Sore throat

Bacterial acute tonsillitis or pharyngitis is commonly due to Str. pyogenes (group A), and a few are caused by groups C and G. Viruses are even more common causes of sore throats, especially the milder, non-exudative forms. However, it is important to make a definitive diagnosis of streptococcal pharyngitis for two reasons:

On the other hand, since Str. pyogenes may account for only 20% of patients presenting with typical symptoms, many courses of antibiotics would be prescribed unnecessarily if all suspected cases were treated. Even in experienced hands it is difficult to predict on clinical grounds alone which cases are streptococcal. This has led to three approaches:

There are pros and cons to each method. One drawback to the early use of antibiotics is that the patient may react to the drug. If ampicillin is used, there is a strong chance of a skin reaction if the sore throat is the harbinger of glandular fever. In defence of the antibiotic lobby, there is no doubt that complications of streptococcal disease are seen far less commonly where there is access to medical service and pharmacies. However, these improvements have occurred in concert with better housing and social conditions.

There was less need to make a virological diagnosis as specific therapy was limited. However, epidemiological studies of patients with throat symptoms have revealed how common and varied are the viruses in the respiratory tract. With the advent of antivirals active against specific viruses, interest has increased in using tests for influenza and RSV.

In the severely ill child with toxaemia and a membrane, diphtheria must be considered and treatment should not await laboratory confirmation. Moreover, the laboratory needs to do special tests to isolate and identify Corynebacterium diphtheriae, and communication (by telephone, if possible) between the clinician and laboratory is essential. Other corynebacteria such as C.ulcerans and Arcanobacterium haemolyticum may rarely cause ulcerated sore throats. In the sexually active, gonococcal pharyngitis should not be missed and again the laboratory needs to be told as they will use special selective media for Neisseria gonorrhoeae.

Common cold (coryza)

This common complaint, characterized by a nasal discharge (acute rhinitis) that is usually watery with scanty cells, afflicts humans of all ages who congregate together. Since there are many types of rhinoviruses, coronaviruses, adenoviruses, etc., and since immunity may be short-lived, individuals in a crowded environment, such as at school and university or travelling on public transport, may suffer three or four clinical infections a year. Most of these do not seek medical help knowing that there is little to offer. This is a condition for which many ‘alternative’ remedies are tried, from garlic to peppermint and vitamin supplements.

Bacterial superinfection with pneumococci and H. influenzae can occur in the nasopharynx but is only symptomatic when the sinuses or middle ear are involved. Pharyngitis and, occasionally, tracheobronchitis may occur with a cold or develop in more susceptible individuals. Respiratory syncytial virus (RSV) may cause upper respiratory symptoms in children and adults, but in those contracting the virus for the first time (usually infants under 1 year of age) acute bronchiolitis is common.

Sinusitis and otitis media

Direct extension of a viral or bacterial infection from the nasopharynx into frontal and maxillary sinuses in adults and into the middle ear in children is not uncommon. Obtaining adequate material for microbiology is difficult and requires the expertise of ear, nose and throat specialists. In most cases of acute sinusitis or otitis media the microbial cause is not found. It is assumed that severe pain and discharge of pus from the nose or ear is suggestive of bacterial infection and antibiotics are usually given to cover streptococci (mainly Str. pneumoniae) and H. influenzae. In adults with recurrent or chronic sinusitis, anaerobes (peptostreptococci or bacteroides) are often found in sinus washings.

Epiglottitis

Although situated in the upper part of the respiratory tract, epiglottitis behaves like a serious systemic infection which requires urgent admission to hospital and treatment. The diagnosis should be made clinically in a toxic child (usually under 5 years old) with respiratory obstruction and stridor. The most useful investigation is blood culture, which invariably grows H. influenzae type b unless antibiotics have been given or the child immunized. The epiglottis, which is swollen and cherry-red in appearance, should only be examined by skilled paediatricians prepared for a respiratory arrest. A lateral radiograph shows a soft tissue swelling in the throat.

