Fever and rash in children: Difference between revisions
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__NOTOC__ | __NOTOC__ | ||
{{SI}} | {{Fever and rash in children}} | ||
{{SI}} | |||
{{CMG}} {{AE}} {{Ifeoma Anaya}} | {{CMG}} {{AE}} {{Ifeoma Anaya}} | ||
{{SK}} Fever and rash in kids | {{SK}} [[Fever]] and [[rash]] in kids | ||
==Overview== | ==Overview== | ||
Fever and | [[Fever]] and [[rash]] are [[symptoms]] encountered frequently in [[pediatrics]]. [[Disease states]] associated with these [[symptoms]] are varied. [[Febrile]] [[rashes]] can be classified based on [[morphology]], [[distribution of spread]], [[pattern]] of occurrence and cause. [[Fever]] results when [[exogenous]] ([[micro-organisms]]) and [[endogenous]] [[Pyrogen|pyrogens]] interact with the Organum Vasculosum of the Lamina Terminalis (OVLT) causing a rise in [[body temperature]] as a result of an increase in the [[hypothalamic]] [[set point]]. [[Fever]] and [[rash]] in kids are caused by [[infectious]] ([[bacterial]], [[viral]], [[fungal]], and [[protozoan]]) and non-[[infectious]] ([[drug]]-related [[Eruption|eruptions]] and [[Immune-mediated disease|immune-mediated]]) causes. [[Patients]] of all [[age]] groups may develop [[diseases]] that present with [[fever]] and [[rash]]. Common [[risk factors]] for the [[development]] of [[diseases]] that present with [[fever]] and [[rash]] include contact with [[Illness|ill]] individuals, poor/depressed [[immunity]], lack of [[vaccination]], very [[Young adult|young]] [[age]], and poor [[hand washing]] habits. The [[symptoms]] of [[diseases]] associated with [[fever]] and [[rash]] usually develop in the first few days from contact. The stages/phases of most [[infectious]] [[Process (anatomy)|processes]] include the [[incubation period]], [[prodromal]] [[Phase (matter)|phase]], [[illness]], decline, and [[convalescence]]. Rapid [[clinical]] [[diagnosis]] is necessary in severe cases to begin immediate [[empiric therapy]] while awaiting the test results. [[Triaging]] kids who present with [[fever]] and [[rash]] into three groups on basis of early [[symptoms and signs]] is essential for making prompt [[diagnosis]] and administering possible treatment regimen. Effective measures for [[primary prevention]] of [[fever]] and [[rash]] in [[children]] may include [[vaccination]], [[coughing]], and [[sneezing]] into [[elbows]] or [[tissue]], [[hand washing]], avoiding contact with [[Illness|ill]] individuals, [[Prevention|preventing]] exposure to [[tick bites]]. | ||
==Classification== | ==Classification== | ||
*[[Febrile]] [[rashes]] can be classified based on: | |||
**[[Morphology]] ([[maculopapular]], [[Pustular rash|pustular]], [[vesicular]] etc) | |||
**[[Distribution of spread]] ([[systemic]] and [[Localized disease|localized]]) | |||
**[[Pattern]] of occurrence ([[acute]] and [[chronic]]) | |||
**Cause ([[infectious]] and [[non-infectious]])<ref name="pmid26483989">{{cite journal| author=Kang JH| title=Febrile Illness with Skin Rashes. | journal=Infect Chemother | year= 2015 | volume= 47 | issue= 3 | pages= 155-66 | pmid=26483989 | doi=10.3947/ic.2015.47.3.155 | pmc=4607768 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26483989 }} </ref> | |||
*Types of [[rashes]] found among [[pediatric]] [[patients]] include the following:<ref name="pmid26483989" /> | |||
**[[Macules]] | |||
**[[Papules]] | |||
**[[Nodules]] | |||
**[[Pustules]] | |||
**[[Vesicles]] | |||
**[[Bullae]] | |||
**[[Petechiae]] | |||
**[[Purpura]] | |||
**[[Ecchymoses]] | |||
*Classification of [[febrile]] [[rashes]] based on [[rash]] [[morphology]] is as follows:<ref>https://www.consultant360.com/articles/rashes-and-fever-children-sorting-out-potentially-dangerous-part-1</ref><ref>https://www.consultant360.com/articles/rashes-and-fever-children-sorting-out-potentially-dangerous-part-2</ref><ref>https://www.consultant360.com/articles/rashes-and-fever-children-sorting-out-potentially-dangerous-part-3</ref><ref>https://www.consultant360.com/articles/rashes-and-fever-children-sorting-out-potentially-dangerous-part-4</ref> | |||
{| class="wikitable" | {| class="wikitable" | ||
|+ | |+ | ||
!style="background:#4479BA; color: #FFFFFF;" align="center" + |Fever + Rash Morphology | ! style="background:#4479BA; color: #FFFFFF;" align="center" + |Fever + Rash Morphology | ||
!style="background:#4479BA; color: #FFFFFF;" align="center" + |Disease | ! style="background:#4479BA; color: #FFFFFF;" align="center" + |Disease | ||
|- | |- | ||
|align="center" style="background:#DCDCDC;" + |Non-blanching lesions (Petechiae, Purpura and Ecchymoses) | | align="center" style="background:#DCDCDC;" + |Non-[[blanching]] [[lesions]] ([[Petechiae]], [[Purpura]] and [[Ecchymoses]]) | ||
|a. Meningococcemia | |a. [[Meningococcemia]] | ||
b. Rocky Mountain Spotted Fever (RMSF) | b. [[Rocky Mountain Spotted Fever]] ([[Rocky Mountain spotted fever|RMSF]]) | ||
c. Hemolytic Uremic Syndrome (HUS) | c. [[Hemolytic Uremic Syndrome]] ([[Hemolytic-uremic syndrome|HUS]]) | ||
d. Henoch- | d. [[Henoch-Schonlein Purpura]] ([[HSP]]) | ||
|- | |- | ||
|align="center" style="background:#DCDCDC;" + |Blanching rash | | align="center" style="background:#DCDCDC;" + |[[Blanching]] [[rash]] | ||
