stresstest : What is a Stress Test

Despite advances in disease prevention, coronary artery disease remains a major cause of illness and death in the United States. The costs of treating this disease and the indirect costs resulting from lost work and wages are substantial. The exercise stress test is a useful tool for detecting coronary artery disease and for evaluating medical therapy and cardiac rehabilitation following myocardial infarction.

In addition to the standard exercise stress test, other methods of cardiovascular stress testing include scintigraphy and echocardiography.

Exercise stress scintigraphy uses a radioactive tracer to enhance abnormal areas of myocardial blood flow. Stress scintigraphy can be performed with pharmacologic agents instead of exercise if the patient's condition does not allow sufficient physical activity for performing the study. Echocardiography has recently been used in combination with exercise or pharmacologic stress testing as yet another form of noninvasive cardiac evaluation.

Competence and Equipment Requirements

The clinical competence to perform exercise stress testing is usually granted by staff privileges in health care institutions. The Joint Commission on Accreditation of Healthcare Organizations requires that institutions assess competence on the basis of criteria established in the medical staff bylaws. A combined specialty task force, composed of members from the American College of Cardiology (ACC), the American College of Physicians and the American Heart Association (AHA), in 1996 issued a statement on clinical competence in exercise testing. Exercise stress testing is appropriate in persons who plan to engage in vigorous exercise. In this situation, the test is recommended for use in women 50 years and older and in men 40 years and older.

Equipment requirements for exercise stress testing include a bicycle ergometer or treadmill, a monitor system, a medical crash cart and a defibrillator. Equipment costs can range from $15,000 to $40,000. Personnel requirements include the examiner and one other person trained in basic cardiac life support, although someone with advanced cardiac life support skills is preferred.

Sensitivity and Specificity

exercise(running, jogging, climbing, etc) stress testing provides a controlled environment for observing the effects of increases in the myocardial demand for oxygen; significant fixed stenoses from coronary artery disease result in electrocardiographic (ECG) evidence of ischemia.

Particularly difficult to detect is evidence of fixed stenoses with collateral blood flow, as well as low-grade (less than 50 percent) stenoses. These abnormalities may not produce sufficient impairment of blood flow to affect the ECG. Some studies indicate that low-grade stenoses are often the source of spontaneous thrombosis, leading to the sudden development of significant stenosis, infarction and sudden death because such lesions do not have the benefit of collateral blood flow.12 An exercise stress test would not be helpful in detecting this type of lesion.

The estimation of the pretest probability of a significant fixed stenosis should be based on the patient's age, gender, symptoms, concurrent medical conditions, medications and physical examination, as well as on the clinician's diagnostic experience with symptoms of myocardial ischemia. This information is helpful for determining the potential utility of an exercise stress test for a given patient.

The sensitivity of exercise stress testing ranges from 23 to 100 percent, and the specificity ranges from 17 to 100 percent. For example, in an abnormal exercise stress test in which a man reaches a heart rate of 85 percent of the predicted maximum for his age, the sensitivity and specificity for the diagnosis of significant coronary artery disease is 65 percent and 85 percent, respectively. A more detailed discussion of sensitivity, specificity, population effect and probability analysis is available in the ACC/AHA Task Force Report on Exercise Stress Testing.

Consideration may be given to obtaining this test when patients present with symptoms of coronary artery disease, including the classic anginal symptoms of chest pressure or pain that occurs with or without exertion. Atypical presentations or anginal equivalents, such as shortness of breath or dyspnea on exertion, are also appropriate indications for this study.

Conditions that may render a patient unable to exercise adequately during the stress test include claudication, severe physical disabilities and pulmonary disease.

Patients with coronary artery disease who have undergone surgical intervention or are receiving medical therapy can perform an exercise stress test when they are medically stable and symptom-free. The study can be used to assess the effectiveness of treatment. After myocardial infarction, patients may be candidates for exercise stress testing at a low level of exercise to determine functional capacity and identify any ECG changes or symptoms during exercise. With this information, the clinician is often able to prescribe an exercise regimen or more aggressive therapy, or to select the appropriate tests for further evaluation.

Asymptomatic healthy persons may be considered as candidates for exercise stress testing if they are in high-risk occupations (e.g., pilots, firefighters, law enforcement officers, mass transit operators). In addition, the American College of Sports Medicine (ACSM) recommends an exercise stress test for all women 50 years of age and older and all men 40 years of age and older who plan to engage in vigorous exercise. The ACSM does not recommend exercise stress testing for asymptomatic healthy persons who are not planning vigorous exercise, regardless of the person's age.

An exercise stress test may also be considered in asymptomatic patients who have two or more risk factors for coronary artery disease or a concurrent chronic disease, such as diabetes, that carries a high risk of coronary disease. Patients with valvular disorders (except those with hemodynamically significant aortic stenosis) may undergo an exercise stress test to evaluate their functional capacity, the effectiveness of treatment, their symptom complex or the need for surgical intervention.