Laryngotracheobronchitis

In adults, some viral infections cause acute laryngitis with voice loss or tracheitis with a dry cough. Respiratory tract infection in children is usually generalized and presents as croup. This may lead to respiratory obstruction and, as with haemophilus epiglottitis, urgent admission to hospital is necessary. The condition may be caused by a variety of respiratory viruses, with para-influenza viruses, adenoviruses and enteroviruses the most common. RSV can also cause croup, but more commonly this virus attacks infants in the first few months of life. In the UK there are winter epidemics of acute bronchiolitis due to RSV. This clinical syndrome which starts as a cold, followed by wheezing. In older children, asthmatic attacks are often precipitated by viral respiratory infections.

Whooping cough

Pertussis may be confused with croup, and, as special specimens need to be taken, the laboratory must be informed. A pernasal swab in special transport medium is required, and Bordetella pertussis will only grow on enriched culture media in conditions of high humidity.

Acute bronchitis

Acute exacerbation of chronic obstructive pulmonary disease (COPD) is the most common adult lower respiratory infection. It is invariably due to pneumococci, non-encapsulated haemophili, or both. Sometimes, acute bronchitis follows a viral infection. Although often examined, expectorated sputum from ambulatory patients with COPD is almost always a waste of effort.

Cystic fibrosis patients have frequent exacerbations and, in those situations, sputum examination is valuable because the causative bacteria (Staphylococcus aureus, H. influenzae, Pseudomonas aeruginosa or Burkholderia cepacia) may show variable antimicrobial resistance and appropriate therapy is essential.

Acute pneumonias

It is sometimes possible on clinical and radiological grounds to distinguish between lobar pneumonia (pneumococcal), bronchopneumonia (staphylococcal and klebsiellal) and ‘atypical’ pneumonias (mycoplasmal and chlamydial). This division is of importance in guiding primary treatment, but should not give the clinician a blinkered view in investigation, as some cases will invariably not follow a textbook! Expectorated sputum is often poorly collected and may not yield the pathogen. Blood cultures should always be taken from pneumonia patients but may not yield an organism, especially if antibiotics have been started. Antigen detection in urine or sputum by fluorescent antibodies, immuno-electrophoresis, latex agglutination or enzyme-linked immunosorbent assay (ELISA) is a useful method for rapid diagnosis but may lack sensitivity. New amplified DNA detection methods are likely to improve diagnostic accuracy in respiratory infections. At present most cases of ‘atypical’ pneumonia are diagnosed by obtaining acute and convalescent sera, and by finding a significant titre or a rising titre of antibodies. Legionnaires’ disease may be diagnosed by culture of Legionella pneumophila from sputum or a biopsy, but this has too low a sensitivity. Urine antigen detection by ELISA or DNA amplification of respiratory secretions have become more widely available methods of diagnosis. However, as with most pneumonias treatment must often be given on clinical suspicion.

Chronic chest disease

Tuberculosis must always be considered in any patient with fever, prolonged cough and weight loss. Again, a request for examination for mycobacteria in sputum must be included on the request card. Blood tests examining for interferon produced by peripheral lymphocytes are of value in detecting latent tuberculosis but are of limited value in diagnosis of the a ctive disease.

In the immunocompromised, various opportunist pathogens may give rise to respiratory infection. Pneumocystis carinii is demonstrated by fluorescent antibody staining of bronchial lavage. Fungal infections are diagnosed by growth of the pathogen or by serology. Special investigations are required for all these situations and unless the diagnosis is considered the laboratory cannot assist the clinician.

Meningitis

Meningeal irritation may occur in association with other acute infections (meningism) or with non-infective conditions such as subarachnoid haemorrhage. In the early stages of meningococcal disease, signs of meningitis may be absent, yet examination of the cerebrospinal fluid (CSF) yields N. meningitidis. Thus, CSF and blood cultures should be examined from all suspected cases. There are contra-indications to performing a lumbar puncture in any patient with raised intracranial pressure because of the danger of herniation through the foramen magnum (coning). Thus, lumbar puncture should only be carried out in hospital. In fulminating disease, especially if it is meningococcal, it is prudent to give penicillin as soon as the diagnosis is suspected and before admission. This has led to a greatly reduced yield by culture of suspected cases. Antigen and DNA detection have become increasingly important in confirming the diagnosis.

