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Jason S. O’Grady, MD Department of Family Fifth and sixth diseases: Medicine, Mayo Clinic, Rochester, Minn

More than a and a [email protected]

The author reported no While most or HHV-6 resolve potential conflict of interest without sequelae, rheumatologic and hemolytic relevant to this article. complications and can develop.

ifth and sixth diseases are frequently encountered viral Practice in family medicine. This article delineates recommendations the unique clinical characteristics of these disorders, › F Reserve serologic testing describes rare but serious sequelae of each, and offers recom- for parvovirus B19 for mendations to guide your practice. pregnant women with known exposure to the , immunocompromised individuals, or patients Parvovirus B19, an infectious agent found worldwide, is the with chronic hemolytic conditions or severe or cause of fifth disease, also known as slapped cheek syndrome persistent arthropathy B or infectiosum. It is transmitted via respiratory drop- lets, most commonly in late winter and early spring. The peak › Keep in mind that incidence of parvovirus B19 is in children ages 5 to 15 up to 15% of children 1 infected with human years. Approximately 20% of parvovirus B19 infections remain 1,2 herpesvirus 6 can experience subclinical. An observational study of children in the United febrile seizures. Treat with Kingdom who were 6 months to 16 years of age and had been an antiepileptic drug, as you immunized for and revealed that parvovirus would for any febrile B19 was the number one identifiable cause of febrile rash, re- that lasts >5 minutes. C sponsible for 17% of cases.3 Seroprevalence increases with age, and 40% to 60% of adults test positive for prior infection.1 Strength of recommendation (SOR) A Good-quality patient-oriented evidence Clinical presentation: B Inconsistent or limited-quality Not necessarily limited to fever and rash patient-oriented evidence Parvovirus B19 has an of 4 to 21 days before C Consensus, usual practice, opinion, disease-oriented the classic symptoms of , fever, and red “slapped” cheeks evidence, case series appear (FIGURE 1). Four to 14 days after the onset of symptoms, a pruritic lacy rash covers the entire body, preferentially on the ex- tensor surfaces (sparing the palms and soles), and may wax and wane for up to 3 weeks, with flaring triggered by stress, exercise, heat, or exposure to sunlight.1,4 Rarely, and usually among young adults, parvovirus B19 can cause papular-purpuric “gloves and stocking” syndrome, with fever, painful , erythema, and pruritus of the distal extremities.5 z Associated . Parvovirus B19 may also cause a symmetric polyarthritis of the hands, wrists, knees, or ankles,

jfponline.com Vol 63, No 10 | OCTOBER 2014 | The Journal of Family Practice E1 particularly in adult females. The course of Figure 1 arthritis usually lasts 1 to 3 weeks, but up to Classic “slapped cheek” rash 20% may evolve into a chronic arthritis.6 In addition, numerous case studies suggest that of fifth disease parvovirus B19 may, in rare cases, cause a vi- ral in infants and children.7 z Hemolytic complications. The target of parvovirus B19 is the erythroid cell line.1 Consequently, immunocompromised patients and those with chronic hemolytic conditions (eg, , thalassemia, spherocytosis, or pyruvate kinase deficiency) may develop hematologic complications such as aplastic crisis, chronic , thrombo- D

cytopenia, neutropenia, or pancytopenia. Pa- M , INE

tients with hemolytic complications can be T A S U

quite ill, presenting with fever, malaise, tachy- . P

cardia, tachypnea, and profound anemia. RD

z Perinatal perils. Approximately one-third ICHA

Parvovirus B19 of pregnant mothers are at risk for parvovirus of: R Y S may cause B19 infection, and having children at home, E RT a severe medical condition, or stressful em-

