Respiratory infections

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35 Respiratory infections

Key points

Respiratory tract infections are the most common group of infections seen in the UK. Most are viral, for which (with some exceptions) only symptomatic therapy is available. In contrast, bacterial infections are a major cause of treatable respiratory illness.

The respiratory tract is divided into upper and lower parts: the upper respiratory tract consists of the sinuses, middle ear, pharynx, epiglottis and larynx, while the lower respiratory tract consists of the structures below the larynx, the bronchi, bronchioles and alveoli. Although there are anatomical and functional divisions both within and between these regions, infections do not always respect such boundaries. Nevertheless, it is clinically and bacteriologically convenient to retain a distinction between upper respiratory tract infections (URTIs) and lower respiratory tract infections (LRTIs).

Upper respiratory tract infections

Colds and flu

Viral URTIs causing coryzal symptoms, rhinitis, pharyngitis and laryngitis, and associated with varying degrees of systemic symptoms, are extremely common. These infections are usually caused by viruses from the rhinovirus, coronavirus, parainfluenza virus, respiratory syncytial virus, influenza virus and adenovirus families, although new viruses continue to be identified. For instance, in 2001, a novel respiratory pathogen was described that has become known as human metapneumovirus (hMPV). This causes a spectrum of respiratory illnesses particularly in young children, the elderly and the immunocompromised (Van Den Hoogen et al., 2001).

Colloquially, milder infections are called ‘colds’, while more severe infections may be known as ‘flu’. This term should be distinguished from true influenza, reserved for infection caused by the influenza virus. In general, the management of these infections is symptomatic and consists of rest, adequate hydration, simple analgesics and antipyretics. Apart from one or two exceptional situations, antiviral drugs are not indicated and in most cases are not active. Antibacterial drugs have no activity against viral infections, although in the past they were widely prescribed, sometimes with spurious rationale such as prophylaxis against bacterial superinfection, sometimes simply because patients demanded them. In recent years, heightened awareness of the adverse consequences of antibiotic overuse has led to national campaigns aimed at discouraging the public from seeking antibiotic treatment for viral infections.

Influenza

True influenza is caused by one of the influenza viruses (influenza A, B or rarely C). It can be a serious condition characterised by severe malaise and myalgia and potentially complicated by life-threatening secondary bacterial infections such as staphylococcal pneumonia. Coryzal symptoms are not usually a feature of influenza, but the patient may have a cough. Influenza tends to occur during the winter months, providing an opportunity to offer preventive vaccination in the autumn. In the UK, influenza vaccine is normally targeted at three groups:

Unfortunately, the virus mutates so rapidly that the circulating strains tend to change from season to season, necessitating annual revaccination against the prevailing virus.

Influenza A and B infections are amenable to both prevention and treatment with neuraminidase inhibitors (NAIs) and include agents such as zanamivir and oseltamivir, although there is controversy about whether the benefits justify the costs involved. Zanamivir is administered by dry powder inhalation, whereas oseltamivir is given orally. Clinical trials on parenteral administration for use in individuals with life-threatening infections are underway.

National guidelines for the UK recommend NAIs should only be used when influenza is circulating in the community (which is carefully defined), and in patients who are both at risk of developing complications and can commence treatment within a defined time window of onset or exposure (NICE, 2008, 2009). Individuals at risk and eligible for treatment include those:

The anti-Parkinsonian drug amantadine, which has activity against influenza A virus, is not recommended for the treatment or prophylaxis of influenza due to emergence of resistance and the high incidence of adverse effects.

Pandemics (or global epidemics) of influenza A occur around every 25 years and affect huge numbers of people. The 1918 ‘Spanish flu’ pandemic is estimated to have killed 20 million people. Further pandemics have taken place in 1957–1958 (Asian flu), 1968–1969 (Hong Kong flu) and 1977 (Russian flu). An avian strain, H5N1, emerged in South East Asia in 2003 and is now considered endemic in many parts of South East Asia and remains a concern for public health (WHO, 2010).

The World Health Organisation declared a worldwide influenza pandemic in June 2009 following the emergence of a novel H1N1 strain of swine lineage. In the UK, NICE guidance was superseded during the pandemic and NAIs were given to all individuals with flu-like illness. A vaccine was also developed. Pandemic planning had been in operation for many years with plans for rapid vaccine development and stockpiling of antivirals. However, in retrospect, infections caused by the pandemic strain were generally associated with much milder disease than seen in previous pandemics, and some authorities have been accused of over-reaction.

The widespread use of NAIs during the 2009 pandemic brought its own problems. Resistance to oseltamavir emerged (Gulland, 2009), and some argued that the cure was worse than the disease (Strong et al., 2009). Further, a Cochrane review (Jefferson et al., 2009) found no good evidence that oseltamivir prevents secondary complications such as pneumonia, one of the main justifications for its widespread use in pandemic influenza. However, the relatively benign course of the 2009 pandemic should not provide false reassurance as to the risks associated with future pandemics.

