Pneumonia pathophysiology: Difference between revisions

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{{Pneumonia}}
{{Pneumonia}}
'''Editor(s)-in-Chief:''' [[C. Michael Gibson, M.S., M.D.]] [mailto:mgibson@perfuse.org] Phone:617-632-7753; [[Philip Marcus, M.D., M.P.H.]][mailto:pmarcus192@aol.com]
{{CMG}}; {{AE}} {{HQ}}, [[Priyamvada Singh|Priyamvada Singh, M.D.]] [mailto:psingh13579@gmail.com]


==Overview==
==Overview==
The symptoms of infectious pneumonia are caused by the invasion of the lungs by [[microorganism]]s and by the [[immune system]]'s response to the infection. Although more than one hundred strains of microorganism can cause pneumonia, only a few are responsible for most cases. The most common causes of pneumonia are [[virus]]es and [[bacteria]]. Less common causes of infectious pneumonia are [[fungi]] and [[parasites]]. The detailed pathophysiology regarding each of these etiologic organisms has been detailed under the respective chapters. The symptoms of CAP are the result of both the invasion of the lungs by [[microorganism]]s and the [[immune system]]'s response to the infection. The mechanisms of infection are quite different for [[virus]]es and the other microorganisms.
Bacteria and fungi typically enter the lung with inhalation. Once inside the [[alveoli]], these microbes travel into the spaces between the cells and also between adjacent alveoli through connecting pores. This invasion triggers the [[immune system]] response by sending white blood cells responsible for attacking microorganisms ([[neutrophil]]s) to the lungs resulting in manifestations of pneumonia.
 
==Pathophysiology==
==Pathophysiology==
===Microscopic Pathology===
===Mode of Transmission===
=====1. Inhalation of Aerosolized Droplets=====
* [[Inhalation]] of aerosolized droplets of 0.5 to 1 micrometer is the most common pathway of acquiring [[pneumonia]].
* A few [[Bacteria|bacterial]] and [[Virus|viral]] [[Infection|infections]] are transmitted in this fashion. 
* The [[lung]] can normally filter out particles between 0.5 to 2 micrometer by recruiting the [[Alveolus|alveolar]] [[macrophages]].<ref name="Wunderink-2004">{{Cite journal  | last1 = Wunderink | first1 = RG. | last2 = Waterer | first2 = GW. | title = Community-acquired pneumonia: pathophysiology and host factors with focus on possible new approaches to management of lower respiratory tract infections. | journal = Infect Dis Clin North Am | volume = 18 | issue = 4 | pages = 743-59, vii | month = Dec | year = 2004 | doi = 10.1016/j.idc.2004.07.004 | PMID = 15555822 }}</ref>
 
=====2. Microaspiration of Oropharyngeal Contents=====
* [[Aspiration pneumonia|Aspiration]] of [[Oropharyngeal airway|oropharyngeal]] contents containing pathogenic microorganisms is one of the mechanism of acquiring [[pneumonia]]. 
* It most commonly occurs in normal persons during [[sleep]], in unconscious persons due to [[Gastroesophageal reflux disease|gastroesopahegeal reflux]] or impaired [[gag reflex]] and [[cough reflex]].<ref name="Wunderink-2004">{{Cite journal  | last1 = Wunderink | first1 = RG. | last2 = Waterer | first2 = GW. | title = Community-acquired pneumonia: pathophysiology and host factors with focus on possible new approaches to management of lower respiratory tract infections. | journal = Infect Dis Clin North Am | volume = 18 | issue = 4 | pages = 743-59, vii | month = Dec | year = 2004 | doi = 10.1016/j.idc.2004.07.004 | PMID = 15555822 }}</ref>
 
=====3. Blood-Borne or Systemic Infection=====
* Microbial entered through circulation may also result in [[Lung|pulmonary]] [[Infection|infections]].
* Blood-borne pneumonia is seen more commonly in intravenous drug users. [[Staphylococcus aureus]] causes pneumonia in this way.
* [[Gram negative bacteria]] typically account for pneumonia in [[immunocompromised]] individuals.
 
=====4. Trauma or Local Spread=====
* Pneumonia can occur after a [[Lung|pulmonary]] procedure or a penetrating trauma to the [[Lung|lungs]].
* A local spread of a [[hepatic abscess]] can also lead to pneumonia.
 
