Parainfluenza viruses are common causes of laryngitis

Viral infections of the upper respiratory tract may spread downwards to involve the larynx and the trachea. Usually the cause is a parainfluenza virus, but sometimes it is RSV, influenza virus or an adenovirus. Diphtheria (see below) may involve the larynx or trachea.

In adults, laryngeal infection (laryngitis) and tracheitis cause hoarseness and a burning retrosternal pain. The larynx and trachea have non-expandable rings of cartilage in the wall, and are easily obstructed in children, due to the narrow passages, leading to hospital admission. Swelling of the mucous membrane may lead to a dry cough and inspiratory stridor (‘crowing’) known as croup. Bacteria such as group A streptococci, Haemophilus influenzae and Staphylococcus aureus are less common causes of laryngitis and tracheitis.

Diphtheria is caused by toxin-producing strains of Corynebacterium diphtheriae and can cause life-threatening respiratory obstruction

Diphtheria is now rare in resource-rich countries due to widespread immunization with toxoid (see Ch. 34), but it is still common in resource-poor countries. Non-toxigenic strains occur in the normal pharynx, but bacteria producing the extracellular toxin (exotoxin; see Ch. 2) must be present to cause disease. They can colonize the pharynx (especially the tonsillar regions), the larynx, the nose and occasionally the genital tract, and in the tropics or in indigent people with poor skin hygiene, the skin.

Adhesion is mediated by pili or fimbriae covalently attached to the bacterial cell wall. The bacteria multiply locally without invading deeper tissues or spreading through the body. The toxin destroys epithelial cells and polymorphs, and an ulcer forms, which is covered with a necrotic exudate forming a ‘false membrane’. This soon becomes dark and malodorous, and bleeding occurs on attempting to remove it. There is extensive inflammation and swelling (Fig. 19.1) and the cervical lymph nodes may be enlarged to give a ‘bull neck’ appearance.

Figure 19.1 Pharyngeal diphtheria. Characteristic diphtheria ‘false membrane’ in a child, with local inflammation.

(Courtesy of Norman Begg.)

Nasopharyngeal diphtheria is the most severe form of the disease. When the larynx is involved, it can result in life-threatening respiratory obstruction. Anterior nasal diphtheria is a mild form of the disease if it occurs on its own, because the toxin is less well absorbed from this site, and a nasal discharge may be the main symptom. The patient will, however, be highly infectious.

Diphtheria toxin can cause fatal heart failure and a polyneuritis

The toxin (Box 19.1 and Fig. 19.2) is absorbed into the lymphatics and blood, and has several effects:

Figure 19.2 Mechanism of action of diphtheria toxin. ADP, adenosine diphosphate; EF-2, elongation factor-2.

Diphtheria is managed by immediate treatment with antitoxin and antibiotic

Diphtheria is a life-threatening disease, and clinical diagnosis is a matter of urgency. As soon as the diagnosis is suspected clinically, the patient is isolated to reduce the risk of the toxigenic strain spreading to other susceptible individuals, and antitoxin treatment is started. The antitoxin is produced in horses, and tests for hypersensitivity to horse serum should be carried out. Penicillin or erythromycin is given as well. Laryngeal diphtheria may result in an obstructed airway and require a tracheotomy to assist with respiration.

The diagnosis is confirmed in the laboratory by isolation and identification of the organism (Ch. 32) and demonstrating toxin production by a gel-diffusion precipitin reaction (Elek test). PCR can be carried out in some reference laboratories to detect the tox gene responsible for producing the toxin.

Contacts may need chemoprophylaxis or immunization

Contacts of diphtheria patients should be tested for carriage of toxigenic C. diphtheriae and if necessary be given chemoprophylaxis or immunization. Toxigenic bacteria may be carried and transmitted by asymptomatic convalescents or by apparently healthy individuals.