Pretest Evaluation

The history, physical examination and laboratory studies necessary to evaluate the patient's suitability for performing an exercise stress test are summarized in Table. A baseline electrocardiogram must be evaluated for changes that might obscure the results of stress testing, such as significant ST-segment changes, ventricular strain patterns and conduction abnormalities.

In addition, the patient should receive the proper preparatory instructions for the exercise stress test as required by the hospital or the testing laboratory. Instructions usually include no food intake for six to 12 hours before the study. Patients should be told to wear loose-fitting, comfortable clothing and comfortable walking shoes. In addition, instructions about modifying the doses of any medications should be given.

History In addition to the presence and character of chest pain, concurrent medical conditions such as claudication, severe physical disabilities and pulmonary disease should be considered in view of their effects on the patient's ability to exercise. Such conditions may render the patient unable to perform the test. Exercise usually worsens uncontrolled hypertension, and the pretest evaluation may be terminated because of this finding.

The patient's general activity level and pulmonary reserve and the presence of arthritic disease may influence the type of exercise test protocol selected and the duration and level of activity achieved. Many exercise protocols exist to accommodate patients who need to walk at a slower pace or advance through exercise stages at a slower rate.

The patient's current medications are important. Nitrates may mask the occurrence of chest pain; beta-adrenergic blockers may blunt the heart rate response to exercise, and digoxin (Lanoxin) may produce abnormal ST-segment depression.

Physical Examination

A general physical examination with special attention usually is adequate for the pretest evaluation. Cardiac examination should include an assessment for the presence of murmurs and valvular disease. Severe valvular dysfunction, especially aortic stenosis, is an absolute contraindication to exercise stress testing. Gallop rhythms are noteworthy because the presence of an S3 may indicate significant congestive heart failure, a contraindication if it is clinically severe. While the development of an S4 during exercise may indicate significant cardiac ischemia, detection of it during a physical examination does not signify ischemia and is not grounds for not performing an exercise stress test.

An assessment of the vascular system should include palpation of the carotid and peripheral pulses, as well as evaluation for the presence of bruits over the abdominal aorta and other larger vessels. Because claudication of the lower extremities or transient ischemic attack­type symptoms can occur during exercise, another type of stress testing that does not require exercise should be considered if the physical examination suggests that these problems are clinically significant.

Assessment of the musculoskeletal system includes evaluation of the patient's ability to walk at a moderate to fast pace without significant gait disturbances. The hips, shoulders, arms and legs should allow relatively full mobility and support during exercise.

Laboratory Studies Screening laboratory studies are obtained to diagnose subclinical disease that may be present. Exercise stress testing should not be performed in patients with symptoms of anemia or severe hepatic, renal or metabolic disorders.

A resting ECG is an essential part of the pretest evaluation. The patient should have a resting ECG that is free of abnormalities. While the presence of any of these ECG changes is not an absolute contraindication to exercise stress testing, they may interfere with the validity of the test by altering the ECG changes that are consistent with ischemia during exercise. Most authorities suggest an imaging study in addition to exercise stress testing as a part of the cardiac evaluation in most patients with these changes on the baseline ECG. It should be noted, however, that in these persons, an exercise stress test could potentially be used to evaluate functional capacity, blood pressure response or other clinically determined parameters.

Potential Contraindications to Exercise Stress Testing

Absolute Contraindications

Exercise stress testing may worsen the patient's condition or place the patient at increased risk of cardiac instability or injury in the setting of acute myocardial infarction, unstable angina, acute cardiac inflammation, severe congestive heart failure, uncontrolled sustained ventricular arrhythmias, symptomatic supraventricular arrhythmia, high-grade block, hemodynamically significant aortic stenosis or severe hypertension. Patients with such conditions usually require immediate medical or surgical intervention as clinically indicated but may be reassessed as candidates for exercise stress testing when the acute problems are resolved. The remaining contraindications render the patient physically unable to perform an exercise stress test.

Relative contraindications to exercise stress testing. While patients with these conditions may undergo a standard exercise(running, jogging, climbing, etc) stress test, they require special consideration because the presence of these conditions may invalidate the test results.

In most cases, medications should not be withheld in preparation for an exercise stress test. Patients can be instructed to take their medications before an exercise stress test, with the exception of insulin and oral hypoglycemic agents. Depending on how stable the patient's diabetic condition is, all of the dose of insulin or the hypoglycemic agent or one half of the dose should be withheld before the test.

Digoxin may depress the ST-segments. If ST-segment depression of 1 mm or more is present on the baseline ECG, use of ECG criteria for exercise-induced ischemia during exercise will be difficult. Type I antiarrhythmic agents and tricyclic antidepressants are proarrhythmogenic. For example, if at baseline a patient receiving any one of these medications has significant ectopy, the patient is at increased risk of hemodynamically significant arrhythmias with exercise and should not undergo exercise stress testing.

