Abstract

Capsulate bacteria cause the majority of community-acquired pneumonia presenting to hospital world-wide, at all ages. They are united by the virulence factor of their differing capsular polysaccharides, enabling them to evade phagocytosis. All cause invasive disease beyond the respiratory tract, including septicaemia and central nervous system infection. Recent advances in vaccine development have made the capsular polysaccharide an achievable target for vaccine strategies across all ages, with impacts already seen upon Streptococcus pneumoniae and Haemophilus influenzae type b pneumonia in countries able to afford these new vaccines.

Encapsulated bacteria maintain a stronghold upon infective lung pathology across the entire age spectrum. From early onset neonatal pneumonia with group B streptococci, Haemophilus influenzae type b childhood disease to Streptococcus pneumoniae pneumonia peaking in the elderly, they are primary community-acquired pathogens of previously healthy lungs. This epidemiological pride of place is largely attributable to the polysaccharide capsule encompassing the external surface of these bacteria. Capsules are composed of repeating oligosaccharides, external to the cell membrane in Gram-negative bacteria and the peptidoglycan layer in Gram-positive bacteria. Many bacteria may reasonably be termed encapsulated. This review will concentrate upon those bacteria that are classified depending upon capsular antigenic differences, where the primary role of the capsule in pathogenesis is established, and cause appreciable respiratory disease. Other ‘capsulate’ bacteria, including Escherichia coli and Klebsiella, will not be dealt with.

This chapter will review the roles of the distinctly different bacteria sharing this virulence factor in lower respiratory disease, from virulence determinants to clinical manifestations and treatment.

Bacterial capsule and respiratory tract

In order to cause disease, an organism must successfully colonise the host, multiply, resist attack from innate and acquired immune responses, and invade. Capsular polysaccharides are repeating oligosaccharides assembled in the cytoplasm and transported external to the cell wall by cell membrane transferases where they are bound to cell wall polysaccharide and peptidoglycan1. Capsule has a primary role in the evasion of phagocytosis by the organism. Possible mechanisms are: (i) lack of phagocyte receptors to the oligosaccharide components; (ii) shielding of cell wall components as well as cell wall bound C3b from antibodies; and (iii) electrochemical repulsion forces1.

All capsulate respiratory pathogens share common features. They are all host-adapted to the human, enjoy commensal status in either the upper respiratory or gastrointestinal tract, and antibody to their specific capsular polysaccharides is protective against invasive disease.

Many capsular polysaccharides are poorly immunogenic, and immune responses to them demonstrate age-related patterns. Children under 2 years frequently fail to demonstrate a specific antibody response following invasive infection with capsulate bacteria. This is attributed to their immature T-cell independent immune responses. Such a response does not induce immunologic memory, even at older ages. This developmental disadvantage has been overcome with the advent of protein–polysaccharide conjugate vaccines, such as the H. influenzae type b (Hib) conjugate vaccines. By covalently linking capsular polysaccharide antigens with an immunogenic protein, the protein is also processed by antigen processing cells and is presented as a peptide in conjunction with MHC class II receptors, enabling T-cell help for the B-lymphocytes recognising the polysaccharide antigen epitopes (Fig. 1). This has been shown to elicit strong responses to the capsular polysaccharide and induce memory, even in infants2.

Fig 1.

How protein–polysaccharide conjugate vaccines work. The protein antigen covalently bound to the polysaccharide antigen of interest, enables T-cell help to be recruited. This allows even very young children to mount strong immune responses and develop immunologic memory to the polysaccharide antigen. Figure courtesy of Dr Jodie McVernon.

Fig 1.

How protein–polysaccharide conjugate vaccines work. The protein antigen covalently bound to the polysaccharide antigen of interest, enables T-cell help to be recruited. This allows even very young children to mount strong immune responses and develop immunologic memory to the polysaccharide antigen. Figure courtesy of Dr Jodie McVernon.

Clinical overview

In the first 5 years of life in non-industrialised countries, there are 0.2–4 episodes per child of pneumonia each year. This equates to between 110 million to 2.2 billion episodes each year world-wide.