|a. Kawasaki disease | |a. [[Kawasaki disease]] | ||
b. Juvenile Rheumatoid Arthritis | b. [[Juvenile Rheumatoid Arthritis]] | ||
c. Juvenile Dermatomyositis | c. [[Juvenile (organism)|Juvenile]] [[Dermatomyositis]] | ||
|- | |- | ||
|align="center" style="background:#DCDCDC;" + |Vesicular or bullous lesions | | align="center" style="background:#DCDCDC;" + |[[Vesicular]] or [[bullous]] [[lesions]] | ||
|a. Erythema multiforme | |a. [[Erythema multiforme]] | ||
b. | b. [[Stevens-Johnson Syndrome]] ([[Stevens-Johnson syndrome|SJS]]) and [[Toxic Epidermal Necrolysis]] ([[Toxic epidermal necrolysis|TEN]]) | ||
c. Staphylococcal Scalded Skin Syndrome (SSSS) | c. [[Staphylococcal scalded skin syndrome|Staphylococcal Scalded Skin Syndrome]] ([[SSSS]]) | ||
d. Disseminated gonococcal disease in adolescents | d. [[Disseminated gonococcal infection|Disseminated]] [[gonococcal]] [[disease]] in [[Adolescent|adolescents]] | ||
e. HSV I & II | e. [[Herpes simplex virus|HSV]] I & II | ||
|- | |- | ||
|align="center" style="background:#DCDCDC;" + |Umbilicated papules and pustules | | align="center" style="background:#DCDCDC;" + |[[Umbilicated lesions|Umbilicated]] [[papules]] and [[pustules]] | ||
|a. Molluscum contagiosum | |a. [[Molluscum contagiosum]] | ||
b. Varicella/Chickenpox | b. [[Varicella]]/[[Chickenpox]] | ||
|- | |- | ||
|align="center" style="background:#DCDCDC;" + |Sandpaper rash | | align="center" style="background:#DCDCDC;" + |Sandpaper [[rash]] | ||
|a. Scarlet fever | |a. [[Scarlet fever]] | ||
|- | |- | ||
|align="center" style="background:#DCDCDC;" + |Viral syndromes | | align="center" style="background:#DCDCDC;" + |[[Viral]] [[syndromes]](mostly [[maculopapular]]) | ||
|a. Measles (Rubeola) | |a. [[Measles]] ([[Rubeola]]) | ||
b. Rubella (German measles) | b. [[Rubella]] ([[German measles]]) | ||
c. Erythema infectiosum (Parvovirus | c. [[Erythema infectiosum]] ([[Parvovirus B19|Parvovirus]] B19) | ||
d. Herpangina (Coxsackie) | d. [[Herpangina]] ([[Coxsackie]]) | ||
e. Hand-foot-and-mouth disease (Coxsackie) | e. [[Hand-foot-and-mouth disease]] ([[Coxsackie]]) | ||
f. Roseola infantum (Human Herpes Virus types 6 or 7) | f. [[Roseola infantum]] ([[Human herpesvirus 6|Human Herpes Virus types 6]] or 7) | ||
|- | |- | ||
|align="center" style="background:#DCDCDC;" + |Limited to certain geographical areas | | align="center" style="background:#DCDCDC;" + |Limited to certain [[Geographical pole|geographical]] [[Area|areas]] | ||
|a. Babesiosis | |a. [[Babesiosis]] | ||
b. Blastomycosis | b. [[Blastomycosis]] | ||
c. Coccidiodomycosis | c. [[Coccidiodomycosis]] | ||
d. Histoplasmosis | d. [[Histoplasmosis]] | ||
e. | e. [[Lyme disease]] | ||
f. | f. [[Relapsing fever]] | ||
g. | g. [[Colorado tick fever|Colorado Tick Fever]] | ||
|} | |} | ||
==Pathophysiology== | ==Pathophysiology== | ||
* | |||
* | *When core [[Body temperature|body temperatures]] vary outside normal ranges, [[Thermoregulation|thermoregulatory]] responses are triggered.<ref name="pmid22772856">{{cite journal| author=Schortgen F| title=Fever in sepsis. | journal=Minerva Anestesiol | year= 2012 | volume= 78 | issue= 11 | pages= 1254-64 | pmid=22772856 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22772856 }} </ref> | ||
* | *It is understood that [[infectious]] [[Process (anatomy)|processes]] accounts for up to 74% of [[fever]] in [[Hospital|hospitalized]] [[patients]], the remainder being caused by [[malignancy]], [[ischemia]] and [[drug]]-related reactions.<ref name="pmid27411542">{{cite journal| author=Walter EJ, Hanna-Jumma S, Carraretto M, Forni L| title=The pathophysiological basis and consequences of fever. | journal=Crit Care | year= 2016 | volume= 20 | issue= 1 | pages= 200 | pmid=27411542 | doi=10.1186/s13054-016-1375-5 | pmc=4944485 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27411542 }} </ref> | ||
* | *[[Fever]] results when [[exogenous]] ([[micro-organisms]]) and [[endogenous]] [[Pyrogen|pyrogens]] interact with the Organum Vasculosum of the Lamina Terminalis (OVLT) causing a rise in [[body temperature]] as a result of an increase in the [[hypothalamic]] [[set point]]. | ||
*This rise in the [[hypothalamic]] [[set point]] is due to an increased production of [[Prostaglandin E2]] ([[PGE2]]) by [[endothelial cells]] of the [[vascular]] OVLT located in the [[preoptic area]] of the [[anterior hypothalamus]]. It lacks the [[Blood brain barrier|Blood-Brain-Barrier (BBB)]] thus easily accessible to [[Pyrogen|pyrogens]]. This resultant increased production of [[PGE2]] results in raised [[body temperature]].<ref name="pmid27411542">{{cite journal| author=Walter EJ, Hanna-Jumma S, Carraretto M, Forni L| title=The pathophysiological basis and consequences of fever. | journal=Crit Care | year= 2016 | volume= 20 | issue= 1 | pages= 200 | pmid=27411542 | doi=10.1186/s13054-016-1375-5 | pmc=4944485 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27411542 }} </ref> | |||
