Diphtheria overview: Difference between revisions
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==Overview== | ==Overview== | ||
'''Diphtheria''' ([[Greek language|Greek]] ''διφθερα'' (''diphthera'') — “pair of leather scrolls”) is an [[upper respiratory tract]] illness characterized by [[sore throat]], low-grade [[fever]], and an adherent membrane (a ''pseudomembrane'') on the [[tonsil|tonsils]], [[pharynx]], and/or [[nasal cavity]].<ref name=CDCDiphtheria> Diphtheria. Centers for Disease Control and Prevention (2016) http://www.cdc.gov/diphtheria/ Accessed on July 28, 2016 </ref><ref name=Sherris>{{cite book | author = Ryan KJ, Ray CG (editors) | title = Sherris Medical Microbiology | edition = 4th ed. | pages =299–302 | publisher = McGraw Hill | year = 2004 | isbn = 0838585299 }}</ref> A milder form of [[diphtheria]] can be restricted to the [[skin]]. It is caused by ''[[Corynebacterium diphtheriae]]'', a [[Facultative anaerobic organism|facultatively anaerobic]] [[ | '''Diphtheria''' ([[Greek language|Greek]] ''διφθερα'' (''diphthera'') — “pair of leather scrolls”) is an [[upper respiratory tract]] illness characterized by [[sore throat]], low-grade [[fever]], and an adherent [[membrane]] (a ''pseudomembrane'') on the [[tonsil|tonsils]], [[pharynx]], and/or [[nasal cavity]].<ref name=CDCDiphtheria> Diphtheria. Centers for Disease Control and Prevention (2016) http://www.cdc.gov/diphtheria/ Accessed on July 28, 2016 </ref><ref name=Sherris>{{cite book | author = Ryan KJ, Ray CG (editors) | title = Sherris Medical Microbiology | edition = 4th ed. | pages =299–302 | publisher = McGraw Hill | year = 2004 | isbn = 0838585299 }}</ref> A milder form of [[diphtheria]] can be restricted to the [[skin]]. It is caused by ''[[Corynebacterium diphtheriae]]'', a [[Facultative anaerobic organism|facultatively anaerobic]] [[gram-positive]] [[bacterium]].<ref>Office of Laboratory Security, Public Health Agency of Canada [http://www.phac-aspc.gc.ca/msds-ftss/msds42e.html ''Corynebacterium diphtheriae''] Material Safety Data Sheet. January 2000.</ref> | ||
Diphtheria is a highly contagious disease that is spread via direct physical contact or breathing the [[particulate|aerosolized]] secretions of infected individuals. Once quite common, diphtheria has largely been eradicated in developed nations through widespread [[vaccination]]. In the [[United States]], for instance, there were only 57 reported cases of diphtheria between 1980 and 2004 (and only five cases since 2000),<ref name =Pinkbook>{{cite book | author = Atkinson W, Hamborsky J, McIntyre L, Wolfe S, eds. | title = Diphtheria. ''in:'' Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book) | edition = 10th ed. | pages = 59–70 | publisher = Washington DC: Public Health Foundation | year = 2007 | url = http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/dip.pdf }}</ref> as the [[DPT vaccine|DPT]](''Diphtheria–[[Pertussis]]–[[Tetanus]]'') vaccine is given to all schoolchildren. Boosters of the vaccine are recommended for adults, since the benefits of | [[Diphtheria]] is a highly contagious disease that is spread via direct physical contact or breathing the [[particulate|aerosolized]] secretions of infected individuals. Once quite common, diphtheria has largely been eradicated in developed nations through widespread [[vaccination]]. In the [[United States]], for instance, there were only 57 reported cases of diphtheria between 1980 and 2004 (and only five cases since 2000),<ref name =Pinkbook>{{cite book | author = Atkinson W, Hamborsky J, McIntyre L, Wolfe S, eds. | title = Diphtheria. ''in:'' Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book) | edition = 10th ed. | pages = 59–70 | publisher = Washington DC: Public Health Foundation | year = 2007 | url = http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/dip.pdf }}</ref> as the [[DPT vaccine|DPT]](''Diphtheria–[[Pertussis]]–[[Tetanus]]'') vaccine is given to all schoolchildren. Boosters of the [[vaccine]] are recommended for adults, since the benefits of [[vaccination]] decrease with age; they are particularly highly recommended for those traveling to areas where the disease has not yet been eradicated. | ||
==Historical perspective== | ==Historical perspective== | ||
Before 1826, diphtheria was known by different names across the world. In 1826, the term "diphtheria" was introduced by French physician [[Pierre Bretonneau]]. The name alludes to the leathery, sheath-like membrane that grows on the [[tonsils]], [[throat]], and in the nose.<ref>Pierre Bretonneau, ''Des inflammations spéciales du tissu muqueux, et en particulier de la diphtérite, ou inflammation pelliculaire, connue sous le nom de croup, d'angine maligne, d'angine gangréneuse, etc.'' [Special inflammations of mucous tissue, and in particular diphtheria or skin inflammation, known by the name of croup, malignant throat infection, gangrenous throat infection, etc.] (Paris, France: Crevot, 1826).<br> | Before 1826, [[diphtheria]] was known by different names across the world. In 1826, the term "diphtheria" was introduced by French physician [[Pierre Bretonneau]]. The name alludes to the leathery, sheath-like [[membrane]] that grows on the [[tonsils]], [[throat]], and in the nose in patients with the disease.<ref>Pierre Bretonneau, ''Des inflammations spéciales du tissu muqueux, et en particulier de la diphtérite, ou inflammation pelliculaire, connue sous le nom de croup, d'angine maligne, d'angine gangréneuse, etc.'' [Special inflammations of mucous tissue, and in particular diphtheria or skin inflammation, known by the name of croup, malignant throat infection, gangrenous throat infection, etc.] (Paris, France: Crevot, 1826).<br> | ||