Diphtheria is prevented by immunization

Diphtheria has almost disappeared from resource-rich countries as a result of the immunization of children with a safe, effective toxoid vaccine (see Ch. 34). However, the disease reappears when immunization is neglected. In 1990, epidemics began in the Russian Federation, and by 1994, all 15 of the newly independent states of the former Soviet Union were involved, with 157 000 reported cases by 1997. The World Health Organization (WHO) website reported in 2011 that the incidence of diphtheria ranged from 0.5–1/100 000 population in Armenia, Estonia, Lithuania and Uzbekistan, to 27–32/100 000 in Russia and Tajikistan. Case fatality rates ranged from 2–3% in Russia to 17–23% in Azerbaijan, Georgia and Turkmenistan. Worldwide, in 2004, the World Health Organization estimated there were 5000 deaths and in 2009, 857 cases were reported.

Whooping cough is caused by the bacterium Bordetella pertussis

Whooping cough or pertussis is a severe disease of childhood. Bordetella pertussis is confined to humans and is spread from person to person by airborne droplets. The organisms attach to, and multiply in, the ciliated respiratory mucosa, but do not invade deeper structures. Surface components such as filamentous haemagglutinin and fimbrial agglutinogens play an important role in specific attachment to respiratory epithelium.

B. pertussis infection is associated with the production of a variety of toxic factors

Some of these toxic factors affect inflammatory processes, while others damage ciliary epithelium. They are:

B. pertussis infection is characterized by paroxysms of coughs followed by a ‘whoop’. After an incubation period of 7–10    days (range 5–21    days), B. pertussis infection is manifest first as a catarrhal illness with little to distinguish it from other upper respiratory tract infections. This is followed up to 1    week later by a dry non-productive cough, which becomes paroxysmal. A paroxysm is characterized by a series of short coughs producing copious mucus, followed by a ‘whoop’, which is a characteristic sound produced by an inspiratory gasp of air. Despite the severity of the cough, the symptoms are confined to the respiratory tract, and lobar or segmental collapse of the lungs can occur (Fig. 19.3).

Figure 19.3 Chest radiograph showing patchy consolidation and collapse of the right middle lobe in whooping cough.

(Courtesy of J.A. Innes.)

Complications include central nervous system (CNS) anoxia, exhaustion and secondary pneumonia due to invasion of the damaged respiratory tract by other pathogens.

The early clinical picture is non-specific, and the true diagnosis may not be suspected until the paroxysmal phase. The organisms can be isolated on suitable media from throat swabs or on ‘cough plates’ (see Ch. 32), but they are fastidious and do not survive well outside the host’s environment.

Whooping cough is managed with supportive care and erythromycin

Supportive care is of prime importance. Infants are at greatest risk of complications, and admission to hospital should be considered for children less than 1    year of age. For specific antibacterial treatment to be effective it must penetrate the respiratory mucosa and inhibit or kill the infecting organism. Treatment with macrolide antibiotics such as erythromycin, clarithromycin or azithromycin is recommended. Although the treatment is often only started when the disease is recognized in the paroxysmal phase, it does appear to reduce its severity and duration. It also reduces the bacterial load in the throat, thereby helping to reduce both the infectivity of the patient and the risk of secondary infections.

Prophylaxis with macrolide antibiotics of close contacts of active cases is helpful in controlling the spread of infection.

Whooping cough can be prevented by active immunization

For many years, a whole cell vaccine comprising a killed suspension of B. pertussis cells was used, combined with purified diphtheria and tetanus toxoids and administered as ‘DPT’ or ‘triple’ vaccine. Although an effective vaccine, there were major concerns about side effects. These included fever, malaise and pain at the site of administration in up to 20% of infants; convulsions, thought to be associated with the vaccine in about 0.5% of vaccinees; and encephalopathy and permanent neurologic sequelae associated with vaccination, with an estimated rate of 1 in 100 000 vaccinations (<    0.001%).

Concern about side effects led to a marked fall in uptake of the vaccine and subsequently to a marked increase in the incidence of whooping cough (see Ch. 31).

