FifthDisease.org
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About FifthDisease.org
Former two words, brandable domain representing a website built to raise the awareness for a virus that commonly infects children and typically causes a mild rash that may resemble a “slapped-cheek”.
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Parvovirus B19 and Pregnancy
What We All Should Know Sean D. Byrne BS, RPA-C Discussion Outline Disease Overview Epidemiology Pathophysiology Clinical Presentations Diagnostic Testing Treatment Prevention Summary Parvovirus B19 Overview • 1975: Discovered accidentally by Yvonne Cossart & colleagues in London, England • 1981: Linked to a disease state by John Pattison and colleagues during transient aplastic crisis in children • Causative agent of “Fifth Disease” – “Slapped Cheek” Syndrome – Erythema Infectiosum • 1984: 1st associated with non-immune hydrops fetalis / fetal death B19 - Background & History Young NS, Brown KE. Mechanisms of disease: Parvovirus B19. NEJM vol.350;6 586-597. Corcoran A, Doyle S. Advances in the biology, diagnosis & host-pathogen interactions of parvovirus B19. J Med Microbiology; 2004;53, 459-475. • Single-stranded DNA virus (Parvoviridae family, erythrovirus genus) • Protein coat made up of 2 antigens: – NS1: nonstructural protein- serves multiple replicative functions and is cytotoxic – Viral Proteins: VP1 = 5% VP2 = 95% – All assays are based on detecting antibody to 1 or both of these proteins • No lipid envelope - therefore survives heat & detergent treatment of blood products Young NS, Brown KE. Mechanisms of disease: Parvovirus B19. NEJM vol.350;6 586-597. • Named as the “fifth” pediatric disease reported (measles, scarlet fever, rubella, Duke’s (?), EI & roseola) • Parvovirus B19 – pathogenic to humans • 3 – 5 year epidemics • Respiratory droplet spread • Incubation period 4 – 20 days • Viremia at 6 – 8 days, persisting 4 –7 days • Rash at approx. day 16 (non-infectious) Young NS, Brown KE. Mechanisms of disease: Parvovirus B19. NEJM vol.350;6 586-597. • Replicates rapidly in “erythroid progenitor” cells, but also on platelets, tissue of heart, lung, kidney, liver, endothelium and synovium • Dependent on host cells to propagate • Humans are only known hosts •These are the cells that make Red Blood Cells (RBC’s). Parvovirus causes a drop in RBC’s and hemoglobin. This may result in severe anemia in certain patient groups. Young NS, Brown KE. Mechanisms of disease: Parvovirus B19. NEJM vol.350;6 586-597. Corcoran A, Doyle S. Advances in the biology, diagnosis & host-pathogen interactions of parvovirus B19. J Med Microbiology; 2004;53, 459-475. Epidemiology • Infections occur globally and are similar in U.S., Europe and Asia • Outbreaks tend to be in Winter & Spring and are common in childhood • Infection continues at a lower rate throughout adult life and >70% of the adult population is seropositive • Epidemics follow a 3-4 year cycle. •Regional variations apply. •50-70% adults are seropositive. Young NS, Brown KE. Mechanisms of disease: Parvovirus B19. NEJM vol.350;6 586-597. (Kerr et al., 1999) Pathophysiology Viral Transmission Native Virus Capsids Image courtesy of the Wadsworth Centre - New York State Dept of Health B19V and the erythroid progenitor cell receptors 2003 BLOOD : K. WEIGEL-KELLEY (alpha5 beta1= integrines), 2005 BLOOD : Y.MUNAKATA (Ku80 = auto-antigen =PN surface GRCD36, LBCD20 et LTCD3) • Respiratory • Hand-to-mouth (resilient on surfaces) • Infected blood products (esp. pooled factors VIII &IX) • Mother to fetus (vertical transmission) • Infectious during 1st 7-14 days only – During outbreaks 25% & 50% infection rates recorded in school & home How is the virus spread? Anderson et al., 1985; Lyon et al., 1989, Erdman et al., 1997 Pathophysiology of Fetal Disease Human erythroid progenitor is natural host Key is globoside or erythrocyte P antigen - a neutral glycolipid that acts as a cellular receptor for virus and site of entry Globoside is present in the placenta and fetal myocardium; also on some megakaryocytes and endothelial cells Rare that erythrocyte lacks P antigen- means immunity (Brown KE, Anderson SM, Young NS. Science 1993) Maternal Infection & Viremia Transmission across placenta Virus attaches to erythroid cells (P-globoside) fetal liver & myocardial cells Virus replicates resulting in cell death Pathophysiology of Fetal Disease Pathophysiology of Fetal Disease Drop in RBC / Hb resulting in fetal anemia Anemia leading to tissue hypoxia Compensatory increase in cardiac output High output cardiac failure & fetal hydrops NB: B19V infection of fetal spleen, liver & heart may be a contributory cause of organ failure Host Immune Response B19 infection B cells divide to