The antihypertensive effect of beta blockers, alpha blockers and nitroglycerin may cause significant hypotension during exercise. In general, orthostatic blood pressure assessment and a careful history will identify most patients susceptible to such a response. Beta blockers may also blunt the heart rate during exercise. While patients receiving beta blockers may perform the exercise required for the test, the usual age-adjusted target heart rate may not be a realistic end point for them.

Most electrolyte and endocrinologic abnormalities can affect the heart rate and ST-segment and T-wave changes on a resting ECG, and they may affect the patient's ability to exercise as well. Vasoregulatory problems from central and peripheral autonomic neuropathy associated with disorders such as diabetes, Parkinson's disease and Shy-Drager's syndrome may cause profound vasodilation and hypotension during exercise. The pretest evaluation should alert the clinician to the presence of this tendency, and exercise stress testing should not be performed if such a response to exercise seems significant.

Patients who have a history of tachyarrhythmias may be considered candidates for exercise stress testing, but those with easily reproduced tachycardia during exercise or other heavy physical activity are not candidates for exercise stress testing. Such a problem may be found in patients with mitral valve prolapse syndrome, Wolff-Parkinson-White syndrome and episodic or periodic supraventricular tachycardia. The occurrence of a tachyarrhythmia during exercise stress testing could cause syncope or, at a minimum, produce an inconclusive result.

Most exercise stress tests are interpreted in a standard format that includes an interpretation (or comment) section and a conclusion. Each section may not be described in every report because some of them may not be relevant or particularly useful in every clinical circumstance. Systolic hypotension, a very significant finding during a stress test, can signify severe coronary artery disease.

An interpretation of the baseline ECG is included in the report, noting any abnormalities and changes that occurred with changes in position (standing, lying or sitting). Symptoms occurring during the exercise stress test are usually reported as well. Most commonly, these comments are described as "fatigue," "legs tired," "chest pain/pressure," "shortness of breath," etc. If these symptoms were severe, they may have been the reason for discontinuing the test. Other reasons cited for stopping the test may be "target heart rate achieved," "exercise stopped per patient's request," "equipment malfunction" or "ECG findings or criteria were met."

Also usually described are the duration of the exercise period and the workload in METS (metabolic equivalents, or resting oxygen consumption of about 3.5 mL per kg per minute). The interpreter may also add subjective comments about the patient's exercise capacity; for example, the report may state "poor exercise tolerance (3 to 4 METS)" or "good exercise tolerance (10 to 11 METS)." The cardiorespiratory fitness levels established by the ACSM can serve as general guidelines.

Increases or decreases in blood pressure during exercise and rest are also noted. Hypotension, defined as a drop of more than 10 mm Hg in the systolic blood pressure during exercise, may signify severe cardiac ischemia. Opinions vary as to the definition of a hypertensive response to exercise, but most authorities accept as a maximal limit a systolic pressure of 230 mm Hg. The diastolic blood pressure during exercise usually varies 10 mm Hg in either direction. A 10 mm Hg decrease in the diastolic blood pressure during the postexercise period is not unusual and is considered physiologic.

While the presence of arrhythmias may or may not carry clinical significance, their frequency, type and appearance or disappearance with exercise and rest are also noted.

The final category of information provided in the report is the ECG response during exercise and recovery. Findings usually include the presence and location of ST-segment changes, P-wave, T-wave and U-wave changes, and the appearance of conduction abnormalities during the exercise and recovery periods.

Test Conclusions - Positive Results. An exercise stress test positive for myocardial ischemia may be further qualified with the terms "probably" and "strongly." For example, hypotension (a drop of more than 10 mm Hg in systolic pressure) or large (more than 2 to 3 mm) ST-segment depressions, either alone or in combination, are strongly positive test results. The presence of these abnormalities leaves little clinical doubt that significant coronary artery disease exists. The appearance during exercise of an S3, S4 or murmur indicates cardiac muscle dysfunction and therefore ischemia. The interpreter may also comment on the recovery or return to baseline of these findings as well as any interventions needed to bring about this change.

Negative Results. A negative test result is simply the lack of any of the above-mentioned findings. Some normal physiologic and ECG changes may occur during exercise.

Electrocardiographic (ECG) findings suggestive of a positive exercise stress test. In addition to the ECG findings depicted here, the occurrence of frequent premature ventricular contractions (PVCs), multifocal PVCs or ventricular tachycardia at mild exercise (less than 70 percent of maximal heart rate) is suggestive of an exercise stress test positive for myocardial ischemia.

Equivocal, or Inconclusive, Findings. Equivocal exercise stress test results are summarized in Table 10. These ECG changes are not diagnostic of ischemia. Alterations in the P-wave and T-wave morphology and changes in atrioventricular conduction with exercise are considered nondiagnostic if the changes revert to baseline in the rest period. The appearance of unifocal, premature atrial contractions or premature ventricular contractions (fewer than five per minute) is not a specific indicator for coronary artery disease. The development of intraventricular blocks, such as right bundle branch block, left bundle branch block and hemiblocks, is a nondiagnostic finding. An intraventricular block may also obscure ischemic changes and hinder further interpretation of the ECG. As with all inconclusive results, additional testing is needed. In most cases, an imaging study, exercise scintigraphy or echocardiography is needed to document ischemia.