===Agent Specific Virulence Factors===
Several strategies are evolved to evade host defence mechanisms and facilitate spreading before establishing an [[infection]].
 
* [[Influenza virus]] possesses [[neuraminidase]]s for cleavage of sialic acid residues on the [[Cell (biology)|cell]] surface and [[Virus|viral]] [[Protein|proteins]], which prevent aggregation and facilitate propagation of [[Virus|viral]] particles.
 
* ''[[Chlamydophila pneumoniae]]'' induces complete abortion of cilia motions which assists colonization at the [[respiratory epithelium]].<ref name="Shemer-Avni-1995">{{Cite journal  | last1 = Shemer-Avni | first1 = Y. | last2 = Lieberman | first2 = D. | title = Chlamydia pneumoniae-induced ciliostasis in ciliated bronchial epithelial cells. | journal = J Infect Dis | volume = 171 | issue = 5 | pages = 1274-8 | month = May | year = 1995 | doi =  | PMID = 7751703 }}</ref>
 
* ''[[Mycoplasma pneumoniae]]'' produces a virulence factor with [[ADP-ribosylation|ADP-ribosylating]] activity which is responsible for airway cellular damage and mucociliary dysfunction.<ref name="Kannan-2006">{{Cite journal  | last1 = Kannan | first1 = TR. | last2 = Baseman | first2 = JB. | title = ADP-ribosylating and vacuolating cytotoxin of Mycoplasma pneumoniae represents unique virulence determinant among bacterial pathogens. | journal = Proc Natl Acad Sci U S A | volume = 103 | issue = 17 | pages = 6724-9 | month = Apr | year = 2006 | doi = 10.1073/pnas.0510644103 | PMID = 16617115 }}</ref>
 
* ''[[Haemophilus influenzae]]'', ''[[Streptococcus pneumoniae]]'', and ''[[Neisseria meningitidis]]'' produce [[protease]]s that split mucosal [[immunoglobulin A|IgA]].
 
* ''[[Streptococcus pneumoniae]]'' possesses [[pneumolysin]] that aid the bacteria during colonization, by facilitating adherence to the host,<ref>{{cite journal|last=Rubins|first=JB|coauthors=Paddock, AH, Charboneau, D, Berry, AM, Paton, JC, Janoff, EN|title=Pneumolysin in pneumococcal adherence and colonization.|journal=Microbial pathogenesis|date=December 1998|volume=25|issue=6|pages=337–42|pmid=9895272|doi=10.1006/mpat.1998.0239}}</ref> during invasion by damaging host cells,<ref>{{cite journal|last=Rubins|first=JB|coauthors=Janoff, EN|title=Pneumolysin: a multifunctional pneumococcal virulence factor.|journal=The Journal of laboratory and clinical medicine|date=January 1998|volume=131|issue=1|pages=21–7|pmid=9452123}}</ref> and during infection by interfering with the host immune response.<ref>{{cite journal|last=Cockeran|first=R|coauthors=Anderson, R, Feldman, C|title=The role of pneumolysin in the pathogenesis of Streptococcus pneumoniae infection.|journal=Current Opinion in Infectious Diseases|date=June 2002|volume=15|issue=3|pages=235–9|pmid=12015456}}</ref>
 
===Host Factors===
* The [[Lung|lungs]] can normally filter out large droplets of [[Aerosol|aerosols]].
* Smaller droplets of the size of 0.5 to 2 micrometer are deposited on the [[alveoli]] and then engulfed by alevolar [[Macrophage|macrophages]].
* These [[macrophages]] release [[cytokines]] and [[chemokines]], which also includes [[tumor necrosis factor-alpha]], [[interleukin]]-8 and [[leukotriene|LTB4]].
* The [[neutrophils]] are recruited by these cells to eliminate these [[Microorganism|microorganisms]].<ref name="Strieter-2003">{{Cite journal  | last1 = Strieter | first1 = RM. | last2 = Belperio | first2 = JA. | last3 = Keane | first3 = MP. | title = Host innate defenses in the lung: the role of cytokines. | journal = Curr Opin Infect Dis | volume = 16 | issue = 3 | pages = 193-8 | month = Jun | year = 2003 | doi = 10.1097/01.qco.0000073766.11390.0e | PMID = 12821807 }}</ref><ref name="Mason-2005">{{Cite journal  | last1 = Mason | first1 = CM. | last2 = Nelson | first2 = S. | title = Pulmonary host defenses and factors predisposing to lung infection. | journal = Clin Chest Med | volume = 26 | issue = 1 | pages = 11-7 | month = Mar | year = 2005 | doi = 10.1016/j.ccm.2004.10.018 | PMID = 15802161 }}</ref>
 