A condensed version of this work is available in: P. Bretonneau (1826) [http://babel.hathitrust.org/cgi/pt?id=mdp.39015062233708;view=1up;seq=217 "Extrait du traité de la diphthérite, angine maligne, ou croup épidémique"] (Extract from the treatise on diphtheria, malignant throat infection, or epidemic croup), ''Archives générales de médecine'', series 1, 11 : 219-254. From p. 230: " … M. Bretonneau a cru convenable de l'appeler diphthérite, dérivé de ΔΙΦθΕΡΑ, … " ( … Mr. Bretonneau thought it appropriate to call it diphtheria, derived from ΔΙΦθΕΡΑ [diphthera], … )</ref><ref>{{cite web|title=Diphtheria|url=http://www.etymonline.com/index.php?term=diphtheria|work=Online Etymology Dictionary|accessdate=29 November 2012}}</ref> | A condensed version of this work is available in: P. Bretonneau (1826) [http://babel.hathitrust.org/cgi/pt?id=mdp.39015062233708;view=1up;seq=217 "Extrait du traité de la diphthérite, angine maligne, ou croup épidémique"] (Extract from the treatise on diphtheria, malignant throat infection, or epidemic croup), ''Archives générales de médecine'', series 1, 11 : 219-254. From p. 230: " … M. Bretonneau a cru convenable de l'appeler diphthérite, dérivé de ΔΙΦθΕΡΑ, … " ( … Mr. Bretonneau thought it appropriate to call it diphtheria, derived from ΔΙΦθΕΡΑ [diphthera], … )</ref><ref>{{cite web|title=Diphtheria|url=http://www.etymonline.com/index.php?term=diphtheria|work=Online Etymology Dictionary|accessdate=29 November 2012}}</ref> | ||
==Classification== | ==Classification== | ||
[[Diphtheria]] can be classified according to the type of [[Corynebacterium]] that causes | [[Diphtheria]] can be classified according to the type of [[Corynebacterium]] that causes a specific case. It can also be classified according to the resulting clinical presentation into [[respiratory]], [[systemic]], or [[cutaneous]] [[diphtheria]].<ref name="pmid6321350">{{cite journal |vauthors=Wong TP, Groman N |title=Production of diphtheria toxin by selected isolates of Corynebacterium ulcerans and Corynebacterium pseudotuberculosis |journal=Infect. Immun. |volume=43 |issue=3 |pages=1114–6 |year=1984 |pmid=6321350 |pmc=264307 |doi= |url=}}</ref><ref name="pmid26189434">{{cite journal |vauthors=Moore LS, Leslie A, Meltzer M, Sandison A, Efstratiou A, Sriskandan S |title=Corynebacterium ulcerans cutaneous diphtheria |journal=Lancet Infect Dis |volume=15 |issue=9 |pages=1100–7 |year=2015 |pmid=26189434 |doi=10.1016/S1473-3099(15)00225-X |url=}}</ref> | ||
==Causes== | ==Causes== | ||
''C. diphtheriae'' is a [[Facultative anaerobic organism|facultatively anaerobic]], [[ | ''C. diphtheriae'' is a [[Facultative anaerobic organism|facultatively anaerobic]], [[gram positive]] organism that is characterized by non-encapsulated, non-sporulated, immobile, straight or curved rods with a length of 1 to 8 µm and width of 0.3 to 0.8 µm. These rods form ramified aggregations in culture that have been described as looking like "Chinese characters." The bacterium may contain polymetaphosphate aggregates called Volutin granules. It is only pathogenic in humans.<ref>{{cite book |last=Nester |first=Eugene W. |year=2004 |title=Microbiology: A Human Perspective |edition=Fourth |location=Boston |publisher=McGraw-Hill |isbn=0-07-247382-7 |display-authors=etal}}</ref> | ||
==Differential diagnosis== | ==Differential diagnosis== | ||
[[Respiratory]] [[diphtheria]] must be differentiated from [[respiratory]] tract or other infections that present with [[fever]], [[neck]] swelling, [[cough]] and/or [[pharyngeal]] exudates. | [[Respiratory]] [[diphtheria]] must be differentiated from [[respiratory]] tract or other infections that present with [[fever]], [[neck]] [[swelling]], [[cough]], and/or [[pharyngeal]] exudates. [[Cutaneous]] [[diphtheria]] must be differentiated from other [[bacteria|bacterial]] and [[fungi|fungal]] causes of [[skin]] [[ulceration]].<ref name= "CDC diphtheria"> Center for Disease Control and Prevention https://www.cdc.gov/diphtheria/downloads/dip-cklist-diag.pdf Accessed on Oct. 7, 2016. </ref><ref name="pmid18572973">{{cite journal |vauthors=Zeegelaar JE, Faber WR |title=Imported tropical infectious ulcers in travelers |journal=Am J Clin Dermatol |volume=9 |issue=4 |pages=219–32 |year=2008 |pmid=18572973 |doi= |url=}}</ref> | ||
==Epidemiology and Demographics== | ==Epidemiology and Demographics== | ||
Diphtheria is | [[Diphtheria]] is observed worldwide, though it is rare in the United States due to widespread [[vaccination]]. [[Diphtheria]] is a significant cause of illness and death in developing countries, where [[vaccination]] coverage tends to be lower. | ||
==Risk factors== | ==Risk factors== | ||
Common risk factors in the development of | Common risk factors in the development of [[diphtheria]] include lack of [[immunization]], history of travel to areas endemic for [[diphtheria]], exposure to overcrowding and/or poor sanitary conditions, and [[immunocompromised]] status.<ref name="pmid10657203">{{cite journal| author=Quick ML, Sutter RW, Kobaidze K, Malakmadze N, Nakashidze R, Murvanidze S et al.| title=Risk factors for diphtheria: a prospective case-control study in the Republic of Georgia, 1995-1996. | journal=J Infect Dis | year= 2000 | volume= 181 Suppl 1 | issue= | pages= S121-9 | pmid=10657203 | doi=10.1086/315563 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10657203 }} </ref><ref name="pmid9950440">{{cite journal| author=Vitek CR, Brennan MB, Gotway CA, Bragina VY, Govorukina NV, Kravtsova ON et al.