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==Overview==
==Overview==
[[Smallpox virus]] may be transmitted from contaminated surfaces or aerosolized particles. It is capable of inducing harm by evading the host's [[immune system]] and replicating inside host's [[cells]]. The [[virus]] may cause 3 forms of the disease: 1) ''ordinary''; 2) ''flat-type''; or 3) ''hemorrhagic [[smallpox]]''. It [[infection|infects]] different [[cells]] of the body, being known by it's propensity to cause characteristic pock like lesions on the [[skin]].


==Infection==
==Transmission==
[[image:4728_lores-1.jpg|thumb|200px|left|Child showing rash due to smallpox variola major virus]]
[[Smallpox virus]] is transmitted by:<ref name=CDC>{{cite web | title = Smallpox disease overview | url = http://www.bt.cdc.gov/agent/smallpox/overview/disease-facts.asp }}</ref>
* Physical contact
* Contact with [[infected]] [[body fluids]]
* Contact with [[infected]] objects
* Air through aerosolized particles


Smallpox is highly contagious, although less so than other infectious diseases. Smallpox is not notably infectious in the [[prodrome|prodromal]] period—viral shedding is usually delayed until the appearance of the rash. Smallpox is transmitted primarily through prolonged social contact or direct contact with infected body fluids or contaminated objects (fomites) such as bedding or clothes. Infection in the natural disease will be via the [[lung]]s. The fact that there has been no recurrence of wild smallpox since its elimination thirty years ago makes the assumptions made at the start of the elimination campaign - that human smallpox carriers do not exist, and that the virus does not exist outside humans - some of the most certain facts in medical science.
==Genetics==
[[Smallpox]] [[pathogenicity]] is due to its ability to evade the host's [[immune system]]. Most [[proteins]] responsible for the [[pathogenesis]] of the [[virus]] are located at the terminal [[DNA]] regions of the [[virus]].


Smallpox is a member of the family [[poxviridae]], subfamily chordopoxvirinae. The lifecycle of poxviruses is complicated by having multiple infectious forms, with differing mechanisms of cell entry. It is a large virus, with a double stranded DNA genome of about 200 [[base pair|kilobases]], making it more complicated than many [[bacteria]].  
[[Genetic]] comparisons of the [[smallpox virus]] with the [[vaccinia virus]] allowed to observe certain [[genetic]] changes that may be responsible for the [[virulence]] of the [[smallpox virus]]. However, without studying the [[gene]] transcripts, it is not possible to draw objective conclusions.<ref name="pmid8184534">{{cite journal| author=Massung RF, Liu LI, Qi J, Knight JC, Yuran TE, Kerlavage AR et al.| title=Analysis of the complete genome of smallpox variola major virus strain Bangladesh-1975. | journal=Virology | year= 1994 | volume= 201 | issue= 2 | pages= 215-40 | pmid=8184534 | doi=10.1006/viro.1994.1288 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8184534  }} </ref>


The incubation period between contraction and the first obvious symptoms of the disease is around 12 days. In the initial growth phase the virus seems to move from cell to cell, but around the 12th day, [[lysis]] of many infected cells occurs and the virus is found in the [[blood]]stream in large numbers. The initial or prodromal symptoms are similar to other viral diseases such as [[influenza]] and the [[common cold]]: [[fever]]s, [[muscle]] pain, [[stomach]] aches, etc. The digestive tract is commonly involved, leading to [[vomit]]ing. Most people become prostrated at this stage.
==Pathogenesis==
The [[smallpox virus]] commonly enters the body through the [[upper respiratory tract]], invading the [[oropharyngeal]] and [[respiratory]] [[mucosa]].<ref>{{cite book | last = Cecil | first = Russell | title = Goldman's Cecil medicine | publisher = Elsevier/Saunders | location = Philadelphia | year = 2012 | isbn = 1437716040 }}</ref> Other possible ports of entry include: [[skin]], [[conjunctiva]] as well as through the [[placenta]].<ref name=WHO>{{cite web | title = Smallpox and its Eradication | url = http://apps.who.int/iris/bitstream/10665/39485/1/9241561106.pdf?ua=1 }}</ref> Although the [[viral]] scabs may contain life [[virus]]es, they are commonly contained within thickened material, which limits [[transmission]].


