Pneumococcal infection

File:Pneumococcal meningitis.jpg

Pneumococcal pneumonia represents 15%–50% of all episodes of community-acquired pneumonia, 30–50% of all cases of acute otitis media, and a significant proportion of bloodstream infections and bacterial meningitis.Verma R, Khanna P (2012) Pneumococcal conjugate vaccine: A newer vaccine available in India. Hum Vaccin Immunother 8(9)

As estimated by the WHO, in 2005 it killed about 1.6 million children every year worldwide with 0.7–1 million of them being under the age of five. The majority of these deaths were in developing countries.{{cite journal|url=https://www.who.int/wer/2007/wer8212.pdf|title=Pneumococcal conjugate vaccine for childhood immunization—WHO position paper|author=WHO|year=2007|volume=82|issue=12|pages=93–104|journal=Wkly Epidemiol Rec|publisher=World Health Organization|location=Geneva|pmid=17380597}}

S. pneumoniae is normally found in the nose and throat of 5–10% of healthy adults and 20–40% of healthy children.{{cite book | editor = Ryan KJ | editor2 = Ray CG | title = Sherris Medical Microbiology | edition = 4th | publisher = McGraw Hill | year = 2004 | isbn = 0-8385-8529-9 }} 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.{{cn|date=June 2021}}

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.{{cn|date=June 2021}}

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, surgical removal of the spleen, or sickle-cell disease predisposes one to a more severe course of infection (overwhelming post-splenectomy infection) and prevention measures are indicated. {{cn|date=June 2022}}

People with a compromised immune system, such as those living with HIV, are also at higher risk of pneumococcal disease.{{cite journal | vauthors = Siemieniuk RA, Gregson DB, Gill MJ | title = The persisting burden of invasive pneumococcal disease in HIV patients: an observational cohort study | journal = BMC Infectious Diseases | volume = 11 | issue = 314 | pages = 314 | date = November 2011 | pmid = 22078162 | pmc = 3226630 | doi = 10.1186/1471-2334-11-314 | doi-access = free }} 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%.

There is an association between pneumococcal pneumonia and influenza. Damage to the lining of the airways (respiratory epithelium) and upper respiratory system caused by influenza may facilitate pneumococcal entry and infection.{{cite journal |vauthors=Walter ND, Taylor TH, Shay DK, etal |title=Influenza Circulation and the Burden of Invasive Pneumococcal Pneumonia during a Non-pandemic Period in the United States|journal=Clin Infect Dis|year=2010|volume=50|pages=175–183|doi=10.1086/649208|pmid=20014948|issue=2|doi-access=free}} Influenza also modifies the innate immune system into a state more accommodating to pneumococcal infections.{{cite journal |last1=Jochems |first1=Simon P. |last2=Marcon |first2=Fernando |last3=Carniel |first3=Beatriz F. |last4=Holloway |first4=Mark |last5=Mitsi |first5=Elena |last6=Smith |first6=Emma |last7=Gritzfeld |first7=Jenna F. |last8=Solórzano |first8=Carla |last9=Reiné |first9=Jesús |last10=Pojar |first10=Sherin |last11=Nikolaou |first11=Elissavet |last12=German |first12=Esther L. |last13=Hyder-Wright |first13=Angie |last14=Hill |first14=Helen |last15=Hales |first15=Caz |last16=de Steenhuijsen Piters |first16=Wouter A. A. |last17=Bogaert |first17=Debby |last18=Adler |first18=Hugh |last19=Zaidi |first19=Seher |last20=Connor |first20=Victoria |last21=Gordon |first21=Stephen B. |last22=Rylance |first22=Jamie |last23=Nakaya |first23=Helder I. |last24=Ferreira |first24=Daniela M. |title=Inflammation induced by influenza virus impairs human innate immune control of pneumococcus |journal=Nature Immunology |date=December 2018 |volume=19 |issue=12 |pages=1299–1308 |doi=10.1038/s41590-018-0231-y|hdl=20.500.11820/943ac1b9-4f26-467e-b290-625aeac1c352 |hdl-access=free }} Most of the deaths in the 1918 influenza pandemic were attributable to bacterial infections, especially pneumococcus.{{cite journal |last1=Klugman |first1=Keith P. |last2=Chien |first2=Yu-Wen |last3=Madhi |first3=Shabir A. |title=Pneumococcal pneumonia and influenza: A deadly combination |journal=Vaccine |date=August 2009 |volume=27 |pages=C9–C14 |doi=10.1016/j.vaccine.2009.06.007}} There is also a link between pneumococcal infection and respiratory syncytial virus infection among children.{{cite journal |last1=Besteman |first1=Sjanna B |last2=Bogaert |first2=Debby |last3=Bont |first3=Louis |last4=Mejias |first4=Asuncion |last5=Ramilo |first5=Octavio |last6=Weinberger |first6=Daniel M |last7=Dagan |first7=Ron |title=Interactions between respiratory syncytial virus and Streptococcus pneumoniae in the pathogenesis of childhood respiratory infections: a systematic review |journal=The Lancet Respiratory Medicine |date=November 2024 |volume=12 |issue=11 |pages=915–932 |doi=10.1016/S2213-2600(24)00148-6}}