======1. Diminished Mucociliary Clearance======
*The [[Respiratory epithelium#Ciliary Escalator|cilia]] lining the [[respiratory epithelium]] serve to move secreted [[mucus]] containing trapped foreign particles including [[Pathogen|pathogens]] towards the [[oropharynx]] for either expectoration or [[swallowing]].
*Elevated incidence of [[pneumonia]] in patients with [[Genetics|genetic]] defects affecting [[mucociliary clearance]] such as [[primary ciliary dyskinesia]] suggests its role in the [[pathogenesis]] of community-acquired pneumonia.
 
======2. Impaired Cough Reflex======
*[[Cough]], together with [[mucociliary clearance]], prevent pathogens from entering the lower [[respiratory tract]].
*Cough suppression or [[cough reflex]] inhibition seen in patients with [[cerebrovascular accident]]s and [[overdose|drug overdosage]]s is associated with an enhanced risk for [[aspiration pneumonia]].
* Another relation to [[cough]] is [[genetic polymorphism]]s in the [[angiotensin-converting enzyme|angiotensin-converting enzyme (ACE)]] gene.
*The role of [[cough]] in preventing [[pneumonia]] may be explained by a higher risk for developing [[pneumonia]] in [[homozygote]]s carrying [[deletion|deletion/deletion (DD)]] [[genotype]] who are found to have lower levels of [[bradykinin]] and [[tachykinins]] such as [[substance P]].<ref name="Morimoto-2002">{{Cite journal  | last1 = Morimoto | first1 = S. | last2 = Okaishi | first2 = K. | last3 = Onishi | first3 = M. | last4 = Katsuya | first4 = T. | last5 = Yang | first5 = J. | last6 = Okuro | first6 = M. | last7 = Sakurai | first7 = S. | last8 = Onishi | first8 = T. | last9 = Ogihara | first9 = T. | title = Deletion allele of the angiotensin-converting enzyme gene as a risk factor for pneumonia in elderly patients. | journal = Am J Med | volume = 112 | issue = 2 | pages = 89-94 | month = Feb | year = 2002 | doi =  | PMID = 11835945 }}</ref><ref>{{Cite journal  | last1 = Rigat | first1 = B. | last2 = Hubert | first2 = C. | last3 = Alhenc-Gelas | first3 = F. | last4 = Cambien | first4 = F. | last5 = Corvol | first5 = P. | last6 = Soubrier | first6 = F. | title = An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. | journal = J Clin Invest | volume = 86 | issue = 4 | pages = 1343-6 | month = Oct | year = 1990 | doi = 10.1172/JCI114844 | PMID = 1976655 }}</ref>
 
======3. Defective Immune System======
*[[Pathogen-associated molecular pattern|Pathogen-associated molecular patterns (PAMPs)]] are initially recognized by [[Toll-like receptor|Toll-like receptors (TLRs)]] and other [[pattern recognition receptor|pattern-recognition receptors (PRRs)]] of the [[innate immune system]].
*Effectors in the [[acquired immunity|acquired immune system]] are involved in elimination of microorganisms and generation of immunological memory.
*Other components in the immune system such as [[complement system]], [[cytokine]]s, and [[collectin]]s, also mediate the defense against [[Microorganism|microorganisms]] causing pneumonia.
 
==Microscopic Pathology==
[[Image:Pneumonia alveolus.jpg|thumb|left|286 px|The ''upper panel'' shows a normal lung under a microscope. The white spaces are [[alveoli]] that contain air.''Lower panel'' shows a lung with pneumonia under a microscope. The alveoli are filled with inflammation and debris.]]
<br clear="left" />
 
{{col-begin|width=80%}} {{col-break|width=50%}}
 
==Microbial Pathogenesis==
 
===Virulence Factors===
 
Several mechanisms have evolved to evade host defense mechanisms and facilitate microbial spread to establish an infection.
 