Smallpox virus preferentially attacks skin cells, and by days 12–15, smallpox infection becomes obvious. The attack on skin cells causes the characteristic [[pimple]]s associated with the disease. The pimples tend to erupt first in the mouth, then on the arms and the hands, and later on the rest of the body. At this point the pimples, called macules, are usually still fairly small. This is the stage at which the victim is most contagious.
Once in the [[respiratory]] [[mucosa]], the [[infection]] commonly progresses as:<ref name="MooreSeward2006">{{cite journal|last1=Moore|first1=Zack S|last2=Seward|first2=Jane F|last3=Lane|first3=J Michael|title=Smallpox|journal=The Lancet|volume=367|issue=9508|year=2006|pages=425–435|issn=01406736|doi=10.1016/S0140-6736(06)68143-9}}</ref><ref name=WHO>{{cite web | title = Smallpox and its Eradication | url = http://apps.who.int/iris/bitstream/10665/39485/1/9241561106.pdf?ua=1 }}</ref><ref name="BremanHenderson2002">{{cite journal|last1=Breman|first1=Joel G.|last2=Henderson|first2=D.A.|title=Diagnosis and Management of Smallpox|journal=New England Journal of Medicine|volume=346|issue=17|year=2002|pages=1300–1308|issn=0028-4793|doi=10.1056/NEJMra020025}}</ref>
* [[Asymptomatic]] [[respiratory]] [[mucosa]] [[infection]]
* [[Viral replication]] within [[respiratory epithelium]]
* Transient primary [[asymptomatic]] [[viraemia]]
* [[Virus]] enters [[macrophages]] and spreads to [[lymph nodes]] and [[reticuloendothelial system]], where it replicates during 4 - 14 days
* Exuberant secondary [[viraemia]], leading to [[symptom]] onset


By days 15–16 the condition worsens, and at this point the disease can take two very different courses, depending on whether it is ordinary or hemorrhagic smallpox. The most common type is classic ordinary smallpox, in which the pimples grow into vesicles and then fill up with pus, turning them into pustules. Ordinary smallpox generally takes one of two basic courses. In ''discrete'' ordinary smallpox, the pustules stand out on the skin separately. There is a greater chance of surviving this form. In ''confluent'' ordinary smallpox, the blisters merge together into sheets which begin to detach the outer layers of skin from the underlying flesh. This form is usually fatal. If the patient survives the course of the disease, the pustules deflate in time (the duration is variable), and start to dry up, usually beginning on day 28. Eventually the pustules completely dry and start to flake off. Once all of the pustules flake off, the patient is considered cured, and is no longer contagious.
During secondary [[viraemia]] the [[virus]] [[infection|infects]] mucous cells of the [[pharynx]] and [[mouth]], and [[endothelium]] of the [[capillaries]] of the [[dermis]], causing [[skin]] lesions. Other [[organs]] with high [[viral]] loads include:<ref name="BremanHenderson2002">{{cite journal|last1=Breman|first1=Joel G.|last2=Henderson|first2=D.A.|title=Diagnosis and Management of Smallpox|journal=New England Journal of Medicine|volume=346|issue=17|year=2002|pages=1300–1308|issn=0028-4793|doi=10.1056/NEJMra020025}}</ref>


[[Chickenpox]] and smallpox can be distinguished in the field via several methods.  An examination of the patient's [[Hand|palm]]s and [[sole]]s is necessary: unlike smallpox, chickenpox does not usually affect the palms and soles. Additionally, chickenpox pustules are of varying size due to variations in the timing of pustule eruption: smallpox pustules are all very nearly the same size since the viral effect progresses more uniformly.
* [[Spleen]]
 
* [[Liver]]
 
* [[Bone marrow]]
 
* [[Kidneys]]
 
Before development of the [[rash]], the first lesions appear on the [[oropharyngeal]] [[mucosa]], at which time the [[virus]] is released through the [[mucosal]] secretions, making that patient [[infectious]].
 
[[Skin lesions]] develop due to migration of [[macrophages]] to the [[infected]] areas of the [[dermis]], leading to [[edema]] and [[necrosis]]. With the influx of more [[polymorphonuclear cells]], [[skin]] [[pustules]] will develop.<ref name="MooreSeward2006">{{cite journal|last1=Moore|first1=Zack S|last2=Seward|first2=Jane F|last3=Lane|first3=J Michael|title=Smallpox|journal=The Lancet|volume=367|issue=9508|year=2006|pages=425–435|issn=01406736|doi=10.1016/S0140-6736(06)68143-9}}</ref>
 