Sore throat (pharyngitis)

Clinical features

The presenting complaint is sore throat, often associated with fever and the usual symptoms of the common cold. It is standard teaching that sore throats of different aetiology cannot be distinguished clinically. Nevertheless, more severe cases are more likely to be caused by EBV or S. pyogenes, and in these patients, there may be marked inflammation of the pharynx with a whitish exudate on the tonsils, plus enlarged and tender cervical lymph nodes.

Group A streptococcal infection has a number of potential complications. Pharyngeal infection may occasionally give rise to disseminated infection elsewhere, but this is rare. More frequent accompaniments are otitis media, peritonsillar abscess and sinusitis. These should be distinguished from the non-suppurative complications of streptococcal infection, rheumatic fever and glomerulonephritis, which are mediated immunologically. Occasional cases are still seen in the UK and remain important causes of renal and cardiac disease in developing countries. Scarlet fever, a toxin-mediated manifestation of streptococcal infection, is associated with a macular rash and sometimes considerable systemic illness.

In the UK, there has been a recent increase in rates of group A streptococcal infection. This includes invasive group A streptococcal infection (iGAS), associated with infection in normally sterile sites such as blood or tissue. The most common serotypes seen in England and Wales are emm 1, 3, and 89; emm 3 infections are associated with higher case fatality rates. The cause of the upsurge is unknown but may represent a natural periodic increase or alternatively excess transmission associated with high rates of influenza in 2008 (Lamagni et al., 2009).

Treatment

Treatment of viral sore throat is directed at symptomatic relief, for example with rest, antipyretics and aspirin gargles. Streptococcal sore throat is usually treated with antibiotics although the extent to which they shorten the duration of symptoms and reduce the incidence of suppurative complications is modest (Del Mar et al., 2004). Antibiotic treatment also reduces the incidence of non-suppurative complications so is likely to be of greater benefit where these are common. There is also an argument that treating to eradicate streptococcal carriage might reduce the risk of relapse or later streptococcal infection at other sites.

Broadly, there are three treatment strategies:

There is no correct approach and each has its advocates, although the problem of resistance has led to increasing pressure on prescribers to restrict empirical antibiotic use particularly for conditions such as pharyngitis that are frequently viral. The prevailing view is that antibiotics should not be routinely prescribed except where there is a high risk of severe infection, for instance, in immunocompromised patients (NICE, 2010).

Antibiotics effective against S. pyogenes include penicillins, cephalosporins and macrolides. Resistance to penicillins and cephalosporins has not (yet) been described in group A streptococci, although about 4% of isolates are resistant to erythromycin. Even against sensitive strains, macrolides such as erythromycin are demonstrably less effective than β-lactams.

Penicillins such as benzylpenicillin (penicillin G) or phenoxymethylpenicillin (penicillin V) have traditionally been regarded as the treatment of choice for streptococcal sore throat, but there is now convincing evidence that cephalosporins are more effective in terms of both clinical response and eradication of the organism from the oropharynx. This was summarised in a large meta-analysis of 40 studies in which 10-day courses of oral cephalosporins and penicillins were compared in the management of children with streptococcal pharyngitis (Casey and Pichichero, 2004). Bacteriological and clinical cure significantly favoured cephalosporins over penicillins, perhaps because penicillins are hydrolysed by β-lactamases produced by organisms such as anaerobes naturally resident in the oropharynx, whereas cephalosporins are not. The 10-day course length became accepted following earlier studies that compared the effect of different durations of penicillin treatment on bacteriological colonisation, but a recent systematic review (Atamimi et al., 2009) found comparable efficacy with shorter courses of newer antibiotics such as azithromycin.

However, despite the therapeutic superiority, it remains debatable whether the extra expense of cephalosporins is justified. Cefalexin is the preferred cephalosporin. Penicillin or amoxicillin is the preferred penicillin, with the proviso that amoxicillin and other aminopenicillins should not be used unless EBV infection is unlikely, since for reasons that are not understood, these drugs often cause skin rashes if used in this condition.

Acute epiglottitis

Acute epiglottitis is a rapidly progressive cellulitis of the epiglottis and adjacent structures. Local swelling has the potential to cause rapid-onset airway obstruction, so the condition is a medical emergency. Previously, almost all childhood cases and a high proportion of adult cases were caused by Haemophilus influenzae type b (Hib), with the rest being caused by other organisms such as pneumococci, streptococci and staphylococci. With the advent of routine vaccination against H. influenzae type b in October 1992, this disease has become uncommon.

The typical patient is a child between 2 and 4 years old with fever and difficulty speaking and breathing. The patient may drool because of impaired swallowing. The diagnosis is made clinically and the initial management is concentrated upon establishing or maintaining an airway. This takes priority over all other diagnostic and therapeutic manoeuvres. Thereafter, the diagnosis may be confirmed by visualisation of the epiglottis, typically described as ‘cherry-red’. Microbiological confirmation may be obtained by culturing the epiglottis and the blood, but not until the airway is secure.