It is often possible to consider the likely pathogen on clinical and epidemiological grounds. H. influenzae type b occurs almost always in infants from 6–24 months-of-age, although use of the Hib vaccine in many countries has almost made this a disease of the past. Str. pneumoniae is seen generally in the very young and the elderly. Meningococcal meningitis is characteristically a disease of children and young adults. In the neonate, coliforms (mainly E. coli K1), Listeria monocytogenes, group B streptococci and pneumococci may be found. In infants a few months old, salmonella meningitis is an important condition in some countries with a warm climate.

If no readily cultivated organism is found, but the CSF shows an increase in cells, the syndrome of aseptic meningitis is present. Table 65.3 shows some of the causes of this condition. If the symptoms are short in duration, viruses are most likely. If the child has been unwell for more than 1 week, tuberculous meningitis must be considered. This is one of the most difficult and important microbiological diagnoses to make. Interferon assays of activated lymphocytes from peripheral blood of patients with tuberculosis have been shown to be a useful adjunct to the clinical diagnosis in such situations.

Table 65.3 Causes of aseptic meningitis

In the immunocompromised, listeria meningitis may be seen in the adult and Cryptococcus neoformans in all age groups, but particularly those with human immunodeficiency virus (HIV) infection. Central nervous system disease in patients with acquired immune deficiency syndrome (AIDS) is a very complicated differential diagnosis (Table 65.4).

Table 65.4 Causes of neurological damage in HIV-infected patients

Cerebral infections

Encephalitis may extend into the meninges with signs and CSF findings of an aseptic meningitis. Many viral infections may, however, only infect the brain cortex and clinical symptoms may be vague: loss of consciousness, fits, localized paralysis. This can also occur in toxaemia, cerebral malaria, electrolyte disturbances or vascular accidents.

In western Europe, herpes simplex or varicella–zoster viruses are the most common causes of encephalitis, but in many parts of the world arboviruses such as Japanese B encephalitis virus are important (see Ch. 51).

Abscesses in the brain or subdural space may arise from haematogenous spread during bacteraemia or by direct extension, either through the cribriform plate from the nasopharynx or from sinuses or the middle ear. They may be clinically silent or present as a space-occupying lesion accompanied by fever and systemic upset. Scanning by computerized axial tomography (CAT) or magnetic resonance imaging (MRI) and early neurosurgical intervention will reduce complications and with appropriate systemic antibiotics given for a prolonged period, the success rate is nowadays good.

Pyrexia of unknown origin

PUO may be defined as a significant fever (greater than 38°C) for a few days without an obvious cause, i.e. no apparent infection of an organ or system. In the classic studies of PUO only patients with persistent fever for at least 3 weeks were included. These chronic cases are often due to non-infective causes such as malignancy (especially lymphomata) or auto-immune and connective tissue diseases (such as systemic lupus erythematosus).

In determining an infective aetiology some of the most important questions to be asked of the patient are:

Endocarditis

Infections of the tissue of the heart usually involve damaged valves, either after rheumatic fever or with atheroma. Another important group of patients are those who have had heart surgery, in particular prosthetic valve replacements. In addition, injecting drug users (IUDs) or patients who have had indwelling vascular devices are liable to bacteraemia and, occasionally, endocarditis may follow. The most common causative organisms are listed in Table 65.6.

Table 65.6 Some causes of infective endocarditis (approximate %)

IDU, injecting drug user.

^a Neisseria, Brucella, Cardiobacterium, Streptobacillus spp.

^b These are rough UK figures; in some parts of the Middle East, brucellae and Q fever cause significant numbers of infective endocarditides.

Septicaemia

It is not clinically useful to distinguish between bacteraemia, organisms isolated from the bloodstream, septicaemia, which is a clinical syndrome, and endotoxaemia, which is circulating bacterial endotoxin. The spectrum of clinical disease ranges from hypotensive shock and disseminated intravascular coagulation (DIC) with a high mortality, to transient bacteraemia, which may occur in healthy individuals during dental manipulations.