Community-acquired pneumonia is a common disorder in both industrialised and non-industrialised countries. With an estimated UK incidence of 12 cases per 1000 population each year, treatment costs are estimated at over £440 million annually, with the vast majority spent upon the 32% requiring hospital admission3.

Establishing the aetiology of lower respiratory tract infection (LRTI) is clouded by diagnostic difficulties. The majority of LRTIs are not bacteraemic, and upper respiratory samples have a poor predictive value in determining LRTI aetiology. Even in bacteraemic pneumonia, the sensitivity of sputum culture is only 40–50%4. Sputum microscopy and culture is hampered by difficulty in obtaining specimens that are not significantly contaminated by upper respiratory flora. LRT sampling by per-bronchial or trans-thoracic routes is rarely performed, and may yield more than one potential pathogen in a particular sample5. ‘Vaccine-probe’ studies are being used increasingly to help determine the respiratory disease attributable to a pathogen. These studies use a vaccine known to be efficacious against other invasive disease. In a controlled trial, predefined respiratory, clinical, and radiographic outcomes are compared between treatment arms. This technique has greatly enhanced understanding of the impact of Hib pneumonia6,7.

The involvement of encapsulated organisms in other LRTIs remains less clear, including acute bronchitis, and exacerbations of chronic obstructive airway disease.

Group B streptococci – Streptococcus agalactiae

Group B streptococci are facultative, Gram-positive diplococci that produce a narrow zone of β-haemolysis on blood agar. The designation of group B is based upon specific cell wall C substance antigens reacting to hyperimmune serum under the Lancefield grouping. S. agalactiae is the species all group B strains belong to, they are subdivided into serotypes I–VIII based upon capsular polysaccharide, and further divided based upon surface proteins. Group B streptococci are the most common cause of neonatal pneumonia in industrialised countries.

The lower gastrointestinal tract is the reservoir for Group B streptococci, with colonisation rates of 5–40% reported from genital or rectal samples in women. Bacteriuria is a sign of heavy colonisation, and may occur asymptomatically in pregnancy8. Maternal genital colonisation is associated with: age less than 20 years; lower socio-economic status; high frequency of sexual intercourse or number of partners; primigravidas; intra-uterine birth control devices; and diabetes mellitus.

The transmission rate from colonised women to the new-born is roughly 50%, and is proportional to the density of maternal colonisation8. Factors associated with increased invasive early-onset perinatal disease include: rupture of amniotic membranes for greater than 18 h prior to delivery; maternal chorio-amnionitis or fever; rupture of membranes under 37 weeks’ gestation; and maternal bacteriuria9. Early onset disease (within the first 7 days of life) is associated with serotypes 1a, III and V, while serotype III causes most late onset disease.

Rates of invasive early onset neonatal disease vary between industrialised countries from 1.15 per 1000 live births in the UK, 0.76 per 1000 live births in Finland up to 3 per 1000 births in some US centres10,11. Only 3% of early onset disease presents as pneumonia. Group B streptococci are important causes of sepsis in pregnant women, and a recognised cause of pneumonia in elderly, non-pregnant adults with underlying liver disease, diabetes mellitus or malignancy12. Late onset disease, presenting up to 3 months, rarely presents as pneumonia.

Pathophysiology

Maternal antibody to type III capsular polysaccharide is protective against early onset type III neonatal disease, and protective roles have also been demonstrated for antibodies to type Ia, Ib and II capsular polysaccharides. Both classical and alternative complement pathways are involved in opsonophagocytosis of group B streptococci, with blockade of Fc neutrophil and complement receptors inhibiting phagocytosis8,13.

Clinical manifestations

New-borns with group B streptococcal pneumonia manifest respiratory distress immediately after delivery or within a few hours of birth, with cyanosis, tachypnoea, apnoea and grunting. Chest films may reveal pulmonary infiltrates, or be consistent with the appearance of hyaline membrane disease. General neonatal signs of sepsis are often present, with temperature instability, poor feeding, lethargy, jaundice and pallor. Late onset disease may infrequently present with empyema, as part of a bacteraemic illness.