In view of the high prevalence of amoxicillin resistance among encapsulated H. influenzae, the treatment of choice is a cephalosporin. It is customary to use a third-generation cephalosporin such as cefotaxime or ceftriaxone, but there is no reason why the infection should not respond to a second-generation agent such as cefuroxime. If a sensitive organism is recovered, high-dose parenteral amoxicillin may be substituted.

Otitis media

Treatment

There has been much debate about whether or not antibiotics should be used for the initial treatment of acute otitis media. A meta-analysis combined seven clinical trials involving 2202 children and concluded that, although antibiotics confer a modest reduction in pain at 2–7 days, they do not reduce the incidence of short-term complications such as hearing problems and they do cause side effects (Glasziou et al., 2004). The benefit of antibiotic treatment may be greater in children under two than in older children (Damoiseaux et al., 2000), but in any case about 80% of cases treated without antibiotics will resolve spontaneously within 3 days. If antibiotic treatment is to be given, it should be effective against the three main bacterial pathogens: S. pneumoniae, H. influenzae and S. pyogenes. The streptococci are usually sensitive to penicillins, but these are much less active against H. influenzae, so the broader spectrum agents amoxicillin or ampicillin are preferred. These drugs have identical antibacterial activity, but amoxicillin is recommended for oral treatment since it is better absorbed from the gastro-intestinal tract. Patients with penicillin allergy may be treated with a later-generation cephalosporin (see later).

About 20% of H. influenzae strains are resistant to amoxicillin due to production of β-lactamase, so if there is no response to amoxicillin, an alternative agent should be chosen. Both erythromycin and the earlier oral cephalosporins such as cefalexin are insufficiently active against H. influenzae and should not be used. Alternatives include co-amoxiclav (a combination of amoxicillin and the β-lactamase inhibitor clavulanic acid) or an orally active later-generation cephalosporin such as cefixime. Cefuroxime axetil, while active in vitro, is poorly absorbed and often causes diarrhoea.

Pneumococcal conjugate vaccines, which are currently given routinely in the childhood vaccination schedule, may reduce the incidence of acute otitis media, although a recent review (Jansen et al., 2009) found only modest benefit. No benefit was found for influenza vaccination (Hoberman et al., 2003). Long-term antibiotic prophylaxis might have a role in some children (Leach and Morris, 2006), but any benefit has to be balanced against the risks.

Acute sinusitis

Lower respiratory infections

Acute bronchitis and acute exacerbations of COPD

Bronchitis means inflammation of the bronchi. It is important to distinguish between acute bronchitis, which is usually, if not always, infective, and chronic bronchitis, which is a chronic inflammatory condition characterised by thickened, oedematous bronchial mucosa with mucus gland hypertrophy and usually caused by smoking. Chronic bronchitis often co-exists with emphysema, both of which lead to airflow limitation and the clinical syndrome of COPD.

The importance of chronic bronchitis is that it renders the patient more susceptible to acute infections and more likely to suffer respiratory compromise as a result. These acute exacerbations of COPD are a frequent cause of morbidity and admission to hospital. An exacerbation is defined as ‘a sustained worsening of the patient’s symptoms from his or her usual stable state that is beyond normal day-to-day variations, and is acute in onset’ (NICE, 2004). Common symptoms include worsening breathlessness, cough, increased sputum production and change in sputum colour. It is important to remember that not all acute exacerbations of COPD have an infective aetiology since atmospheric pollutants are sometimes implicated.

Treatment

Younger patients without pre-existing respiratory disease are likely to recover rapidly and might not require specific treatment. For more severe cases, including exacerbations of COPD, the two main arms of treatment are airflow optimisation and antibiotic therapy. Airflow optimisation consists of physiotherapy to aid expectoration of secretions, adjunctive oxygen if appropriate, bronchodilators and sometimes short-course corticosteroids. In severe cases, a period of artificial ventilation may be required, an intervention which has become more common with the advent of non-invasive ventilation techniques.

Despite the reservation that many cases are non-infective, current guidelines recommend that antibiotics are prescribed when an exacerbation is associated with more purulent sputum (NICE, 2004). There is no unequivocal evidence that one antibiotic is better than another, so recommendations for empiric treatment are based generally upon spectrum, side effects and cost. Most authorities favour either a tetracycline such as doxycycline or an aminopenicillin such as amoxicillin, since these agents cover most strains of S. pneumoniae and H. influenzae. Some people argue in favour of co-amoxiclav, which covers β-lactamase producing strains of H. influenzae and M. catarrhalis that are therefore resistant to amoxicillin, but this agent is more expensive and has a greater incidence of side effects. For penicillin-allergic patients for whom tetracyclines are contraindicated, neither the macrolide erythromycin nor the earlier oral cephalosporins such as cefalexin or cefradine are sufficiently active against H. influenzae for empiric use. However, both clarithromycin and newer oral cephalosporins such as cefixime are active against haemophili while retaining activity against pneumococci.

The following recommendations can be made for the empiric antibiotic treatment of acute bronchitis and exacerbations of COPD. If a plausible pathogen is isolated, treatment can be modified accordingly.

Second-line agents

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