| title=Risk of diphtheria among schoolchildren in the Russian Federation in relation to time since last vaccination. | journal=Lancet | year= 1999 | volume= 353 | issue= 9150 | pages= 355-8 | pmid=9950440 | doi=10.1016/S0140-6736(98)03488-6 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9950440 }} </ref><ref name="pmid805182">{{cite journal| author=Koopman JS, Campbell J| title=The role of cutaneous diphtheria infections in a diphtheria epidemic. | journal=J Infect Dis | year= 1975 | volume= 131 | issue= 3 | pages= 239-44 | pmid=805182 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=805182 }} </ref><ref name="pmid4972946">{{cite journal| author=Belsey MA, Sinclair M, Roder MR, LeBlanc DR| title=Corynebacterium diphtheriae skin infections in Alabama and Louisiana. A factor in the epidemiology of diphtheria. | journal=N Engl J Med | year= 1969 | volume= 280 | issue= 3 | pages= 135-41 | pmid=4972946 | doi=10.1056/NEJM196901162800304 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4972946 }} </ref><ref name="pmid5814141">{{cite journal| author=Favorova LA| title=The risk of infection in droplet infections. The influence of overcrowding and prolonged contact on transmission of the diphtheria pathogen. | journal=J Hyg Epidemiol Microbiol Immunol | year= 1969 | volume= 13 | issue= 1 | pages= 73-82 | pmid=5814141 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5814141 }} </ref> | ||
==Screening== | ==Screening== | ||
There are no screening recommendations for [[diphtheria]]. <ref name= "USPSTF">USPSTF https://www.uspreventiveservicestaskforce.org/BrowseRec/Search?s=diphtheria Accessed on Oct. 7, 2016. </ref> | There are no screening recommendations for [[diphtheria]].<ref name= "USPSTF">USPSTF https://www.uspreventiveservicestaskforce.org/BrowseRec/Search?s=diphtheria Accessed on Oct. 7, 2016. </ref> | ||
==Natural History, Complications, and Prognosis== | ==Natural History, Complications, and Prognosis== | ||
Diphtheria is a vaccine preventable disease | Diphtheria is a vaccine-preventable disease that can lead to such severe complications as [[respiratory failure]], [[myocarditis]], [[polyneuropathies]], and death.<ref name="pmid490806">{{cite journal| author=Dobie RA, Tobey DN| title=Clinical features of diphtheria in the respiratory tract. | journal=JAMA | year= 1979 | volume= 242 | issue= 20 | pages= 2197-201 | pmid=490806 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=490806 }} </ref><ref name="pmid14069096">{{cite journal| author=MORGAN BC| title=CARDIAC COMPLICATIONS OF DIPHTHERIA. | journal=Pediatrics | year= 1963 | volume= 32 | issue= | pages= 549-57 | pmid=14069096 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14069096 }} </ref><ref name="pmid24365424">{{cite journal| author=Sanghi V| title=Neurologic manifestations of diphtheria and pertussis. | journal=Handb Clin Neurol | year= 2014 | volume= 121 | issue= | pages= 1355-9 | pmid=24365424 | doi=10.1016/B978-0-7020-4088-7.00092-4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24365424 }} </ref><ref name="pmid27260583">{{cite journal| author=Jain A, Samdani S, Meena V, Sharma MP| title=Diphtheria: It is still prevalent!!! | journal=Int J Pediatr Otorhinolaryngol | year= 2016 | volume= 86 | issue= | pages= 68-71 | pmid=27260583 | doi=10.1016/j.ijporl.2016.04.024 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27260583 }} </ref><ref name=WHOD>http://www.who.int/immunization/topics/diphtheria/en/index1.html Accessed on October 7, 2016</ref><ref name="pmid16528112">{{cite journal| author=Jayashree M, Shruthi N, Singhi S| title=Predictors of outcome in patients with diphtheria receiving intensive care. | journal=Indian Pediatr | year= 2006 | volume= 43 | issue= 2 | pages= 155-60 | pmid=16528112 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16528112 }} </ref> The overall case-fatality rate for [[diphtheria]] is 5–10%, with higher death rates (up to 20%) among patients younger than 5 or older than 40 years of age.<ref name=CDCD>http://www.cdc.gov/diphtheria/clinicians.html Accessed on October 7, 2016</ref> | ||
==Diagnosis== | ==Diagnosis== | ||
===History and Symptoms=== | ===History and Symptoms=== | ||
[[Respiratory]] [[diphtheria]] presents with a wide range of [[systemic]] and [[respiratory]] symptoms.<ref name="pmid490806">{{cite journal |vauthors=Dobie RA, Tobey DN |title=Clinical features of diphtheria in the respiratory tract |journal=JAMA |volume=242 |issue=20 |pages=2197–201 |year=1979 |pmid=490806 |doi= |url=}}</ref> [[Cutaneous]] [[diphtheria]] usually presents with [[ulcer|ulcers]] or pustular [[lesions]], which can involve various different parts of the body. [[Lesions]] may be covered by a grayish-white pseudomembrane, similar to tonsillar exudates of [[respiratory]] [[diphtheria]].<ref name="pmid27373251">{{cite journal |vauthors=Rappold LC, Vogelgsang L, Klein S, Bode K, Enk AH, Haenssle HA |title=Primary cutaneous diphtheria: management, diagnostic workup, and treatment as exemplified by a rare case report |journal=J Dtsch Dermatol Ges |volume=14 |issue=7 |pages=734–6 |year=2016 |pmid=27373251 |doi=10.1111/ddg.12722 |url=}}</ref> | |||
===Physical Examination=== | ===Physical Examination=== | ||
A patient with [[diptheria]] usually looks ill | A patient with [[diptheria]] usually looks ill; systemic signs such as [[fever]], [[tachypnea]], and [[tachycardia]] are common. [[Pharyngeal]], [[respiratory]], [[neurologic]], [[cardiac]], and other physical examination findings depend upon the extent and severity of the infection.<ref name="pmid490806">{{cite journal |vauthors=Dobie RA, Tobey DN |title=Clinical features of diphtheria in the respiratory tract |journal=JAMA |volume=242 |issue=20 |pages=2197–201 |year=1979 |pmid=490806 |doi= |url=}}</ref><ref name="pmid10657201">{{cite journal |vauthors=Kadirova R, Kartoglu HU, Strebel PM |title=Clinical characteristics and management of 676 hospitalized diphtheria cases, Kyrgyz Republic, 1995 |journal=J. Infect. Dis. |volume=181 Suppl 1 |issue= |pages=S110–5 |year=2000 |pmid=10657201 |doi=10.1086/315549 |url=}}</ref><ref name="pmid15578357">{{cite journal |vauthors=Kneen R, Nguyen MD, Solomon T, Pham NG, Parry CM, Nguyen TT, Ha TL, Taylor A, Vo TT, Nguyen TT, Day NP, White NJ |title=Clinical features and predictors of diphtheritic cardiomyopathy in Vietnamese children |journal=Clin. Infect. Dis. |volume=39 |issue=11 |pages=1591–8 |year=2004 |pmid=15578357 |doi=10.1086/425305 |url=}}</ref> | ||
