Community-acquired pneumonia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
Overview
Because the lower respiratory tract is kept sterile by different pulmonary defence mechanisms,[1] community-acquired pneumonia connotes a breach of host defence mechanisms and/or overwhelming inoculation of virulent infectious agents. Modes of transmission include: macro- or micro-aspiration, circulation, local spead, traumatic inoculation, or iatrogenic. Impaired immunity and inability to filter out pathogens increase the risk for developing pneumonia. Causative etiologies vary with age, immune status, geographical area, and comorbid conditions.
Pathophysiology
The symptoms of CAP are the result of both, the invasion of the lungs by microorganisms and the immune system's response to the infection. The mechanisms of infection are quite different for viruses and the other microorganisms.
Viruses
- Viruses must invade cells to reproduce. Typically, a virus reaches 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 to cell death either through direct killing by the virus or by self-destruction through apoptosis.
- Further lung damage occurs when the immune system responds to the infection.
- White blood cells, in particular lymphocytes, activate a variety of chemicals (cytokines), which make fluid leak 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 organs 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 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 (neutrophils) to the lungs.
- The neutrophils engulf and kill the offending organisms, but also release cytokines, which result in a general activation of the immune system. This causes 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
- A variety of parasites can affect the lungs.
- 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.
Mode of Transmission
1. Microaspiration of Oropharyngeal Contents
Aspiration of 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 gastroesopahegeal reflux or impaired gag reflex and cough reflex.[2]
2. Inhalation of Aerosolized Droplets
Inhalation of aerosolized droplets of 0.5 to 1 micrometer is the most common pathway of acquiring pneumonia. A few bacterial and viral infections are transmitted in this fashion. The lung can normally filter out particles between 0.5 to 2 micrometer by recruiting the alveolar macrophages.[2]
3. Blood-Borne or Systemic Infection
Microbial entered through circulation may also result in pulmonary infections. Blood-borne pneumonia is seen more commonly in intravenous drug users. Staphylococcal 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 pulmonary procedure or a penetrating trauma to the lungs. A local spread of a hepatic abscess can also lead to pneumonia.
Pathogenesis
Virulence Factors
Several strategies are evolved to evade host defence mechanisms and facilitate speading before establishing an infection.
- Influenza virus possesses neuraminidases for cleavage of sialic acid residues on the cell surface and viral proteins, which prevent aggregation and facilitate propagation of viral particles.
- Chlamydophila pneumoniae induces complete abortion of cilia motions which assists colonization at the respiratory epithelium.[3]
- Mycoplasma pneumoniae produces a virulence factor with ADP-ribosylating activity which is responsible for airway cellular damage and mucociliary dysfunction.[4]
- Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis produce proteases that split mucosal IgA.
- Streptococcus pneumoniae possesses pneumolysin that aid the bacteria during colonization, by facilitating adherence to the host,[5] during invasion by damaging host cells,[6] and during infection by interfering with the host immune response.[7]
Host Factors
The lungs can normally filter out large droplets of aerosols. Smaller droplets of the size of 0.5 to 2 micrometer are deposited on the alveoli and then engulfed by alevolar macrophages. These macrophages release cytokines and chemokines, which also includes tumor necrosis factor-alpha, interleukin-8 and LTB4. The neutrophils are recruited by these cells to eliminate these microorganisms.[8][1]
Diminished Mucociliary Clearance
The cilia lining the respiratory epithelium serve to move secreted mucus containing trapped foreign particles including pathogens towards the oropharynx for either expectoration or swallowing. Elevated incidence of pneumonia in patients with genetic defects affecting mucociliary clearance such as primary ciliary dyskinesia suggests its role in the pathogenesis of community-acquired pneumonia.
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 accidents and drug overdosages is associated with an enhanced risk for aspiration pneumonia. Another relation to cough is genetic polymorphisms in the angiotensin-converting enzyme (ACE) gene. The role of cough in preventing pneumonia may be explained by a higher risk for developing pneumonia in homozygotes carrying deletion/deletion (DD) genotype who are found to have lower levels of bradykinin and tachykinins such as substance P.[9][10]
Defective Immnue System
Pathogen-associated molecular patterns (PAMPs) are initially recognized by Toll-like receptors (TLRs) and other pattern-recognition receptors (PRRs) of the innate immune system. Effectors in the acquired immune system are involved in elimination of microorganisms and generation of immunological memory. Other components in the immune system such as complement system, cytokines, and collectins, also mediate the defense against microorganisms causing pneumonia.
References
- ↑ 1.0 1.1 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) - ↑ 2.0 2.1 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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)