*[[Lipopolysaccharide]] (LPS) on [[gram negative bacteria]] is a common [[exogenous]] [[pyrogen]] which stimulates the production of [[endogenous]] [[cytokines]] such as [[IL-1|IL]]-1, [[IL-6]] an<nowiki/>d [[Tumor necrosis factor-alpha|TNF]]-α via the [[Toll-like receptor]] (TL<nowiki/>Rs) [[cascade]].<ref name="pmid27411542">{{cite journal| author=Walter EJ, Hanna-Jumma S, Carraretto M, Forni L| title=The pathophysiological basis and consequences of fever. | journal=Crit Care | year= 2016 | volume= 20 | issue= 1 | pages= 200 | pmid=27411542 | doi=10.1186/s13054-016-1375-5 | pmc=4944485 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27411542 }} </ref><ref name="pmid22772856">{{cite journal| author=Schortgen F| title=Fever in sepsis. | journal=Minerva Anestesiol | year= 2012 | volume= 78 | issue= 11 | pages= 1254-64 | pmid=22772856 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22772856 }} </ref> | |||
*[[PGE2]] production can also be stimulated via the [[vagus nerve]] by [[inflammatory processes]] and directly by [[microbial]] [[Product (biology)|products]] through [[TLR10|TLRs]].<ref name="pmid22772856">{{cite journal| author=Schortgen F| title=Fever in sepsis. | journal=Minerva Anestesiol | year= 2012 | volume= 78 | issue= 11 | pages= 1254-64 | pmid=22772856 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22772856 }} </ref> | |||
*[[Skin]] [[lesions]] ([[rash]]) could be primarily [[vascular]] or from [[infection]] spread to [[tissues]] (e.g. [[skin]]).<ref name="pmid5342519">{{cite journal| author=Mims CA| title=Pathogenesis of rashes in virus diseases. | journal=Bacteriol Rev | year= 1966 | volume= 30 | issue= 4 | pages= 739-60 | pmid=5342519 | doi= | pmc=441013 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5342519 }} </ref> | |||
*The first step in the formation of a [[skin]] [[lesion]]/[[rash]] is the presence of the [[micro-organism]] in the [[vascular]] [[endothelium]].<ref name="pmid5342519">{{cite journal| author=Mims CA| title=Pathogenesis of rashes in virus diseases. | journal=Bacteriol Rev | year= 1966 | volume= 30 | issue= 4 | pages= 739-60 | pmid=5342519 | doi= | pmc=441013 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5342519 }} </ref> | |||
*A [[macule]] forms from sustained [[local]] [[dilation]] of subpapilary [[dermal]] [[blood vessels]]. | |||
*[[Edema]] with [[Infiltration (medical)|infiltration]] of [[Cells (biology)|cells]] turns a [[macule]] to [[papule]]. | |||
*Primary [[epidermal]] involvement results in [[vesicles]], [[ulcers]], [[Scab|scabs]], and secondary [[Epidermis (skin)|epidermal]] changes can lead to [[desquamation]] and [[pigment]] changes.<ref name="pmid5342519">{{cite journal| author=Mims CA| title=Pathogenesis of rashes in virus diseases. | journal=Bacteriol Rev | year= 1966 | volume= 30 | issue= 4 | pages= 739-60 | pmid=5342519 | doi= | pmc=441013 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=5342519 }} </ref> | |||
==Causes== | ==Causes== | ||
*Common causes of [[fever]] and [[rash]] in kids may include: | |||
{| class="wikitable" | {| class="wikitable" | ||
|+ | |+ | ||
Line 145: | Line 115: | ||
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Causative Organism | ! style="background:#4479BA; color: #FFFFFF;" align="center" + |Causative Organism | ||
|- | |- | ||
| align="center" style="background:#DCDCDC;" + |Viral | | align="center" style="background:#DCDCDC;" + |[[Viral]] | ||
|Measles | |[[Measles]] | ||
German Measles | [[German Measles]] | ||
Erythema infectiosum | [[Erythema infectiosum]] | ||
Roseola infantum | [[Roseola infantum]] | ||
Herpangina | [[Herpangina]] | ||
Hand-foot-and-mouth disease | [[Hand-foot-and-mouth disease]] | ||
Molluscum contagiosum | [[Molluscum contagiosum]] | ||
Chickenpox | [[Chickenpox]] | ||
|Rubeola | |[[Rubeola]] | ||
Rubella | [[Rubella]] | ||
Parvovirus B19 | [[Parvovirus B19]] | ||
Human Herpes Virus 6 & 7 | [[Human herpesvirus 6|Human Herpes Virus]] 6 & 7 | ||
Coxsackie virus | [[Coxsackie virus|Coxsackievirus]] | ||
Coxsackie virus | [[Coxsackie virus]] | ||
Poxvirus | [[Poxvirus]] | ||
Varicella Zoster virus | [[Varicella Zoster]] virus | ||
|- | |- | ||
| rowspan="8" align="center" style="background:#DCDCDC;" + |Bacterial | | rowspan="8" align="center" style="background:#DCDCDC;" + |[[Bacterial]] | ||
|Meningococcemia<br /> | |[[Meningococcemia]]<br /> | ||
|Neisseria meningitidis | |[[Neisseria meningitidis]] | ||
Hemophilus influenzae | [[Hemophilus influenzae]] | ||
Streptococcus pneumoniae | [[Streptococcus pneumoniae|Streptococcus pneumoniae<br />]] | ||
<br /> | |||
|- | |- | ||
|RMSF | |[[RMSF]] | ||
|Rickettsia rickettsii | |[[Rickettsia rickettsii]] | ||
|- | |- | ||
|HUS | |[[Hemolytic-uremic syndrome|HUS]] | ||
|Enterohemorrhagic E.coli (EHEC) | |[[Enterohemorrhagic escherichica coli|Enterohemorrhagic E.coli]] ([[EHEC]]) | ||
|- | |- | ||
|Scarlet Fever | |[[Scarlet Fever]] | ||
|Streptococcus pyogenes (Group A Streptococci, GAS) | |[[Streptococcus pyogenes]] (Group A [[Streptococci]], GAS) | ||
|- | |- | ||
|Disseminated gonococcal disease in adolescents | |[[Disseminated gonococcal infection|Disseminated gonococcal]] [[disease]] in [[Adolescent|adolescents]] | ||
| | |[[Neisseria gonorrhoeae|Neisseria gonorrhoea]] | ||
|- | |- | ||
|SSSS | |[[SSSS]] | ||
TSS | [[Toxic shock syndrome|TSS]] | ||
|Staphylococcus aureus | |[[Staphylococcus aureus]] | ||
|- | |- | ||
|Lyme disease | |[[Lyme disease]] | ||
|Borrelia burgdorferi | |[[Borrelia burgdorferi]] | ||
|- | |- | ||
|Relapsing fever | |[[Relapsing fever]] | ||
