Avian Flu and Other Respiratory illnesses

Gary Podolsky MD

Respiratory illnesses

Each year respiratory infections are very common. Often people will self diagnose themselves with a 'cold',' flu' or 'strep throat' on the basis of their symptoms. Likewise many practitioners may reinforce these spot diagnoses without taking an adequate history or physical. In order to treat people best it is important to have a specific diagnosis and a specific treatment for the correct illness.

This is as important for mundane illnesses such as the common cold and flus as well as more severe infections such as Group A Streptococci ("strep throat"), tuberculosis and even non-infectious illnesses such as lung cancer. Recently both SARS and Avian flu have become newcomers to the differential diagnosis. Respiratory symptoms such as malaise, sore throat, sore muscles, fever and a cough with or without phlegm only describe illnesses and do not define any specific entity but provide a starting point towards forming an accurate diagnosis.

Table 1 Differences between Colds and Influenza

Common Colds

Colds as a group are benign and are caused by over 200 viruses. There are wide variations in severity and duration of different types of colds. Colds tend to have a gradual onset with a slight sore throat.

A sickly feeling develops behind the ears along with sneezes and sniffles. Later, a runny nose with a more sore throat and dry hacking cough develops. People are usually achy although fever is usually below 120 degrees F. On average symptoms may last 7-10 days but may last longer.

Children develop more colds because of the way they are cloistered and average about 6/year with adult 3/year. Parents with children develop more colds than single adults living alone.

Colds are a year round phenomena but there is an increase in incidence beginning Late August with a peak in September and October. A second peak of incidence occurs in Late Spring. When outdoor temperatures drop indoor heating is started. This dries out the air, which also dries the mucous membranes of the nose and throat, impairing the body's first line of defence against infections.

Infection

In order to catch an infection the immune system must be overwhelmed.

The body's first lines of defences include ciliary action in the respiratory tract, secretory immune globulins and barrier protection from the skin. Moist mucous membranes are the first lines of defence. When dry they are much less effective and this is also true when the body is dehydrated. Smoking will paralyse ciliary action as well as less direct effects (Arsenic, Carbon Monoxide) on the immune system. Stress in general adversely affects the immune system whether it is physical or mental. Exercise in moderate amounts leads to optimal immune function, but both undertraining (unfit) and overtraining have been shown to decrease T cell function.

Common misunderstandings regarding catching colds include- not wearing a hat, being overheated, being chilled and having wet hair.

Catching a cold

Approximately one half to three quarters of people with colds do not develop symptoms. Cold viruses incubate for 1-4 days before sickness. They are contagious during that interval even though they may not be aware that they are sick. Cold viruses are transmitted by inanimate objects (fomites such as telephones, doorknobs) and respiratory droplets released into the air and then inhaled. Kissing rarely spreads colds.

Treating colds

Colds have many proposed treatments with many divergent opinions on what works best. There are over 200 strains of cold viruses making a vaccine very difficult to develop. The military has developed an adenovirus vaccine with limited success. Interferon treatments do not wok. Vitamins have also been intensely studied and evidence shows that Vitamin C has some modest effects. Vitamin C will not prevent colds but it may alleviate symptoms and shorten the duration of sickness. A dose of 1000mg every 4-6 hours and this is only effective against some colds about a third of the time.

Influenza

Influenza or the "flu" is named after the early medieval belief that those afflicted were under "the influence" of Astrological phenomena. In general individuals may develop influenza from once per year to every several years on average. Prevalence per year has been estimated as up to 10-25% of the populace. Average deaths per year in US are 10-20,000.

Influenza A is the most common (97%) circulating disease. Type B is currently at low levels and Influenza C is rarely a cause of human disease. In the 2003 Southern Hemisphere Winter and 2003-2004 Northern Hemisphere Winter 97% of Flus were due to Type A and of these 99% were H3N2 by the end of the season.

Symptoms of influenza typically begin with a sudden onset high fever of 102-104 degrees F, headache, extreme fatigue, weakness, and muscle aches and pains. Less commonly are symptoms of runny nose and sneezing. The sore throat generally gets worse over 2-3 days with a dry hacking cough. Sometimes vomiting and diarrhoea also develop. The duration of illness usually lasts for 3-7 days although some may have fatigue and lassitude for weeks.