produce plasma and memory cells Plasma cells secrete IgM- detectable 7-10 days post-infection IgG is detectable ~15 days post-infection against VP1 & VP2 Usually infection leads to lifelong protection due to the development of memory B cells APCs process virus and present peptides to Th cells secrete cytokines that mediate antiviral immunity BUT Th cells can also be associated with the pathogenesis of B19 (seen in chronic arthropathies Mitchell et al., 2001.) Loss of Th response can cause serious infections in the immunocompromised host Young, 1996, Kurtzman et al., 1989. Antibody Response Various Clinical Presentations of Parvovirus B19 Different Disease Manifestations of Parvovirus B19 “Fifth Disease” or Erythema Infectiosum Hydrops Fetalis and congenital infection Arthropathies Transient Aplastic Crisis Persistent Infection Assorted syndromes (less common and not proven) – Seronegative hepatitis, chronic fatigue syndrome, vasculitides, meningitis, encephalitis Young NS, Brown KE. Mechanisms of disease: Parvovirus B19. NEJM vol.350;6 586-597. Parvovirus B19 in Pediatrics and Pregnancy Pediatrics First phase- fever and non-specific viral symptoms occur early- high viral shedding and transmission Second phase- Childhood exanthem of “slapped cheek rash”- no transmission at this time Cutaneous eruption and rheumatic symptoms occur two weeks after viral infection- correspond to appearance of viral antibodies Rash likely due to formation of immune complexesusually IgM +/- IgG Rash can be lacy, reticular or evanescent and recur with expose to sunlight, heat, emotion or exercise Pathogenesis of B19V & Clinical Presentation Typical presentation of slapped cheek syndrome Fifth Disease in Pregnancy Usually asymptomatic- can see exanthema & arthralgia may cause fetal hydrops; may resolve spontaneously may lead to severe fetal anemia and hydrops may cause stillbirth and spontaneous abortion B19 infects fetal erythroid precursor cells Lytic infection results in anemia development of generalized fetal hydrops with massive edema cause of fetal death: acute cardiac failure Recent Statistics •4 million births in Europe or US per annum •30% of women non-immune, therefore 1.2 million women at risk •Conservative estimate of fetal loss per annum is 3000 Corcoran A, Doyle S. Advances in the biology, diagnosis & host-pathogen interactions of parvovirus B19. J Med Microbiology; 2004;53, 459-475. • 50-60% of women of child-bearing age are immune • If seronegative – 1% overall risk of infection – 13.5% during epidemics – 50% if direct household contact – 20 –30% from school exposure – Overall fetal loss rate after infection is between 2% and 10%. Risk of Infection Goff, M. Parvovirus B19 in Pregnancy. J of Midwifery & Women’s Health. Vol. 50;6, Nov/Dec 2005 536-538. • 1/3 of infected mothers will pass the virus on to their baby • B19 affects 1/400 pregnancies • Greatest risk during 2nd trimester – Fetal RBC’s have 45-70 day life span and RBC mass increases by 3-4x between 3-6 months gestation • When to test? – Following suspected rash exposure or symptoms – May be included in “TORCH” panel – During suspected outbreaks B19 Infection in Pregnancy Fetal Complications Fetal Death usually occurs 4-6 weeks post-infection, but can go out 12- 20 wks (Hedrick, 1996, Miller et al., 1998) Greatest risk during 2nd trimester – May be most vulnerable because fetal RBC’s have a shortened 45-70 day life span and RBC mass increases by 3-4x between 3-6 months gestation (Rodis et al., 1988) B19 replication with erythroid progenitor cells which leads to apoptosis and ultimately inhibits erythropoiesis causing severe anemia (Morey et al., 1993) Fetal Complications In 1984, Fetal Hydrops was first associated with B19 Up to 20% of NIHF is felt to be related to B19 Anemia is the underlying factor in the development of hydrops Rare and controversial cause of third-trimester fetal loss Making the Diagnosis When to test? What test to order? How do I interpret the results? What do I do with the results? What do I tell my patients? When is imaging necessary? What interventions are out there? Laboratory Testing High index of suspicion and the timing of B19 testing is critical Pre-natal screening is an option- allows you to assess prior exposure, current infection or past infection “routine screening for symptoms of B19 infection or [evidence] of seroconversion would overcome this problem” [ of overlooking B19] Corcoran A, Doyle S. Advances in the biology, diagnosis & host-pathogen interactions of parvovirus B19. J Med Microbiology; 2004;53, 459-475. Use most sensitive assays available to avoid falsepositives and negatives Can follow msAFP, but normals are less predictive especially after 20 wks (Murphy J, Jones D. OBG Management