|Borrelia recurrentis | |[[Borrelia recurrentis]] | ||
|- | |- | ||
| align="center" style="background:#DCDCDC;" + |Protozoan | | align="center" style="background:#DCDCDC;" + |[[Protozoan]] | ||
|Babesiosis | |[[Babesiosis]] | ||
|Babesia microti | |[[Babesia microti]] | ||
|- | |- | ||
| align="center" style="background:#DCDCDC;" + |Fungal | | align="center" style="background:#DCDCDC;" + |[[Fungal]] | ||
|Histoplasmosis | |[[Histoplasmosis]] | ||
Blastomycosis | [[Blastomycosis]] | ||
Coccidiodomycosis | [[Coccidiodomycosis]] | ||
Paracoccidiodomycosis | [[Paracoccidiodomycosis]] | ||
|Histoplasma capsulatum | |[[Histoplasma capsulatum]] | ||
Blastomyces dermatitidis | [[Blastomyces dermatitidis]] | ||
Coccidioides immitis | [[Coccidioides immitis]] | ||
Paracoccidioides brasiliensis | [[Paracoccidioides brasiliensis]] | ||
|} | |} | ||
Line 231: | Line 200: | ||
! style="background:#4479BA; color: #FFFFFF;" align="center" + |Disease | ! style="background:#4479BA; color: #FFFFFF;" align="center" + |Disease | ||
|- | |- | ||
| align="center" style="background:#DCDCDC;" + |Immune-mediated/Autoimmune | | align="center" style="background:#DCDCDC;" + |[[Immune-mediated disease|Immune-mediated]]/[[Autoimmune]] | ||
|Kawasaki Disease | |[[Kawasaki Disease]] | ||
Henoch- | [[Henoch-Schonlein Purpura]] | ||
Juvenile Rheumatoid Arthritis | [[Juvenile Rheumatoid Arthritis]] | ||
Juvenile Dermatomyositis | [[Juvenile (organism)|Juvenile]] [[Dermatomyositis]] | ||
|- | |- | ||
| align="center" style="background:#DCDCDC;" + |Drug-related eruptions | | align="center" style="background:#DCDCDC;" + |[[Drug]]-related [[Eruption|eruptions]] | ||
|Erythema multiforme | |[[Erythema multiforme]] | ||
SJS | [[SJS]] | ||
TEN | [[Toxic epidermal necrolysis|TEN]] | ||
|} | |} | ||
== | ==Epidemiology and Demographics== | ||
===Age=== | |||
*[[Patients]] of all [[age]] [[Group (sociology)|groups]] may develop [[diseases]] that present with [[fever]] and [[rash]]. | |||
===Race=== | |||
*There is no [[racial]] predilection to [[diseases]] that present with [[fever]] and [[rash]]. | |||
===Gender=== | ===Gender=== | ||
* | |||
*No known gender predilection. | |||
*[ | |||
*Most [[children]] become susceptible to some of the [[diseases]] from 6 months of [[age]] when [[maternal]] [[antibodies]] begin to wane.<ref name="pmid25462439">{{cite journal| author=Tesini BL, Epstein LG, Caserta MT| title=Clinical impact of primary infection with roseoloviruses. | journal=Curr Opin Virol | year= 2014 | volume= 9 | issue= | pages= 91-6 | pmid=25462439 | doi=10.1016/j.coviro.2014.09.013 | pmc=4267952 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25462439 }} </ref> | |||
=== | |||
==Risk Factors== | ==Risk Factors== | ||
*Common [[risk factors]] for the [[development]] of [[diseases]] that present with [[fever]] and [[rash]] include: | |||
* | **Contact with [[Illness|ill]] individuals | ||
**Poor/depressed [[immunity]] | |||
* | **Lack of [[vaccination]] | ||
* | **Very young [[age]] (6 months-12 months) | ||
* | **Poor [[hand washing]] habits | ||
==Natural History, Complications, and Prognosis== | |||
===Natural History=== | |||
*The [[symptoms]] of [[diseases]] associated with [[fever]] and [[rash]] usually develop in the first few days from contact. The stages/phases of most [[infectious]] [[Process (anatomy)|processes]] include the: | |||
**[[Incubation period]] is defined as the period between [[Exposure (photography)|exposure]] to an [[infection]] and the [[appearance]] of the first [[symptoms]]. | |||
**[[Prodromal]] [[Phase (matter)|phase]] is defined as the [[period]] of early [[symptoms]] of a [[disease]]. | |||
* | **[[Illness]] is defined as [[appearance]] of characteristic [[symptoms]] of the [[disease]]. | ||
* | **Decline phase | ||
* | **[[Convalescence]] phase | ||
=== | ===Complications=== | ||
*Common [[complications]] of [[diseases]] presenting with [[fever]] and [[rash]] include: | |||
**[[Febrile seizure]] | |||
* | **[[Rhabdomyolysis]] | ||
* | **[[Shock]] ([[septic]] or [[hypovolemic]]) | ||
* | **[[Disseminated Intravascular Coagulation]] (in [[Meningococcemia]]) | ||
* | **[[Reye syndrome]] (especially in [[children]] that have been given [[aspirin]]). | ||
* | |||
* | |||
* | |||
* | |||
* | |||
=== | ===Prognosis=== | ||
* | *[[Prognosis]] is generally excellent for [[viral]] [[syndromes]]. Prompt [[diagnosis]], [[treatment]], and close follow-up of [[patients]] presenting with other [[causes]] of [[fever]] and [[rash]] also result in a good [[prognosis]]. | ||
==Diagnosis== | |||
*Rapid [[clinical]] [[diagnosis]] is necessary in severe cases to begin immediate [[empiric therapy]] while awaiting test results. | |||
=== | ===Symptoms=== | ||
*Besides [[fever]] and [[rash]], additional [[symptoms]] may include: | |||
**[[Cough]] | |||
**[[Sore throat]] | |||
**[[Runny nose]] | |||
**[[Red eyes]] ([[conjunctivitis]]) | |||
**[[Irritability]] | |||
*The above additional [[symptoms]] are usually seen in the [[prodromal]] [[Phase (matter)|phase]] of most [[infectious diseases]]. Other [[symptoms]] are: | |||