The vascular compartment is sterile and usually intact. Microbes gain entry from breakages of blood vessels adjacent to skin or mucosal surfaces or by phagocytic cells carrying organisms into capillaries or the lymphatic system. Active multiplication within the bloodstream probably only occurs terminally, but in many cases of septicaemia there are high numbers of bacteria recovered from blood cultures, which often only sample 10 mL at a time. This occurs from a heavily contaminated site such as an indwelling urinary catheter which releases bacteria into veins on movement. Septic shock may be due to Gram-negative lipids (endotoxins) or Gram-positive toxins (e.g. staphylococcal enterotoxin), which are usually proteins. The end result of both is to initiate a cascade of events involving cytokines, especially tumour necrosis factor and interleukin-2, vascular mediators and platelets, which combined lead to DIC and hypotension. This process becomes irreversible and produces failure of all major organs. Patients die from a variety of terminal events which make up the syndrome of septic shock. The main microbial causes are listed with approximate frequency in Table 65.7.

Table 65.7 Major causes of septicaemia (approximate %)

Clinical features may occasionally suggest the aetiological agent, e.g. the characteristic purpuric rash of meningococcal disease and the black lesions (ecthyma gangrenosum) seen on the skin of compromised patients with pseudomonas septicaemia, but in the majority of bacteraemias the agent can only be determined after blood culture. Sometimes, prior antibiotic therapy may render cultures negative and new methods of antigen detection or gene probes may be useful. Non-specific investigations, such as those shown in Figure 65.1, may offer some help that the cause of the illness is infective. C-reactive protein (CRP), an acute-phase protein which is often greatly elevated in the serum during bacterial infections, may be the most useful of these but, as with peripheral leucocyte counts, there are a significant number of errant results.

Imported infections

An important group of patients with fever are those who have recently returned from abroad. In whichever country a doctor may practice, travellers with unfamiliar disease will be encountered. Knowledge of medical geography is useful but conditions vary greatly within one country and with time. Up-to-date information is held, often on computer, by communicable disease centres and tropical disease hospitals and schools. The World Health Organization and the Centers for Disease Control, Atlanta, USA, publish international notification data and maps (see Ch. 70 for websites). Undoubtedly the most important condition to diagnose is malaria due to Plasmodium falciparum, which may be rapidly fatal without appropriate treatment in the non-immune subject. The wide distribution of drug resistance in P. falciparum has led to difficulties in giving adequate prophylaxis and in treating an acute attack. Other common febrile illnesses which are imported into northern countries are typhoid and paratyphoid. These do not usually present with diarrhoea so the possibility of an enteric fever may not be considered. It is also obvious, but sometimes overlooked, that the fever may not be related to the travel history and that the cause is a microbe which could have been caught at home.

Table 65.8 lists some of the more common causes of infectious diseases imported from tropical countries into temperate regions where the diseases are not normally transmitted. There are three groups of patients which are considered separately, but the separation of diseases and microbes is not exclusive:

Table 65.8 Some important infective conditions imported to temperate regions from the tropics

Individuals who travel abroad vary in their risk behaviour and their exposure to potential pathogens. Generally, advice given by travel operators, tourist offices, embassies and medical sources has greatly improved in the past few years. Companies sending out expatriate workers tend to look after their staff well. Nevertheless, many tourists (up to 50% in some studies) have episodes of travellers’ diarrhoea, which in some cases results in admission to hospital. The major groups who are missed in preventative programmes are overland travellers and immigrants returning to their homeland, often with young families who have never been exposed to the infectious risks of their parents’ home. Immigrants returning for visits to malarious areas seldom take prophylactic advice, believing themselves to be immune, but protective immunity wanes with prolonged absence.

Cryptogenic infections

Some of the commonly encountered sites of infection which may give rise to fever, and must be considered in the differential diagnosis of PUO, are listed in Table 65.9.

Table 65.9 Some common sites of infection in pyrexia of unknown origin