Elsevier

The Lancet

Volume 374, Issue 9700, 31 October–6 November 2009, Pages 1543-1556
The Lancet

Seminar
Pathogenesis, treatment, and prevention of pneumococcal pneumonia

https://doi.org/10.1016/S0140-6736(09)61114-4Get rights and content

Summary

Pneumococcus remains the most common cause of community-acquired pneumonia worldwide. Streptococcus pneumoniae is well adapted to people, and is a frequent inhabitant of the upper airways in healthy hosts. This seemingly innocuous state of colonisation is a dynamic and competitive process in which the pathogen attempts to engage the host, proliferate, and invade the lower airways. The host in turn continuously deploys an array of innate and acquired cellular and humoral defences to prevent pneumococci from breaching tissue barriers. Discoveries into essential molecular mechanisms used by pneumococci to evade host-sensing systems that are designed to contain the pathogen provide new insights into potential treatment options. Versatility of the genome of pneumococci and the bacteria's polygenic virulence capabilities show that a multifaceted approach with many vaccine antigens, antibiotic combinations, and immunoadjuvant therapies will be needed to control this microbe.

Introduction

Nearly a century ago, Sir William Osler proclaimed Streptococcus pneumoniae (or pneumococcus) as “the captain of all the men of death”.1 This statement remains as true today as it was then. Severe community-acquired pneumonia is the most common cause of death from infection in developed countries, and the pneumococcus is the most frequent cause of lower respiratory tract infection. We can now control many other respiratory pathogens of man reasonably well (eg, influenza, pertussis, tuberculosis, and Haemophilus influenzae), yet pneumococcus remains the main cause of community-acquired pneumonia worldwide.1

Reasons for the success of this obligate human pathogen are becoming increasingly apparent as the basic pathogenic mechanisms of pneumococcal pneumonia are discovered. This pathogen causes at least 1·2 million infant deaths every year worldwide.2, 3 The yearly death toll attributable to pneumococci in patients with AIDS and other immunocompromised states, elderly people, and those with comorbid illnesses is difficult to quantify, but probably exceeds the infant mortality rate.

Advances in comparative genomics and insights into innate and acquired immune-signalling mechanisms could provide new treatment options for pneumococcal disease.2, 3, 4, 5, 6, 7, 8 We focus on the clinical outcomes after the initial host–pathogen interaction when S pneumoniae first reaches the airways and invades the lower respiratory tract.

Section snippets

Epidemiology

S pneumoniae is a common inhabitant of the upper respiratory tract, existing mainly as a commensal bacterium along with other co-resident microorganisms identified on the respiratory epithelium. After colonisation by one of 91 presently recognised serotypes, a new strain eliminates other competing pneumococcal serotypes, and persists for weeks (in adults) or months (in children), usually without any adverse sequelae. This carrier state maintains the organism within human populations, and

Genetics and virulence of S pneumoniae

Knowledge of genomes of many invasive and non-invasive strains of S pneumoniae enable detailed comparative analyses.23, 24, 25, 26, 27, 28, 29 The pneumococcal genome has between 2 million and 2·1 million basepairs, dependent on strain virulence (figure 2). It is a covalently closed, circular DNA structure often accompanied by small cryptic plasmids. The guanine–cytosine content of S pneumoniae DNA (39·7%) is lower than that of many other bacterial pathogens. One of the original pneumococcal

Pneumococcal virulence factors

Table 1 shows a summary of virulence traits identified in pneumococci.38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 An array of virulence factors needs to be expressed in a coordinated way for tissue invasion to be successful (phenotype for invasive pneumococcal disease). The most important virulence determinants include the antiphagocytic and adherence properties of capsular polysaccharides, adherence factors, invasion genes, iron and other heavy-metal transporters, oxidative stress

Mechanisms of host recognition

Pattern-recognition receptors are key components of the innate immune system.50, 51 They recognise conserved motifs expressed by pathogens that are referred to as pathogen-associated molecular patterns. Several of these receptors contribute to initiation of an effective, innate immune response to the pneumococcus (figure 4). C-reactive protein, an acute-phase protein, functions as a pattern-recognition receptor for S pneumoniae. It binds phosphorylcholine in the pneumococcal cell wall and

Immunology

Respiratory epithelial cells not only provide the mucociliary carpet to continually remove potential pathogens from the lower airways, but also actively respond to the presence of pathogens. Respiratory epithelium releases various mediators such as cytokines, chemokines, and antimicrobial peptides (eg, lysozyme, defensins, and cathelicidins), contributing to innate immunity against pneumococci.78 Transgenic mice that overexpress nuclear factor inhibitor κB-α (IκB-α) and block nuclear factor κB

Clinical features

Pneumococcal pneumonia usually presents as typical, acute community-acquired pneumonia. It generally begins with a mild upper-airway irritation attributable to a respiratory viral infection. When pneumococci are deposited into the lower airways they are usually expelled by mucociliary clearance, cough, antimicrobial peptides, and local innate immune defences. Should these systems fail to eliminate the pathogen, systemic inflammation ensues with characteristic signs and symptoms of bacterial

Diagnosis

Diagnostic methods for pneumococcal pneumonia have not changed appreciably since Pasteur and Sternberg first isolated S pneumoniae in 1881, and Christian Gram used his famous stain to reveal pneumococci under the microscope in 1886 (figure 7). Pneumococci grow readily on blood agar plates in a CO2 incubator at 37°C. S pneumoniae colonies are α haemolytic and often umbilicate because of autolysis. Cultures from sputum, blood, and other tissue sites should be obtained before empirical antibiotic

Treatment

The initial, uniform activity of penicillin against S pneumoniae resulted in this antibiotic being treatment of choice for community-acquired pneumonia since the late 1940s.1 Penicillin-resistant strains of S pneumoniae were first noted in the mid 1970s and resistant clones have now spread worldwide.1, 118, 126 Penicillin resistance is related to structurally modified penicillin-binding proteins of S pneumoniae. These modified binding proteins allow peptidoglycan synthesis despite the presence

Vaccine strategies

Prevalence and intrinsic virulence of pneumococci, and progressive resistance to antimicrobial agents has rekindled an interest in improved vaccines against S pneumoniae. Two vaccine formulations are available to prevent pneumococcal infection. The polysaccharide vaccine consists of the 23 most common capsular serotypes that cause invasive pneumococcal disease in the developed world.1, 3, 5 This vaccine induces T-cell-independent B-cell responses and is in widespread use.118 Its effectiveness

Conclusions

The pneumococcus fascinates immunologists, yet frustrates clinicians and public-health officials attempting to control it. Although the human respiratory tract has many local and systemic immune defences, a range of pneumococcal virulence factors work together to cause invasive disease. The capacity of S pneumoniae to resist antimicrobial agents and escape immune defences shows that control of this pathogen will not be easy to achieve. Thus a multifaceted approach with new generation vaccines,

Search strategy and selection criteria

We searched Medline and PubMed in English with the search terms “pneumococci”, “Streptococcus pneumoniae”, “pneumococcal pneumonia”, “community acquired pneumonia”, and “pneumococcal pathogenesis” for reports relating to pneumococcal pneumonia published in the past 10 years until January, 2009. We reviewed the publications and searched the reference lists of identified articles for older reports we judged to be of major importance.

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