The [[immune system]] responds to the [[viremia]] with activation of [[lymphocytes]] T and B and concomitant production of:<ref name="BremanHenderson2002">{{cite journal|last1=Breman|first1=Joel G.|last2=Henderson|first2=D.A.|title=Diagnosis and Management of Smallpox|journal=New England Journal of Medicine|volume=346|issue=17|year=2002|pages=1300–1308|issn=0028-4793|doi=10.1056/NEJMra020025}}</ref>
 
* Neutralizing [[antibodies]], during first week of disease, remaining for many years
 
* Hemagglutination-inhibition [[antibodies]], by the 16th day of [[infection]], beginning to decrease after 1 year
 
* Complement-fixation [[antibodies]], by the 18th day of [[infection]], beginning to decrease after 1 year
 
* [[Memory T cell]]s, remaining for 50 years
 
Death by [[smallpox]] was commonly due to [[toxemia]], following:<ref name="MooreSeward2006">{{cite journal|last1=Moore|first1=Zack S|last2=Seward|first2=Jane F|last3=Lane|first3=J Michael|title=Smallpox|journal=The Lancet|volume=367|issue=9508|year=2006|pages=425–435|issn=01406736|doi=10.1016/S0140-6736(06)68143-9}}</ref>
 
* [[Hypotension]]
 
* [[Coagulopathy]]
 
* [[Multiorgan failure]]
 
* [[Bacterial infections]]
 
==Gross Pathology==
Depending on the status of the patient's [[immune system]], there are 3 forms of [[smallpox]]:<ref>{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | year = 2010 | isbn = 0443068399 }}</ref>
 
===Ordinary Smallpox===
Ordinary smallpox is characterized by the following progression of lesions:<ref>{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | year = 2010 | isbn = 0443068399 }}</ref>
* Initial [[Hypopigmentation|hypopigmented]] [[macules]], which appear first in the [[mouth]]
* [[Macules]] progress into [[papules]] and subsequently to [[vesicles]]
* [[Vesicles]] become [[pustules]]
* At the 14th day, [[pustules]] loose liquid content and become crusted
* At the 3rd week, most crusts will separate (palms and soles last)
This form of [[smallpox]] is typical of an [[immunocompetent]] patient, in whom the [[immune system]] is able to inhibit [[viral replication]].
 
===Flat-type Smallpox===
Flat-type smallpox is characterized by the following progression of lesions:<ref>{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | year = 2010 | isbn = 0443068399 }}</ref>
* Delayed appearance of [[macules]]
* Slow progression of the lesions, usually with flat and soft appearance
* Possible slough of [[skin]] sections
Most cases are fatal with presence of severe [[toxemia]]. This form of [[smallpox]] is typical of patients with weak [[Cell-mediated immunity|cellular immune response]] to the [[virus]].
 
===Hemorrhagic-type smallpox===
Hemorrhagic-type smallpox is characterized by the following progression of lesions:<ref>{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | year = 2010 | isbn = 0443068399 }}</ref>
* [[Skin]] [[petechiae]]
* [[Mucous membrane]] and [[conjunctival]] [[bleeding]]
* [[Subcutaneous]] [[hemorrhage]] gives [[skin]] and [[conjunctiva|conjunctivae]] deep red appearance
* Organ bleeding
* Early death by multi organ failure, usually before appearance of [[macula|maculae]].
This rare form of [[smallpox]] is typical of patients with severely compromised [[immune response]], in which there is intense [[viral replication]] in the [[bone marrow]] and [[spleen]]. It is also associated with intense [[toxemia]].
 
==Microscopic Pathology==
The typical [[skin]] [[vesicles]] observed in [[smallpox]] occur following:<ref>{{cite book | last = Cecil | first = Russell | title = Goldman's Cecil medicine | publisher = Elsevier/Saunders | location = Philadelphia | year = 2012 | isbn = 1437716040 }}</ref>
* [[Viral infection]] of the [[epidermal]] [[cell]]
* [[Cells]] in [[malpighian layer]] entering balloon degeneration, from formation of [[vacuoles]]
* [[Cytoplasmic]] enlargement leading to loss of [[nuclear]] material
* Destruction of upper and middle layers of [[stratum spinosum]]
* Formation of [[vesicles]], with high [[viral]] index
 