===Laboratory Findings=== | ===Laboratory Findings=== | ||
A presumptive diagnosis of [[diphtheria]] is usually based on clinical features. A definitive diagnosis is made by growing the specific [[Corynebacterium]] species on special cultures from the [[respiratory]] tract secretions or [[cutaneous]] lesions. | A presumptive diagnosis of [[diphtheria]] is usually based on clinical features. A definitive diagnosis is made by growing the specific [[Corynebacterium]] species on special cultures from the [[respiratory]] tract secretions or [[cutaneous]] [[lesions]]. | ||
Culture of the lesion is | Culture of the [[lesion]] is performed to confirm the diagnosis. It is critical to take a swab of the [[pharyngeal]] area, especially any discolored areas, [[ulcerations]], and tonsillar crypts. Culture medium containing [[tellurite]] is preferred. | ||
[[PCR]] assays can also be performed on isolates, swabs, or [[membrane]] specimens to rapidly confirm the presence of the tox gene responsible for production of diphtheria toxin.<ref name="pmid10657205">{{cite journal |vauthors=Efstratiou A, Engler KH, Mazurova IK, Glushkevich T, Vuopio-Varkila J, Popovic T |title=Current approaches to the laboratory diagnosis of diphtheria |journal=J. Infect. Dis. |volume=181 Suppl 1 |issue= |pages=S138–45 |year=2000 |pmid=10657205 |doi=10.1086/315552 |url=}}</ref><ref name="pmid1740514">{{cite journal |vauthors=Colman G, Weaver E, Efstratiou A |title=Screening tests for pathogenic corynebacteria |journal=J. Clin. Pathol. |volume=45 |issue=1 |pages=46–8 |year=1992 |pmid=1740514 |pmc=495813 |doi= |url=}}</ref><ref name="pmid18017268">{{cite journal |vauthors=Widelock D |title=Laboratory Diagnosis of Diphtheria |journal=Am J Public Health Nations Health |volume=41 |issue=1 |pages=120 |year=1951 |pmid=18017268 |pmc=1525936 |doi= |url=}}</ref> | [[PCR]] assays can also be performed on isolates, swabs, or [[membrane]] specimens to rapidly confirm the presence of the ''tox'' gene responsible for the production of [[diphtheria toxin]].<ref name="pmid10657205">{{cite journal |vauthors=Efstratiou A, Engler KH, Mazurova IK, Glushkevich T, Vuopio-Varkila J, Popovic T |title=Current approaches to the laboratory diagnosis of diphtheria |journal=J. Infect. Dis. |volume=181 Suppl 1 |issue= |pages=S138–45 |year=2000 |pmid=10657205 |doi=10.1086/315552 |url=}}</ref><ref name="pmid1740514">{{cite journal |vauthors=Colman G, Weaver E, Efstratiou A |title=Screening tests for pathogenic corynebacteria |journal=J. Clin. Pathol. |volume=45 |issue=1 |pages=46–8 |year=1992 |pmid=1740514 |pmc=495813 |doi= |url=}}</ref><ref name="pmid18017268">{{cite journal |vauthors=Widelock D |title=Laboratory Diagnosis of Diphtheria |journal=Am J Public Health Nations Health |volume=41 |issue=1 |pages=120 |year=1951 |pmid=18017268 |pmc=1525936 |doi= |url=}}</ref> | ||
===X ray=== | ===X ray=== | ||
Diphtheric [[myocarditis]] may result in [[systolic]] [[ventricular]] [[heart failure]], | Diphtheric [[myocarditis]] may result in [[systolic]] [[ventricular]] [[heart failure]], which is evident by [[cardiomegaly]] on chest x-ray ([[CXR]]).<ref name="pmid14069096">{{cite journal |vauthors=MORGAN BC |title=CARDIAC COMPLICATIONS OF DIPHTHERIA |journal=Pediatrics |volume=32 |issue= |pages=549–57 |year=1963 |pmid=14069096 |doi= |url=}}</ref> Diphtheric patients may also present with [[bronchopneumonia]]. In this case, [[CXR]] may be normal, or it may show increased [[pulmonary]] [[vascular]] markings and/or [[inflammatory]] [[infiltrates]]. <ref name= "google books"> Radiology of Infectious Disease https://books.google.com/books?id=8PlrCgAAQBAJ&pg=PA87&lpg=PA87&dq=imaging+diphtheria&source=bl&ots=ksaVMwGJ3P&sig=ZMvNuUCCQk7aE0V2hGGT__kPDls&hl=en&sa=X&ved=0ahUKEwi09ev8-9DPAhVB2R4KHcxxBhsQ6AEISjAJ#v=onepage&q=imaging%20diphtheria&f=false Accessed on Oct 10, 2016 </ref> | ||
===CT=== | ===CT=== | ||
In [[respiratory]] [[diphtheria]], a [[CT]] scan may reveal swelling of the soft tissue of the [[nasopharynx]], [[oropharynx]], [[larynx]] [[uvula]] and [[soft palate]].<ref name= "google books"> Radiology of Infectious Disease https://books.google.com/books?id=8PlrCgAAQBAJ&pg=PA87&lpg=PA87&dq=imaging+diphtheria&source=bl&ots=ksaVMwGJ3P&sig=ZMvNuUCCQk7aE0V2hGGT__kPDls&hl=en&sa=X&ved=0ahUKEwi09ev8-9DPAhVB2R4KHcxxBhsQ6AEISjAJ#v=onepage&q=imaging%20diphtheria&f=false Accessed on Oct 10, 2016 </ref> | In cases of [[respiratory]] [[diphtheria]], a [[CT]] scan may reveal [[swelling]] of the soft tissue of the [[nasopharynx]], [[oropharynx]], [[larynx]] [[uvula]], and [[soft palate]].<ref name= "google books"> Radiology of Infectious Disease https://books.google.com/books?id=8PlrCgAAQBAJ&pg=PA87&lpg=PA87&dq=imaging+diphtheria&source=bl&ots=ksaVMwGJ3P&sig=ZMvNuUCCQk7aE0V2hGGT__kPDls&hl=en&sa=X&ved=0ahUKEwi09ev8-9DPAhVB2R4KHcxxBhsQ6AEISjAJ#v=onepage&q=imaging%20diphtheria&f=false Accessed on Oct 10, 2016 </ref> | ||
===MRI=== | ===MRI=== | ||
[[MRI]] may be | An [[MRI]] may be performed to document diphtheric [[neuropathy]].<ref name="pmid26962337">{{cite journal |vauthors=Manikyamba D, Satyavani A, Deepa P |title=Diphtheritic polyneuropathy in the wake of resurgence of diphtheria |journal=J Pediatr Neurosci |volume=10 |issue=4 |pages=331–4 |year=2015 |pmid=26962337 |pmc=4770643 |doi=10.4103/1817-1745.174441 |url=}}</ref> | ||
===Electrocardiogram=== | ===Electrocardiogram=== | ||