Acellular pertussis vaccines became the dominant vaccine preparation as they provide the same or better protection against whooping cough and cause fewer side effects as they are highly purified with much reduced levels of endotoxin compared with whole cell vaccines. The acellular vaccines contain pertussis toxoid and other bacterial components, including the filamentous haemagglutinin and fimbriae, and are given in combination with other vaccines such as diphtheria, tetanus, polio and Haemophilus influenzae type B. In 2008, about 82% of all infants worldwide received three doses of pertussis vaccine. WHO estimated that global pertussis immunization prevented about 687 000 deaths that year and that about 16 million cases of pertussis occurred worldwide. Ninety-five per cent were in resource-poor countries and whooping cough led to about 195 000 childhood deaths.

Acute bronchitis is an inflammatory condition of the tracheobronchial tree, usually due to infection

Causative agents include rhinoviruses and coronaviruses, which also infect the upper respiratory tract, and lower tract pathogens such as influenza viruses, adenoviruses and Mycoplasma pneumoniae. Secondary bacterial infection with Streptococcus pneumoniae and Haemophilus influenzae may also play a role in pathogenesis. The degree of damage to the respiratory epithelium varies with the infecting agent:

Figure 19.4 Opsonized Mycoplasma pneumoniae cells (arrowed) phagocytosed by an alveolar macrophage (bar, 2    μm). The insert shows M. pneumoniae cells adhering with the tip organelle (T) to macrophage surfaces.

(From Jacobs E. Rev Med Microbiol 2:83–90, © 1991.)

Infection is only one component of chronic bronchitis

Chronic bronchitis is a condition characterized by cough and excessive mucus secretion in the tracheobronchial tree that is not attributable to specific diseases such as bronchiectasis, asthma or tuberculosis. Infection appears to be only one component of the syndrome, the others being cigarette smoking and inhalation of dust or fumes from the workplace. Bacterial infection does not appear to initiate the disease, but is probably significant in perpetuating it and in producing the characteristic acute exacerbations. Streptococcus pneumoniae and unencapsulated strains of Haemophilus influenzae are the organisms most frequently isolated, but interpretation of the significance of their presence in sputum is difficult because they are also commonly found in the normal throat flora and can therefore contaminate expectorated sputum. Other bacteria such as Staphylococcus aureus and Mycoplasma pneumoniae are less commonly associated with infection and exacerbation. Viruses are frequent causes of acute infection.

Antibiotic therapy may be helpful in the treatment of acute exacerbations, although its efficacy is difficult to assess.

Around 75% of bronchiolitis presentations are caused by respiratory syncytial virus infection

Bronchiolitis is a disease restricted to childhood, and usually to children less than 2    years of age. The bronchioles of a young child have such a fine bore that if their lining cells are swollen by inflammation the passage of air to and from the alveoli can be severely restricted. Infection results in necrosis of the epithelial cells lining the bronchioles and leads to peribronchial infiltration, which may spread into the lung fields to give an interstitial pneumonia (see below). As many as 75% of these infections are caused by respiratory syncytial virus (RSV) and the other 25% are also of viral aetiology, although Mycoplasma pneumoniae is implicated occasionally.

Respiratory syncytial virus is the most important cause of bronchiolitis and pneumonia in infants

Respiratory syncytial virus (RSV) is a typical paramyxovirus, and two major strains have been identified: group A and group B. Its surface spikes bear G protein (not haemagglutinin or neuraminidase) for attachment to the cell, and fusion (F) protein. The latter initiates viral entry by fusing the viral envelope to the cell membrane, and also fuses host cells to form syncytia.

RSV infection is transmitted by droplets and to some extent by hands. Outbreaks occur each winter, and during the RSV season, infection can spread in hospitals as well as in the community. Nearly all individuals have been infected by 2    years of age. About 1 in every 100 infants with RSV bronchiolitis or pneumonia requires admission to hospital.

Respiratory syncytial virus infection can be particularly severe in young infants

After inhalation, the virus establishes infection in the nasopharynx and lower respiratory tract. Clinical illness appears after an incubation period of 4–5    days. The illness can be particularly severe in young infants, with peak mortality at 3    months of age, the virus invading the lower respiratory tract by direct surface spread to cause bronchiolitis or pneumonia. Young infants develop a cough, rapid respiratory rate and cyanosis. In young children and adults, however, the virus is restricted to the upper respiratory tract, causing a less severe common cold-type illness. Otitis media is quite common. Secondary bacterial infection is rare.