On the other hand, in the [[infected]] [[mucous]] surfaces, the [[viral]] proliferation and absence of the [[stratum corneum]], lead to the formation of [[ulcers]]. These ultimately lead to the release of greater loads of [[virus]] into the [[oropharynx]].<ref>{{cite book | last = Cecil | first = Russell | title = Goldman's Cecil medicine | publisher = Elsevier/Saunders | location = Philadelphia | year = 2012 | isbn = 1437716040 }}</ref>
 
===Histopathology===
Poxviruses are characterized by [[cytoplasmic]] inclusions, however, these do not identify specifically the [[smallpox virus]] on a [[biopsy]]. There are 2 types of [[inclusion bodies]]:<ref>{{cite book | last = Mandell | first = Gerald | title = Mandell, Douglas, and Bennett's principles and practice of infectious diseases | publisher = Churchill Livingstone/Elsevier | location = Philadelphia, PA | year = 2010 | isbn = 0443068399 }}</ref>
====A-type====
Typical of some [[viruses]] of the:
* Genus Orthopoxvirus:
:* Cowpox virus
:* Ectromelia virus
* Genus Avipoxvirus
 
====B-type, or Guarnieri bodies====
* In areas of active [[viral replication]]
* Present in [[infections]] by all poxviruses
* Appear as [[basophilic]] bodies near the [[nucleus]] on hematoxylin and eosin-stained samples
* Evident at [[epithelial cells]] underlying [[vesicles]] and [[pustules]]
 
==Gallery==
<gallery>
Image:Smallpox-1.jpg|Hematoxylin and eosin (H&E)-stained tissue sample, reveals some of the histopathologic changes found in a human skin tissue sample from the site of a smallpox lesion. <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image:Smallpox-2.jpg|hematoxylin and eosin (H&E)-stained tissue sample, reveals some of the histopathologic changes found in a human skin tissue sample from the site of a smallpox lesion. <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image:Smallpox-5.jpg| This is a chickenpox scab (left), and smallpox scab (right) viewed in profile as a demonstration in comparative morphology. <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image:Smallpox-7.jpg| This image depicts three mounted chickenpox scabs seen from the side revealing the superficiality of these scabs when morphologically compared to a smallpox scab.<SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image:Smallpox-9.jpg| Viewed from above, this image depicts a smallpox scab (left), and chickenpox scab (right) as a demonstration in comparative morphology. <SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
Image:Smallpox-74.jpg| Cytoarchitectural pathologic changes found in a sample of skin tissue from a eczema vaccinatum lesion, which had manifested itself after this patient had received a smallpox vaccination.<SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
 
 
Image:Smallpox-76.jpg| Cytoarchitectural pathologic changes found in a sample of skin tissue from a eczema vaccinatum lesion, which had manifested itself after this patient had received a smallpox vaccination.<SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
</gallery>


==References==
==References==
{{reflist|2}}
{{Reflist|2}}
 
[[Category:Needs overview]]
[[Category:Disease]]
 
[[Category:Pediatrics]]
[[Category:Smallpox]]
[[Category:Viral diseases]]
[[Category:Poxviruses]]


{{WH}}
{{WH}}
{{WS}}
{{WS}}
[[Category:Disease]]
[[Category:Infectious disease]]
[[Category:Pediatrics]]

Latest revision as of 19:04, 18 September 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Overview

Smallpox virus may be transmitted from contaminated surfaces or aerosolized particles. It is capable of inducing harm by evading the host's immune system and replicating inside host's cells. The virus may cause 3 forms of the disease: 1) ordinary; 2) flat-type; or 3) hemorrhagic smallpox. It infects different cells of the body, being known by it's propensity to cause characteristic pock like lesions on the skin.

Transmission

Smallpox virus is transmitted by:[1]

Genetics

Smallpox pathogenicity is due to its ability to evade the host's immune system. Most proteins responsible for the pathogenesis of the virus are located at the terminal DNA regions of the virus.

Genetic comparisons of the smallpox virus with the vaccinia virus allowed to observe certain genetic changes that may be responsible for the virulence of the smallpox virus. However, without studying the gene transcripts, it is not possible to draw objective conclusions.[2]

Pathogenesis

The smallpox virus commonly enters the body through the upper respiratory tract, invading the oropharyngeal and respiratory mucosa.[3] Other possible ports of entry include: skin, conjunctiva as well as through the placenta.[4] Although the viral scabs may contain life viruses, they are commonly contained within thickened material, which limits transmission.