[[ECG]] in patients with [[diphtheria]] | An [[ECG]] in patients with [[diphtheria]] may be normal. However, in patients with [[diphtheria]] [[myocarditis]], a wide range of abnormalities related to conduction and rhythm may be observed. | ||
===Echocardiography=== | ===Echocardiography=== | ||
[[Echocardiography]] may be | [[Echocardiography]] may be performed to document [[ejection fraction]] (EF) and any signs of [[ventricular]] [[systolic]] dysfunction if [[diphtheria]] infection has been complicated by systemic involvement of the [[myocardium]].<ref name="pmid15686793">{{cite journal |vauthors=Lakkireddy DR, Kondur AK, Chediak EJ, Nair CK, Khan IA |title=Cardiac troponin I release in non-ischemic reversible myocardial injury from acute diphtheric myocarditis |journal=Int. J. Cardiol. |volume=98 |issue=2 |pages=351–4 |year=2005 |pmid=15686793 |doi=10.1016/j.ijcard.2003.10.062 |url=}}</ref> | ||
===Other Imaging Findings=== | ===Other Imaging Findings=== | ||
There are no other imaging findings in [[diphtheria]]. | There are no other imaging findings in cases of [[diphtheria]]. | ||
===Other Diagnostic Studies=== | ===Other Diagnostic Studies=== | ||
There are no other diagnostic studies | There are no other diagnostic studies for [[diphtheria]]. | ||
==Treatment== | ==Treatment== | ||
===Medical Therapy=== | ===Medical Therapy=== | ||
The treatment of [[diphtheria]] consists of administering the [[diphtheria]] [[antitoxin]] (if the disease is identified early), administering the proper [[antibiotic]] therapy, and identifying individuals in close contact with the patient so as to provide them with the appropriate [[prophylaxis]].<ref name= "Bartlett">{{cite book | last = Bartlett | first = John | title = Johns Hopkins ABX guide : diagnosis and treatment of infectious diseases | publisher = Jones and Bartlett Learning | location = Burlington, MA | year = 2012 | isbn = 978-1449625580 }}</ref><ref name= "CDC">{{cite web | title = Diphtheria CDC| url =http://www.cdc.gov/vaccines/pubs/pinkbook/dip.html }}</ref><ref name="pmid19866893">{{cite journal |vauthors=Park WH, Atkinson JP |title=THE RELATION OF THE TOXICITY OF DIPHTHERIA TOXIN TO ITS NEUTRALIZING VALUE UPON ANTITOXIN AT DIFFERENT STAGES IN THE GROWTH OF CULTURE |journal=J. Exp. Med. |volume=3 |issue=4-5 |pages=513–32 |year=1898 |pmid=19866893 |pmc=2117979 |doi= |url=}}</ref><ref name="pmid9798043">{{cite journal |vauthors=Kneen R, Pham NG, Solomon T, Tran TM, Nguyen TT, Tran BL, Wain J, Day NP, Tran TH, Parry CM, White NJ |title=Penicillin vs. erythromycin in the treatment of diphtheria |journal=Clin. Infect. Dis. |volume=27 |issue=4 |pages=845–50 |year=1998 |pmid=9798043 |doi= |url=}}</ref><ref name="pmid15828187">{{cite journal |vauthors=Miller LW, Bickham S, Jones WL, Heather CD, Morris RH |title=Diphtheria carriers and the effect of erythromycin therapy |journal=Antimicrob. Agents Chemother. |volume=6 |issue=2 |pages=166–9 |year=1974 |pmid=15828187 |pmc=444622 |doi= |url=}}</ref><ref name="pmid8448320">{{cite journal |vauthors=Farizo KM, Strebel PM, Chen RT, Kimbler A, Cleary TJ, Cochi SL |title=Fatal respiratory disease due to Corynebacterium diphtheriae: case report and review of guidelines for management, investigation, and control |journal=Clin. Infect. Dis. |volume=16 |issue=1 |pages=59–68 |year=1993 |pmid=8448320 |doi= |url=}}</ref> | |||
===Surgical Therapy=== | ===Surgical Therapy=== | ||
There is no role for surgery in management of [[diphtheria]]. | There is no role for surgery in the management of [[diphtheria]]. | ||
===Primary prevention=== | ===Primary prevention=== | ||
The best way to prevent diphtheria is to get vaccinated. In the United States, there are four vaccines used to prevent diphtheria: DTaP, Tdap, DT, and Td. Each of these vaccines prevents diphtheria and [[tetanus]]. | The best way to prevent diphtheria is to get vaccinated. In the United States, there are four vaccines used to prevent diphtheria: [[DTaP]], [[Tdap]], DT, and Td. Each of these vaccines prevents diphtheria and [[tetanus]]. | ||
The current childhood immunization schedule for diphtheria includes five doses of DTaP for children younger than seven years old | The current childhood [[immunization]] schedule for diphtheria includes five doses of DTaP for children younger than seven years old. Preteens get a booster dose of [[Tdap]] at 11 or 12 years old, and teens who did not get Tdap when they were 11 or 12 years old should get a dose the next time they see their doctor. Adults should get a dose of Td every 10 years, according to the adult immunization schedule.<ref name=CDC-Diph-Vaccination-3>Centers for Disease Control and Prevention. Diphtheria Prevention (2016) http://www.cdc.gov/diphtheria/about/prevention.html Accessed on October 9th, 2016</ref> | ||
===Secondary prevention=== | ===Secondary prevention=== | ||
There are no established guidelines for secondary prevention of diphtheria. However, early diagnosis and prompt and adequate | There are no established guidelines for the secondary prevention of diphtheria. However, early diagnosis and prompt and adequate treatment with the appropriate antibiotic therapy and diphtheria antitoxin, good nursing care, and adequate airway management may help reduce the progression of the disease and prevent complications in affected individuals.<ref name=AAP>American Academy of Pediatrics. Diphtheria. 2015 Report of the Committee on Infectious Diseases, 30th ed, Kimberlin DW, Brady MT, Jackson MA, Long SS (Eds), American Academy of Pediatrics, Elk Grove Village, IL 2015. Diphtheria </ref> | ||
==References== | ==References== | ||
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Latest revision as of 21:23, 29 July 2020