The manifestations of RSV infection appear to have an immunopathologic basis

Maternal antibodies in the infant react with virus antigens, perhaps with the liberation of histamine and other mediators from the host’s cells. In early trials, a killed vaccine was used and, during subsequent natural RSV infection, the vaccinees had more frequent and severe lower respiratory tract disease compared with unimmunized children, supporting an immune-mediated pathogenesis.

Neutralizing antibodies are formed, at lower levels in younger infants, but cell-mediated immunity (CMI) is needed to terminate the infection. The virus continues to be shed from the lungs of children lacking CMI for many months. Apparently healthy children may continue to show depressed pulmonary function or wheeze even 1–2    years after apparent recovery.

Recurrent infections are common, but are less severe. The reason for recurrence, which is also a feature of parainfluenza virus infection, is unknown.

Respiratory syncytial virus RNA is detectable in throat swab specimens, and ribavirin is indicated for severe disease

Molecular methods, such as PCR, used to detect RSV RNA in throat swab specimens, have a higher diagnostic sensitivity than immunofluorescence (Fig. 19.5) or enzyme-linked immunosorbent assay (ELISA) methods (see Ch. 32), detecting RSV-specific antigens in smears of exfoliated cells obtained by nasopharyngeal aspiration. However, virus isolation is less helpful due to the time taken to detect a cytopathic effect, and success depends on inoculating respiratory secretions as soon as possible into cell cultures.

Figure 19.5 Immunofluorescent preparation from the nasopharynx showing respiratory syncytial virus-infected cells (bright green).

(Courtesy of H. Stern.)

In most children, treatment is supportive, involving rehydration, bronchodilators and, if needing admission to hospital, oxygen. The antiviral agent ribavirin, given as an aerosol, has been used successfully in a number of clinical settings, including children with severe infection and immunosuppressed individuals at risk of severe disease. A monoclonal antibody, palivizumab, can be used as prophylaxis to prevent RSV infection in infants less than 2    years old at risk of severe disease such as those with chronic lung disease, congenital heart disease or those born at less than 32    weeks of age. At present, there is no vaccine available.

Microorganisms reach the lungs by inhalation, aspiration or via the blood

Microorganisms gain access to the lower respiratory tract by inhalation of aerosolized material or by aspiration of the normal flora of the upper respiratory tract. The size of inhaled particles is important in determining how far they travel down the respiratory tract; only those less than about 5    mm in diameter reach the alveoli. Less frequently, the lungs become seeded with organisms as a result of spread via the blood from other infected sites. Healthy individuals are susceptible to infection by a range of pathogens possessing adhesins, which allow the pathogens to attach specifically to the respiratory epithelium. In addition, people with impaired defences, for example, if immunocompromised, with preceding viral damage, or with cystic fibrosis, may develop infections with organisms that do not cause infections in health. An example is Pneumocystis jirovecii, an important cause of pneumonia in individuals with AIDS.

The respiratory tract has a limited number of ways in which it can respond to infection

The host’s response can be defined by the pathologic and radiologic findings, but the terms can be confusing because they are applied differently in different situations. However, four descriptive terms are in common use (Fig. 19.6):

Figure 19.6 Four types of pneumonia. (A) Pneumococcal lobar pneumonia, showing consolidated alveoli filled with neutrophils and fibrin. (H&E stain) (Courtesy of I.D. Starke and M.E. Hodson.) (B) Mycoplasma bronchopneumonia, with patchy consolidation in several areas of both lungs. (Courtesy of J.A. Innes.) (C) Interstitial pneumonia due to influenza virus. (Courtesy of I.D. Starke and M.E. Hodson.) (D) Lung abscess, showing an abscess cavity in the lower lobe of the right lung.

(Courtesy of J.A. Innes.)

The outcomes common to all these conditions are respiratory distress resulting from the interference with air exchange in the lungs, and systemic effects as a result of infection in any part of the body.