Differential diagnosis

The principal difficulty in early onset differentiating group B streptococcal sepsis in new-borns is with hyaline membrane disease. Respiratory distress combined with features of sepsis may also be due to other early onset pathogens such as E. coli and Strep. pneumoniae. Late onset disease often presents non-specifically, and needs to be differentiated from Gram-negative sepsis and nosocomial pathogens.

Treatment

Prevention

The identification of ‘high-risk’ pregnancies by bacteriological screening or clinical risk factors has formed the backbone of antibiotic chemoprophylaxis approaches. Intrapartum treatment with intravenous antibiotics (usually ampicillin or penicillin G) reduces the risk of sepsis in new-borns born to colonised mothers14,15. Oral therapy has a high failure rate in eradicating colonisation from women. Screening all women at 35–37 weeks' gestation, with subsequent intrapartum prophylaxis, involves therapy for 20–25% of women, but prevents an estimated 95% of new-born group B streptococcal disease. Treatment based upon clinical risk factors as described previously as well as prior babies with group B streptococcal sepsis involves treating 15–25% of women, and prevents an estimated 60–90% of sepsis. Healthy infants born to known colonised women who have not received at least 2 doses of preventive treatment are cultured and observed carefully in the first 48 h of life14,15.

Vaccines

Type-specific, capsular polysaccharide vaccines are immunogenic in adults with pre-existing immunity, but do not reliably induce antibody in naïve subjects. Antibodies produced by these vaccines cross the placenta and are protective in animal models of neonatal group B streptococcal sepsis. Polysaccharide–protein conjugate vaccines have been developed to increase the immunogenicity in naïve recipients. Human trials have been reported in monovalent serotype II and III vaccines, demonstrating improved immunogenicity and good safety profiles in non-pregnant women16. Multivalent vaccines are under development for maternal vaccination to protect new-borns by transplacentally acquired maternal antibody.

Therapy

Group B streptococci are sensitive to β-lactam antibiotics. Treatment is recommended with ampicillin or penicillin for 10 days for lower respiratory infection. In new-borns, aminoglycosides are used for synergistic effect until meningitis can be excluded. Carbapenems and glycopeptides are active in vitro. Clindamycin and erythromycin are also active in vitro, but 3–15% of isolates are resistant8.

Pneumococcus – Streptococcus pneumoniae

Strep. pneumoniae is an encapsulated, lanceolate Gram-positive diplococcus that is the leading cause of bacterial pneumonia throughout life, with the exception of the neonatal period in industrialised countries3,4. Catalase negative, the organism produces pneumolysin, which breaks down haemoglobin, resulting in a green zone (termed α-haemolysis) surrounding the organism when grown upon blood agar.

Epidemiology

Carriage

Strep. pneumoniae is carried intermittently in the nasopharynx by healthy individuals throughout life. Carriage rates peak in early childhood, with 20–40% of healthy children growing Strep. pneumoniae at any one time. Up to 60% in children in out-of-home day care, and 5–10% of adults yield Strep. pneumoniae from their nasopharynx1,17. In UK infants, 40% have had an episode of carriage by 3 months of age, and 99% by 2 years. The presence of siblings, and attendance of day care is associated with increased risk of carriage. Risk factors for increased colonisation in early infancy in Southern India include female gender, household cigarette consumption over 20 per day, decreased maternal schooling and being fed colostrum. By 6 months of age, these factors were no longer significant18.

Invasive pneumococcal disease

As illustrated in Figure 2, invasive Strep. pneumoniae disease peaks at either end of life, with high levels of invasive disease before 5 years and after 65 years of age. UK reported rates of invasive Strep. pneumoniae disease peak at 48.1 per 105 population less than 1 year of age, and 36.2 cases per 105 in adults over 65 years. Overall incidence is 6.6–9.6 cases per 105 population19. Pneumonia represents 19% of invasive disease reports in children less than 5 years20. Reported rates of invasive Strep. pneumoniae disease are much lower in UK and Europe than the US, although they follow a similar age pattern. This may represent real differences or simply differing practices in how and whether blood cultures are performed17,19,21. Similarly, reported rates are dependant upon surveillance mechanisms in place and diagnostic practices used19,22,23. Enhanced surveillance in Oxfordshire since 1995 has documented higher rates than national figures19.