* [[Influenza virus]]es possess [[neuraminidase]] that cleaves sialic acid residues on the cell surface, which prevents viral aggregation and facilitates the propagation of viral particles.
 
* ''[[Chlamydophila pneumoniae]]'' induces complete paralysis of the respiratory cilia, which assists with the colonization of the [[respiratory epithelium]].<ref name="Shemer-Avni-1995">{{Cite journal  | last1 = Shemer-Avni | first1 = Y. | last2 = Lieberman | first2 = D. | title = Chlamydia pneumoniae-induced ciliostasis in ciliated bronchial epithelial cells. | journal = J Infect Dis | volume = 171 | issue = 5 | pages = 1274-8 | month = May | year = 1995 | doi =  | PMID = 7751703 }}</ref>


[[Image:Streptococcus pneumoniae.jpg|200px]]
* ''[[Mycoplasma pneumoniae]]'' produces a virulence factor with [[ADP-ribosylation|ADP-ribosylating]] activity that is responsible for airway cellular damage and mucociliary dysfunction.<ref name="Kannan-2006">{{Cite journal  | last1 = Kannan | first1 = TR. | last2 = Baseman | first2 = JB. | title = ADP-ribosylating and vacuolating cytotoxin of Mycoplasma pneumoniae represents unique virulence determinant among bacterial pathogens. | journal = Proc Natl Acad Sci U S A | volume = 103 | issue = 17 | pages = 6724-9 | month = Apr | year = 2006 | doi = 10.1073/pnas.0510644103 | PMID = 16617115 }}</ref>
===Viruses===
* Viruses must invade cells in order to reproduce.
* Typically, a virus will reach the lungs by traveling in droplets through the [[mouth]] and [[nose]] with [[inhalation]].
* There, the virus invades the cells lining the airways and the alveoli.
* This invasion often leads cell death either through direct killing by the virus or by self-destruction through [[apoptosis]].
* Further damage to the lungs occurs when the immune system responds to the infection. [[White blood cell]]s, in particular [[lymphocyte]]s, are responsible for activating a variety of chemicals ([[cytokine]]s) which cause leaking of fluid into the alveoli.
* The combination of cellular destruction and fluid-filled alveoli interrupts the transportation of oxygen into the bloodstream.
* In addition to the effects on the lungs, many viruses affect other [[Organ (anatomy)|organ]]s and can lead to illness affecting many different bodily functions.
* Viruses also make the body more susceptible to bacterial infection; for this reason, bacterial pneumonia often complicates viral CAP.
===Bacteria and fungi===
* Bacteria and fungi also typically enter the lung with inhalation, though they can reach the lung through the bloodstream if other parts of the body are infected.
* Often, bacteria live in parts of the [[upper respiratory tract]] and are constantly being inhaled into the alveoli.
* Once inside the alveoli, [[bacteria]] and [[fungus|fungi]] travel into the spaces between the cells and also between adjacent alveoli through connecting pores.
* This invasion triggers the [[immune system]] to respond by sending white blood cells responsible for attacking microorganisms ([[neutrophil]]s) to the lungs. The neutrophils [[phagocytosis|engulf]] and kill the offending organisms but also release cytokines which result in a general activation of the immune system.
* This results in the fever, chills, and fatigue common in CAP. The neutrophils, bacteria, and fluid leaked from surrounding blood vessels fill the alveoli and result in impaired oxygen transportation.
* Bacteria often travel from the lung into the blood stream and can result in serious illness such as [[septic shock]], in which there is low blood pressure leading to damage in multiple parts of the body including the [[brain]], [[kidney]], and [[heart]].


===Parasites===
* ''[[Haemophilus influenzae]]'', ''[[Streptococcus pneumoniae]]'', and ''[[Neisseria meningitidis]]'' produce [[protease]]s that cleave mucosal [[immunoglobulin A|IgA]].
* In general, these parasites enter the body through the skin or by being swallowed.
* Once inside the body, these parasites travel to the lungs, most often through the blood. There, a similar combination of cellular destruction and immune response causes disruption of oxygen transportation.


