown that staff vaccination reduces influenza-related morbidity and death among nursing facility residents.60,61

Adverse side effects of vaccination include soreness at the vaccination site for typically fewer than two days. Since this is a killed vaccine, patients should be warned that the vaccine itself cannot cause influenza. However, the injection may result in myalgia, fever, malaise, and rare allergic reactions.

Drug Prophylaxis. If an influenza outbreak occurs before less than two weeks after vaccination, or if influenza strains prove to be different from the vaccine strains, prophylaxis with an oral antiviral drug may be useful, especially for high-risk populations. Oral amantadine or rimantadine started before exposure can prevent illness due to influenza A in 70-90% of adults.56

The dose of amantadine is 100 mg bid or 200 mg daily in one dose. The pediatric dose is 5 mg/kg/day, up to a maximum of 150 mg/day. It has not been evaluated for children younger than 1 year of age. Dosage should be halved in patients older than 65 years or with a creatinine clearance of less than 50 mL/min. Side effects of amantadine largely are neurologic, and include delirium, seizures, hallucinations, and insomnia. These effects are more common in the elderly, and in patients taking antihistamines, CNS stimulants, or anticholinergic medications concurrently. Amantadine levels may be elevated in patients taking hydrochlorothiazide plus triamterene. Amantadine is approved for chemoprophylaxis of influenza A in adults and in children older than 1 year. People sensitive to egg protein and not eligible for vaccine may benefit from prophylaxis. Some naturally occurring strains of influenza A are resistant to amantadine.40

The dose of rimantadine is also 100 mg bid or 200 mg once daily, or 5 mg/kg/day in children. It inhibits viral replication of influenza A subtypes H1N1, H2N2, and H3N2.37 Dosage for prophylaxis is 100 mg per day. The dosage should be halved in patients older than 65 years or in patients with severe liver dysfunction or renal insufficiency (creatinine clearance less than 10 mL/min). The pediatric dose for children weighing fewer than 40 kg is 5 mg/kg/day orally. The central nervous system effects of rimantadine are less frequent than those of amantadine.56

Drug Treatment. Two neuraminidase inhibitors have been approved for oral treatment of either influenza A or B. Release of viruses from infected cells and viral spread are decreased with use of these agents. They are approximately 70-90% effective for pre-exposure or post-exposure prophylaxis in households with either A or B strains. Zanamivir and oseltamavir can reduce the duration of influenza A and B illness by approximately one day compared with placebo. They have not been demonstrated to be effective in preventing serious complications or death. The recommended duration of therapy for neuraminidase inhibitors is five days. Oseltamivir has been approved for prophylaxis; zanamivir has not.53 Each should be administered within two days of symptom onset.

The dose of oseltamavir (Tamiflu) is 75 mg once daily in patients older than 12 years. For patients with creatinine clearance of 10-30 mL/min, the dose should be adjusted to 75 mg every other day. Oseltamavir may cause nausea, vomiting, and headache.64 It also is approved for chemoprophylaxis in persons ages 13 years and older. It has been approved for treatment of children 1 year and older, and for prophylaxis in persons 13 years of age and older. In contacts of an influenza-positive index case, oseltamavir has shown an overall protective efficacy of approximately 89% for individuals and 84% for households.65 The pediatric dose is 2 mg/kg up to 30 mg twice a day for children weighing fewer than 15 kg, 45 mg twice daily for children weighing 15-23 kg, and 60 mg twice a day for children weighing 23-40 kg.53

The second agent, zanamivir (Relenza), is 10 mg by inhalation once per day. It is supplied as a dry powder.56,66 It is approved for treating persons 7 years and older.67 A meta-analysis of neuraminidase inhibitors for treatment of influenza A and B indicate that they lower the risk of complications that require antibiotics by approximately 29-43%.67

Table 4 summarizes agents available for influenza treatment and prevention.

Antipyretic therapy may include acetaminophen. Aspirin should be withheld from patients younger than 16 years of age due to the risk of Reye’s syndrome. Other treatment and prevention considerations include frequent hand washing, and not touching one’s eyes or nose after patient contact.

The Role of Emergency Services in Prevention of Influenza.