Fig 2.

Age specific incidence of invasive pneumococcal disease in the Oxford region 1995–1999. Reproduced with permission from Sleeman et al19.

Fig 2.

Age specific incidence of invasive pneumococcal disease in the Oxford region 1995–1999. Reproduced with permission from Sleeman et al19.

Groups at increased risk of invasive Strep. pneumoniae infection include people with humoral immune defects, patients with sickle cell disease, HIV infected children and adults, specific populations of children including children of Native American descent, Alaskan Natives and Aboriginal Australians17. Out-of-home child-care is associated with increased risk of pneumococcal disease17. In the US, blacks have an incidence 2.6 times that of whites24.

Serotype distribution and antibiotic resistance

Based upon serological reactions to distinct capsular polysaccharide antigens, Strep. pneumoniae is classified into serogroups, then further into at least 90 known serotypes . The most common serotypes isolated in the Oxford region surveillance were: 14, 1, 9V, 23F, 19F, 19A, 3, 4, 18C, 8, and 6A19.

In the last 3 decades, penicillin resistance in Strep. pneumoniae has become a clinical problem world-wide. Resistance occurs due to an alteration in penicillin binding proteins, reducing the ability of penicillin to bind to Strep. pneumoniae cell wall components. This leads to some degree of cross-resistance to other β-lactam antibiotics25. Minimum inhibitory concentrations (MIC) of 0.1–1.0 μg/ml of penicillin denote intermediate resistance, with high level resistance showing MICs of > 1 μg/ml. Penicillin resistance may be associated with resistance to erythromycin and other antibiotics, including third generation cephalosporins. Penicillin non-susceptibility rates have been reported as high as 40% in South Africa and 65% in Spain1,26. Although rising in recent years, UK levels have remained lower, with 8.9% of isolates non-susceptible in 1997, with erythromycin resistance higher at 13.7%19. Antibiotic resistance is not evenly spread among Strep. pneumoniae serotypes, with most common disease-causing serotypes more frequently non-susceptible. In children, invasive disease with non-susceptible Strep. pneumoniae is associated with day-care attendance, recent antibiotic use and recent ear infection. Community-acquired LRTI isolates have the same frequency of resistance as blood isolates, although hospital-acquired isolates are more often non-susceptible25.

Community-acquired pneumonia

Strep. pneumoniae causes between 15–48% of community-acquired pneumonia (CAP) admitted to hospital3,23,27. It is implicated in two-thirds of bacteraemic pneumonia and fatal pneumonias4. However, in 25–60% of cases, no cause is found for CAP4,27. A recent prospective survey of 267 adults admitted to Nottingham City Hospital with CAP attributed 129 (48%) cases to Strep. pneumoniae27. In patients with negative blood and sputum cultures, transthoracic lung biopsies, antigen testing of urine and polymerase chain reaction detection of Strep. pneumoniae DNA in blood have increased the proportion attributable to Strep. pneumoniae22,23,27. Strep. pneumoniae accounts for 5–10% of empyema overall, but 18% in children4,17.

Chronic obstructive pulmonary disease

Strep. pneumoniae has been grown from the sputum of 7–26% of patients with exacerbations of chronic obstructive pulmonary disease, although its aetiological role remains uncertain28.

Pathophysiology

Nasopharyngeal colonisation represents the first step in invasive Strep. pneumoniae infection. Identified virulence factors of Strep. pneumoniae, together with their role in pathogenesis, are listed in Table 1. Although Strep. pneumoniae pneumonia patients at presentation have similar levels of antibody directed at capsular polysaccharide to healthy controls, their functional ability to opsonize Strep. pneumoniae for phagocytosis is impaired, suggesting poor functional antibody29. The time from colonisation to disease is unknown, and may vary significantly. Local host factors predisposing to disease include impairment of normal respiratory defences, particularly ciliary action and clearance of secretions. This may occur due to obstruction from allergy or co-existing viral infection, or damage to ciliated epithelial cells (e.g. from cigarette smoking or acute viral infection) and increased secretions. Recent influenza-like illness significantly predisposes children to severe Strep. pneumoniae pneumonia, with positive serology to influenza A and family members with a history of influenza-like symptoms also found more frequently in cases than controls30.

