Pneumococcal infections
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pneumococcal infection refers to an infection caused by Streptococcus pneumoniae.
Types of infection caused
S. pneumoniae is responsible for 15-50% of all episodes of community acquired pneumonia, 30-50% of all cases of acute otitis media and a significant proportion of bacteremia and bacterial meningitis.[1] It kills at least one million children under the age of five every year: >70% of these deaths are in developing countries. This total is greater than that due to malaria, AIDS and measles combined.
Pathogenesis
S. pneumoniae is normally found in the nasopharynx of 5-10% of healthy adults, and 20-40% of healthy children.[2] It can be found in higher amounts in certain environments, especially those where people are spending a great deal of time in close proximity to each other (day care centers, military barracks). It attaches to nasopharyngeal cells through interaction of bacterial surface adhesins. This normal colonization can become infectious if the organisms are carried into areas such as the Eustachian tube or nasal sinuses where it can cause otitis media and sinusitis, respectively. Pneumonia occurs if the organisms are inhaled into the lungs and not cleared (again, viral infection, or smoking-induced ciliary paralysis might be contributing factors). The organism's polysaccharide capsule makes it resistant to phagocytosis, and if there is no pre-existing anticapsular antibody, alveolar macrophages cannot adequately kill the pneumococci. The organism spreads to the blood stream (where it can cause bacteremia) and is carried to the meninges, joint spaces, bones, and peritoneal cavity, and may result in meningitis, brain abscess, septic arthritis, or osteomyelitis.
S. pneumoniae has several virulence factors, including the polysaccharide capsule mentioned earlier, that help it evade a host's immune system. It has pneumococcal surface proteins that inhibit complement-mediated opsonization, and it secretes IgA1 protease that will destroy secretory IgA produced by the body and mediates its attachment to respiratory mucosa.
The risk of pneumococcal infection is much increased in persons with impaired IgG synthesis, impaired phagocytosis, or defective clearance of pneumococci. In particular, the absence of a functional spleen, through congenital asplenia, splenectomy, or sickle-cell disease predisposes one to a more severe course of infection (Overwhelming post-splenectomy infection) and prevention measures are indicated (see asplenia).
People whose immune system is compromised, such as those living with HIV, are also at higher risk of pneumococcal disease.[3] In HIV patients with access to treatment, the risk of invasive pneumoccal disease is 0.2%-1% per year and has a fatality rate of 8%.[3]
There is an association between pneumococcal pneumonia and influenza.[4] Damage to the lining of the airways (respiratory epithelium) caused by influenza may facilitate pneumococcal entry and infection.
Other risk factors include smoking, injection drug use, Hepatitis C, and COPD.[3]
Virulence factors
S. pneumoniae expresses different virulence factors on its cell surface and inside the organism. These virulence factors contribute to some of the clinical manifestations during infection with S. pneumoniae.
- Polysaccharide capsule - prevents phagocytosis by host immune cells by inhibiting C3b opsonization of the bacterial cells
- Pneumolysin (Ply) - a 53-kDa pore-forming protein that can cause lysis of host cells and activate complement
- Autolysin (LytA) - activation of this protein lyses the bacteria releasing its internal contents (i.e., pneumolysin)
- Hydrogen peroxide - causes damage to host cells (can cause apoptosis in neuronal cells during meningitis) and has bactericidal effects against competing bacteria (Haemophilus influenzae, Neisseria meningitidis, Staphylococcus aureus)[5][6]
- Pili - hair-like structures that extend from the surface of many strains of S. pneumoniae. They contribute to colonization of upper respiratory tract and increase the formation of large amounts of TNF by the immune system during sepsis, raising the possibility of septic shock[7]
- Choline binding protein A/Pneumococcal surface protein A (CbpA/PspA) -an adhesin that can interact with carbohydrates on the cell surface of pulmonary epithelial cells and can inhibit complement-mediated opsonization of pneumococci
Humoral immunity
In the 19th century, it was demonstrated that immunization of rabbits with killed pneumococci protected them against subsequent challenge with viable pneumococci. Serum from immunized rabbits or from humans who had recovered from pneumococcal pneumonia also conferred protection. In the 20th century, the efficacy of immunization was demonstrated in South African miners.
It was discovered that the pneumococcus's capsule made it resistant to phagocytosis, and in the 1920s it was shown that an antibody specific for capsular polysaccharide aided the killing of S. pneumoniae. In 1936, a pneumococcal capsular polysaccharide vaccine was used to abort an epidemic of pneumococcal pneumonia. In the 1940s, experiments on capsular transformation by pneumococci first identified DNA as the material that carries genetic information.
In 1900, it was recognized that different serovars of pneumococci exist, and that immunization with a given serovar did not protect against infection with other serovars. Since then over ninety serovars have been discovered, each with a unique polysaccharide capsule that can be identified by the quellung reaction. Because some of these serovars cause disease more commonly than others, it is possible to provide reasonable protection by immunizing with less than 90 serovars; the current vaccine contains 23 serovars (i.e., it is "23-valent").