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Diphtheria Microchapters |
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Diphtheria overview On the Web |
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American Roentgen Ray Society Images of Diphtheria overview |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]
Overview
Diphtheria (Greek διφθερα (diphthera) — “pair of leather scrolls”) is an upper respiratory tract illness characterized by sore throat, low-grade fever, and an adherent membrane (a pseudomembrane) on the tonsils, pharynx, and/or nasal cavity.[1][2] A milder form of diphtheria can be restricted to the skin. It is caused by Corynebacterium diphtheriae, a facultatively anaerobic gram-positive bacterium.[3]
Diphtheria is a highly contagious disease that is spread via direct physical contact or breathing the aerosolized secretions of infected individuals. Once quite common, diphtheria has largely been eradicated in developed nations through widespread vaccination. In the United States, for instance, there were only 57 reported cases of diphtheria between 1980 and 2004 (and only five cases since 2000),[4] as the DPT(Diphtheria–Pertussis–Tetanus) vaccine is given to all schoolchildren. Boosters of the vaccine are recommended for adults, since the benefits of vaccination decrease with age; they are particularly highly recommended for those traveling to areas where the disease has not yet been eradicated.
Historical perspective
Before 1826, diphtheria was known by different names across the world. In 1826, the term "diphtheria" was introduced by French physician Pierre Bretonneau. The name alludes to the leathery, sheath-like membrane that grows on the tonsils, throat, and in the nose in patients with the disease.[5][6]
Classification
Diphtheria can be classified according to the type of Corynebacterium that causes a specific case. It can also be classified according to the resulting clinical presentation into respiratory, systemic, or cutaneous diphtheria.[7][8]
Causes
C. diphtheriae is a facultatively anaerobic, gram positive organism that is characterized by non-encapsulated, non-sporulated, immobile, straight or curved rods with a length of 1 to 8 µm and width of 0.3 to 0.8 µm. These rods form ramified aggregations in culture that have been described as looking like "Chinese characters." The bacterium may contain polymetaphosphate aggregates called Volutin granules. It is only pathogenic in humans.[9]
Differential diagnosis
Respiratory diphtheria must be differentiated from respiratory tract or other infections that present with fever, neck swelling, cough, and/or pharyngeal exudates. Cutaneous diphtheria must be differentiated from other bacterial and fungal causes of skin ulceration.[10][11]
Epidemiology and Demographics
Diphtheria is observed worldwide, though it is rare in the United States due to widespread vaccination. Diphtheria is a significant cause of illness and death in developing countries, where vaccination coverage tends to be lower.
Risk factors
Common risk factors in the development of diphtheria include lack of immunization, history of travel to areas endemic for diphtheria, exposure to overcrowding and/or poor sanitary conditions, and immunocompromised status.[12][13][14][15][16]
Screening
There are no screening recommendations for diphtheria.[17]
Natural History, Complications, and Prognosis
Diphtheria is a vaccine-preventable disease that can lead to such severe complications as respiratory failure, myocarditis, polyneuropathies, and death.[18][19][20][21][22][23] The overall case-fatality rate for diphtheria is 5–10%, with higher death rates (up to 20%) among patients younger than 5 or older than 40 years of age.[24]
Diagnosis
History and Symptoms
Respiratory diphtheria presents with a wide range of systemic and respiratory symptoms.[18] Cutaneous diphtheria usually presents with ulcers or pustular lesions, which can involve various different parts of the body. Lesions may be covered by a grayish-white pseudomembrane, similar to tonsillar exudates of respiratory diphtheria.[25]
Physical Examination
A patient with diptheria usually looks ill; systemic signs such as fever, tachypnea, and tachycardia are common. Pharyngeal, respiratory, neurologic, cardiac, and other physical examination findings depend upon the extent and severity of the infection.[18][26][27]
Laboratory Findings
A presumptive diagnosis of diphtheria is usually based on clinical features. A definitive diagnosis is made by growing the specific Corynebacterium species on special cultures from the respiratory tract secretions or cutaneous lesions. Culture of the lesion is performed to confirm the diagnosis. It is critical to take a swab of the pharyngeal area, especially any discolored areas, ulcerations, and tonsillar crypts. Culture medium containing tellurite is preferred. PCR assays can also be performed on isolates, swabs, or membrane specimens to rapidly confirm the presence of the tox gene responsible for the production of diphtheria toxin.[28][29][30]
X ray
Diphtheric myocarditis may result in systolic ventricular heart failure, which is evident by cardiomegaly on chest x-ray (CXR).[19] Diphtheric patients may also present with bronchopneumonia. In this case, CXR may be normal, or it may show increased pulmonary vascular markings and/or inflammatory infiltrates. [31]
CT
In cases of respiratory diphtheria, a CT scan may reveal swelling of the soft tissue of the nasopharynx, oropharynx, larynx uvula, and soft palate.[31]
MRI
An MRI may be performed to document diphtheric neuropathy.[32]
Electrocardiogram
An ECG in patients with diphtheria may be normal. However, in patients with diphtheria myocarditis, a wide range of abnormalities related to conduction and rhythm may be observed.