Other risk factors include smoking, injection drug use, hepatitis C, and COPD.

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.{{cn|date=June 2022}}

• 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){{cite journal | vauthors = Pericone CD, Overweg K, Hermans PW, Weiser JN | title = Inhibitory and bactericidal effects of hydrogen peroxide production by Streptococcus pneumoniae on other inhabitants of the upper respiratory tract | journal = Infection and Immunity | volume = 68 | issue = 7 | pages = 3990–3997 | date = July 2000 | pmid = 10858213 | pmc = 101678 | doi = 10.1128/IAI.68.7.3990-3997.2000 }}{{cite journal | vauthors = Regev-Yochay G, Trzcinski K, Thompson CM, Malley R, Lipsitch M | title = Interference between Streptococcus pneumoniae and Staphylococcus aureus: In vitro hydrogen peroxide-mediated killing by Streptococcus pneumoniae | journal = Journal of Bacteriology | volume = 188 | issue = 13 | pages = 4996–5001 | date = July 2006 | pmid = 16788209 | pmc = 1482988 | doi = 10.1128/JB.00317-06 }}
• 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{{cite journal |vauthors=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 |title=A pneumococcal pilus influences virulence and host inflammatory responses |journal=Proc Natl Acad Sci USA |volume=103 |issue=8 |pages=2857–2862 |year=2006 |pmid=16481624 |doi=10.1073/pnas.0511017103 |pmc=1368962|bibcode=2006PNAS..103.2857B |doi-access=free }}
• 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
• Competence for genetic transformation likely plays an important role in nasal colonization fitness and virulence (lung infectivity){{cite journal |vauthors=Li G, Liang Z, Wang X, Yang Y, Shao Z, Li M, Ma Y, Qu F, Morrison DA, Zhang JR |title=Addiction of Hypertransformable Pneumococcal Isolates to Natural Transformation for In Vivo Fitness and Virulence |journal=Infect. Immun. |volume=84 |issue=6 |pages=1887–901 |year=2016 |pmid=27068094 |doi=10.1128/IAI.00097-16 |pmc=4907133}}
• Extracellular vesicles (pEVs)—secretory vesicles that carry virulence factors, such as serine-threonine kinase, which, upon internalization by host epithelial cells, phosphorylates Beclin 1, leading to autophagy-mediated degradation of the tight junction protein occludin (OCLN), subsequent disruption of the alveolar epithelial barrier, and dissemination of S. pneumoniae{{cite journal | vauthors = Cui L, Yang R, Huo D, Li L, Qu X, Wang J, Wang X, Liu H, Chen H, Wang X | title = Streptococcus pneumoniae extracellular vesicles aggravate alveolar epithelial barrier disruption via autophagic degradation of OCLN (occludin) | journal = Autophagy | volume = 20 | issue = 7 | pages = 1577–1596 | date = July 2024 | pmid = 38497494 | pmc = 11210924 | doi = 10.1080/15548627.2024.2330043 }}