The serovars are numbered according to two systems: the American system, which numbers them in the order in which they were discovered, and the Danish system, which groups them according to antigenic similarities.
Diagnosis
Depending on the nature of infection, an appropriate sample is collected for laboratory identification. Pneumococci are typically gram-positive, cocci, seen in pairs or chains. When cultured on blood agar plates with added optochin antibiotic disk, they show alpha-hemolytic colonies and a clear zone of inhibition around the disk meaning they're sensitive to the antibiotic. Pneumococci are also bile soluble. Just like other streptococci, they are catalase-negative. A Quellung test can identify specific capsular polysaccharides.[8]
Pneumococcal antigen (cell wall C polysaccharide) may be detected in various body fluids. Older detection kits, based on latex agglutination, added little value above Gram staining and were occasionally false-positive. Better results are achieved with rapid immunochromatography, which has a sensitivity (identifies the cause) of 70-80% and >90% specificity (when positive identifies the actual cause) in pneumococcal infections. The test was initially validated on urine samples, but has been applied successfully to other body fluids.[8] Chest X-rays can also be conducted to confirm an infection.
Treatment
Throughout history, treatment relied primarily on β-lactam antibiotics. In the 1960s, nearly all strains of S. pneumoniae were susceptible to penicillin, but, since that time, there has been an increasing prevalence of penicillin resistance, especially in areas of high antibiotic use. A varying proportion of strains may also be resistant to cephalosporins, macrolides (such as erythromycin), tetracycline, clindamycin and the quinolones. Penicillin-resistant strains are more likely to be resistant to other antibiotics. Most isolates remain susceptible to vancomycin, though its use in a β-lactam-susceptible isolate is less desirable because of tissue distribution of the drug and concerns of development of vancomycin resistance. More advanced beta-lactam antibiotics (cephalosporins) are commonly used in combination with other drugs to treat meningitis and community-acquired pneumonia. In adults, recently developed fluoroquinolones such as levofloxacin and moxifloxacin are often used to provide empiric coverage for patients with pneumonia, but, in parts of the world where these drugs are used to treat tuberculosis, resistance has been described.[9] Susceptibility testing should be routine, with empiric antibiotic treatment guided by resistance patterns in the community in which the organism was acquired, pending the results. There is currently debate as to how relevant the results of susceptibility testing are to clinical outcome.[10][11] There is slight clinical evidence that penicillins may act synergistically with macrolides to improve outcomes.[12]
Prevention
Vaccination in the USA
In the USA, a heptavalent pneumococcal conjugate vaccine vaccine (PCV 7) (e.g. Prevenar[13]) is recommended since 2000 for all children aged 2–23 months and for at-risk children aged 24–59 months. The normally 4-doses series is given at 2, 4, 6 & 12–14 months of age. Protection is good against deep pneumococcal infections (especially septicemia and meningitis). Similar 9- and 13-valent vaccines are being tested. Yet, if the child is exposed to a serotype of pneumococcus that is not contained in the vaccine, he/she is not afforded any protection. This limitation, and the ability of capsular-polysaccharide conjugate vaccines to promote the spread of non-covered serotypes, has led to research into vaccines that would provide species-wide protection.
Pneumococcal polysaccharide vaccine (Pneumovax is one brand) gives at least 85% protection in those under 55 years of age for five years or longer. Immunization is suggested for those at highest risk of infection, including those 65 years or older; generally the vaccine should be a single lifetime dose, as there is a high risk of side effects if repeated. The standard 23-valent vaccines are ineffective for children under two years old.
The current guidelines of the American College of Physicians call for administration of the immunization between ages 2 and 65 when indicated, or at age 65. If someone received the immunization before age 60, the guidelines call for a one-time revaccination.
Revaccination at periodic intervals is also indicated for those with other conditions such as asplenia or nephrotic syndrome.
Vaccination in the UK
It was announced in February 2006 that the UK government would introduce vaccination with the conjugate vaccine in children aged 2, 4 and 13 months.[14][15] This is expected to start on September 4, 2006 and is to include changes to the immunisation programme in general.[16]
Vaccination worldwide
Pneumococcal vaccines Accelerated Development and Introduction Plan (PnemoADIP) is a program to accelerate the evaluation and access to new pneumococcal vaccines in the developing world. PneumoADIP is funded by the Global Alliance for Vaccines and Immunization (GAVI). Thirty GAVI countries have expressed interest in participating by 2010. PneumoADIP aims to save 5.4 million children by 2030.[17]
Vaccine research
There is currently research into producing vaccines than can be given into the nose rather than by injection.[18] It is believed that this improves vaccine efficacy and also avoids the need for injection.
The development of serotype-specific anticapsular monoclonal antibodies has also been researched in recent years. These antibodies have been shown to prolong survival in a mouse model of pneumococcal infection characterized by a reduction in bacterial loads and a suppression of the host inflammatory response.[19][20]
References
- ↑ Verma R, Khanna P (2012) Pneumococcal conjugate vaccine: A newer vaccine available in India. Hum Vaccin Immunother 8(9)
- ↑ Ryan KJ; Ray CG (editors) (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill. ISBN 0-8385-8529-9.