[[Image:Pneumonia alveolus.jpg|200px|''Upper panel'' shows a normal lung under a microscope. The white spaces are [[alveoli]] that contain air.''Lower panel'' shows a lung with pneumonia under a microscope. The alveoli are filled with inflammation and debris.]]
* ''[[Streptococcus pneumoniae]]'' possesses [[pneumolysin]] that aid the bacteria during colonization, by facilitating adherence to the host,<ref>{{cite journal|last=Rubins|first=JB|coauthors=Paddock, AH, Charboneau, D, Berry, AM, Paton, JC, Janoff, EN|title=Pneumolysin in pneumococcal adherence and colonization.|journal=Microbial pathogenesis|date=December 1998|volume=25|issue=6|pages=337–42|pmid=9895272|doi=10.1006/mpat.1998.0239}}</ref> during invasion by damaging host cells,<ref>{{cite journal|last=Rubins|first=JB|coauthors=Janoff, EN|title=Pneumolysin: a multifunctional pneumococcal virulence factor.|journal=The Journal of laboratory and clinical medicine|date=January 1998|volume=131|issue=1|pages=21–7|pmid=9452123}}</ref> and during infection by interfering with the host immune response.<ref>{{cite journal|last=Cockeran|first=R|coauthors=Anderson, R, Feldman, C|title=The role of pneumolysin in the pathogenesis of Streptococcus pneumoniae infection.|journal=Current Opinion in Infectious Diseases|date=June 2002|volume=15|issue=3|pages=235–9|pmid=12015456}}</ref>
==Aspiration pneumonia pathophysiology==
The location is often gravity dependent, and depends on the patient position. Generally the right middle and lower lung lobes are the most common sites of infiltrate formation due to the larger caliber and more vertical orientation of the right mainstem bronchus.  


Patients who aspirate while standing can have bilateral lower lung lobe infiltrates. The right upper lobe is a common area of consolidation in alcoholics who aspirate in the prone position. Depending on the acidity of the aspirate, a chemical pneumonitis can develop, and bacterial pathogens (particularly [[anaerobic bacteria]]) may add to the inflammation.
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== Histopathological Findings in Aspiration Pneumonia==
===Aspiration Pneumonia===


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==Histopathological Findings==
=== Lobar Pneumonia===
 
=== Lobar pneumonia===


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=== Pneumocystis pneumonia===
=== Pneumocystis Pneumonia===


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=== Pneumocystis Pneumonia===


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=== Aspiration pneumonia, infant===
=== Aspiration Pneumonia, Infant===


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=== Desquamative interstitial pneumonia===
=== Desquamative Interstitial Pneumonia===


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=== Legionella pneumonia===
=== Legionella Pneumonia===


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=== Measles pneumonia===
=== Measles Pneumonia===


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=== Abscess, bronchopneumonia===
=== Abscess, Bronchopneumonia===


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==References==
==References==
{{reflist|2}}
{{reflist|2}}


[[Category:Diseaase]]
[[Category:Disease]]
[[Category:Pulmonology]]
[[Category:Pulmonology]]
[[Category:Infectious disease]]
 
[[Category:Pneumonia|Pneumonia]]
[[Category:Pneumonia|Pneumonia]]
[[Category:Emergency medicine]]
[[Category:Emergency medicine]]

Latest revision as of 20:48, 11 November 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hamid Qazi, MD, BSc [2], Priyamvada Singh, M.D. [3]

Overview

Bacteria and fungi typically enter the lung with inhalation. Once inside the alveoli, these microbes travel into the spaces between the cells and also between adjacent alveoli through connecting pores. This invasion triggers the immune system response by sending white blood cells responsible for attacking microorganisms (neutrophils) to the lungs resulting in manifestations of pneumonia.

Pathophysiology

Mode of Transmission

1. Inhalation of Aerosolized Droplets
2. Microaspiration of Oropharyngeal Contents
3. Blood-Borne or Systemic Infection
4. Trauma or Local Spread
  • Pneumonia can occur after a pulmonary procedure or a penetrating trauma to the lungs.
  • A local spread of a hepatic abscess can also lead to pneumonia.

Agent Specific Virulence Factors

Several strategies are evolved to evade host defence mechanisms and facilitate spreading before establishing an infection.

  • Streptococcus pneumoniae possesses pneumolysin that aid the bacteria during colonization, by facilitating adherence to the host,[4] during invasion by damaging host cells,[5] and during infection by interfering with the host immune response.[6]

Host Factors

1. Diminished Mucociliary Clearance
2. Impaired Cough Reflex
3. Defective Immune System

Microscopic Pathology

The upper panel shows a normal lung under a microscope. The white spaces are alveoli that contain air.Lower panel shows a lung with pneumonia under a microscope. The alveoli are filled with inflammation and debris.