Echocardiography
Echocardiography may be performed to document ejection fraction (EF) and any signs of ventricular systolic dysfunction if diphtheria infection has been complicated by systemic involvement of the myocardium.[33]
Other Imaging Findings
There are no other imaging findings in cases of diphtheria.
Other Diagnostic Studies
There are no other diagnostic studies for diphtheria.
Treatment
Medical Therapy
The treatment of diphtheria consists of administering the diphtheria antitoxin (if the disease is identified early), administering the proper antibiotic therapy, and identifying individuals in close contact with the patient so as to provide them with the appropriate prophylaxis.[34][35][36][37][38][39]
Surgical Therapy
There is no role for surgery in the management of diphtheria.
Primary prevention
The best way to prevent diphtheria is to get vaccinated. In the United States, there are four vaccines used to prevent diphtheria: DTaP, Tdap, DT, and Td. Each of these vaccines prevents diphtheria and tetanus. The current childhood immunization schedule for diphtheria includes five doses of DTaP for children younger than seven years old. Preteens get a booster dose of Tdap at 11 or 12 years old, and teens who did not get Tdap when they were 11 or 12 years old should get a dose the next time they see their doctor. Adults should get a dose of Td every 10 years, according to the adult immunization schedule.[40]
Secondary prevention
There are no established guidelines for the secondary prevention of diphtheria. However, early diagnosis and prompt and adequate treatment with the appropriate antibiotic therapy and diphtheria antitoxin, good nursing care, and adequate airway management may help reduce the progression of the disease and prevent complications in affected individuals.[41]
References
- ↑ Diphtheria. Centers for Disease Control and Prevention (2016) http://www.cdc.gov/diphtheria/ Accessed on July 28, 2016
- ↑ Ryan KJ, Ray CG (editors) (2004). Sherris Medical Microbiology (4th ed. ed.). McGraw Hill. pp. 299–302. ISBN 0838585299.
- ↑ Office of Laboratory Security, Public Health Agency of Canada Corynebacterium diphtheriae Material Safety Data Sheet. January 2000.
- ↑ Atkinson W, Hamborsky J, McIntyre L, Wolfe S, eds. (2007). Diphtheria. in: Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book) (PDF) (10th ed. ed.). Washington DC: Public Health Foundation. pp. 59&ndash, 70.
- ↑ Pierre Bretonneau, Des inflammations spéciales du tissu muqueux, et en particulier de la diphtérite, ou inflammation pelliculaire, connue sous le nom de croup, d'angine maligne, d'angine gangréneuse, etc. [Special inflammations of mucous tissue, and in particular diphtheria or skin inflammation, known by the name of croup, malignant throat infection, gangrenous throat infection, etc.] (Paris, France: Crevot, 1826).
A condensed version of this work is available in: P. Bretonneau (1826) "Extrait du traité de la diphthérite, angine maligne, ou croup épidémique" (Extract from the treatise on diphtheria, malignant throat infection, or epidemic croup), Archives générales de médecine, series 1, 11 : 219-254. From p. 230: " … M. Bretonneau a cru convenable de l'appeler diphthérite, dérivé de ΔΙΦθΕΡΑ, … " ( … Mr. Bretonneau thought it appropriate to call it diphtheria, derived from ΔΙΦθΕΡΑ [diphthera], … ) - ↑ "Diphtheria". Online Etymology Dictionary. Retrieved 29 November 2012.
- ↑ Wong TP, Groman N (1984). "Production of diphtheria toxin by selected isolates of Corynebacterium ulcerans and Corynebacterium pseudotuberculosis". Infect. Immun. 43 (3): 1114–6. PMC 264307. PMID 6321350.
- ↑ Moore LS, Leslie A, Meltzer M, Sandison A, Efstratiou A, Sriskandan S (2015). "Corynebacterium ulcerans cutaneous diphtheria". Lancet Infect Dis. 15 (9): 1100–7. doi:10.1016/S1473-3099(15)00225-X. PMID 26189434.
- ↑ Nester, Eugene W.; et al. (2004). Microbiology: A Human Perspective (Fourth ed.). Boston: McGraw-Hill. ISBN 0-07-247382-7.
- ↑ Center for Disease Control and Prevention https://www.cdc.gov/diphtheria/downloads/dip-cklist-diag.pdf Accessed on Oct. 7, 2016.
- ↑ Zeegelaar JE, Faber WR (2008). "Imported tropical infectious ulcers in travelers". Am J Clin Dermatol. 9 (4): 219–32. PMID 18572973.
- ↑ Quick ML, Sutter RW, Kobaidze K, Malakmadze N, Nakashidze R, Murvanidze S; et al. (2000). "Risk factors for diphtheria: a prospective case-control study in the Republic of Georgia, 1995-1996". J Infect Dis. 181 Suppl 1: S121–9. doi:10.1086/315563. PMID 10657203.
- ↑ Vitek CR, Brennan MB, Gotway CA, Bragina VY, Govorukina NV, Kravtsova ON; et al. (1999). "Risk of diphtheria among schoolchildren in the Russian Federation in relation to time since last vaccination". Lancet. 353 (9150): 355–8. doi:10.1016/S0140-6736(98)03488-6. PMID 9950440.
- ↑ Koopman JS, Campbell J (1975). "The role of cutaneous diphtheria infections in a diphtheria epidemic". J Infect Dis. 131 (3): 239–44. PMID 805182.
- ↑ Belsey MA, Sinclair M, Roder MR, LeBlanc DR (1969). "Corynebacterium diphtheriae skin infections in Alabama and Louisiana. A factor in the epidemiology of diphtheria". N Engl J Med. 280 (3): 135–41. doi:10.1056/NEJM196901162800304. PMID 4972946.
- ↑ Favorova LA (1969). "The risk of infection in droplet infections. The influence of overcrowding and prolonged contact on transmission of the diphtheria pathogen". J Hyg Epidemiol Microbiol Immunol. 13 (1): 73–82. PMID 5814141.
- ↑ USPSTF https://www.uspreventiveservicestaskforce.org/BrowseRec/Search?s=diphtheria Accessed on Oct. 7, 2016.