**Recent [[upper respiratory tract infections]] or [[diarrheal]] [[illness]] | |||
**[[Ear pain]] | |||
**[[Pruritus]] (which could be severe in [[drug]] related [[rashes]]) | |||
**[[Poor appetite]] | |||
**[[Headaches]] | |||
**[[Diarrhea]] | |||
**[[Pallor]] | |||
**[[Pains]] in certain [[body]] [[Area|areas]] ([[arthritis]]) | |||
*Important details in the history include: | |||
**Onset and progression of [[symptoms]] | |||
**[[Site]] of the [[rash]] ([[central]] or peripheral) | |||
**Relation with the season(s) | |||
**Travel history | |||
**[[Tick bites|Tick bite]](s) | |||
**Contact with an [[Illness|ill]] [[person]] or animal | |||
**[[Medication]] history (most especially [[sulfonamides]], [[NSAIDs]] and [[anticonvulsants]]) | |||
**[[Exposure]] to [[Forest plot|forest]] or other [[natural environment]] | |||
**Also important to evaluate the [[immune]] status of the [[patient]] | |||
===Physical Examination=== | |||
*Findings on [[examination]] include: | |||
**[[Illness]] severity | |||
**Type of [[rash]], its [[Location parameter|location]], and [[Distribution constant|distribution]] | |||
**[[Lymphadenopathy]] | |||
**[[Conjunctival]], [[oral]] and [[genital]] changes | |||
**[[Nuchal rigidity]] (especially in older kids) | |||
**[[Nikolsky's sign]] | |||
**[[Area|Areas]] of [[tenderness]] (e.g. at the [[joints]]) | |||
**[[Hepatomegaly]] | |||
**[[splenomegaly]] | |||
**[[Hypotension]] | |||
**[[Tachycardia]] | |||
===Laboratory Findings=== | |||
=== | *[[Laboratory]] findings needed to support [[diagnosis]] or determine [[illness]] severity of some [[diseases]] are as follows: | ||
**[[Complete blood count]] with differentials which might reveal: | |||
***[[anemia]] | |||
***[[thrombocytopenia]] | |||
***[[elevated white blood cell count]] | |||
**[[Factor analysis|Factor]] assays show low [[coagulation factors]] in severe [[Meningococcemia]] with [[Disseminated Intravascular Coagulation]] ([[Disseminated intravascular coagulation|DIC]]) | |||
**[[Serum]] chemistries: [[Electrolyte imbalance|Electrolyte imbalance]] in ([[HUS]], [[Meningococcemia]]) | |||
**Labs to isolate offending [[organisms]] in [[Infectious disease|infectious diseases]] for targeted [[antibiotics]] regimen are: | |||
***[[Nasal]]/[[throat]] [[Swabbing|swab]] for [[rapid strep test]] and/or [[Culture collection|culture]] | |||
***[[Blood cultures]] | |||
***[[Stool culture|Stool]] and [[Urine culture|urine]] [[microscopy]]/[[Culture medium|culture]]/[[Sensitivity (tests)|sensitivity]] | |||
***[[Cerebrospinal fluid]] ([[CSF]]) [[analysis]] | |||
***[[Antibody]] and [[Polymerase chain reaction|PCR]] assays- [[Rocky Mountain spotted fever|RMSF]]<ref name="pmid25092818">{{cite journal| author=McQuiston JH, Wiedeman C, Singleton J, Carpenter LR, McElroy K, Mosites E | display-authors=etal| title=Inadequacy of IgM antibody tests for diagnosis of Rocky Mountain Spotted Fever. | journal=Am J Trop Med Hyg | year= 2014 | volume= 91 | issue= 4 | pages= 767-70 | pmid=25092818 | doi=10.4269/ajtmh.14-0123 | pmc=4183402 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25092818 }} </ref> | |||
***[[Skin biopsy]] of [[lesions]] in [[HSP]] show [[leukocytoclastic vasculitis]] | |||
***[[Immunofluorescence assay|Immunofluorescence]] | |||
*[[Immunohistochemistry]] for diagnosing [[Systemic]] [[mycoses]] ([[fungal infections]] related to certain [[Geographical isolation|geographical]] [[Area|areas]]).<ref name="pmid8645463">{{cite journal| author=Jensen HE, Schønheyder HC, Hotchi M, Kaufman L| title=Diagnosis of systemic mycoses by specific immunohistochemical tests. | journal=APMIS | year= 1996 | volume= 104 | issue= 4 | pages= 241-58 | pmid=8645463 | doi=10.1111/j.1699-0463.1996.tb00714.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8645463 }} </ref> | |||
*The [[viral]] [[syndromes]], [[varicella]], [[molluscum contagiosum]], [[lyme disease]], [[immune-mediated disease|immune-mediated]] [[vasculitis]] and [[drug]]-related [[Eruption|eruptions]] rely heavily on a good [[History and Physical examination|history]] and [[physical examination]] findings to make a [[diagnosis]]. | |||
*Peripheral thick and thin [[blood smear]] shows [[Babesia microti]].<ref name="pmid26629450">{{cite journal| author=Parija SC, Kp D, Venugopal H| title=Diagnosis and management of human babesiosis. | journal=Trop Parasitol | year= 2015 | volume= 5 | issue= 2 | pages= 88-93 | pmid=26629450 | doi=10.4103/2229-5070.162489 | pmc=4557163 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26629450 }} </ref> | |||
=== | ===X-ray=== | ||
*[[X-rays]] might be useful in managing severely [[Illness|ill]] individuals to look for [[complications]] but not routinely needed to make [[diagnosis]]. | |||
=== | ===Echocardiography or Ultrasound=== | ||
*There are no [[echocardiography]] findings associated with [[fever]] and [[rash]] but can be used to [[Monitor role|monitor]] for [[coronary aneurysm]] in a [[patient]] with [[kawasaki disease]]. | |||
* | |||
==Treatment== | |||
===Medical therapy=== | |||
* Group | *[[Triaging]] kids who present with [[fever]] and [[rash]] into three groups based on early [[symptoms and signs]] is essential for making prompt [[diagnosis]] and administering possible treatment regimen. These groups are: | ||