a symmetric COU polyarthritis, ployment have been shown to increase their particularly in risk of active infection.8 The annual incidence image The onset of this rash occurs at the end of the adult females, of symptomatic parvovirus B19 during preg- prodromal period and signals that the child is no usually lasting nancy is 1.5%, increasing to 13% during epi- longer infectious. one to 3 weeks. demics.9 Such infection can cause significant But it can evolve morbidity and mortality for the fetus. Moth- cated. However, consider serologic testing into a chronic ers newly infected during the first trimester for pregnant women with known exposure arthritis. have experienced a 71% increased risk of in- to the virus, immunocompromised patients, trauterine fetal demise (fetal loss <20 weeks patients with chronic hemolytic conditions, gestation) when compared with baseline risk or patients with severe or persistent arthrop- of fetal loss.9 In one prospective observation- athy. Serum can usually al study, fetal death was only observed when be detected 10 days after infection and can mothers were infected prior to 20 weeks of persist for 3 months, while serum immuno- gestation.10 Intrauterine B19 infection dur- globulin G is produced 2 weeks after inocula- ing any trimester carries a 4% overall risk of tion and presumably lasts for life.11 , thought to be due to high output cardiac failure secondary to severe Treat supportively anemia.10 No specific treatment exists for parvovirus B19 infection. Management is supportive and Rely on clinical findings to diagnose; the infection is usually mild and self-limiting. restrict serologic testing A nonsteroidal anti-inflammatory agent may The characteristic “slapped cheek” rash usu- be sufficient for associated arthritis; if need- ally distinguishes fifth disease from other ed, a low-dose oral can be used causes of febrile rash. without prolonging the viral illness.6 Refer for includes measles, , in- hematologic consultation any immunocom- fantum, enterovirus, and adenovirus. A diag- promised patient with confirmed parvovirus nostic tool (TABLE) can help differentiate fifth who develops a hematologic , disease from other viral exanthems. which may require intravenous immuno- In most cases of suspected parvovirus globulin treatment or, in severe cases, bone B19 infection, serologic testing is not indi- marrow transplantation.

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TABLE Diagnostic aid for distinguishing among pediatric exanthems

First disease Second disease Third disease Fifth disease Sixth disease (rubeola) (scarlet fever) (German measles) (erythema (roseola infantum) infectiosum) Causative agent Measles virus Pyrogenic exotoxin- Parvovirus B19 producing group A (HHV-6) Streptococcus Mode of Respiratory Respiratory Respiratory Respiratory Saliva via mucosal droplets droplets droplets droplets surfaces Incubation period 8-12 days 2-5 days 14-21 days 4-21 days 10-15 days Symptoms Fever, sore throat, red eyes, headache, 1st stage Mild fever, Fever, sore throat Malaise, fever, red Mild rhinorrhea, sore malaise, coalescing , “slapped” cheeks throat, conjunctival pink macules , coryza, redness, high fever starting on the Koplik spots head and neck and

spreading to

the trunk and 2nd stage Red maculopapular Fine, papular Pruritic lacy body After fever abates, extremities, rash beginning on erythematous rash that spares tiny erythematous Forchheimer the forehead and eruption around the palms and papules develop spots, petechial neck, spreading the neck, trunk, soles on the trunk and hemorrhage on soft to trunk, arms, and extremities spread to neck and palate and legs. (Involves (face is usually extremities palms and soles spared), followed 50% of the time) by Treatment Supportive Supportive Supportive Supportive (penicillin or cephalosporins) Duration of illness 1st stage 2-4 days 1-2 days 3 days 4-14 days 3-5 days 2nd stage 7-10 days 3-4 days Up to 3 weeks 1-3 days Sequelae , Peritonsillar Congenital Polyarthritis, Febrile seizures, , abscess, otitis rubella syndrome, aplastic crisis, , , , sinusitis, thrombocytopenia, chronic anemia, acute disseminated media, death pneumonia, arthritis, encephalitis pancytopenia, demyelination, rheumatic fever, intrauterine fetal , myocarditis poststreptococcal demise, hydrops glomerulone- fetalis phritis, reactive arthritis preventable Yes No Yes No No