Once in the respiratory mucosa, the infection commonly progresses as:[5][4][6]

During secondary viraemia the virus infects mucous cells of the pharynx and mouth, and endothelium of the capillaries of the dermis, causing skin lesions. Other organs with high viral loads include:[6]

Before development of the rash, the first lesions appear on the oropharyngeal mucosa, at which time the virus is released through the mucosal secretions, making that patient infectious.

Skin lesions develop due to migration of macrophages to the infected areas of the dermis, leading to edema and necrosis. With the influx of more polymorphonuclear cells, skin pustules will develop.[5]

The immune system responds to the viremia with activation of lymphocytes T and B and concomitant production of:[6]

  • Neutralizing antibodies, during first week of disease, remaining for many years
  • Hemagglutination-inhibition antibodies, by the 16th day of infection, beginning to decrease after 1 year
  • Complement-fixation antibodies, by the 18th day of infection, beginning to decrease after 1 year

Death by smallpox was commonly due to toxemia, following:[5]

Gross Pathology

Depending on the status of the patient's immune system, there are 3 forms of smallpox:[7]

Ordinary Smallpox

Ordinary smallpox is characterized by the following progression of lesions:[8]

This form of smallpox is typical of an immunocompetent patient, in whom the immune system is able to inhibit viral replication.

Flat-type Smallpox

Flat-type smallpox is characterized by the following progression of lesions:[9]

  • Delayed appearance of macules
  • Slow progression of the lesions, usually with flat and soft appearance
  • Possible slough of skin sections

Most cases are fatal with presence of severe toxemia. This form of smallpox is typical of patients with weak cellular immune response to the virus.

Hemorrhagic-type smallpox

Hemorrhagic-type smallpox is characterized by the following progression of lesions:[10]

This rare form of smallpox is typical of patients with severely compromised immune response, in which there is intense viral replication in the bone marrow and spleen. It is also associated with intense toxemia.

Microscopic Pathology

The typical skin vesicles observed in smallpox occur following:[11]

On the other hand, in the infected mucous surfaces, the viral proliferation and absence of the stratum corneum, lead to the formation of ulcers. These ultimately lead to the release of greater loads of virus into the oropharynx.[12]

Histopathology

Poxviruses are characterized by cytoplasmic inclusions, however, these do not identify specifically the smallpox virus on a biopsy. There are 2 types of inclusion bodies:[13]

A-type

Typical of some viruses of the:

  • Genus Orthopoxvirus:
  • Cowpox virus
  • Ectromelia virus
  • Genus Avipoxvirus

B-type, or Guarnieri bodies

Gallery

References

  1. ↑ "Smallpox disease overview".
  2. ↑ Massung RF, Liu LI, Qi J, Knight JC, Yuran TE, Kerlavage AR; et al. (1994). "Analysis of the complete genome of smallpox variola major virus strain Bangladesh-1975". Virology. 201 (2): 215–40. doi:10.1006/viro.1994.1288. PMID 8184534.
  3. ↑ Cecil, Russell (2012). Goldman's Cecil medicine. Philadelphia: Elsevier/Saunders. ISBN 1437716040.
  4. ↑ 4.0 4.1 "Smallpox and its Eradication" (PDF).
  5. ↑ 5.0 5.1 5.2 Moore, Zack S; Seward, Jane F; Lane, J Michael (2006). "Smallpox". The Lancet. 367 (9508): 425–435. doi:10.1016/S0140-6736(06)68143-9. ISSN 0140-6736.
  6. ↑ 6.0 6.1 6.2 Breman, Joel G.; Henderson, D.A. (2002). "Diagnosis and Management of Smallpox". New England Journal of Medicine. 346 (17): 1300–1308. doi:10.1056/NEJMra020025. ISSN 0028-4793.
  7. ↑ Mandell, Gerald (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 0443068399.
  8. ↑ Mandell, Gerald (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 0443068399.
  9. ↑ Mandell, Gerald (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 0443068399.
  10. ↑ Mandell, Gerald (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 0443068399.
  11. ↑ Cecil, Russell (2012). Goldman's Cecil medicine. Philadelphia: Elsevier/Saunders. ISBN 1437716040.
  12. ↑ Cecil, Russell (2012). Goldman's Cecil medicine. Philadelphia: Elsevier/Saunders. ISBN 1437716040.
  13. ↑ Mandell, Gerald (2010). Mandell, Douglas, and Bennett's principles and practice of infectious diseases. Philadelphia, PA: Churchill Livingstone/Elsevier. ISBN 0443068399.
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 14.6 "Public Health Image Library (PHIL), Centers for Disease Control and Prevention".

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