**[[Children]] presenting with severe [[illness]] necessitating immediate [[Intervention (counseling)|intervention]]. This is especially true for the non-[[blanching]] [[lesions]]. | |||
**[[Children]] presenting with [[viral]] [[syndromes]] which are easily recognized and require [[symptomatic]] [[treatment]] and reassurance. | |||
**[[Children]] presenting [[undifferentiated]] [[rashes]] which could be [[benign]] or an unusual presentation of severe [[illness]]. | |||
*The '''first group''' is usually managed in the [[hospital]] with: | |||
**[[Intravenous fluids|Intravenous fluid]] [[therapy]] with/without [[Vasopressors|vasopressor]] | |||
**Initiation of [[empirical]] [[antibiotics]] while awaiting [[Culture collection|culture]] results. | |||
**Third generation [[Cephalosporins|cephalosporin]] is first line [[drug]] for [[meningococcemia]]. | |||
**[[Doxycycline]] is drug of choice for [[Rocky Mountain spotted fever|RMSF]]. | |||
**[[Treatment]] for [[Hemolytic-uremic syndrome|HUS]] is supportive with a [[consultation]] to [[Nephrologist]] to manage [[renal failure]]. | |||
*The '''second group''' as earlier mentioned is managed conservatively with measures like: | |||
**[[Antipyretics]] | |||
**[[Fluid]] [[therapy]] | |||
**[[antihistamines]] to soothe the [[patient]] | |||
**Reassurance to care-givers | |||
**Most recover without any [[complications]] | |||
**Majority of [[children]] in this [[Group (sociology)|group]] have [[benign]] [[viral]] [[illness]] that resolves spontaneously. | |||
**Others may have unusual presentations of serious [[illness]] and would require close monitoring with further evaluation and easy access to care. Maybe sometimes needful to admit. | |||
*In general, most [[bacterial diseases]] are treated with the appropriate [[antibiotics]], [[Antifungal drug|antifungal]] therapy for diseases of [[fungal]] origin, [[viral]] [[syndromes]] tend to resolve spontaneously with [[symptomatic]] [[treatment]], [[drug]] related eruption require cessation of offending [[drug]] with adequate [[treatment]] of [[symptoms]], and [[fluid]] [[therapy]]. | |||
===Prevention=== | |||
=== Prevention === | |||
* | *Effective measures for [[primary prevention]] of [[fever]] and [[rash]] in [[children]] may include: | ||
**[[Vaccinations|Vaccination]] done in a timely manner can [[Prevention|prevent]] occurrence of many [[childhood]] [[illnesses]] presenting with [[fever]] and [[rash]] such as the [[viral]] [[syndromes]].<ref name="pmid18803578">{{cite journal| author=Fölster-Holst R, Kreth HW| title=Viral exanthems in childhood--infectious (direct) exanthems. Part 1: Classic exanthems. | journal=J Dtsch Dermatol Ges | year= 2009 | volume= 7 | issue= 4 | pages= 309-16 | pmid=18803578 | doi=10.1111/j.1610-0387.2008.06868.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18803578 }} </ref> | |||
**Frequently and thoroughly [[washing]] [[hands]] with [[soap]] and [[water]]. | |||
**[[Sneeze]] and [[cough]] into [[elbows]] and/or [[tissues]] (which should be thrown away). | |||
**Avoid contact with [[infected]] individuals and contaminated surfaces. | |||
**Wearing clothes to cover upper and [[lower limbs]] to [[Prevention|prevent]] [[tick bites]]. | |||
==References== | ==References== | ||
{{Reflist|2}} | {{Reflist|2}} | ||
[[Category:Up-To-Date]] | |||
[[Category:Primary care]] | |||
[[Category:Pediatrics]] | [[Category:Pediatrics]] |
Latest revision as of 21:10, 24 February 2021
Fever and rash in children Microchapters |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ifeoma Anaya, M.D.[2]
Synonyms and keywords: Fever and rash in kids
Overview
Fever and rash are symptoms encountered frequently in pediatrics. Disease states associated with these symptoms are varied. Febrile rashes can be classified based on morphology, distribution of spread, pattern of occurrence and cause. Fever results when exogenous (micro-organisms) and endogenous pyrogens interact with the Organum Vasculosum of the Lamina Terminalis (OVLT) causing a rise in body temperature as a result of an increase in the hypothalamic set point. Fever and rash in kids are caused by infectious (bacterial, viral, fungal, and protozoan) and non-infectious (drug-related eruptions and immune-mediated) causes. Patients of all age groups may develop diseases that present with fever and rash. Common risk factors for the development of diseases that present with fever and rash include contact with ill individuals, poor/depressed immunity, lack of vaccination, very young age, and poor hand washing habits. The symptoms of diseases associated with fever and rash usually develop in the first few days from contact. The stages/phases of most infectious processes include the incubation period, prodromal phase, illness, decline, and convalescence. Rapid clinical diagnosis is necessary in severe cases to begin immediate empiric therapy while awaiting the test results. Triaging kids who present with fever and rash into three groups on basis of early symptoms and signs is essential for making prompt diagnosis and administering possible treatment regimen. Effective measures for primary prevention of fever and rash in children may include vaccination, coughing, and sneezing into elbows or tissue, hand washing, avoiding contact with ill individuals, preventing exposure to tick bites.
