RESPIRATORY INFECTIONS

What are respiratory infections?

Respiratory infections affect the nasal passages, throat, larynx and lungs. They can be caused by bacteria, viruses or, less commonly, by fungi or rickettsia. Laryngitis, tonsillitis, bronchitis, influenza, the common cold, and pneumonia are well-known examples of respiratory infections. Bacterial infections in the lungs may be chronic, as in people with cystic fibrosis or bronchitis, and are often very resistant to antibiotics. Common bacteria causing lung infections are various streptococci and Haemophilus influenzae. Pseudomonas is especially problematical in cystic fibrosis (see Bacterial Infections and Cystic Fibrosis). This section, however, deals primarily with respiratory diseases caused by viruses.

Influenza (Figure 1) is a virus with three major subtypes (A, B and C) that causes potentially serious respiratory infections and periodically causes epidemics or even pandemics (world-wide epidemics). Type A influenza virus is the most common cause of influenza in humans and can also infect birds (avian flu). The pandemic influenza of 1918/19 has recently been shown to have originated in birds and it is feared that if current strains of avian flu in poultry and wild birds acquire the ability to spread from one human being to another, this could cause another pandemic of similar seriousness.

Another virus (a coronavirus) has been found to be responsible for the viral pneumonia known as severe acute respiratory syndrome (SARS), which also has a high death rate. Other important respiratory viruses are less well known. They include respiratory syncytial virus (RSV), which causes inflammation of the airways in about 20,000 infants each year and may lead to pneumonia, and cytomegalovirus (CMV), which can cause a type of pneumonia in those with a depressed immune system.

Who do respiratory infections affect?

It has been estimated that 120 million people get influenza every year in the US, Europe and Japan. During a pandemic, very many people may die, especially the very young, infirm and elderly. Over 20 million people are estimated to have died worldwide during the great influenza pandemic of 1918/19. Pneumonia is a leading cause of death, especially among the elderly - 30,649 deaths in England and Wales in 2004 were recorded as being primarily due to pneumonia, 87 per cent of these being in those aged 75 and over. Many cases of pneumonia are due to bacteria, but the specific infection is rarely recorded on death reports. The yearly number of influenza-related deaths is uncertain.

Present treatments and shortcomings

Over-the-counter medicines such as aspirin and decongestants provide relief of symptoms and reduce fever, but there are no medicines that cure either the common cold or influenza. Amantadine (Lysovir, Alliance) is available for the prophylaxis and treatment of flu, but is mainly used in those at risk, such as immunocompromised patients, as the benefits are too modest for general use. It is only active against Type A flu viruses, which account for 65 per cent of outbreaks. Two neuraminidase inhibitors are available for the treatment of the symptoms of influenza, which must be started within 48 hours of the first appearance of symptoms. One, zanamivir (Relenza, GlaxoSmithKline), is inhaled. It shortens the period of symptoms only modestly and can induce contraction of the airways and serious respiratory deterioration in patients with asthma or chronic obstructive pulmonary disease. The other, oseltamivir (Tamiflu, Roche), is taken by mouth. Both are indicated for the prevention as well as treatment of influenza. Nausea, vomiting and gastric pain, mainly on first starting treatment, were the most common adverse reactions to oseltamivir seen in clinical trials.

Prevention of influenza depends on the rapid production of vaccines tailored to the specific strain at the first signs of an epidemic. Each vaccine is, in effect, a new product each year. A variety of preparations are available for use in the UK, including vaccines from GlaxoSmithKline, Novartis, Wyeth, Solvay, and Sanofi Pasteur MSD.

The monoclonal antibody palivizumab (Synagis, Abbott) can be used to prevent RSV infections in children at high risk for RSV disease, but is considered too expensive for more general use. Ribavirin (Virazole, Valeant) is currently the only medicine for the treatment of RSV infections.

What's in the development pipeline?