References

  1. ↑ 1.0 1.1 Wunderink, RG.; Waterer, GW. (2004). "Community-acquired pneumonia: pathophysiology and host factors with focus on possible new approaches to management of lower respiratory tract infections". Infect Dis Clin North Am. 18 (4): 743–59, vii. doi:10.1016/j.idc.2004.07.004. PMID 15555822. Unknown parameter |month= ignored (help)
  2. ↑ 2.0 2.1 Shemer-Avni, Y.; Lieberman, D. (1995). "Chlamydia pneumoniae-induced ciliostasis in ciliated bronchial epithelial cells". J Infect Dis. 171 (5): 1274–8. PMID 7751703. Unknown parameter |month= ignored (help)
  3. ↑ 3.0 3.1 Kannan, TR.; Baseman, JB. (2006). "ADP-ribosylating and vacuolating cytotoxin of Mycoplasma pneumoniae represents unique virulence determinant among bacterial pathogens". Proc Natl Acad Sci U S A. 103 (17): 6724–9. doi:10.1073/pnas.0510644103. PMID 16617115. Unknown parameter |month= ignored (help)
  4. ↑ Rubins, JB (December 1998). "Pneumolysin in pneumococcal adherence and colonization". Microbial pathogenesis. 25 (6): 337–42. doi:10.1006/mpat.1998.0239. PMID 9895272. Unknown parameter |coauthors= ignored (help)
  5. ↑ Rubins, JB (January 1998). "Pneumolysin: a multifunctional pneumococcal virulence factor". The Journal of laboratory and clinical medicine. 131 (1): 21–7. PMID 9452123. Unknown parameter |coauthors= ignored (help)
  6. ↑ Cockeran, R (June 2002). "The role of pneumolysin in the pathogenesis of Streptococcus pneumoniae infection". Current Opinion in Infectious Diseases. 15 (3): 235–9. PMID 12015456. Unknown parameter |coauthors= ignored (help)
  7. ↑ Strieter, RM.; Belperio, JA.; Keane, MP. (2003). "Host innate defenses in the lung: the role of cytokines". Curr Opin Infect Dis. 16 (3): 193–8. doi:10.1097/01.qco.0000073766.11390.0e. PMID 12821807. Unknown parameter |month= ignored (help)
  8. ↑ Mason, CM.; Nelson, S. (2005). "Pulmonary host defenses and factors predisposing to lung infection". Clin Chest Med. 26 (1): 11–7. doi:10.1016/j.ccm.2004.10.018. PMID 15802161. Unknown parameter |month= ignored (help)
  9. ↑ Morimoto, S.; Okaishi, K.; Onishi, M.; Katsuya, T.; Yang, J.; Okuro, M.; Sakurai, S.; Onishi, T.; Ogihara, T. (2002). "Deletion allele of the angiotensin-converting enzyme gene as a risk factor for pneumonia in elderly patients". Am J Med. 112 (2): 89–94. PMID 11835945. Unknown parameter |month= ignored (help)
  10. ↑ Rigat, B.; Hubert, C.; Alhenc-Gelas, F.; Cambien, F.; Corvol, P.; Soubrier, F. (1990). "An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels". J Clin Invest. 86 (4): 1343–6. doi:10.1172/JCI114844. PMID 1976655. Unknown parameter |month= ignored (help)
  11. ↑ Rubins, JB (December 1998). "Pneumolysin in pneumococcal adherence and colonization". Microbial pathogenesis. 25 (6): 337–42. doi:10.1006/mpat.1998.0239. PMID 9895272. Unknown parameter |coauthors= ignored (help)
  12. ↑ Rubins, JB (January 1998). "Pneumolysin: a multifunctional pneumococcal virulence factor". The Journal of laboratory and clinical medicine. 131 (1): 21–7. PMID 9452123. Unknown parameter |coauthors= ignored (help)
  13. ↑ Cockeran, R (June 2002). "The role of pneumolysin in the pathogenesis of Streptococcus pneumoniae infection". Current Opinion in Infectious Diseases. 15 (3): 235–9. PMID 12015456. Unknown parameter |coauthors= ignored (help)

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