Nov 2000.) • Complete history, including occupational and recent viral syndromes • IgM- & IgG- – No infection / susceptible- repeat testing in 2 weeks • IgM- & IgG+ – Immune- reassure your patient- no risk • IgM+ & IgG+- infection in last 7-120 days – Current infection- HIGH FETAL RISK requires fetal surveillance with weekly ultrasounds for 10-12 weeks • IgM+ & IgG- infection in last 7 days – Current infection- HIGH FETAL RISK requires fetal surveillance with weekly ultrasounds for 10-12 weeks Devine PA. Parvovirus infection in women. Prim Care Update Obstet Gynecol 2002;9:149-53. Diagnosis Laboratory Testing Cost of blood tests and sonograms to patient and healthcare system is an issue IgM EIA- $95- serum/speckled tube IgG EIA- $95- serum/speckled tube IgG/IgM EIA- $190- serum/speckled tube B19 DNA by PCR- $162- lavender-top & frozen These are approximate costs provided by Quest Diagnostics® Somewhere between 70%-100% of the cost is covered by insurance. WARN YOUR PATIENTS THAT THEY MAY GET A BILL. • “Wait & see” - expectant management – Weekly monitoring by ultrasound – Monitor middle cerebral artery-peak systolic velocity (MCA-PSV)- if >95th percentile higher risk of anemia – If anemia present, the blood is less viscous and has higher velocity; – Delivery of the fetus – Only an option post-34 weeks gestation • Intrauterine transfusion – Post 18-20 weeks gestation – 83.8% success rate! – Review of literature puts survival between 50% and 90%. Schild RL, Bald R, Plath, Eis-Hubinger AM, Enders G, Hansmann M. 1999. Intrauterine management of fetal parvovirus B19 infection. Ultrasound Obstet Gynecol 13: 161-166 Treatment Options Typical presentation of hydrops fetalis associated with Parvovirus B19 infection Hydropic Fetus Arthritic Joint with Rash Clinical Manifestations of Parvovirus B19 Infection. panel A shows typical cutaneous eruptions in fifth disease, including “slapped” cheeks in children and a more generalized lacy, reticular pattern of erythema. Panel B shows a bone marrow aspirate with no mature erythroid precursors and with characteristic giant pronormoblasts. In Panel C, hydrops fetalis is evident in an infant who was infected in utero in midtrimester (courtesy of Dr. O. Caul). NEJM 2004; 350, 586-97 Fetal hydrops Treatment Options 5-10 day course of (0.4g/kg) IVIG for fetal hydrops reduces viral burden and can improve anemia (Selbing et al., 1995; Alger, 1997) Spontaneous resolution may occur, but difficult to predict- 54% observed vs. 83.5% transfused survival rate (Rodis et al., 1998) If hydrops is found than percutaneous umbilical blood sampling (PUBS) is indicated to assess fetal blood prior to RBC transfusion – 1% complication rate (fetal hemorrhage) – Determines MCV, Hct, plts, WBC and viral DNA Prevention Strategies Educate the medical provider and the patient Take a good history and assess risk Screen patients up front and when there is risk of exposure Vaccines are in development, but are not currently available (available in animals) Currently not recommended by ACOG “that high risk groups” be excluded from the workplace during epidemics (day care, school), but opinions vary and decided on a case-by case basis (ACOG practice bulletin Sept 2000) Screening the blood supply- not always routinely done, but most manufacturers do Websites Fifth Disease - General Information: http://www.fifthdisease.org http://kidshealth.org/parent/infections/bacterial_viral/fifth http://www.cdc.gov/ncidod/diseases/parvovirus/B19.htm http://www.drreddy.com/shots/fifth.html http://www.emedicinehealth.com/articles/15841-1.asp Medline Plus: http://www.nlm.nih.gov/medlineplus/ency/article/000977.htm Medicine.net: http://www.medicinenet.com/Fifth_Disease/article.htm http://www.biotrin.com Websites Fifth Disease And Pregnancy: http://www.cdc.gov/ncidod/diseases/parvovirus/B19.htm http://www.fifthdisease.org Medline Plus: http://www.nlm.nih.gov/medlineplus/fifthdisease.html New York State Dept of Health: http://www.health.state.ny.us/nysdoh/communicable_disea ses/en/fifth.htm Websites Treatment and Diagnosis: Health Link USA: http://www.healthlinkusa.com/cgibin/foxweb.exe/hl/linkindex1?searchtext=Fifth+Disease&words=all&f romrelated=519 E medicine: http://www.emedicinehealth.com/articles/15841-1.asp http://www.cdc.gov/ncidod/diseases/parvovirus/B19.htm http://www.emedicine.com/derm/topic136.htm http://www.caringforkids.cps.ca/whensick/FifthDisease.htm http://www.mayoclinic.com/invoke.cfm?id=DS00437 http://www.ivillage.com/topics/health/0,,296127,00.html?arrivalSA=1 &cobran dRef=0&arrival_freqCap=1&pba=adid=10506657 Summary Educate yourself and the patient High-index of suspicion Order and interpret tests appropriately Refer to high-risk OB/GYN if fetal compromise suspected