A wide range of microorganisms can cause pneumonia

Age is an important determinant (Table 19.1):

Table 19.1 Causes of pneumonia related to age

Pneumonia acquired in hospital tends to be caused by a different spectrum of organisms, particularly Gram-negative bacteria. The causative agents of adult pneumonia are summarized in Figure 19.7. Although clinical and epidemiologic clues help to suggest the likely cause, microbiologic investigations are essential to confirm the diagnosis and ensure optimal antimicrobial therapy.

Figure 19.7 Many pathogens are capable of causing pneumonia in adults, and the aetiology is related to risk factors such as the exposure to pathogens through occupation, travel and contact with animals. The elderly are more likely to be infected and tend to have a more severe illness than young adults. * These infections are often reactivating endogenous infections rather than community or hospital acquired. C., Coxiella; CMV, cytomegalovirus; H., Haemophilus; K., Klebsiella; L., Legionella; M., Mycobacterium; P., Pseudomonas; Staph., Staphylococcus; Strep., Streptococcus.

Viral pneumonias show a characteristic interstitial pneumonia on chest radiography more often than bacterial pneumonias (see Fig. 19.6C), and for the sake of clarity are described separately below. Infections with RSV have been described earlier in this chapter, and opportunist pathogens, such as Pneumocystis jirovecii, associated specifically with pneumonia in the immunocompromised, are described in Chapter 30.

Streptococcus pneumoniae is the classic bacterial cause of acute community-acquired pneumonia

In the past, 50–90% of pneumonias were caused by Streptococcus pneumoniae (the ‘pneumococcus’), but the relative importance of this pathogen has decreased and it now causes only 25–60% of cases (Table 19.2). Haemophilus influenzae is estimated to be the cause of 5–15% of cases, but the true incidence is difficult to determine because this organism frequently colonizes the upper respiratory tract of bronchitic patients (see above).

Table 19.2 Common causes of pneumonia in community-based studies in three countries

A variety of bacteria cause primary atypical pneumonia

When penicillin, an effective antibiotic treatment for pneumococcal infection, became widely available, a significant proportion of cases of pneumonia failed to respond to this treatment and were labelled ‘primary atypical pneumonia’. ‘Primary’ refers to pneumonia occurring as a new event, not secondary to influenza, for example, and ‘atypical’ to the fact that Strep. pneumoniae is not isolated from sputum from such patients, the symptoms are often general as well as respiratory, and the pneumonia fails to respond to penicillin or ampicillin. The causes of atypical pneumonia include Mycoplasma pneumoniae, Chlamydophila (formerly Chlamydia) pneumoniae and Chlamydophila (formerly Chlamydia) psittaci, Legionella pneumophila and Coxiella burnetii. The relative importance of these pathogens varies in different studies (Table 19.2). Infection with Chlamydophila pneumoniae is common. About 50% of adults have antibodies, and in the USA it causes up to 300 000 cases of pneumonia each year in adults. Mycoplasma pneumoniae and Chlamydophila pneumoniae appear to be solely human pathogens, whereas Chlamydophila psittaci and Coxiella burnetii are acquired from infected animals, and Legionella pneumophila is acquired from contaminated environmental sources (see Fig. 19.7).

Moraxella catarrhalis (previously Branhamella catarrhalis) is recognized increasingly as a cause of pneumonia, particularly in patients with carcinoma of the lung or other underlying lung disease. Other aetiologic agents of pneumonia associated with particular underlying diseases, occupations or exposure to animals and travel are summarized in Figure 19.7 and described in other chapters. It is important to note that a causative organism is not isolated in up to 35% of lower respiratory tract infections.

Patients with pneumonia usually present feeling unwell and with a fever

Signs and symptoms of a chest infection include:

Some infections result in symptoms confined mainly to the chest, whereas others such as Legionnaires’ disease caused by Legionella pneumophila have a much wider systemic involvement, and the patient may present with mental confusion, diarrhea and evidence of renal or liver dysfunction. However, the distinction between localized and systemic symptoms is not usually reliable enough for an accurate diagnosis.