Uninterpretable Results. In addition to equipment failure, other causes of uninterpretable test results include the patient's or operator's inability to complete the test before any goals are met. Further diagnostic studies should be planned, and any information that could have contributed to this result should be included in the report. For example, the patient may have appeared on physical examination to be a good exercise candidate but was unable or unwilling to comply with the requirements of the exercise stress test. In this case, the reason for noncompliance can help the clinician choose another examination that would be more appropriate for the patient.

Maximal and Submaximal Exercise Stress Test. A maximal exercise stress test is one that achieves the target heart rate, exercise level or time limit established for the patient. In most cases, the goal is the target heart rate, as calculated with the following formula: (220 - patient's age) × 0.85 beats per minute. An exercise stress test that does not meet the expected goal is called a submaximal study. If the stress test is submaximal because of decreased exercise capacity or noncardiac symptoms, consideration should be given to obtaining radionuclide scintigraphy or echocardiographic studies that do not include exercise as a component of the evaluation.

Avian influenza is an infection caused by avian (bird) influenza (flu) viruses. These influenza viruses occur naturally among birds. Wild birds worldwide carry the viruses in their intestines, but usually do not get sick from them. However, avian influenza is very contagious among birds and can make some domesticated birds, including chickens, ducks, and turkeys, very sick and kill them.

Infected birds shed influenza virus in their saliva, nasal secretions, and feces. Susceptible birds become infected when they have contact with contaminated secretions or excretions or with surfaces that are contaminated with secretions or excretions from infected birds. Domesticated birds may become infected with avian influenza virus through direct contact with infected waterfowl or other infected poultry, or through contact with surfaces (such as dirt or cages) or materials (such as water or feed) that have been contaminated with the virus.

Infection with avian influenza viruses in domestic poultry causes two main forms of disease that are distinguished by low and high extremes of virulence. The “low pathogenic” form may go undetected and usually causes only mild symptoms (such as ruffled feathers and a drop in egg production). However, the highly pathogenic form spreads more rapidly through flocks of poultry. This form may cause disease that affects multiple internal organs and has a mortality rate that can reach 90-100% often within 48 hours.

Human infection with avian influenza viruses There are many different subtypes of type A influenza viruses. These subtypes differ because of changes in certain proteins on the surface of the influenza A virus (hemagglutinin [HA] and neuraminidase [NA] proteins). There are 16 known HA subtypes and 9 known NA subtypes of influenza A viruses. Many different combinations of HA and NA proteins are possible. Each combination represents a different subtype. All known subtypes of influenza A viruses can be found in birds.

Usually, "avian influenza virus" refers to influenza A viruses found chiefly in birds, but infections with these viruses can occur in humans. The risk from avian influenza is generally low to most people, because the viruses do not usually infect humans. However, confirmed cases of human infection from several subtypes of avian influenza infection have been reported since 1997. Most cases of avian influenza infection in humans have resulted from contact with infected poultry (e.g., domesticated chicken, ducks, and turkeys) or surfaces contaminated with secretion/excretions from infected birds. The spread of avian influenza viruses from one ill person to another has been reported very rarely, and transmission has not been observed to continue beyond one person.

"Human influenza virus" usually refers to those subtypes that spread widely among humans. There are only three known A subtypes of influenza viruses (H1N1, H1N2, and H3N2) currently circulating among humans. It is likely that some genetic parts of current human influenza A viruses came from birds originally. Influenza A viruses are constantly changing, and they might adapt over time to infect and spread among humans.

During an outbreak of avian influenza among poultry, there is a possible risk to people who have contact with infected birds or surfaces that have been contaminated with secretions or excretions from infected birds.

Symptoms of avian influenza in humans have ranged from typical human influenza-like symptoms (e.g., fever, cough, sore throat, and muscle aches) to eye infections, pneumonia, severe respiratory diseases (such as acute respiratory distress), and other severe and life-threatening complications. The symptoms of avian influenza may depend on which virus caused the infection.

Studies done in laboratories suggest that some of the prescription medicines approved in the United States for human influenza viruses should work in treating avian influenza infection in humans. However, influenza viruses can become resistant to these drugs, so these medications may not always work. Additional studies are needed to demonstrate the effectiveness of these medicines.

Avian Influenza A (H5N1)

Influenza A (H5N1) virus – also called "H5N1 virus" – is an influenza A virus subtype that occurs mainly in birds, is highly contagious among birds, and can be deadly to them. H5N1 virus does not usually infect people, but infections with these viruses have occurred in humans. Most of these cases have resulted from people having direct or close contact with H5N1-infected poultry or H5N1-contaminated surfaces.