Only a few compounds are in development for treating respiratory infections due to viruses. A nasal spray formulation of the antiviral pleconaril is in Phase 2 development by sanofi-aventis for treating the common cold. Daiichi-Sankyo has CS-8958 in Phase 1 trial for influenza infections. NexBio is preparing Phase 1 studies with NEX-DAS181 (Fludase), which is designed to prevent influenza virus entering and infecting airways cells. BioCryst's injected peramivir is also in Phase 1 study, as is Alnylam Pharma's ALN-RSV01, which is designed to treat RSV. Novartis also has an antiviral (RSV604) against RSV in development which has reached Phase 2.

Intensive research is, however, going into the development of new flu vaccines. The main aspects can be summarised as the development of:

• seasonal flu vaccines, some combined with other compounds to increase their effect
• vaccines against pandemic flu
• cell culture-based production methods.

Adjuvants have been used for many years in other vaccines. They are substances that stimulate a stronger antibody response and are used to increase the effectiveness of vaccines. GlaxoSmithKline and Novartis both have seasonal influenza vaccines in Phase 3 trial that contain new adjuvants.

The use of an adjuvant will be particularly important in vaccines against pandemic flu, as there will be a great need to vaccinate the largest possible number of people as rapidly as possible following the start of a pandemic, and this will mean using vaccines with the maximum effect. Both Novartis and GSK are therefore also incorporating adjuvants into their experimental vaccines directed against the H5N1 strains of pandemic flu. Both companies are working with the regulatory authorities in advance of the appearance of human pandemic strains, in order to reduce as far as possible the time needed for review once this emergency situation arises.

Cell culture-based production methods will also be of great importance in the response to a flu pandemic. Virus growth in chicken eggs, as at present, is difficult to scale up and takes several months to produce sufficient quantities for vaccine production. Cell culture methods are quicker, more flexible and more easily controlled. Novartis has a seasonal flu vaccine made by cell culture on a mammalian cell line (MDCK cells) and Solvay has built a new plant for producing its own seasonal flu vaccine on the same cells. Solvay is also developing a nasal spray form of its vaccine that has reached Phase 2 trial. Baxter has a cell production system that has already been used to make vaccine against smallpox, and this is now being used to produce a stockpile of whole-virus (H5N1) pandemic flu vaccine (Phase 2) under contract for the NHS.

Sanofi-Pasteur is now developing PER.C6 cell line technology to produce both seasonal flu vaccine and experimental (H7N1) pandemic flu vaccines (both at Phase 1). (The company also has an experimental H5N1 vaccine in Phase 2 trials that is made by the standard chicken-egg process). Crucell has three vaccines based on the H9N2 strain of avian flu grown by the cell culture method in Phase 1 trial.

Lastly, two interesting developments are still at the pre-clinical stage:

• Vical is developing an adjuvant-containing DNA vaccine, based on avian flu virus surface protein, which could be grown by fermentation methods
• Acambis has started development of a 'universal' flu vaccine, directed against the M2 surface protein of the influenza A virus and which shows little variation between strains. If this approach were successful, it would remove the need to create a new vaccine each year.

Such developments raise exciting prospects for the future of influenza vaccination. However, the threat of a pandemic is very real, and this could start at any time if an unlucky mutation in the avian flu virus should produce a strain that can easily be passed from one human being to another. It must therefore be hoped that some at least of the projects just discussed come to fruition very quickly.

The longer-term future

There have been a number of attempts to use gene therapy in peripheral vascular disease. These projects typically aim to promote the growth of new blood vessels to bypass an obstructed artery. Several companies (sanofi-aventis, Daiichi-Sankyo, Genzyme) have projects of this type in Phase 2 trials. Lastly, Cardium Therapeutics has an agent (Genvascor) based on the enzyme endothelial nitric oxide synthase (eNOS) that, by increasing local production of artery-relaxing nitric oxide, may alleviate ischaemic pain in critical limb ischaemia. This project is still at the pre-clinical stage.

While these gene therapy approaches do not cure the blockage that causes symptoms, they may provide a relatively simple way of improving functional status that would bring welcome relief in patients whose lives are limited by peripheral vascular disease.