Flu season typically begins in November/December until May/April in the Temperate Northern Hemisphere. It is an all year phenomena in Tropical Equatorial countries and in the Southern Hemisphere occurs from April to October. Travellers may also spread flu from one geographic area to another. The two hemispheres also may have different circulating strains of the flu at different times so that yearly immunization may not necessarily cover imported flu strains.

Catching a Flu

Influenza is more easily spread than colds. Both airborne water droplets released by sneezing, coughing and conversation; and inanimate objects spread it.

Both flu and cold viruses can persist on hands and inanimate objects for 1-3 hours. Incubation times between encountering the viruses and becoming sick may vary between 1-3 hours. This follows then that many apparently well people are infectious. Flu patients are also infectious for another 5-7 days after onset of symptoms.

The influenza virus is a specific virus that is constantly changing its surface proteins. The N and H type proteins expressed on their surfaces type flu viruses. (There are 15 H proteins and 9 N proteins). Both antigen shifts and drifts occur which allows the influenza to continue to not be recognized by individual immune systems that have never encountered that specific strain of flu before. Haemophilis Influenza is a bacterium with a similar sounding name to influenza and is not related. Hib vaccine against Haemophilis does not confer any protection against influenza.

Vaccine effectiveness

The vaccine is felt to be effective between 70-90% from developing disease or significant illness in young healthy adults.

Older adults, those with chronic illnesses and the very young have less of a response to the vaccine but do benefit from protection against severe illness.

By immunizing a large amount of the healthy population they become protected from the flu but they also indirectly provide herd immunity for those who are much more susceptible- very young and very old and sick. Several large studies have shown the flu shot to be protective and cost effective even for young healthy adults.

Travellers and Flu

Influenza may quickly travel throughout households, institutions and in close confined areas. In one case an aircraft with one known influenza case was kept grounded for 3 hours and led to 72% of the crafts 54 patients developing the flu. In another study 42% of a naval ship's crew were similarly infected from one index case. Cruise ships are known for frequent outbreaks. The cruise ship company, Holland America has reacted to this by immunizing all crew and stockpiling antiviral medications at the earliest warning of an outbreak among the passengers and crew (Personal communication SAILS II meeting, November 2004).

Immunizing Travellers as a distinct risk group

Special considerations for immunizing travellers include: travel aboard cruise ships (year round), travel to tropics (year round), travel with large organized groups, and travel during flu season (Northern Hemisphere Nov-April, Southern Hemisphere April -Oct). Although one must travel to the right hemisphere to get the right flu vaccine there is some talk that Southern Hemisphere Flu vaccines be made available in specialized travel clinics for far reaching travellers. The "wrong hemisphere" vaccine will give some protection since the two are often similar. A Traveller to Australia might also be encouraged to seek a local physician there to receive the correct vaccine while away. The flu vaccine may take up to one week to be effective. This is an important concept as such travellers may serve as carriers of atypical strains on their return.

In North America the Flu vaccine is typically recalled and destroyed in June (April in Manitoba) so that the stock may not be inappropriately used next year. It is still safe and effective into August but clinicians are not encouraged to use it. Immunizing more than once with one years' vaccine is not felt to be of any benefit.

Birds and Influenza

Birds remain a large reservoir of Influenza A viruses. Even Influenza A may be thought of as a zoonosis. Currently two main circulating strains of Influenza A are H3N2 and H1N1. Pandemics of Flues occur every several years with the last one developing in 1968. H1N1 emerged in 1971 without a pandemic because there were enough people who had previous contact with this strain.

Unfortunately a flu pandemic has been considered long overdue by pessimists expecting one soon.

Based on information collected on antigenic shifts and drifts the WHO makes 2 annual vaccine recommendations:

In February for the next Northern Hemisphere winter season (November-April); and in September for the next Southern Hemisphere winter (April-Oct). Every February and September manufacturers make their respective vaccines for the next season. Currently using chicken embryo viral growth techniques this takes 6 months although faster alternative technologies are being explored.