Clinical recommendations a child with erythema infectiosum is no lon- Parvovirus B19 is communicable only dur- ger infectious. At this stage, exclusion from ing the nonspecific prodromal period—the school or child care is unnecessary.1 4 to 21 days of incubation in which the pa- Perform serologic testing to determine tient seems to have a common cold, with for all pregnant women with docu- coryza, sore throat, and headache. With the mented exposure to parvovirus B19.12 Retest appearance of the “slapped cheek” rash (an women who are initially nonimmune after 3 to immune-mediated, postinfectious sequela), 4 weeks. Patients who seroconvert should un-

jfponline.com Vol 63, No 10 | OCTOBER 2014 | The Journal of Family Practice E3 FIGURE 2 junctival redness, followed by a high fever Sixth disease: The rash (100.4º F to 104º F).16 Cervical, postauricular, or occipital usually de- velops. Other symptoms are usually absent but may include abdominal pain, vomiting,

or diarrhea. After 3 to 5 days, the fever abates ; s

la and the rash of roseola may begin—if at all— t

ma as tiny, erythematous, raised papules on the r trunk that spread to the neck and extremities D, De M (FIGURE 2), lasting 1 to 3 days. Interestingly,

ohen, while 93% of those infected are symptomatic C

rd (, fussiness, rhinorrhea), only 20% of

na 1 r

g those infected exhibit the rash of roseola. r .o

s Nagayama spots (ulcers at the uvulopalato­ la t ion. © Be glassal junction) can be seen in Asian ss ma r mi e r infants. d

h pe z Complications. Fifteen percent of in- t 1 wi

p://www. fected children have febrile seizures. Based d e tt h Us on several case reports, HHV-6 infection This rash occurs in just 20% of infected patients and appears as tiny, erythematous, has been associated with meningoencepha- raised papules on the trunk and spreads to the neck and extremities. litis, acute disseminated demyelination, hepatitis, and myocarditis.17 It is unknown whether seizures increase the risk of these complications. Long-term sequelae from dergo serial ultrasounds for 10 weeks to evalu- these manifestations of HHV-6 infection in- ate for hydrops fetalis or growth restriction. clude developmental disorders and - Repeat testing is unwarranted for those who do spectrum disorders.18,19 not seroconvert. There is no evidence to sug- gest that seronegative pregnant women should Treat supportively avoid work environments during peri- Patients with primary HHV-6 infection usu- ods of infection.13 ally require antipyretics and frequent hydra- tion. Reserve antivirals such as , , and cidofovir for immunocom- Sixth disease promised patients or those with HHV-6 Human herpesvirus 6 (HHV-6) causes sixth encephalitis.20 disease, also known as roseola infantum or subitum. Ninety percent of chil- Clinical recommendations dren have been infected by 2 years of age, Treat seizures associated with HHV-6 infec- with peak incidence occurring between tion as you would any other , 9 and 21 months of age.14 HHV-6 is most giving an antiepileptic (diazepam, lorazepam, likely transmitted via the saliva of healthy or midazolam) if the seizure lasts >5 min- individuals and enters the body via a muco- utes. Risk of seizure recurrence with HHV-6 sal surface. One percent of HHV-6 infection is equivalent to that seen with other causes of is acquired congenitally without known se- febrile seizure.1 quelae, similar to the transmission rate of Because of the ubiquitous prevalence of .15 HHV-6 infection, there are no effective pre- ventive measures. Little is known about the Clinical presentation: effect of HHV-6 exposure during Only 20% may exhibit a rash because most pregnant mothers are immune After an incubation period of 10 to 15 days, to the virus.21 Exclusion from school or child sixth disease is characterized by a care is not recommended because of the pro- of mild rhinorrhea, sore throat, and con- longed shedding of the virus.16,22 JFP

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Correspondence Acknowledgement Jason S. O’Grady, MD, Department of Family Medicine, The author thanks Anne Mounsey, MD, Department of Mayo Clinic, 200 First Street SW, Rochester, MN 55905; Family Medicine, University of North Carolina at Chapel [email protected] Hill, for her invaluable assistance in editing this manuscript.