Avian influenza A (H5N1) outbreaks For current information about avian influenza A (H5N1) outbreaks, see our Outbreaks page.

Human health risks during the H5N1 outbreak

Of the few avian influenza viruses that have crossed the species barrier to infect humans, H5N1 has caused the largest number of detected cases of severe disease and death in humans. In the current outbreaks in Asia and Europe more than half of those infected with the virus have died. Most cases have occurred in previously healthy children and young adults. However, it is possible that the only cases currently being reported are those in the most severely ill people, and that the full range of illness caused by the H5N1 virus has not yet been defined.

So far, the spread of H5N1 virus from person to person has been limited and has not continued beyond one person. Nonetheless, because all influenza viruses have the ability to change, scientists are concerned that H5N1 virus one day could be able to infect humans and spread easily from one person to another. Because these viruses do not commonly infect humans, there is little or no immune protection against them in the human population. If H5N1 virus were to gain the capacity to spread easily from person to person, an influenza pandemic (worldwide outbreak of disease) could begin.

No one can predict when a pandemic might occur. However, experts from around the world are watching the H5N1 situation in Asia and Europe very closely and are preparing for the possibility that the virus may begin to spread more easily and widely from person to person.

Treatment and vaccination for H5N1 virus in humans

The H5N1 virus that has caused human illness and death in Asia is resistant to amantadine and rimantadine, two antiviral medications commonly used for influenza. Two other antiviral medications, oseltamavir and zanamavir, would probably work to treat influenza caused by H5N1 virus, but additional studies still need to be done to demonstrate their effectiveness.

There currently is no commercially available vaccine to protect humans against H5N1 virus that is being seen in Asia and Europe. However, vaccine development efforts are taking place. Research studies to test a vaccine to protect humans against H5N1 virus began in April 2005, and a series of clinical trials is under way.

Avian influenza, or “bird flu”, is a contagious disease of animals caused by viruses that normally infect only birds and, less commonly, pigs. Avian influenza viruses are highly species-specific, but have, on rare occasions, crossed the species barrier to infect humans.

In domestic poultry, infection with avian influenza viruses causes two main forms of disease, distinguished by low and high extremes of virulence. The so-called “low pathogenic” form commonly causes only mild symptoms (ruffled feathers, a drop in egg production) and may easily go undetected. The highly pathogenic form is far more dramatic. It spreads very rapidly through poultry flocks, causes disease affecting multiple internal organs, and has a mortality that (or this, or whatever) can approach 100%, often within 48 hours.

Which viruses cause highly pathogenic disease?

Influenza A viruses1 have 16 H subtypes and 9 N subtypes2. Only viruses of the H5 and H7 subtypes are known to cause the highly pathogenic form of the disease. However, not all viruses of the H5 and H7 subtypes are highly pathogenic and not all will cause severe disease in poultry.

On present understanding, H5 and H7 viruses are introduced to poultry flocks in their low pathogenic form. When allowed to circulate in poultry populations, the viruses can mutate, usually within a few months, into the highly pathogenic form. This is why the presence of an H5 or H7 virus in poultry is always cause for concern, even when the initial signs of infection are mild.

Do migratory birds spread highly pathogenic avian influenza viruses?

The role of migratory birds in the spread of highly pathogenic avian influenza is not fully understood. Wild waterfowl are considered the natural reservoir of all influenza A viruses. They have probably carried influenza viruses, with no apparent harm, for centuries. They are known to carry viruses of the H5 and H7 subtypes, but usually in the low pathogenic form. Considerable circumstantial evidence suggests that migratory birds can introduce low pathogenic H5 and H7 viruses to poultry flocks, which then mutate to the highly pathogenic form.

In the past, highly pathogenic viruses have been isolated from migratory birds on very rare occasions involving a few birds, usually found dead within the flight range of a poultry outbreak. This finding long suggested that wild waterfowl are not agents for the onward transmission of these viruses.

Recent events make it likely that some migratory birds are now directly spreading the H5N1 virus in its highly pathogenic form. Further spread to new areas is expected.

What is special about the current outbreaks in poultry?

The current outbreaks of highly pathogenic avian influenza, which began in South-East Asia in mid-2003, are the largest and most severe on record. Never before in the history of this disease have so many countries been simultaneously affected, resulting in the loss of so many birds.

The causative agent, the H5N1 virus, has proved to be especially tenacious. Despite the death or destruction of an estimated 150 million birds, the virus is now considered endemic in many parts of Indonesia and Viet Nam and in some parts of Cambodia, China, Thailand, and possibly also the Lao People’s Democratic Republic. Control of the disease in poultry is expected to take several years.

The H5N1 virus is also of particular concern for human health, as explained below.

Which countries have been affected by outbreaks in poultry?