Although not standard, there have been EDs that have vaccinated patients against influenza since 1992. A sample of ED visits obtained from National Hospital Ambulatory Medical Care Survey data indicated that, during the nine-year period from 1992-2000, approximately 247,000 influenza vaccinations were administered in the ED setting. In 77% of these cases, patients requested vaccination as their chief complaint. Clearly, there is room for expansion of vaccination programs in the emergency setting, if resources permit.68 Of note is that paramedics have implemented influenza immunization programs as well, at retail establishments, community events, EMS stations, churches, and senior citizen complexes.69

Preparing for Pandemic. The WHO has a network of approximately 110 influenza centers worldwide that submit new influenza isolates to four WHO collaborating centers, located in the United States, the United Kingdom, Australia, and Japan, respectively. The aim is to detect new strains of influenza at the earliest possible moment so that measures may be enacted in the event of a pandemic.

Although a detailed plan is not within the scope of this update, it is clear that a community-wide response will be essential in the event of a pandemic. Genetic shift, which has occurred from time to time, may present a situation in which previous vaccines become ineffective, and large segments of the population have no immunity to a new influenza virus. Any plan, therefore, must address the following:39,72

1) reducing health care staff absenteeism;

2) ensuring expeditious patient discharge from hospitals

3) ensuring that EDs are prepared for high patient volumes;

4) reviewing policies for admission to hospitals and for scheduling of elective procedures;

5) planning for limited availability of equipment and supplies, such as respirators and gurneys; and

6) developing in advance, patient isolation plans for use during a pandemic.

The priorities identified have included:

a) promoting adult immunization programs and improving vaccination coverage for high-risk groups;

b) working with industry to ensure adequate capacity for production of influenza vaccine and antiviral drugs;

c) development of communication networks and protocols for dissemination of information to public health officials, news media, health care providers, and the general public;

d) fostering a sustained basic research program targeted at pandemic influenza; and

e) working with public and private entities to ensure adequate health care capacity across the nation.39

An influenza virus pandemic would cause social disruption dependent upon the rates of illness, sick leave, hospitalization, and death. Sensitivity analysis has been performed based upon efficiency of neuraminidase inhibitors, vaccines (including pneumococcal vaccine), age distribution of influenza cases, and hospitalization rates.73

Conclusions. Influenza is best controlled via immunization. Some experts view another pandemic as very possible, especially if genetic shift occurs and entire populations are without immunity to a new strain. There is a concerted effort worldwide to detect new strains as soon as they arise.

References

1. World Health Organization. Case definitions for surveillance of severe acute respiratory distress syndrome (SARS). Available at www.who.int/csr/sars/casedefinition/en/. Accessed 3/5/2004.

2. Ho W. Guideline on management of severe acute respiratory syndrome (SARS). Lancet 2003;361:1313-1315.

3. Centers for Disease Control. Severe acute respiratory syndrome—United States 2003. MMWR 2003;52:332.

4. World Health Organization. Cumulative number of reported cases of severe acute respiratory syndrome (SARS). Available at www.who.int/csr/sars/country/2003_03_31/en/. Accessed 7/7/2004.

5. Booth CM, Matukas LM, Tomlinson GA, et al. Clinical features and short-term outcomes of 144 patients with SARS in the Greater Toronto area. JAMA 2003;289:2801-2809.

6. World Health Organization (2003a). Cumulative number of reported probable cases of SARS. www.who.int/csr/sars/country/2003_06_25/en, retrieved 6/25/2003.

7. Woodend K. SARS in perspective—Are we ready for the next round? Can J Cardiov Nurs 2003;13:3-4.

8. Drosten C, Gunther S, Preiser W, et al. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med 2003;348:1967-1976.

9. Weekly Epidemiological Record 2003;78:258-259.

10. World Health Organization. New case of laboratory-confirmed SARS in Guangdong, China—Update 5, January 31, 2004. www.who.int/csr/don/2004_01_31/en.

11. Tham K-T. An emergency department response to severe acute respiratory syndrome: A prototype response to bioterrorism. Ann Emerg Med 2004;43:6-14.

12. Poutanen SM, Low DE, Henry B, et al. Identification of severe acute respiratory syndrome in Canada. N Eng J Med 2003;348:1995-2005.

13. Young D. Lessons learned from the SARS outbreak. Am J Health-System Pharm 2003;60:1204-1206.

14. Parry J. WHO issues guidelines to manage any future SARS outbreak. BMJ 2003;327:411.

15. Rainer TH, Cameron PA, Smit D, et al. Evaluation of WHO criteria for identifying patients with severe acute respiratory syndrome out of hospital: Prospective observational study. BMJ 2003;326:1154-1158.

16. Centers For Disease Control. Revised US surveillance case definition for severe acute respiratory syndrome (SARS) and update on SARS cases—United States and worldwide, December 2003. MMWR 52:1202-1206.