References 1. Kliegman RM, Stanton BMD, St. Geme J, et al. Nelson Textbook September 2000. (Replaces educational bulletin number 177, of Pediatrics. 19th ed. Philadelphia, PA: Elsevier/Saunders; February 1993). Int J Gynaecol Obstet. 2002;76:95-107. 2011. 13. Harger JH, Adler SP, Koch WC, et al. Prospective evaluation of 2. Tuckerman JG, Brown T, Cohen BJ. Erythema infectiosum in a vil- 618 pregnant women exposed to parvovirus B19: risks and symp- lage primary school: clinical and virological studies. J R Coll Gen toms. Obstet Gynecol. 1998;91:413-420. Pract. 1986;36:267-270. 14. Zerr DM, Meier AS, Selke SS, et al. A population-based study 3. Ramsay M, Reacher M, O’Flynn C, et al. Causes of of primary human herpesvirus 6 infection. N Engl J Med. rash in a highly immunised English population. Arch Dis Child. 2005;352:768-776. 2002;87:202-206. 15. Hall CB, Caserta MT, Schnabel KC, et al. Congenital infections 4. Anderson LJ. Role of parvovirus B19 in human disease. Pediatr with human herpesvirus 6 (HHV6) and human herpesvirus 7 Infect Dis J. 1987;6:711-718. (HHV7). J Pediatr. 2004;145:472-477. 5. Smith PT, Landry ML, Carey H, et al. Papular-purpuric gloves and 16. Richardson M, Elliman D, Maguire H, et al. Evidence base of incu- socks syndrome associated with acute parvovirus B19 infection: bation periods, periods of infectiousness and exclusion policies case report and review. Clin Infect Dis. 1998;27:164-168. for the control of communicable diseases in schools and pre- 6. Tello-Winniczuk N, Diaz-Jouanen E, Diaz-Borjón A. Parvovirus schools. Pediatr Infect Dis J. 2001;20:380-391. B19-associated arthritis: report on a community outbreak. J Clin 17. Gewurz BE, Marty FM, Baden LR, et al. Human herpesvirus 6 en- Rheumatol. 2011;17:449-450. cephalitis. Curr Infect Dis Rep. 2008;10:292-299. 7. Molina KM, Garcia X, Denfield SW, et al. Parvovirus B19 myocar- 18. Howell KB, Tiedemann K, Haeusler G, et al. Symptomatic gener- ditis causes significant morbidity and mortality in children.Pedi - alized epilepsy after HHV6 posttransplant acute limbic encepha- atr Cardiol. 2013;34:390-397. litis in children. Epilepsia. 2012;53:e122-e126. 8. Jensen IP, Thorsen P, Jeune B, et al. An epidemic of parvovirus B19 19. Nicolson GL, Gan R, Nicolson NL, et al. Evidence for Mycoplasma Most patients in a population of 3,596 pregnant women: a study of sociodemo- ssp., Chlamydia pneunomiae, and human herpes virus-6 coin- graphic and medical risk factors. BJOG. 2000;107:637-643. fections in the blood of patients with autistic spectrum disorders. infected with 9. Lassen J, Jensen AK, Bager P, et al. Parvovirus B19 infection in the J Neurosci Res. 2007;85:1143-1148. HHV-6 have first trimester of pregnancy and risk of fetal loss: a population- 20. De Bolle L, Naesens L, De Clercq E. Update on human herpesvi- based case-control study. Am J Epidemiol. 2012;176:803-807. rus 6 biology, clinical features, and therapy. Clin Microbiol Rev. fever and 10. Enders M, Weidner A, Zoellner I, et al. Fetal morbidity and mortality 2005;18:217-245. rhinorrhea, after acute human parvovirus B19 infection in pregnancy: prospec- 21. Baillargeon J, Piper J, Leach CT. Epidemiology of human herpes- tive evaluation of 1018 cases. Prenat Diagn. 2004;24:513-518. virus 6 (HHV-6) infection in pregnant and nonpregnant women. J and are fussy. 11. Heegaard ED, Brown KE. Human parvovirus B19. Clin Microbiol Clin Virol. 2000;16:149-157. Only 20% Rev. 2002;15:485-505. 22. Levy JA, Ferro F, Greenspan D, et al. Frequent isolation of HHV-6 12. American College of Obstetrics and Gynecologists. ACOG prac- from saliva and high seroprevalence of the virus in the popula- exhibit the rash tice bulletin. Perinatal viral and parasitic infections. Number 20, tion. Lancet. 1990;335:1047-1050. of roseola.

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