- ↑ 3.0 3.1 3.2 Siemieniuk, Reed A.C. (2011). "The persisting burden of invasive pneumococcal disease in HIV patients: an observational cohort study". BMC Infectious Diseases. 11 (314). doi:10.1186/1471-2334-11-314. PMC 3226630. PMID 22078162. Unknown parameter
|coauthors=ignored (help); Unknown parameter|month=ignored (help) - ↑ Walter ND, Taylor TH, Shay DK; et al. (2010). "Influenza Circulation and the Burden of Invasive Pneumococcal Pneumonia during a Non‐pandemic Period in the United States". Clin Infect Dis. 50 (2): 175–183. doi:10.1086/649208. PMID 20014948.
- ↑ Pericone, Christopher D., Overweg, Karin, Hermans, Peter W. M., Weiser, Jeffrey N. (2000). "Inhibitory and Bactericidal Effects of Hydrogen Peroxide Production by Streptococcus pneumoniae on Other Inhabitants of the Upper Respiratory Tract". Infect Immun. 68 (7): 3990&ndash, 3997. doi:10.1128/IAI.68.7.3990-3997.2000. PMC 101678. PMID 10858213.
- ↑ Regev-Yochay G, Trzcinski K, Thompson CM, Malley R, Lipsitch M. (2006). "Interference between Streptococcus pneumoniae and Staphylococcus aureus: In vitro hydrogen peroxide-mediated killing by Streptococcus pneumoniae". J Bacteriol. 188 (13): 4996&ndash, 5001. doi:10.1128/JB.00317-06. PMC 1482988. PMID 16788209.
- ↑ Barocchi M, Ries J, Zogaj X, Hemsley C, Albiger B, Kanth A, Dahlberg S, Fernebro J, Moschioni M, Masignani V, Hultenby K, Taddei A, Beiter K, Wartha F, von Euler A, Covacci A, Holden D, Normark S, Rappuoli R, Henriques-Normark B (2006). "A pneumococcal pilus influences virulence and host inflammatory responses". Proc Natl Acad Sci USA. 103 (8): 2857&ndash, 2862. doi:10.1073/pnas.0511017103. PMC 1368962. PMID 16481624.
- ↑ 8.0 8.1 Werno AM, Murdoch DR (2008). "Medical microbiology: laboratory diagnosis of invasive pneumococcal disease". Clin. Infect. Dis. 46 (6): 926–32. doi:10.1086/528798. PMID 18260752. Unknown parameter
|month=ignored (help) - ↑ Template:Cite doi
- ↑ Peterson LR (2006). "Penicillins for treatment of pneumococcal pneumonia: does in vitro resistance really matter?". Clin Infect Dis. 42 (2): 224&ndash, 33. doi:10.1086/497594. PMID 16355333.
- ↑ Tleyjeh IM, Tlaygeh HM, Hejal R, Montori VM, Baddour LM (2006). "The impact of penicillin resistance on short-term mortality in hospitalized adults with pneumococcal pneumonia: a systematic review and meta-analysis". Clin Infect Dis. 42 (6): 788&ndash, 97. doi:10.1086/500140. PMID 16477555.
- ↑ Martínez JA, Horcajada JP, Almela M; et al. (2003). "Addition of a Macrolide to a β-Lactam based empirical antibiotic regimen is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia". Clin Infect Dis. 36 (4): 389–395. doi:10.1086/367541. PMID 12567294.
- ↑ E.M.E.A.:Prevenar - Annex I: Summary of Product Characteristics
- ↑ "Children to be given new vaccine" BBC News, February 08, 2006, retrieved August 25, 2006
- ↑ "Pneumococcal vaccine added to the childhood immunisation programme" February 08, 2006
- ↑ "Changes to the immunisation programme in the UK" Meningitis Research Foundation, retrieved August 25, 2006
- ↑ "PneumoADIP website"
- ↑ Malley R. Lipsitch M, Stack A, Saladino R, Fleisher G, Pelton S, Thompson C, Briles D, Anderson P. (2001). "Intranasal immunization with killed unencapsulated whole cells prevents colonization and invasive disease by capsulated pneumococci". Infect Immun. 69: 4870&ndash, 4873. doi:10.1128/IAI.69.8.4870-4873.2001. PMID 11447162.
- ↑ Burns T, Abadi M, Pirofski L (2005). "Modulation of the lung inflammatory response to serotype 8 pneumococcal infection by a human immunoglobulin m monoclonal antibody to serotype 8 capsular polysaccharide". Infect Immun. 73 (8): 4530&ndash, 8. doi:10.1128/IAI.73.8.4530-4538.2005. PMID 16040964.
- ↑ Fabrizio K, Groner A, Boes M, Pirofski L. "A Human Monoclonal IgM Reduces Bacteremia and Inflammation in a Mouse Model of Systemic Pneumococcal Infection". Clin Vaccine Immunol. PMID 17301214.
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