Classification
- Febrile rashes can be classified based on:
- Morphology (maculopapular, pustular, vesicular etc)
- Distribution of spread (systemic and localized)
- Pattern of occurrence (acute and chronic)
- Cause (infectious and non-infectious)[1]
- Types of rashes found among pediatric patients include the following:[1]
- Classification of febrile rashes based on rash morphology is as follows:[2][3][4][5]
Fever + Rash Morphology | Disease |
---|---|
Non-blanching lesions (Petechiae, Purpura and Ecchymoses) | a. Meningococcemia
b. Rocky Mountain Spotted Fever (RMSF) |
Blanching rash | a. Kawasaki disease |
Vesicular or bullous lesions | a. Erythema multiforme
b. Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) c. Staphylococcal Scalded Skin Syndrome (SSSS) d. Disseminated gonococcal disease in adolescents e. HSV I & II |
Umbilicated papules and pustules | a. Molluscum contagiosum |
Sandpaper rash | a. Scarlet fever |
Viral syndromes(mostly maculopapular) | a. Measles (Rubeola)
b. Rubella (German measles) c. Erythema infectiosum (Parvovirus B19) d. Herpangina (Coxsackie) e. Hand-foot-and-mouth disease (Coxsackie) f. Roseola infantum (Human Herpes Virus types 6 or 7) |
Limited to certain geographical areas | a. Babesiosis
e. Lyme disease |
Pathophysiology
- When core body temperatures vary outside normal ranges, thermoregulatory responses are triggered.[6]
- It is understood that infectious processes accounts for up to 74% of fever in hospitalized patients, the remainder being caused by malignancy, ischemia and drug-related reactions.[7]
- Fever results when exogenous (micro-organisms) and endogenous pyrogens interact with the Organum Vasculosum of the Lamina Terminalis (OVLT) causing a rise in body temperature as a result of an increase in the hypothalamic set point.
- This rise in the hypothalamic set point is due to an increased production of Prostaglandin E2 (PGE2) by endothelial cells of the vascular OVLT located in the preoptic area of the anterior hypothalamus. It lacks the Blood-Brain-Barrier (BBB) thus easily accessible to pyrogens. This resultant increased production of PGE2 results in raised body temperature.[7]
- Lipopolysaccharide (LPS) on gram negative bacteria is a common exogenous pyrogen which stimulates the production of endogenous cytokines such as IL-1, IL-6 and TNF-α via the Toll-like receptor (TLRs) cascade.[7][6]
- PGE2 production can also be stimulated via the vagus nerve by inflammatory processes and directly by microbial products through TLRs.[6]
- Skin lesions (rash) could be primarily vascular or from infection spread to tissues (e.g. skin).[8]
- The first step in the formation of a skin lesion/rash is the presence of the micro-organism in the vascular endothelium.[8]
- A macule forms from sustained local dilation of subpapilary dermal blood vessels.
- Edema with infiltration of cells turns a macule to papule.
- Primary epidermal involvement results in vesicles, ulcers, scabs, and secondary epidermal changes can lead to desquamation and pigment changes.[8]
Causes
Non-Infectious | Disease |
---|---|
Immune-mediated/Autoimmune | Kawasaki Disease |
Drug-related eruptions | Erythema multiforme |
Epidemiology and Demographics
Age
Race
Gender
- No known gender predilection.
- Most children become susceptible to some of the diseases from 6 months of age when maternal antibodies begin to wane.[9]
Risk Factors
- Common risk factors for the development of diseases that present with fever and rash include:
- Contact with ill individuals
- Poor/depressed immunity
- Lack of vaccination
- Very young age (6 months-12 months)
- Poor hand washing habits
Natural History, Complications, and Prognosis
Natural History
- The symptoms of diseases associated with fever and rash usually develop in the first few days from contact. The stages/phases of most infectious processes include the:
- Incubation period is defined as the period between exposure to an infection and the appearance of the first symptoms.
- Prodromal phase is defined as the period of early symptoms of a disease.
- Illness is defined as appearance of characteristic symptoms of the disease.
- Decline phase
- Convalescence phase
Complications
- Common complications of diseases presenting with fever and rash include:
- Febrile seizure
- Rhabdomyolysis
- Shock (septic or hypovolemic)
- Disseminated Intravascular Coagulation (in Meningococcemia)
- Reye syndrome (especially in children that have been given aspirin).
Prognosis
- Prognosis is generally excellent for viral syndromes. Prompt diagnosis, treatment, and close follow-up of patients presenting with other causes of fever and rash also result in a good prognosis.
Diagnosis
- Rapid clinical diagnosis is necessary in severe cases to begin immediate empiric therapy while awaiting test results.
Symptoms
- Besides fever and rash, additional symptoms may include:
- The above additional symptoms are usually seen in the prodromal phase of most infectious diseases. Other symptoms are:
- Important details in the history include:
- Onset and progression of symptoms
- Site of the rash (central or peripheral)
- Relation with the season(s)
- Travel history
- Tick bite(s)
- Contact with an ill person or animal
- Medication history (most especially sulfonamides, NSAIDs and anticonvulsants)
- Exposure to forest or other natural environment
- Also important to evaluate the immune status of the patient
Physical Examination
- Findings on examination include:
- Illness severity
- Type of rash, its location, and distribution
- Lymphadenopathy
- Conjunctival, oral and genital changes
- Nuchal rigidity (especially in older kids)
- Nikolsky's sign
- Areas of tenderness (e.g. at the joints)
- Hepatomegaly
- splenomegaly
- Hypotension
- Tachycardia
Laboratory Findings
- Laboratory findings needed to support diagnosis or determine illness severity of some diseases are as follows:
- Complete blood count with differentials which might reveal:
- Factor assays show low coagulation factors in severe Meningococcemia with Disseminated Intravascular Coagulation (DIC)
- Serum chemistries: Electrolyte imbalance in (HUS, Meningococcemia)
- Labs to isolate offending organisms in infectious diseases for targeted antibiotics regimen are:
- Nasal/throat swab for rapid strep test and/or culture
- Blood cultures
- Stool and urine microscopy/culture/sensitivity
- Cerebrospinal fluid (CSF) analysis
- Antibody and PCR assays- RMSF[10]
- Skin biopsy of lesions in HSP show leukocytoclastic vasculitis
- Immunofluorescence
- Immunohistochemistry for diagnosing Systemic mycoses (fungal infections related to certain geographical areas).[11]
- The viral syndromes, varicella, molluscum contagiosum, lyme disease, immune-mediated vasculitis and drug-related eruptions rely heavily on a good history and physical examination findings to make a diagnosis.