From mid-December 2003 through early February 2004, poultry outbreaks caused by the H5N1 virus were reported in eight Asian nations (listed in order of reporting): the Republic of Korea, Viet Nam, Japan, Thailand, Cambodia, Lao People’s Democratic Republic, Indonesia, and China. Most of these countries had never before experienced an outbreak of highly pathogenic avian influenza in their histories.

In early August 2004, Malaysia reported its first outbreak of H5N1 in poultry, becoming the ninth Asian nation affected. Russia reported its first H5N1 outbreak in poultry in late July 2005, followed by reports of disease in adjacent parts of Kazakhstan in early August. Deaths of wild birds from highly pathogenic H5N1 were reported in both countries. Almost simultaneously, Mongolia reported the detection of H5N1 in dead migratory birds. In October 2005, H5N1 was confirmed in poultry in Turkey and Romania. Outbreaks in wild and domestic birds are under investigation elsewhere.

Japan, the Republic of Korea, and Malaysia have announced control of their poultry outbreaks and are now considered free of the disease. In the other affected areas, outbreaks are continuing with varying degrees of severity.

What are the implications for human health?

The widespread persistence of H5N1 in poultry populations poses two main risks for human health.

The first is the risk of direct infection when the virus passes from poultry to humans, resulting in very severe disease. Of the few avian influenza viruses that have crossed the species barrier to infect humans, H5N1 has caused the largest number of cases of severe disease and death in humans. Unlike normal seasonal influenza, where infection causes only mild respiratory symptoms in most people, the disease caused by H5N1 follows an unusually aggressive clinical course, with rapid deterioration and high fatality. Primary viral pneumonia and multi-organ failure are common. In the present outbreak, more than half of those infected with the virus have died. Most cases have occurred in previously healthy children and young adults.

A second risk, of even greater concern, is that the virus – if given enough opportunities – will change into a form that is highly infectious for humans and spreads easily from person to person. Such a change could mark the start of a global outbreak (a pandemic).

Where have human cases occurred?

In the current outbreak, laboratory-confirmed human cases have been reported in four countries: Cambodia, Indonesia, Thailand, and Viet Nam.

Hong Kong has experienced two outbreaks in the past. In 1997, in the first recorded instance of human infection with H5N1, the virus infected 18 people and killed 6 of them. In early 2003, the virus caused two infections, with one death, in a Hong Kong family with a recent travel history to southern China.

How do people become infected?

Direct contact with infected poultry, or surfaces and objects contaminated by their faeces, is presently considered the main route of human infection. To date, most human cases have occurred in rural or periurban areas where many households keep small poultry flocks, which often roam freely, sometimes entering homes or sharing outdoor areas where children play. As infected birds shed large quantities of virus in their faeces, opportunities for exposure to infected droppings or to environments contaminated by the virus are abundant under such conditions. Moreover, because many households in Asia depend on poultry for income and food, many families sell or slaughter and consume birds when signs of illness appear in a flock, and this practice has proved difficult to change. Exposure is considered most likely during slaughter, defeathering, butchering, and preparation of poultry for cooking.

Is it safe to eat poultry and poultry products?

Yes, though certain precautions should be followed in countries currently experiencing outbreaks. In areas free of the disease, poultry and poultry products can be prepared and consumed as usual (following good hygienic practices and proper cooking), with no fear of acquiring infection with the H5N1 virus.

In areas experiencing outbreaks, poultry and poultry products can also be safely consumed provided these items are properly cooked and properly handled during food preparation. The H5N1 virus is sensitive to heat. Normal temperatures used for cooking (70oC in all parts of the food) will kill the virus. Consumers need to be sure that all parts of the poultry (includes edible birds and fowl) are fully cooked (no “pink” parts) and that eggs, too, are properly cooked (no “runny” yolks).

Consumers should also be aware of the risk of cross-contamination. Juices from raw poultry and poultry products should never be allowed, during food preparation, to touch or mix with items eaten raw. When handling raw poultry or raw poultry products, persons involved in food preparation should wash their hands thoroughly and clean and disinfect surfaces in contact with the poultry products Soap and hot water are sufficient for this purpose.

In areas experiencing outbreaks in poultry, raw eggs should not be used in foods that will not be further heat-treated as, for example by cooking or baking.

Avian influenza is not transmitted through cooked food. To date, no evidence indicates that anyone has become infected following the consumption of properly cooked poultry or poultry products, even when these foods were contaminated with the H5N1 virus.

No. Though more than 100 human cases have occurred in the current outbreak, this is a small number compared with the huge number of birds affected and the numerous associated opportunities for human exposure, especially in areas where backyard flocks are common. It is not presently understood why some people, and not others, become infected following similar exposures.

What about the pandemic risk?

A pandemic can start when three conditions have been met: a new influenza virus subtype emerges; it infects humans, causing serious illness; and it spreads easily and sustainably among humans. The H5N1 virus amply meets the first two conditions: it is a new virus for humans (H5N1 viruses have never circulated widely among people), and it has infected more than 100 humans, killing over half of them. No one will have immunity should an H5N1-like pandemic virus emerge.