Table 1.

Virulence factors of Streptococcus pneumoniae

Virulence factor Site Role Antibodies protective? 
Capsular polysaccharide External to cell wall Prevents phagocytosis, conceal complement binding sites, electrochemical repulsion +++ 
Teichoic acid Cell wall Induce inflammation  
Peptidoglycan Cell wall Induce inflammation  
PspA Cell wall Binds lactoferrin, ?cleaves secretory IgA 
PsaA Cell wall Attachment to type II pneumocytes 
Pneumolysin Cytoplasm-secreted Cytotoxic, activates complement 
Autolysin  Bacterial disintegration  
Neuraminidase Cell wall ?adherence  
CbdA Cell wall surface Adhesin – binds choline  
Virulence factor Site Role Antibodies protective? 
Capsular polysaccharide External to cell wall Prevents phagocytosis, conceal complement binding sites, electrochemical repulsion +++ 
Teichoic acid Cell wall Induce inflammation  
Peptidoglycan Cell wall Induce inflammation  
PspA Cell wall Binds lactoferrin, ?cleaves secretory IgA 
PsaA Cell wall Attachment to type II pneumocytes 
Pneumolysin Cytoplasm-secreted Cytotoxic, activates complement 
Autolysin  Bacterial disintegration  
Neuraminidase Cell wall ?adherence  
CbdA Cell wall surface Adhesin – binds choline  

Known Strep. pneumoniae virulence factors, their likely roles, and whether antibodies directed at them provide protection from invasive disease in animal or human models. From Musher1 and Sethi et al28.

Clinical features

The classical presentation with Strep. pneumoniae pneumonia is with fever, cough, sputum production (in older children and adults), dyspnoea and pleuritic chest pain. Fever is found in 80%, crackles are heard on auscultation in 80%, and signs of consolidation are present in 30%. Elderly patients report fewer symptoms than younger adults3. In children, crackles are often not heard, particularly in the setting of dehydration31.

Investigations

The majority of community acquired pneumonia (CAP) does not present to hospital, and is managed in primary care. For CAP presenting to hospital, the following investigations are recommended as standard:

  • • Blood cultures – 11% of blood cultures are positive in both adults and children presenting with CAP; two-thirds of these grow Strep. pneumoniae4

  • • Sputum cultures – in older children and adults well enough to produce sputum. Due to difficulty in obtaining properly collected sputum, sputum in adult studies has a sensitivity and specificity of only 40–50% in bacteraemic Strep. pneumoniae pneumonia4

  • • Chest radiography – to confirm diagnosis of pneumonia, and detect complications including effusions and empyemas

Additional tests that may be performed for Strep. pneumoniae pneumonia include: bronchoscopy using quantitative culture of aspirates or protected brush catheter specimens; percutaneous lung needle aspiration which has reported yields of 40–80%; and transtracheal aspiration.

Management

The mainstay of pneumonia therapy due to Strep. pneumoniae remains β-lactam antibiotics. Benzyl penicillin (15–30 mg/kg per dose up to 1 g given 4–6 hourly) is indicated as empirical therapy in the UK, even for penicillin intermediate resistant Strep. pneumoniae. Treatment failure of pneumonia, even in the context of highly resistant Strep. pneumoniae, is rare31. However, third generation cephalosporins (ceftriaxone or cefotaxime) are recommended for highly resistant Strep. pneumoniae. Alternative empirical choices for patients with penicillin hypersensitivity include macrolides (e.g. clindamycin), doxicycline, or a fluoroquinolone with enhanced activity against Strep. pneumoniae. Appropriate fluoroquinolones include levofloxacin, sparfloxacin and grepafloxacin, but none are licensed for use in children. Vancomycin may also be used for resistant organisms. Clinical failure has been reported with ciprofloxacin, which is less active in vitro. For penicillin non-susceptible isolates, therapy should always be guided by antibiotic sensitivity data. Macrolide resistance in UK Strep. pneumoniae isolates had risen to 13% by 199819. Trimethoprim-sulphamethoxazole resistance has also been described, with reported levels in the US of 15–20% of all Strep. pneumoniae. Doxicycline or clindamycin resistance has only occasionally been reported.