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 indicating sensitivity to the antibiotic. Pneumococci are also bile soluble. Just like other streptococci they are catalase-negative. A Quellung test can identify specific capsular polysaccharides.{{cite journal |vauthors=Werno AM, Murdoch DR |title=Medical microbiology: laboratory diagnosis of invasive pneumococcal disease |journal=Clin. Infect. Dis. |volume=46 |issue=6 |pages=926–32 |date=March 2008 |pmid=18260752 |doi=10.1086/528798 |doi-access=free }}

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. Chest X-rays can also be conducted to confirm inflammation though are not specific to the causative agent.{{cn|date=June 2021}}

{{Main|Pneumococcal vaccine}}

Due to the importance of disease caused by S. pneumoniae, several vaccines have been developed to protect against invasive infection. The World Health Organization recommend routine childhood pneumococcal vaccination;{{cite journal|title=Pneumococcal vaccines WHO position paper—2012|journal=Wkly Epidemiol Rec|date=Apr 6, 2012|volume=87|issue=14|pages=129–44|pmid=24340399|url=https://www.who.int/wer/2012/wer8714.pdf?ua=1}} it is incorporated into the childhood immunization schedule in a number of countries including the United Kingdom,{{cite web |title=Children to be given new vaccine |date=8 February 2006 |publisher=BBC News |url=http://news.bbc.co.uk/1/hi/health/4692908.stm}} United States,{{cite web |url= https://www.cdc.gov/vaccines/vpd-vac/pneumo/hcp/index.html |title= Pneumococcal Vaccination: Information for Health Care Providers|author= |website= cdc.org |access-date= 26 July 2016 }} and South Africa.{{cite web|url=http://www.nicd.ac.za/?page=alerts&id=5&rid=448|title=Critical decline in pneumococcal disease and antibiotic resistance in South Africa|work=NICD|access-date=20 July 2015|archive-date=23 July 2015|archive-url=https://web.archive.org/web/20150723025857/http://www.nicd.ac.za/?page=alerts&id=5&rid=448|url-status=dead}}

Throughout history treatment relied primarily on β-lactam antibiotics. In the 1960s nearly all strains of S. pneumoniae were susceptible to penicillin, but more recently 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 fluoroquinolones. Notably, macrolide-resistant S. pneumoniae has been declared a medium-priority pathogen by the WHO due to its growing clinical and public health significance.{{Cite web |title=WHO bacterial priority pathogens list, 2024: Bacterial pathogens of public health importance to guide research, development and strategies to prevent and control antimicrobial resistance |url=https://www.who.int/publications/i/item/9789240093461 |access-date=2024-12-12 |website=www.who.int |language=en}} 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 medication and concerns of development of vancomycin resistance.{{cn|date=June 2021}}

More advanced beta-lactam antibiotics (cephalosporins) are commonly used in combination with other antibiotics 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 medications are used to treat tuberculosis, resistance has been described.{{cite journal | vauthors = von Gottberg A, Klugman KP, Cohen C, Wolter N, de Gouveia L, du Plessis M, Mpembe R, Quan V, Whitelaw A, Hoffmann R, Govender N, Meiring S, Smith AM, Schrag S | title = Emergence of levofloxacin-non-susceptible Streptococcus pneumoniae and treatment for multidrug-resistant tuberculosis in children in South Africa: a cohort observational surveillance study | journal = Lancet | volume = 371 | issue = 9618 | pages = 1108–1113 | date = March 2008 | pmid = 18359074 | doi = 10.1016/S0140-6736(08)60350-5 | s2cid = 205950081 }}