- Peripheral thick and thin blood smear shows Babesia microti.[12]
X-ray
- X-rays might be useful in managing severely ill individuals to look for complications but not routinely needed to make diagnosis.
Echocardiography or Ultrasound
- There are no echocardiography findings associated with fever and rash but can be used to monitor for coronary aneurysm in a patient with kawasaki disease.
Treatment
Medical therapy
- Triaging kids who present with fever and rash into three groups based on early symptoms and signs is essential for making prompt diagnosis and administering possible treatment regimen. These groups are:
- Children presenting with severe illness necessitating immediate intervention. This is especially true for the non-blanching lesions.
- Children presenting with viral syndromes which are easily recognized and require symptomatic treatment and reassurance.
- Children presenting undifferentiated rashes which could be benign or an unusual presentation of severe illness.
- The first group is usually managed in the hospital with:
- Intravenous fluid therapy with/without vasopressor
- Initiation of empirical antibiotics while awaiting culture results.
- Third generation cephalosporin is first line drug for meningococcemia.
- Doxycycline is drug of choice for RMSF.
- Treatment for HUS is supportive with a consultation to Nephrologist to manage renal failure.
- The second group as earlier mentioned is managed conservatively with measures like:
- Antipyretics
- Fluid therapy
- antihistamines to soothe the patient
- Reassurance to care-givers
- Most recover without any complications
- Majority of children in this group have benign viral illness that resolves spontaneously.
- Others may have unusual presentations of serious illness and would require close monitoring with further evaluation and easy access to care. Maybe sometimes needful to admit.
- In general, most bacterial diseases are treated with the appropriate antibiotics, antifungal therapy for diseases of fungal origin, viral syndromes tend to resolve spontaneously with symptomatic treatment, drug related eruption require cessation of offending drug with adequate treatment of symptoms, and fluid therapy.
Prevention
- Effective measures for primary prevention of fever and rash in children may include:
- Vaccination done in a timely manner can prevent occurrence of many childhood illnesses presenting with fever and rash such as the viral syndromes.[13]
- Frequently and thoroughly washing hands with soap and water.
- Sneeze and cough into elbows and/or tissues (which should be thrown away).
- Avoid contact with infected individuals and contaminated surfaces.
- Wearing clothes to cover upper and lower limbs to prevent tick bites.
References
- ↑ 1.0 1.1 Kang JH (2015). "Febrile Illness with Skin Rashes". Infect Chemother. 47 (3): 155–66. doi:10.3947/ic.2015.47.3.155. PMC 4607768. PMID 26483989.
- ↑ https://www.consultant360.com/articles/rashes-and-fever-children-sorting-out-potentially-dangerous-part-1
- ↑ https://www.consultant360.com/articles/rashes-and-fever-children-sorting-out-potentially-dangerous-part-2
- ↑ https://www.consultant360.com/articles/rashes-and-fever-children-sorting-out-potentially-dangerous-part-3
- ↑ https://www.consultant360.com/articles/rashes-and-fever-children-sorting-out-potentially-dangerous-part-4
- ↑ 6.0 6.1 6.2 Schortgen F (2012). "Fever in sepsis". Minerva Anestesiol. 78 (11): 1254–64. PMID 22772856.
- ↑ 7.0 7.1 7.2 Walter EJ, Hanna-Jumma S, Carraretto M, Forni L (2016). "The pathophysiological basis and consequences of fever". Crit Care. 20 (1): 200. doi:10.1186/s13054-016-1375-5. PMC 4944485. PMID 27411542.
- ↑ 8.0 8.1 8.2 Mims CA (1966). "Pathogenesis of rashes in virus diseases". Bacteriol Rev. 30 (4): 739–60. PMC 441013. PMID 5342519.
- ↑ Tesini BL, Epstein LG, Caserta MT (2014). "Clinical impact of primary infection with roseoloviruses". Curr Opin Virol. 9: 91–6. doi:10.1016/j.coviro.2014.09.013. PMC 4267952. PMID 25462439.
- ↑ McQuiston JH, Wiedeman C, Singleton J, Carpenter LR, McElroy K, Mosites E; et al. (2014). "Inadequacy of IgM antibody tests for diagnosis of Rocky Mountain Spotted Fever". Am J Trop Med Hyg. 91 (4): 767–70. doi:10.4269/ajtmh.14-0123. PMC 4183402. PMID 25092818.
- ↑ Jensen HE, Schønheyder HC, Hotchi M, Kaufman L (1996). "Diagnosis of systemic mycoses by specific immunohistochemical tests". APMIS. 104 (4): 241–58. doi:10.1111/j.1699-0463.1996.tb00714.x. PMID 8645463.
- ↑ Parija SC, Kp D, Venugopal H (2015). "Diagnosis and management of human babesiosis". Trop Parasitol. 5 (2): 88–93. doi:10.4103/2229-5070.162489. PMC 4557163. PMID 26629450.
- ↑ Fölster-Holst R, Kreth HW (2009). "Viral exanthems in childhood--infectious (direct) exanthems. Part 1: Classic exanthems". J Dtsch Dermatol Ges. 7 (4): 309–16. doi:10.1111/j.1610-0387.2008.06868.x. PMID 18803578.