- ↑ 18.0 18.1 18.2 Dobie RA, Tobey DN (1979). "Clinical features of diphtheria in the respiratory tract". JAMA. 242 (20): 2197–201. PMID 490806.
- ↑ 19.0 19.1 MORGAN BC (1963). "CARDIAC COMPLICATIONS OF DIPHTHERIA". Pediatrics. 32: 549–57. PMID 14069096.
- ↑ Sanghi V (2014). "Neurologic manifestations of diphtheria and pertussis". Handb Clin Neurol. 121: 1355–9. doi:10.1016/B978-0-7020-4088-7.00092-4. PMID 24365424.
- ↑ Jain A, Samdani S, Meena V, Sharma MP (2016). "Diphtheria: It is still prevalent!!!". Int J Pediatr Otorhinolaryngol. 86: 68–71. doi:10.1016/j.ijporl.2016.04.024. PMID 27260583.
- ↑ http://www.who.int/immunization/topics/diphtheria/en/index1.html Accessed on October 7, 2016
- ↑ Jayashree M, Shruthi N, Singhi S (2006). "Predictors of outcome in patients with diphtheria receiving intensive care". Indian Pediatr. 43 (2): 155–60. PMID 16528112.
- ↑ http://www.cdc.gov/diphtheria/clinicians.html Accessed on October 7, 2016
- ↑ Rappold LC, Vogelgsang L, Klein S, Bode K, Enk AH, Haenssle HA (2016). "Primary cutaneous diphtheria: management, diagnostic workup, and treatment as exemplified by a rare case report". J Dtsch Dermatol Ges. 14 (7): 734–6. doi:10.1111/ddg.12722. PMID 27373251.
- ↑ Kadirova R, Kartoglu HU, Strebel PM (2000). "Clinical characteristics and management of 676 hospitalized diphtheria cases, Kyrgyz Republic, 1995". J. Infect. Dis. 181 Suppl 1: S110–5. doi:10.1086/315549. PMID 10657201.
- ↑ Kneen R, Nguyen MD, Solomon T, Pham NG, Parry CM, Nguyen TT, Ha TL, Taylor A, Vo TT, Nguyen TT, Day NP, White NJ (2004). "Clinical features and predictors of diphtheritic cardiomyopathy in Vietnamese children". Clin. Infect. Dis. 39 (11): 1591–8. doi:10.1086/425305. PMID 15578357.
- ↑ Efstratiou A, Engler KH, Mazurova IK, Glushkevich T, Vuopio-Varkila J, Popovic T (2000). "Current approaches to the laboratory diagnosis of diphtheria". J. Infect. Dis. 181 Suppl 1: S138–45. doi:10.1086/315552. PMID 10657205.
- ↑ Colman G, Weaver E, Efstratiou A (1992). "Screening tests for pathogenic corynebacteria". J. Clin. Pathol. 45 (1): 46–8. PMC 495813. PMID 1740514.
- ↑ Widelock D (1951). "Laboratory Diagnosis of Diphtheria". Am J Public Health Nations Health. 41 (1): 120. PMC 1525936. PMID 18017268.
- ↑ 31.0 31.1 Radiology of Infectious Disease https://books.google.com/books?id=8PlrCgAAQBAJ&pg=PA87&lpg=PA87&dq=imaging+diphtheria&source=bl&ots=ksaVMwGJ3P&sig=ZMvNuUCCQk7aE0V2hGGT__kPDls&hl=en&sa=X&ved=0ahUKEwi09ev8-9DPAhVB2R4KHcxxBhsQ6AEISjAJ#v=onepage&q=imaging%20diphtheria&f=false Accessed on Oct 10, 2016
- ↑ Manikyamba D, Satyavani A, Deepa P (2015). "Diphtheritic polyneuropathy in the wake of resurgence of diphtheria". J Pediatr Neurosci. 10 (4): 331–4. doi:10.4103/1817-1745.174441. PMC 4770643. PMID 26962337.
- ↑ Lakkireddy DR, Kondur AK, Chediak EJ, Nair CK, Khan IA (2005). "Cardiac troponin I release in non-ischemic reversible myocardial injury from acute diphtheric myocarditis". Int. J. Cardiol. 98 (2): 351–4. doi:10.1016/j.ijcard.2003.10.062. PMID 15686793.
- ↑ Bartlett, John (2012). Johns Hopkins ABX guide : diagnosis and treatment of infectious diseases. Burlington, MA: Jones and Bartlett Learning. ISBN 978-1449625580.
- ↑ "Diphtheria CDC".
- ↑ Park WH, Atkinson JP (1898). "THE RELATION OF THE TOXICITY OF DIPHTHERIA TOXIN TO ITS NEUTRALIZING VALUE UPON ANTITOXIN AT DIFFERENT STAGES IN THE GROWTH OF CULTURE". J. Exp. Med. 3 (4–5): 513–32. PMC 2117979. PMID 19866893.
- ↑ Kneen R, Pham NG, Solomon T, Tran TM, Nguyen TT, Tran BL, Wain J, Day NP, Tran TH, Parry CM, White NJ (1998). "Penicillin vs. erythromycin in the treatment of diphtheria". Clin. Infect. Dis. 27 (4): 845–50. PMID 9798043.
- ↑ Miller LW, Bickham S, Jones WL, Heather CD, Morris RH (1974). "Diphtheria carriers and the effect of erythromycin therapy". Antimicrob. Agents Chemother. 6 (2): 166–9. PMC 444622. PMID 15828187.
- ↑ Farizo KM, Strebel PM, Chen RT, Kimbler A, Cleary TJ, Cochi SL (1993). "Fatal respiratory disease due to Corynebacterium diphtheriae: case report and review of guidelines for management, investigation, and control". Clin. Infect. Dis. 16 (1): 59–68. PMID 8448320.
- ↑ Centers for Disease Control and Prevention. Diphtheria Prevention (2016) http://www.cdc.gov/diphtheria/about/prevention.html Accessed on October 9th, 2016
- ↑ American Academy of Pediatrics. Diphtheria. 2015 Report of the Committee on Infectious Diseases, 30th ed, Kimberlin DW, Brady MT, Jackson MA, Long SS (Eds), American Academy of Pediatrics, Elk Grove Village, IL 2015. Diphtheria