In 2002 the Fujian H3N2 strain emerged too late to make corrections for both the Northern and Southern Hemisphere vaccine production lines. The vaccine did not resemble the Fujian strain enough to reap maximal benefit but there were enough cross-antigenic matches to make it effective enough to lessen the severity. For the next Southern vaccine the Fujian strain will be replaced by the Wellington strain because of its relative current prevalence.

Most Recent North and South Flu Vaccine Recommendations

Other causes for Flu like symptoms

In clinical medicine the term "flu like illnesses" have come to describe a variable set of symptoms that are most commonly associated with the flu. This reflects the wide variety of other illnesses that are often confused with the flu. Local epidemiology helps since in a flu epidemic the diagnosis of one more case seems likely enough, conversely an isolated case in the summertime is much less likely to a true flu case.

A differential diagnosis may commonly include allergies, ear infections, sinus infections, strep throat and even other colds such as adenovirus. More exotic or uncommon alternatives include pneumonia, meningitis, tuberculosis, SARS, malaria, tropical illnesses, as well as cancers. The history and physical will help to clinically sort these out but this may not be so obvious earlier in their presentation.

Specialized tests to detect specific febrile conditions

Antiviral Flu drugs

Immunizations are still the first line in prevention against the flu. Antivirals also have a role in people with early influenza disease, those who cannot take the flu shot or if it is unavailable.

The class of M2 inhibitors (amantadine) work effectively against influenza A but not B..

Neuramnidase inhibitors (Oseltmivar-tamiflu) work against both type A and B and is the only effective treatment for unknown or type b infection as well as the Avian Flu.

Amantadine also has several side effects when used. It is generally agreed that neuramindase inhibitors are preferred over M2 inhibitors and new ones besides Oseltmivar are being researched.

The cruise ship industry will do rapid test flu tests on pharyngeal swabs for sick passenger s and crew to confirm a Type A outbreak. In this case amantadine is used in both prophylaxis and treatment aboard the ship. Outside of closed populations it is unlikely amantadine will be used.

Treatment of flu with Oseltmivar is most effective within 72hrs of symptoms and preferably 48hr where it may limit illness by 1.5 days. The dose is 75 mg twice per day for 5 days.

Prophylaxis with Oseltmivar is 90% effective if started within 48hr of exposure. A minimum duration of 7 days is suggested and evidence of safety and usefulness of up to 6 weeks has been reported. For adults one daily pill is used. A pediatric version exists for ages 1-12. Safety in pregnancy has not been established.

Avian Flu

Widespread outbreaks in chickens and ducks of the highly pathogenic Avian Flu - Influenza A H5N1 began in December 2003 in South Korea, Vietnam, Japan, Thailand, Cambodia, Laos, China, and Indonesia. Initially infected animals were culled but the virus appeared to be permanently established by Aug 2004 in ducks, and chickens in Thailand, China, Indonesia, and Vietnam.

H5N1 is transmitted by direct contact with ill birds and their faeces.

Between Dec 2003 and Sep 2004, 40 humans were infected with 28 deaths.

There is no human immunity against the H5 protein and not enough similarity with it and H3 or H1 so infections tend to be very severe and devastating.

The greatest concern is that a human infected with H5N1 might also have a regular flu infection concurrently and that the Flu virus might reassort itself to acquire enough genes to make it easily transmissible among humans. By encouraging universal vaccination against human flus circulating this scenario becomes less likely.

Research is moving towards an Avian Flu vaccine but there have been enough difficulties with developing regular flu vaccines.

Antiviral treatment for Avian Flu

Many governments have begun to stockpile Oseltmivar (Tamiflu). This drug which may prevent and treat influenza is currently not used much and if needed will become scarce. A comparison to the irrational hoarding of Ciprofloxacin against the recent perceived Anthrax threat is worrisome.

Health Canada has begun to stockpile Oseltmivar for release during an impending Flu Pandemic or Avian Flu outbreak. In both situations there may be rapid spread of a very virulent flu that most people would not have immunity to. It is estimated that the first wave of a flu outbreak may last for 6 weeks and that hopefully an effective avian flu vaccine will be developed before a second wave occurs. Health Canada has begun to run strategies to make the best use of what antivirals we will have and use them efficiently for the greatest good.