Initiation of therapy should occur as soon as possible. Delay in commencement of antibiotic therapy in hospital has been associated with increased mortality4. Duration of therapy is less clear, with scant controlled clinical trial data identified. For an uncomplicated Strep. pneumoniae pneumonia, therapy may be given orally once the patient is clinically improving, and is haemodynamically stable with a functioning gastrointestinal tract. Therapy should be continued until the patient has been afebrile for at least 3 days.

Vaccines

The 23-valent polysaccharide vaccine is the mainstay of preventative strategies in adults, containing serotypes covering 89% of invasive strains seen in UK adults. The efficacy of this vaccine remains controversial, despite over 30 years of use. It has been shown efficacious in preventing disease in a variety of case control studies and randomised controlled trials in Papua New Guinean natives and South African miners. Meta-analyses of randomised controlled trials have found no efficacy for the prevention of pneumonia in high-risk patients and the elderly32. Recommendations for the use of this vaccine in the UK include: patients from high-risk groups over 2 years of age: splenic dysfunction including sickle cell disease; chronic heart, renal, liver or lung disease; diabetes mellitus and immunodeficiency33.

A 7-valent polysaccharide–protein conjugate vaccine has recently been licensed in the UK, Europe and the US after trials showed it to be effective in preventing invasive disease (bacteraemia or meningitis), pneumococcal pneumonia and otitis media. Trial data from 34,000 Californian infants showed a reduction in X-ray confirmed pneumonia of 33%, and 73% reduction in pneumonia associated with consolidation of ≥ 2.5 cm, compared to controls31. If cross-serotype protection for types 6A and 19A occurs, this vaccine covers 75–79% of invasive isolates causing invasive disease in UK children, and 63.5% of carried serotypes19.

This vaccine has been incorporated into the recommended US infant immunisation schedule. It reduces carriage due to serotypes contained in the vaccine, with increased risk of carriage due to non-vaccine serotypes reported, termed ‘serotype replacement’34. Serotype replacement has been shown to occur in otitis media isolates, but not for bacteraemia35.

Haemophilus influenzae type b (Hib)

Hib is a small, non-motile, pleomorphic, Gram-negative coccobacillus that infects only humans. Its genus name Haemophilus (blood loving) derives from its requirement for growth factors present in blood. The species name influenzae originates from the erroneous belief at the time of its original description in 1892, that it was responsible for epidemic influenza.

H. influenzae strains are typed according to their polysaccharide capsular status. Non-encapsulated strains are termed ‘non-typeable’, with typeable species belonging to six antigenically distinct types, a–f (Pittman types). Most unencapsulated strains are genetically unrelated to capsulate strains, which are frequently clonal. Type b capsule is composed of repeating subunits of polyribosylribitol phosphate (PRP).

Epidemiology

Most respiratory disease attributed to H. influenzae is due to non-encapsulated strains, which have been associated with both upper and lower respiratory tract infections. These include otitis media, sinusitis, pneumonia and exacerbations of COPD28,36. The burden of this disease in both non-industrialised and industrialised countries is substantial. The overwhelming majority of disease from encapsulated strains is due to Hib. In addition to causing septicaemia, meningitis, and joint infection, the understanding of the role of Hib in causing pneumonia as well as epiglottitis has been aided by assessing the impact of Hib conjugate vaccines.

Non-typeable strains are carried in the upper respiratory tract in 30–80% of the population. Hib is an infrequent coloniser of the nasopharynx, being carried in 2–4% of children prior to the introduction of the Hib vaccine37. Higher carriage rates have been documented in non-industrialised countries7. Spread occurs by direct contact with respiratory secretions or by aerolised droplets.