17. Chen S-Y, Su C-P, Ma MH, et al. Predictive model of diagnosing probable cases of severe acute respiratory syndrome in febrile patients with exposure risk. Ann Emerg Med 2004;43:1-5.

18. Wang T-L, Jang T-N, Huang C-H, et al. Establishing a clinical decision rule of severe acute respiratory syndrome at the emergency department. Ann Emerg Med 2004;43:17-22.

19. Falsey AR, Walsh EE, Hayden FG. Rhinovirus and coronavirus infection- associated hospitalizations among older adults. Jour Inf Dis 2002;185:1338-1341.

20. Lee N, Hui D, Wu A, et al. A major outbreak of severe adult respiratory syndrome in Hong Kong. N Engl J Med 2003;348:1986-1994.

21. World Health Organization. Severe acute respiratory syndrome (SARS): Laboratory diagnostic tests. Available at www.who.int/csr/sars/diagnostictests/en/.

22. Wick RL, Irvine LA. The microbial composition of airliner cabin air. Aviation, Space, and Env Med 1995;66:220-224.

23. World Health Organization, Communicable Diseases Cluster. Tuberculosis and air travel: Guidelines for prevention and control. WHO 1998:23-24.

24. Centers for Disease Control and Prevention. Updated interim domestic infection control guidance in the health care and community setting for patients with suspected SARS. At www.cdc.gov/ncidod/sars/infectioncontrol.htm. Accessed April 22, 2003.

25. Qian Y, Willeke K, Grinshpun SA, et al. Performance of N95 respirators: Filtration efficiency for airborne microbial and inert particles. Am Ind Hyg Assoc J 1998;59: 128-132.

26. No authors listed. Protecting against SARS during equipment maintenance. Health Devices 2003;32:213-219.

27. Yassi A, Noble MA, Daly P. Severe acute respiratory syndrome: Guidelines were drawn up collaboratively to protect healthcare workers in British Columbia. BMJ 2003;326: 1394-1395.

28. No authors listed. Mechanical ventilation of SARS patients. Health Devices 2003;32: 220-222.

29. Wei WI, Tuen HH, Ng RW, et al. Safe tracheostomy for patients with severe acute respiratory syndrome. Laryngoscope 2003;113:1777-1779.

30. Normile D. SARS experts want labs to improve safety practices. Science 2003;302:31.

31. Health Canada. Severe acute respiratory syndrome case definitions. Available at: www.hc-sc.gc.ca/.

32. Seven steps to submit suspicious samples for SARS testing. ED Management 2003;15: suppl 1 (anon).

33. World Health Organization. Management of Severe Acute Respiratory Syndrome, at www.who.int/csr/sars/management/en. Accessed 2/29/2004.

34. Tsang KW, Ho PL, Ooi GC, et al. A cluster of severe acute respiratory syndrome in Hong Kong. N Engl J Med 2003;348:1977-1985.

35. Su C-P, Chiang W-C, Ma, MH, et al. Validation of a novel severe acute respiratory syndrome scoring system. Ann Emerg Med 2004;43:34-42.

36. Centers for Disease Control and Prevention. Prevention and control of influenza. MMWR 2003;52 (RR08):12.

37. Leblebicioglu H. E-medicine Influenza. Updated June 19, 2003, at www.emedicine.com/ped/topic3006.htm. Accessed March 9, 2004.

38. Stevenson CG, McArthur MA, Naus M, et al. Prevention of influenza and pneumococcal pneumonia in Canadian long-term care facilities: How are we doing? CMAJ 2001; 164:1413-1419.

39. Strikas RA, Wallace GS, Myers Mg. Influenza pandemic preparedness action plan for the United States: 2002 update. Clin Inf Dis 2002;35:590-596.

40. Influenza Viruses. At www.virology-online.com/viruses/Influenza.htm. Accessed March 9, 2004.

41. Yuen KY, Chan PKS, Peiris M, et al. Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus. Lancet 1998;351:467-471.

42. Patriarca PA, Cox NJ. Influenza preparedness plan for the United States. J Infect Dis 1997;176 (Suppl 1):S4-7.

43. National Center for Health Statistics. Fast Stats. Influenza, at www.cdc.gov/nchs/fastats/flu.htm.

44. Peltola V, Ziegler T, Ruskanen O. Influenza A and B virus infections in children. Clin Infect Dis 2003;36:299-305.

45. Bridges CB, Harper SA, Fukuda K, et al. Prevention and control of influenza. Recommendations of the advisory Committee on Immunization Practices. MMWR April 25, 2003 52:1-33.

