Human Parvovirus B19 infection

1. Human Parvovirus B19 infection Presented by: Dr. M. Mizyed Moderator: Dr. A. Hammam

2. INTRODUCTION • Human parvovirus B19 (B19) belongs to the Erythrovirus genus . • B19 was first discovered in 1975 while screening units of blood for hepatitis B virus in asymptomatic donors . • Sample 19 in panel B (hence the name parvovirus B19) was read as a false positive result on a counterimmunoelectrophoresis assay.

3. B19 is the predominant parvovirus pathogen in humans, and as such, B19 is the prototype strain for genotype 1. • The other less common and more recently described erythroviruses infecting humans include genotype 2 (prototype strain, LaLi) and genotype 3 (prototype strain, V9) . • Parvovirus B19 was first associated with clinical disease in 1981.

4. VIROLOGY •  Parvovirus B19 is a small (26 nm), non-enveloped, ssDNA virus. • The capsid consists of a minor structural protein, VP1 and a major structural protein, VP2. • The only known host for B19 is humans .

5. The virus replicates in erythroid progenitor cells of the bone marrow and blood leading to inhibition of erythropoeisis, which can result in symptoms of anemia. • During its attempts to exit the cell, B19 causes cell lysis.

6. Bone marrow specimen.Virus particles in the nucleus by electron microscopy (EM)

7. INFECTIVITY • B19 viremia begins approximately 7-10 days after exposure and lasts for one week in immunocompetent individuals. • An infected person is contagious before the onset of symptoms. • B19 can be detected in blood and secretions as early as 5 to 10 days after exposure.

8. Patients with normal immune systems probably are not infectious after the onset of B19-associated rash, arthralgias, or arthritis. • Individuals with B19 IgG generally are considered immune to recurrent infection. • However reinfection is possible .

9. IMMUNOLOGY •  Viremia occurs 7 to 10 days after exposure and usually lasts approximately one week. • Parvovirus B19-specific IgM antibodies are detected at day 10 - 12 and can persist for up to five months. • Specific IgG antibodies are detectable about 15 days post-infection and persist long-term.

10. CLINICAL MANIFESTATIONS • The clinical presentations associated with B19 infection vary greatly, ranging from benign to life threatening. • The clinical presentation is influenced by the infected individual's age, hematologic and immunologic status . • Most immunocompetent people with detectable B19-specific IgG do not recall ever having any specific symptoms .

11. Approximately 25% of infected individuals will be completely asymptomatic during their infection. • while 50% will have only non-specific flu-like symptoms . • The remaining 25% of infected individuals will present with the classic symptoms of B19 infection.

12. There are five well-established syndromes associated with B19 infection: • Fifth disease ( Erythema infectiosum ). • Arthropathy . • Non-immune hydrops fetalis, intrauterine fetal death, or miscarriage . • Transient aplastic crisis in those with chronic hemolytic disorders . • Chronic pure red blood cell aplasia in immunocompromised individuals .

13. I. Erythema infectiosum • Erythema infectiosum (EI) often occurs in outbreaks among school-aged children, although it can occur in adults as well . • The illness begins with nonspecific prodromal symptoms, such as fever, coryza, headache, nausea, and diarrhea . • These constitutional symptoms coincide with onset of viremia.

14. Two to five days later, the classic erythematous malar rash appears (the so-called slapped cheek rash) with relative circumoral pallor. • This facial rash is often followed by a reticulated or lacelike rash on the trunk and extremities . • The rash is thought to be immunologically-mediated. • Approximately 75% of patients will develop a rash, although less than 20% will have the appearance of the typical malar rash seen in EI .

15. Slapped cheek rash of parvovirus B19

16. Erythema infectiosum

17. The estimated incubation period from exposure to the onset of rash has usually been between 1 - 2 weeks but can be as long as three weeks . • A typical feature of EI is recrudescence of rash after a variety of nonspecific stimuli, such as change in temperature, exposure to sunlight, exercise, or emotional stress. • In most patients, symptoms resolve within a few weeks, but symptoms can last for months, or rarely even years, in some patients .

18. II. Arthralgia and/or arthritis • Parvovirus B19 infection can present as an acute arthritis and may be mistaken for acute rheumatoid arthritis in the absence of rash. • Arthralgia and/or arthritis is more common in adult females. • Joint symptoms are usually symmetric and most frequently involve the small joints of the hands, wrists, knees, and feet .

19. Joint symptoms usually resolve in three weeks, although a minority of patients may develop persistent or recurring arthropathy . • The arthritis associated with acute B19 infection does not cause joint destruction. • Pathogenesis of arthropathy • The pathogenesis of joint disease is unclear. • It is not yet clear whether viral DNA represents direct infection of the synovial tissue or systemic viremia with seeding of the joint space.

20. III. Transient aplastic crisis •  Individuals with a history of hematologic abnormalities, including increased RBC destruction (eg, sickle cell disease, hereditary spherocytosis) or decreased RBC production (eg, iron deficiency anemia), are at increased risk of developing transient aplastic crisis (TAC) secondary to parvovirus infection. • Patients with TAC usually present with pallor, weakness, and lethargy secondary to severe anemia.