Chest examination may reveal abnormal crackling sounds, called ‘rales’, and evidence of consolidation, even before changes become evident on radiography.

Patients with pneumonia usually have shadows in one or more areas of the lung

The chest radiograph is an important adjunct to the clinical diagnosis. Patients with pneumonia usually have shadows indicating consolidation (see above for descriptions of lobar, broncho- and interstitial pneumonia). However, careful interpretation is required to differentiate between infection and non-infective processes such as tumours.

Pneumonia is the most common cause of death from infection in the elderly

It is also an important cause of death in the young and previously healthy. Complications of infection include spread of the infecting organisms:

For example, the majority of patients with pneumococcal pneumonia have positive blood cultures, and pneumococcal meningitis not infrequently follows pneumonia in the elderly.

Sputum samples are best collected in the morning and before breakfast

Microscopic examination and culture of expectorated sputum remain the mainstays of respiratory bacteriology, despite doubts about the value of these procedures. Collection of sputum is non-invasive, but more invasive techniques, such as transtracheal aspiration, bronchoscopy and bronchoalveolar lavage and open lung biopsy, may yield more useful results.

Sputum samples are best collected in the morning because sputum tends to accumulate while the patient is lying in bed, and before breakfast to reduce contamination by food particles and bacteria from food. It is important that the specimen submitted for examination is truly sputum and not simply saliva. A physiotherapist can be of great assistance to ill patients who may be unable to cough unaided.

The usual laboratory procedures on sputum specimens from patients with pneumonia are Gram stain and culture

Examination of the Gram-stained sputum (see Ch. 32) can give a presumptive diagnosis within minutes if the film reveals a host response in the form of abundant polymorphs and the putative pathogen, e.g. Gram-positive diplococci characteristic of Streptococcus pneumoniae (Fig. 19.8). The presence of organisms in the absence of polymorphs is suggestive of contamination of the specimen rather than infection, but it is important to remember that immunocompromised patients may not be able to mount a polymorph leukocyte response. Also, remember that the causative agents of atypical pneumonia, with the exception of Legionella pneumophila (Fig. 19.9), will not be seen in Gram-stained smears.

Figure 19.8 Gram-stained smears of sputum can help the physician make a rapid diagnosis if, like this, they contain abundant Gram-positive diplococci characteristic of pneumococci, as well as polymorphs. However, many of the important causes of pneumonia will not be stained by Gram stain.

Figure 19.9 Legionella pneumophila. (A) Gram stain of a bronchial biopsy specimen in a patient with fulminant Legionnaires’ disease. (Courtesy of S. Fisher-Hoch.) (B) Culture plate showing white colonies on buffered charcoal yeast extract medium.

(Courtesy of I. Farrell.)

Standard culture techniques will allow the growth of the bacterial pathogens such as Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae and Klebsiella pneumoniae and other non-fastidious Gram-negative rods. Special media or conditions are required for the causative agents of atypical pneumonia, including Legionella pneumophila (Fig. 19.9).

Rapid non-cultural techniques have been applied successfully to the diagnosis of pneumococcal pneumonia. Detection of pneumococcal antigen by agglutination of antibody-coated latex particles (see Ch. 32) can be used with both sputum and urine specimens, as antigen is excreted in the urine. Use of this technique means the result is available within 1    h of receipt of the specimen, but antibiotic susceptibility tests cannot be performed unless the organisms are isolated.

Microbiologic diagnosis of atypical pneumonia is usually confirmed by serology

As mentioned above, several important causes of pneumonia will not be revealed in Gram-stained sputum smears and cannot be grown on simple routine culture media. For these reasons, the diagnosis is usually confirmed by serologic tests rather than by culture. In some infections, IgM, antigen or genome detection is being used to make the diagnosis at an early stage. The classic techniques involve detection of a single high titre of specific antibodies, or preferably demonstration of a rising titre between the acute and convalescent phase of the disease, but the diagnosis is often made retrospectively. The important serologic tests are shown in Table 19.3.

Table 19.3 Serological diagnosis of ‘atypical’ pneumonia