A treatment dose would require Tamiflu 75 mg BID for 6 days

A preventative prescription would involve Tamiflu 75mg once daily for 42 days (based on the proposed 6 week duration of the average first wave based on prior flu pandemics and modern demographics)

The following proposal has been put forth by the Public Health Agency of Canada:

Summary

What may clinicians do?

First when confronted with a febrile or respiratory illness make a clinical decision-is this a self-limited cold?

Is the patient significantly sick to have a reasonable suspicion of something worse?

Is Influenza circulating?

Are their any atypical respiratory infections reported by public health ?

(SARS, Para influenza, Pertussis, Imported malaria, avian flu or anything else)

If reasonably convinced of a flu diagnosis consider starting antiviral treatment within 48hr

(This may not be possible but is worth keeping in mind)

If someone asks for antiviral prophylaxis during the flu season consider this if clinically warranted and patient knows the price. Patients may also ask for flu chemoprophylaxis for sick relatives.

The flu shot is still recommended as a first line treatment with antiviral treatment for all those who get infected with the flu. Some individuals may not be able to take a flu shot (scarcity, allergies) and these may be offered a 5-day treatment course or a 6-week prevention course.

In the face of flu pandemic it is very likely that there will be a shortage of Oseltmivar.

But there is no current shortage. Purchasing their medication from the pharmacy now may be an effective way to protect patients in advance by having them obtain this medication now and store it securely with its long shelf life. This will not interfere with Health Canada obtaining their stock now either so there is no ethical dilemma that may occur later when the demand for Oseltmivar exceeds supply. Also there is only one maker of Oseltmivar, Hoffman Roche for the world. In a pandemic the entire world will look to them to obtain stock. Health Canada is investigating if large companies will initiate their own stockpiles for their own employees to remove some of the burden from the government.

In the so-called interpandemic flu period (now) clinicians should familiarize themselves with the appropriate use of Oseltmivar and prescribe it for their eligible patients now so that they will be familiar with this useful therapeutic option when a pandemic occurs. This is also felt to increase confidence in antivirals for both doctors and patients.

Educating our patients is important and clinicians will find it daunting to now recommend that people seek consultation within 2 days for high fever while avoiding superfluous visits for likely cold symptoms. In the face of a pandemic it is very likely that specialized fever clinics may be established to sort people with symptoms and expedite treatment. During such a crisis the clinical encounter will be complicated by also trying to isolate potentially contagious patients regular hospital and clinic patients.

References and Further reading:

Influenza: Changing Approaches to Prevention and treatment in Travellers . Freedman and Leder. J of Travel Medicine 2005;12:36-44.

Influenza in the World. Wkly Epidemiol rec 2004;79;94-96

Prevention and Control of Influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP) Harper SA, Fukuda K,Uyeki TM,. et al MMWR Recomm Rep 2004;53:1-40.

Influenza A outbreak on a cruise ship . Can Commun Rep 1998;24:9-11.

Influenza a common viral infection among Hajj pilgrims: time for routine surveillance and vaccination . Balkhy HH, Memish ZA, Bafaqeer S, lmuneef MA. J Travel Med 2004; 11:82-86

Effectiveness of Neuraminidase inhibitors in treatment and prevention of Influenza A and B: systemic review and meta-analyses of randomised controlled trials . Cooper NJ, Sutton AJ, Abrams KR, et al. BMJ 2003;326:1235-1240.

Pandemic Influenza and the global vaccine supply . Fedson DS. Clinic Infect Dis 2003; 1552-1561.

WHO consultation on priority public health interventions before and during an influenza pandemic.2004 World Health Organization. www.who.int/csr/dis/avian_influenza/consultation/en/

Canadian National Anti-viral Conference Public Health Agency of Canada Winnipeg Manitoba, March 22-23 2005 (Proceedings soon to published )

Health Canada Flu watch www.hc-sc.gc.ca/pphb-dgspsp/fluwatch/index.html

Centre for disease control Flu Prevention www.cdc.gov/ncidod/diseases/flu/weekly.htm

European Influenza Surveillance System www.eiss.org/index.cgi

Current WHO Vaccine recommendations w ww.who.int/csr/disease/influenza/vaccinerecommendations/en/