21. Infection can rarely be fatal due to congestive heart failure, cerebrovascular accidents, and acute splenic sequestration • The dramatic decrease or absence of measurable reticulocytes is a hallmark laboratory finding in persons with B19 infection. • Red cell production returns to baseline after resolution of infection. • Occasionally, white cell and platelet counts may also fall during TAC .

22. IV. Anemia in immunocompromised hosts •  Immunosuppressed patients are at risk of developing acute or chronic anemia following B19 infection due to lack of protective antibodies . • Life-threatening anemia can develop due to the inability of immune system to clear viremia. • Chronic infection leads to chronic hypoplasia or aplasia of the erythroid series in the bone marrow, resulting in reticulocytopenic anemia .

23. Chronic infection and anemia have been described in the following groups of patients: • Patients with certain leukemias or cancers . • HIV-infected patients with advanced immunodeficiency. • Patients with congenital immunodeficiencies . • Recipients of organ transplants.

24. Pathogenesis of anemia • The pathogenesis of anemia is due to destruction of erythrocyte progenitor cells, which dramatically reduces red cell production. • During an acute infection, this results in a significant drop in hematocrit. • In healthy individuals, RBC production returns in 10 to 14 days with little anemia.

25. V. Non-immune hydrops fetalis and intrauterine fetal death •  B19 infection during pregnancy can result in fetal complications including : _Miscarriage. _Intrauterine fetal death . _Non-immune hydrops fetalis. • Because of this potential, it is critical to determine the serologic status of the pregnant woman who has a history of significant exposure to the virus or who has any of the classic symptoms of B19 infection .

26. Conditions associated with parvovirus B19 infection

27. Treatment of parvovirus B19 infection • Erythema infectiosum • Erythema infectiosum ("fifth" disease) is a self-limited, mild illness most often occurring in children. • There is no specific therapy and usually no indication for symptomatic treatment. In some patients, symptomatic therapy for arthralgias, arthritis, or pruritus may be indicated .

28. Arthritis or arthralgia •  Arthritis or arthralgia are most often reported in adult females, but can occur in either gender and at any age. • The joint symptoms usually last one to two weeks, but can persist for weeks, months, and even years . • Nonsteroidal antiinflammatory drugs can provide symptomatic relief.

29. Transient aplastic crisis • TAC most often occurs when B19 infection develops in patients with underlying hematologic abnormalities such as sickle cell disease, thalassemia, and hereditary spherocytosis . • The anemia is often sufficiently severe to require transfusion until the patient's immune response eliminates the infection and red cell production returns. • The usual course of parvovirus associated-anemia is spontaneous resolution within a few days to weeks. • More aggressive therapy with IGIV is generally limited to patients with chronic B19 infection and chronic anemia .

30. Chronic infection • Chronic infection with anemia: • Most patients with chronic B19 infection and anemia have received immunosuppressive therapy for cancer, leukemia, or tissue transplantation, have a congenital immunodeficiency, or have HIV-associated immunodeficiency. • The anemia responded to IGIV treatment with a reticulocytosis within one week, and the chronic viremia was cured after periodic IGIV infusions over four months.

31. Chronic infection without anemia: • Chronic B19 infection has been demonstrated in patients without anemia or underlying immunodeficiency . • It is not clear if IGIV treatment is helpful in this setting.

32. Treatment for symptomatic parvovirus B19 infection

33. Parvovirus B19 infection during pregnancy • Epidemiology: • Pregnant women lacking antibody to the virus are as susceptible as any other immunocompetent adult to B19 infection. • However, 35% to 53 % of pregnant women have preexisting IgG to the virus, indicating immunity from a prior infection . • The incidence of acute B19 infection in pregnancy is 3.3% to 3.8 %, this risk varies among different occupational groups.

34. Maternal-fetal effects • Fetal loss • The initial reports linking B19 and poor fetal outcome suggested that the risk of fetal loss was greater than 30%. • The largest prospective study of B19 infection in pregnant women included 1018 women with acute infection based upon serological studies .

35. Major findings from this report were: • Fetal death occurred in 6.3% (64/1018) of pregnancies and was limited to B19 infections . • 13% (34/256 )in women diagnosed with first trimester infection. • 9 % (30/322)for infections diagnosed at 13 to 20 weeks of gestation. • 0% (0/439) after 20 weeks. • A summary of the available data suggests that the risk of fetal loss in pregnancies infected before and after 20 weeks of gestation is 11% and <1 %, respectively.

36. Transient effusions • Maternal parvovirus infection has been associated with transient isolated fetal pleural or pericardial effusions that resolve spontaneously before term . • These effusions are thought to result from direct pleural or myocardial inflammation.

37. Fetal hydrops • In addition to causing fetal loss, B19 is cytotoxic to fetal red blood cell precursors and may cause anemia and hydrops fetalis . • Hydrops can lead rapidly to fetal death (within a few days to weeks) or can resolve spontaneously with an apparently normal infant at delivery.. • The hydrops and fetal death are thought to result from severe B19-associated anemia.