All prerequisites for the start of a pandemic have therefore been met save one: the establishment of efficient and sustained human-to-human transmission of the virus. The risk that the H5N1 virus will acquire this ability will persist as long as opportunities for human infections occur. These opportunities, in turn, will persist as long as the virus continues to circulate in birds, and this situation could endure for some years to come.

What changes are needed for H5N1 to become a pandemic virus?

The virus can improve its transmissibility among humans via two principal mechanisms. The first is a “reassortment” event, in which genetic material is exchanged between human and avian viruses during co-infection of a human or pig. Reassortment could result in a fully transmissible pandemic virus, announced by a sudden surge of cases with explosive spread.

The second mechanism is a more gradual process of adaptive mutation, whereby the capability of the virus to bind to human cells increases during subsequent infections of humans. Adaptive mutation, expressed initially as small clusters of human cases with some evidence of human-to-human transmission, would probably give the world some time to take defensive action.

What is the significance of limited human-to-human transmission?

Though rare, instances of limited human-to-human transmission of H5N1 and other avian influenza viruses have occurred in association with outbreaks in poultry and should not be a cause for alarm. In no instance has the virus spread beyond a first generation of close contacts or caused illness in the general community. Data from these incidents suggest that transmission requires very close contact with an ill person. Such incidents must be thoroughly investigated but – provided the investigation indicates that transmission from person to person is very limited – such incidents will not change the WHO overall assessment of the pandemic risk. There have been a number of instances of avian influenza infection occurring among close family members. It is often impossible to determine if human-to-human transmission has occurred since the family members are exposed to the same animal and environmental sources as well as to one another.

How serious is the current pandemic risk?

The risk of pandemic influenza is serious. With the H5N1 virus now firmly entrenched in large parts of Asia, the risk that more human cases will occur will persist. Each additional human case gives the virus an opportunity to improve its transmissibility in humans, and thus develop into a pandemic strain. The recent spread of the virus to poultry and wild birds in new areas further broadens opportunities for human cases to occur. While neither the timing nor the severity of the next pandemic can be predicted, the probability that a pandemic will occur has increased.

Are there any other causes for concern?

Yes. Several.

• Domestic ducks can now excrete large quantities of highly pathogenic virus without showing signs of illness, and are now acting as a “silent” reservoir of the virus, perpetuating transmission to other birds. This adds yet another layer of complexity to control efforts and removes the warning signal for humans to avoid risky behaviours.

• When compared with H5N1 viruses from 1997 and early 2004, H5N1 viruses now circulating are more lethal to experimentally infected mice and to ferrets (a mammalian model) and survive longer in the environment.

• H5N1 appears to have expanded its host range, infecting and killing mammalian species previously considered resistant to infection with avian influenza viruses.

• The behaviour of the virus in its natural reservoir, wild waterfowl, may be changing. The spring 2005 die-off of upwards of 6,000 migratory birds at a nature reserve in central China, caused by highly pathogenic H5N1, was highly unusual and probably unprecedented. In the past, only two large die-offs in migratory birds, caused by highly pathogenic viruses, are known to have occurred: in South Africa in 1961 (H5N3) and in Hong Kong in the winter of 2002–2003 (H5N1).

Influenza pandemics are remarkable events that can rapidly infect virtually all countries. Once international spread begins, pandemics are considered unstoppable, caused as they are by a virus that spreads very rapidly by coughing or sneezing. The fact that infected people can shed virus before symptoms appear adds to the risk of international spread via asymptomatic air travellers.

The severity of disease and the number of deaths caused by a pandemic virus vary greatly, and cannot be known prior to the emergence of the virus. During past pandemics, attack rates reached 25-35% of the total population. Under the best circumstances, assuming that the new virus causes mild disease, the world could still experience an estimated 2 million to 7.4 million deaths (projected from data obtained during the 1957 pandemic). Projections for a more virulent virus are much higher. The 1918 pandemic, which was exceptional, killed at least 40 million people. In the USA, the mortality rate during that pandemic was around 2.5%.

Pandemics can cause large surges in the numbers of people requiring or seeking medical or hospital treatment, temporarily overwhelming health services. High rates of worker absenteeism can also interrupt other essential services, such as law enforcement, transportation, and communications. Because populations will be fully susceptible to an H5N1-like virus, rates of illness could peak fairly rapidly within a given community. This means that local social and economic disruptions may be temporary. They may, however, be amplified in today’s closely interrelated and interdependent systems of trade and commerce. Based on past experience, a second wave of global spread should be anticipated within a year.

As all countries are likely to experience emergency conditions during a pandemic, opportunities for inter-country assistance, as seen during natural disasters or localized disease outbreaks, may be curtailed once international spread has begun and governments focus on protecting domestic populations.

What are the most important warning signals that a pandemic is about to start?