Susceptibility testing should be routine with empiric antibiotic treatment guided by resistance patterns in the community in which the organism was acquired. There is currently debate as to how relevant the results of susceptibility testing are to clinical outcome.{{cite journal | vauthors = Peterson LR | title = Penicillins for treatment of pneumococcal pneumonia: does in vitro resistance really matter? | journal = Clinical Infectious Diseases | volume = 42 | issue = 2 | pages = 224–233 | date = January 2006 | pmid = 16355333 | doi = 10.1086/497594 | doi-access = free }}{{cite journal | vauthors = Tleyjeh IM, Tlaygeh HM, Hejal R, Montori VM, Baddour LM | title = The impact of penicillin resistance on short-term mortality in hospitalized adults with pneumococcal pneumonia: a systematic review and meta-analysis | journal = Clinical Infectious Diseases | volume = 42 | issue = 6 | pages = 788–797 | date = March 2006 | pmid = 16477555 | doi = 10.1086/500140 | doi-access = }} There is slight clinical evidence that penicillins may act synergistically with macrolides to improve outcomes.{{cite journal | vauthors = Martínez JA, Horcajada JP, Almela M, Marco F, Soriano A, García E, Marco MA, Torres A, Mensa J | title = Addition of a macrolide to a beta-lactam-based empirical antibiotic regimen is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia | journal = Clinical Infectious Diseases | volume = 36 | issue = 4 | pages = 389–395 | date = February 2003 | pmid = 12567294 | doi = 10.1086/367541 | s2cid = 18795735 | doi-access = }}

Resistant pneumococci strains are called penicillin-resistant pneumococci (PRP),{{cite journal | vauthors = Nilsson P, Laurell MH | title = Carriage of penicillin-resistant Streptococcus pneumoniae by children in day-care centers during an intervention program in Malmo, Sweden | journal = The Pediatric Infectious Disease Journal | volume = 20 | issue = 12 | pages = 1144–1149 | date = December 2001 | pmid = 11740321 | doi = 10.1097/00006454-200112000-00010 }} penicillin-resistant Streptococcus pneumoniae (PRSP),{{cite journal | vauthors = Block SL, Harrison CJ, Hedrick JA, Tyler RD, Smith RA, Keegan E, Chartrand SA | title = Penicillin-resistant Streptococcus pneumoniae in acute otitis media: risk factors, susceptibility patterns and antimicrobial management | journal = The Pediatric Infectious Disease Journal | volume = 14 | issue = 9 | pages = 751–759 | date = September 1995 | pmid = 8559623 | doi = 10.1097/00006454-199509000-00005 }} Streptococcus pneumoniae penicillin resistant (SPPR),{{cite journal | vauthors = Koiuszko S, Białucha A, Gospodarek E | title = [The drug susceptibility of penicillin-resistant Streptococcus pneumoniae] | journal = Medycyna Doswiadczalna I Mikrobiologia | volume = 59 | issue = 4 | pages = 293–300 | year = 2007 | pmid = 18416121 }} or drug-resistant Strepotococcus pneumomoniae (DRSP).{{cite web |title=Drug Resistance |url=https://www.cdc.gov/pneumococcal/drug-resistance.html |website=cdc.gov |access-date=17 February 2019|date=2019-02-13 }}

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.{{cn|date=June 2022}}

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.{{cite journal |vauthors=Avery OT, Macleod CM, McCarty M |journal=J. Exp. Med. |volume=79 |issue=2 |pages=137–58 |year=1944 |pmid=19871359 |pmc=2135445 |doi= 10.1084/jem.79.2.137|title=Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumococcal Types }}

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; current vaccines contain up to 23 serovars (i.e., it is "23-valent").{{cn|date=June 2022}}

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.{{cn|date=June 2022}}

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• [https://web.archive.org/web/20090410171209/http://www.worldpneumoniaday.org/ November 2nd: World Pneumonia Day Website]
• [http://www.preventpneumo.org Pneumococcal Vaccine Accelerated Development and Introduction Plan]

{{Gram-positive bacterial diseases}}

{{Diseases of meninges}}

{{Respiratory pathology}}

Category:Pneumonia

Category:Vaccine-preventable diseases