The principal risk group for invasive Hib disease is children under 6 years. Meningitis affects children usually less than 2 years, while epiglottitis is primarily seen between 2–7 years. Approximately 10–15% of Hib disease occurs in adults. Due to difficulty in diagnosis of non-bacteraemic pneumonia, less is known regarding the epidemiology of Hib pneumonia5. Annual estimated incidence in industrialised countries (prevaccine) was 6 per 105, while non-industrialised countries have an estimated incidence of 300 per 105. The world-wide burden of Hib pneumonia is estimated at 1.7 billion cases each year, causing up to 400,000 deaths. Rates as high as 3% of children each year aged 0–4 years with culture-proven pneumonia have been documented in Papua New Guinea38. Reported incidences vary considerably between studies, depending upon the populations being studied and the diagnostic methods used.

Hib appears responsible for 12–75% of pneumonia cases due to H. influenzae. In Europe, prior to the introduction of Hib vaccine, the rate of Hib meningitis was 23 per 100,000 per annum for children aged 0–4 years. Rates in the US were approximately double. Many other countries in the Americas, Oceania and Asia have reported rates in between these figures. Extremely high rates over 200 per 105 per annum have been described in Alaskan Eskimo, Native American, Australian Aborigine and black American populations, but not in Africa. Lower incidences have been reported in some, but not all, South East Asian populations38.

Evidence for aetiology

Most Hib pneumonia is non-bacteraemic. This is based upon studies using percutaneous lung aspiration and upon ‘vaccine probe’ studies. Vaccine studies in The Gambia and Chile have demonstrated that 21% and 22%, respectively, of radiologically confirmed consolidative pneumonia was due to Hib in children less than 3 years7. Hib does not appear to have a significant role in either the colonisation of the lungs of patients with COPD, or its exacerbations. In lung aspiration studies in non-industrialised countries, Hib has been found co-existing with other potential pathogens5. In China, children admitted with pneumonia have higher rates of Hib carriage than control children, after adjustment for carriage risk factors39.

Pathophysiology

Colonisation by Hib of the upper respiratory tract appears to occur in mucus-rich areas containing non-ciliated epithelium. It is unclear whether carriage increases the risk of invasive disease or decreases it by allowing protective immune responses to develop37. In animal rat models after intranasal inoculation, invasion into the bloodstream can occur within minutes. There are a number of virulence factors associated with adhesion to epithelial cells and mucus, including fimbriae, outer membrane proteins, surface fibrils and lipopolysaccharide. Capsular polysaccharide PRP is thought to help the organism evade phagocytosis, and is the primary virulence determinant37. Anti-PRP antibodies administered passively increase phagocytosis of Hib in CSF of meningitis patients. Immunity to Hib has been associated with anti-PRP levels of greater than 0.15 μg/ml, although bactericidal activity has also been shown in adults without detectable anti-PRP antibody.

Clinical features

The specific clinical picture of Hib pneumonia is complicated by the difficulty in diagnosing causes of non-bacteraemic pneumonia. Classically, children aged 4 months to 4 years present with alveolar consolidation, with pleural involvement common. The onset may be more insidious than that seen with Strep. pneumoniae or Staphylococcus aureus. Frequently, there are other clinical foci of infection and pericarditis is an uncommon, but well recognised, complication.

Treatment

Hib frequently produces β-lactamases, decreasing its susceptibility to penicillins without the use of additional β-lactamase inhibitors, such as amoxicillin/clavulanic acid. Second generation cephalosporins, such as cefuroxime, and third generation cephalosporins are active against Hib. Macrolides have reduced activity against H. influenzae, with azithromycin having the most in vitro activity. All quinolones in use for pulmonary infections (including ciprofloxacin, ofloxacin and sparfloxacin) have activity against Hib.

Vaccines

A capsular PRP plain polysaccharide vaccine was introduced in the 1970s. It achieved efficacy against invasive disease of 90% in children over 18 months, but was not efficacious in younger children. Like other plain polysaccharide vaccines, it did not induce immunologic memory or impact upon nasopharyngeal carriage. Protein–polysaccharide conjugate Hib vaccines were developed in the late 1980s, and showed efficacy of over 90% in early studies, apart from in the Inuit population in Alaska. These vaccines used PRP, covalently linked to various carrier proteins based upon diphtheria toxoid, mutant diphtheria toxins, meningococcal outer membrane protein or tetanus toxoid. Hib conjugate vaccine was introduced into the UK schedule in 1993 with doses at 2, 3 and 4 months. Initial studies showed high efficacy of 95% (95% CI 74, 100), with subsequent high efficacy continuing up to 6 years of age (Fig. 3)40. The vaccine reduces nasopharyngeal Hib carriage, increasing the herd protective effect37. As shown in ‘vaccine probe’ studies, it reduces all Hib invasive disease, including pneumonia6,38.