38. The median interval between diagnosis of maternal infection and hydrops was three weeks. • 50% of cases occurred two to five weeks after maternal infection . • 93 % occurred within eight weeks of maternal diagnosis.

39. Neonatal and developmental considerations • Parvovirus appears to be teratogenic in fetal animals. • Case reports describe congenital abnormalities in four human newborn infants with parvovirus infection including Ocular anomalies ,Hydrocephalus, Cleft lip or Palate, Hepatocellular damage, Myocarditis and Congenital cardiomyopathy . • Despite the above associations, most intrauterine parvovirus infections do not have an adverse outcome and the bulk of the available data suggest that parvovirus B19 is not a teratogen .

40. DIAGNOSIS • During pregnancy, the laboratory diagnosis of maternal parvovirus B19 infection relies primarily on IgG and IgM antibody testing, although PCR assays may also be helpful in certain situations. • Parvovirus B19 is difficult to culture.

41. Maternal parvovirus infection • Circulating IgM antibodies can be detected approximately 10 days after exposure and just prior to the onset of symptoms; they may persist for three months or longer. • B19 IgG antibodies are detected several days after IgM and usually persist for years; they are a marker of past infection. • However, reliance on a negative IgM serologic result alone can be misleading in a patient with a significant exposure history, because in some instances maternal IgM levels may be below the detection limit. In such cases, polymerase chain reaction can be useful.

42. Fetal parvovirus infection • Polymerase chain reaction (PCR) is a sensitive method to detect small amounts of B19 DNA. • Use of this technique on amniotic fluid is the method of choice to make the fetal diagnosis . • Another option is to obtain fetal blood for B19 IgM. • Other methods •  Other techniques such as electron microscopy, detection of viral DNA, and probe hybridization assays for nucleic acids are available but typically are not necessary to detect acute maternal infection.

43. APPROACH TO PATIENT EXPOSED TO B19 • Pregnant women who are exposed to or have symptoms of parvovirus infection should have serologic testing for IgG and IgM antibodies. • Past infection • A positive IgG antibody and a negative IgM indicates maternal immunity. • thus, the fetus is protected from infection.

44. Acute infection • A positive IgM antibody is consistent with acute parvovirus infection. The significance of this will depend on when testing is done relative to the stage of pregnancy: • Women who are diagnosed with acute infection in the first half of pregnancy should be counseled that there is no proven risk of parvovirus-induced congenital anomalies, but there is a risk for fetal loss. • The only potentially effective intervention is intrauterine fetal transfusion for treatment of severe fetal anemia.

45. Women who are diagnosed with acute infection beyond 20 weeks gestation should receive periodic ultrasounds (weekly beginning as early as 22 weeks) to look for signs of fetal hydrops . • Although serial ultrasounds commonly are performed, the risk of hydrops is low. • There is also controversy about how long to continue ultrasound monitoring. • There have been cases of hydrops reported more than eight weeks after the initial maternal infection.

46. Susceptible host • A pregnant woman who is negative for both IgG and IgM parvovirus antibody is susceptible to infection, especially if she has contact with small children and there are parvovirus cases in the community. • No history of exposure • Ideally, susceptible pregnant women should avoid contact with B19. • However, there is no proven benefit to removal of seronegative women from high-risk employment for the duration of pregnancy. • However, careful hand washing and avoiding sharing food or drinks is likely to at least partially prevent the spread of B19.

47. Recent history of exposure • If a pregnant patient has a history of recent parvovirus exposure and initial serologies are negative, we suggest additional screening for maternal B19 DNA . • However, if B19 DNA results are positive, the level of viremia should also be scrutinized, since low-level viremia may indicate a false positive NAAT(nucleic acid amplification testing ). • Repeat serologic testing at three weeks is helpful in this scenario since IgM antibody responses should be seen at this time in true infection.

48. MANAGEMENT OF ANEMIA AND HYDROPS • Mild to moderate anemia generally is well tolerated by the fetus and resolves without sequelae. • Severe anemia, although uncommon, can lead to hydrops fetalis and death. • When severe anemia is suspected the fetus requires close monitoring and assessment of fetal hematocrit by percutaneous umbilical vein sampling. • Intrauterine fetal blood transfusion usually is performed if severe anemia is confirmed.

49. Delivery room and postnatal management of the hydropic infant  • Resuscitation of such infants frequently is difficult and advance preparation is advisable. • The majority of hydropic infants require respiratory assistance and mechanical ventilation. • Abdominal paracentesis and thoracocentesis of fetal ascites and pleural effusions may be needed either just prior to delivery or immediately after to facilitate resuscitation. • Infants with severe anemia and cardiovascular instability may benefit from an isovolumetric or partial exchange transfusion with packed red blood cells

50. PREVENTIONOF B19 INFECTION • The best measures currently available to prevent B19 infection are those designed to interrupt transmission by good infection control practices. • A recombinant human parvovirus B19 vaccine, composed of the VP1 and VP2 capsid proteins under evaluation . • The vaccine was found to be safe and highly immunogenic.