46. Chiu SS, Lau YL, Chan KH, et al. Influenza related hospitalizations among children in Hong Kong. N Engl J Med 2002;347:2097-2103.

47. Considerations for distinguishing influenza-like illness from inhalational anthrax. MMWR 2001;50:984-986.

48. Monto AS. Viral respiratory infections in the community: Epidemiology, agents, and interventions. Am J Med 1995;99:6B24S-27S.

49. Fine AM, Wong JB, Fraser HS, et al. Is it influenza or anthrax? A decision analytic approach to the treatment of patients with influenza-like illness. Ann Emerg Med 2004;43:318-328.

50. Cox NJ, Subbarao K. Influenza. Lancet 1999; 354:1277-1282.

51. Preboth M. ACIP releases guidelines on the prevention and control of influenza. Am Fam Phys 2001;64:1270-1275.

52. Schmid ML, Kudesia G, Wake S, et al. Prospective comparative study of culture specimens and methods in diagnosing influenza in adults. BMJ 1998;316:275.

53. Ressel GW. Advisory Committee on Immunization Practices. ACIP releases 2003 guidelines on the prevention and control of influenza. Am Fam Phys 2003;68:1426-1433.

54. Kaiser L, Briones MS, Hayden FG. Performance of virus isolation and Directigen Fla A to detect influenza A virus in experimental human infection. J Clin Virol 1999;14: 191-197.

55. Belli N, benfica D, Perosa AH, et al. Evaluation of a rapid test (Quickvue) compared with the shell vial assay for detection of influenza virus clearance after antiviral treatment. J Virol Methods 2003;109:85-88.

56. Influenza Prevention 2003-2004. Medical Letter September 29, 2003;45:78-80.

57. Gall SA. Influenza and current guidelines for its control. Inf Dis in Obst and Gynecol 2001;9:193-195.

58. Influenza. www.medceu.com/tests/influenza.htm. Accessed March 9, 2004.

59. Flumist: An intranasal live influenza vaccine. Med Lett 2003;45:65-66.

60. Carman WF, Elder AG, Wallace LA, et al. Effects of influenza vaccination of health care workers on mortality of elderly people in long-term care: A randomized controlled trial. Lancet 2000;355:93-97.

61. Potter J, Stott DJ, Roberts MA, et al. Influenza vaccination of health care workers in long-term-care hospitals reduces the mortality of elderly patients. J Infect Dis 1997;175:1-6.

62. Dowdle WR. The swine flu vaccine program. Am Soc Micro 1997; 43:243-244.

63. Morgan R, O’Donnell C, Bresnitz E. Influenza vaccine. Past and present. New Jersey Medicine 2001;98:27-34.

64. McClellan K, Perry CM. Oseltamivir: A review of its use in influenza. Drugs 2001;61: 263-283.

65. Welliver R, Monto A, Carewicz O, et al. Effectiveness of oseltamivir in preventing influenza in household contacts. JAMA 2001;286:748-754.

66. Penn CR, Osterhaus A. Zanamivir: A rational approach to influenza B. Scand J Infect Dis 2001;33:33-40.

67. Cooper NJ, Sutton AJ, Abrams KR, et al. Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: Systematic review and meta-analysis of randomized controlled trials. BMJ 2003;326:1235-1240.

68. Pallin DJ, Kim S, Emond JA, et al. National study of pneumococcal and influenza vaccinations among adult emergency department patients, 1992 to 2000. Ann Emerg Med 2003;42:S70 (abstr).

69. Mosesso VN, Packer CR, McMahon J, et al. Influenza immunizations provided by EMS agencies: The MEDICVAX Project. Prehosp Emerg Care 2003;7:74-78.

70. Draft WHO Guidelines on the Use of vaccines and Antivirals during Influenza Pandemics. Weekly Epidemiologic Record 2002;77:394-404.

71. Gust ID, Hampson AW, Lavanchy D. Planning for the next pandemic of influenza. Reviews in Medical Virology 2001;11:59-70.

72. Influenza pandemic preparedness plan: The role of WHO and guidelines for national and regional planning. Geneva: World Health Organization, Switzerland, April 1999. Available at www.who.int/csr/resources/publications/influenza/WHO_CDS_CSR_EDC_99_1/en/.

73. Van Genugten ML, Heijnen MA, Jager JC, et al. Pandemic influenza and healthcare demand in the Netherlands: Scenario analysis. Emerging Inf Dis 2003;9:531-538.