Fig 3.

Invasive Hib disease in England and Wales prior to and after Hib vaccine introduction. Reproduced from Buttery et al2 with permission.

Fig 3.

Invasive Hib disease in England and Wales prior to and after Hib vaccine introduction. Reproduced from Buttery et al2 with permission.

Neisseria meningitidis

N. meningitidis, a Gram-negative diplococcus, is an infrequent cause of community-acquired pneumonia. It causes invasive disease in both non-industrialised and industrialised countries, with the majority of disease presenting as septic shock and/or meningitis. There are 13 serogroups based upon serological reactions with the capsular polysaccharide, with 5 serogroups (A, B, C, W135 and Y) causing the majority of disease. In the UK, approximately 60% of disease is due to serogroup B, with most of the remainder due to serogroup C. There are two peaks of infection, the largest under 2 years of age and a secondary peak in adolescence. Sporadic disease continues at much lower rates throughout life. Seasonally, disease peaks each winter. In epidemic regions, particularly sub-Saharan Africa, there are epidemic of disease in 4 yearly cycles, with attack rates as high as 500 per 105 population.

Like Hib and Strep. pneumoniae, N. meningitidis colonises the nasopharynx prior to invasion. Carriage of N. meningitidis peaks in adolescence and young adults, with up to 25% carrying asymptomatically at any one time. Adhesion to epithelial cells involves pili and outer membrane proteins, Opa and Opc2. Capsule is involved in the evasion of complement fixation and subsequent phagocytosis. Lipopolysaccharide (endotoxin) stimulates release of inflammatory mediators, including TNF-α, IL-1β, IL-6 and IL-8, and has a crucial role in the pathogenesis of meningococcal septic shock2.

The role of N. meningitidis in community-acquired pneumonia aetiology has been documented in North American and other European studies, particularly in adults over 50 years of age27,41,42. It has also been described in outbreaks involving military recruits4,43. In one military serogroup Y outbreak of 68 cases, it was associated with pharyngitis in over 80%, with fever and wheeze a common feature. A history of cough, chest pains, chills and previous upper respiratory tract infection occurred in more than half the cases. Disease most frequently involved the right middle or lower lobes, with multilobar involvement in 40%. N. meningitidis may also cause a purulent tracheobronchitis43. The mortality of meningococcal respiratory disease is not known, although invasive disease per se carries an overall mortality of 8–10%.

Treatment

Most N. meningitidis strains are sensitive to penicillin, although insensitive strains have been reported in the UK. Parenteral penicillin is recommended for the community treatment by primary care practitioners of suspected invasive meningococcal disease, prior to transfer to hospital. The recommended first line hospital therapy for invasive N. meningitidis disease is third generation cephalosporins. If antibiotic susceptibility to penicillin is confirmed, penicillin may be substituted.

Vaccines

A plain polysaccharide tetravalent vaccine, containing capsular polysaccharide of serogroups A, C, W135 and Y has been licensed for over 30 years. It has been demonstrated to be efficacious in the prevention of invasive N. meningitidis disease in the setting of an outbreak. Like other polysaccharide vaccines, it is poorly immunogenic in children less than 2 years of age (with the exception of serogroup A). In November 1999, a conjugate group C meningococcal vaccine was introduced into the UK immunisation schedule, with a catch-up programme targeting all children up to 18 years. In the groups first targeted, high short-term efficacy of 97% (95% CI 77–99) for teenagers and 92% (95% CI 65–98) for infants has been documented44.

Correspondence to: Dr Jim Buttery, Oxford Vaccine Group, University Department of Paediatrics, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK Email: butterj@cryptic.rch.unimelb.edu.aujim.buttery@paediatrics.ox.ac.uk

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