The most important warning signal comes when clusters of patients with clinical symptoms of influenza, closely related in time and place, are detected, as this suggests human-to-human transmission is taking place. For similar reasons, the detection of cases in health workers caring for H5N1 patients would suggest human-to-human transmission. Detection of such events should be followed by immediate field investigation of every possible case to confirm the diagnosis, identify the source, and determine whether human-to-human transmission is occurring.

Studies of viruses, conducted by specialized WHO reference laboratories, can corroborate field investigations by spotting genetic and other changes in the virus indicative of an improved ability to infect humans. This is why WHO repeatedly asks affected countries to share viruses with the international research community.

What is the status of vaccine development and production?

Vaccines effective against a pandemic virus are not yet available. Vaccines are produced each year for seasonal influenza but will not protect against pandemic influenza. Although a vaccine against the H5N1 virus is under development in several countries, no vaccine is ready for commercial production and no vaccines are expected to be widely available until several months after the start of a pandemic.

Some clinical trials are now under way to test whether experimental vaccines will be fully protective and to determine whether different formulations can economize on the amount of antigen required, thus boosting production capacity. Because the vaccine needs to closely match the pandemic virus, large-scale commercial production will not start until the new virus has emerged and a pandemic has been declared. Current global production capacity falls far short of the demand expected during a pandemic.

What drugs are available for treatment?

Two drugs (in the neuraminidase inhibitors class), oseltamivir (commercially known as Tamiflu) and zanamivir (commercially known as Relenza) can reduce the severity and duration of illness caused by seasonal influenza. The efficacy of the neuraminidase inhibitors depends, among others, on their early administration ( within 48 hours after symptom onset). For cases of human infection with H5N1, the drugs may improve prospects of survival, if administered early, but clinical data are limited. The H5N1 virus is expected to be susceptible to the neuraminidase inhibitors. Antiviral resistance to neuraminidase inhibitors has been clinically negligible so far but is likely to be detected during widespread use during a pandemic.

An older class of antiviral drugs, the M2 inhibitors amantadine and rimantadine, could potentially be used against pandemic influenza, but resistance to these drugs can develop rapidly and this could significantly limit their effectiveness against pandemic influenza. Some currently circulating H5N1 strains are fully resistant to these the M2 inhibitors. However, should a new virus emerge through reassortment, the M2 inhibitors might be effective.

For the neuraminidase inhibitors, the main constraints – which are substantial – involve limited production capacity and a price that is prohibitively high for many countries. At present manufacturing capacity, which has recently quadrupled, it will take a decade to produce enough oseltamivir to treat 20% of the world’s population. The manufacturing process for oseltamivir is complex and time-consuming, and is not easily transferred to other facilities.

So far, most fatal pneumonia seen in cases of H5N1 infection has resulted from the effects of the virus, and cannot be treated with antibiotics. Nonetheless, since influenza is often complicated by secondary bacterial infection of the lungs, antibiotics could be life-saving in the case of late-onset pneumonia. WHO regards it as prudent for countries to ensure adequate supplies of antibiotics in advance.

Can a pandemic be prevented?

No one knows with certainty. The best way to prevent a pandemic would be to eliminate the virus from birds, but it has become increasingly doubtful if this can be achieved within the near future.

Following a donation by industry, WHO will have a stockpile of antiviral medications, sufficient for 3 million treatment courses, by early 2006. Recent studies, based on mathematical modelling, suggest that these drugs could be used prophylactically near the start of a pandemic to reduce the risk that a fully transmissible virus will emerge or at least to delay its international spread, thus gaining time to augment vaccine supplies.

The success of this strategy, which has never been tested, depends on several assumptions about the early behaviour of a pandemic virus, which cannot be known in advance. Success also depends on excellent surveillance and logistics capacity in the initially affected areas, combined with an ability to enforce movement restrictions in and out of the affected area. To increase the likelihood that early intervention using the WHO rapid-intervention stockpile of antiviral drugs will be successful, surveillance in affected countries needs to improve, particularly concerning the capacity to detect clusters of cases closely related in time and place.

What strategic actions are recommended by WHO?

In August 2005, WHO sent all countries a document outlining recommended strategic actions for responding to the avian influenza pandemic threat. Recommended actions aim to strengthen national preparedness, reduce opportunities for a pandemic virus to emerge, improve the early warning system, delay initial international spread, and accelerate vaccine development.

Is the world adequately prepared?

No. Despite an advance warning that has lasted almost two years, the world is ill-prepared to defend itself during a pandemic. WHO has urged all countries to develop preparedness plans, but only around 40 have done so. WHO has further urged countries with adequate resources to stockpile antiviral drugs nationally for use at the start of a pandemic. Around 30 countries are purchasing large quantities of these drugs, but the manufacturer has no capacity to fill these orders immediately. On present trends, most developing countries will have no access to vaccines and antiviral drugs throughout the duration of a pandemic.