Case 4 -

Fetal parvovirus B19 infection Beverly B. Rogers Children's Medical Center Dallas, TX

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Clinical History: This 1170 stillborn male fetus was delivered to a 26 year- old G3P2 mother at a gestational age of 27 weeks. The mother had been receiving prenatal care and was referred to Parkland Hospital after documentation of severe fetal hydrops. The fetus was re-imaged, with significant findings including severe fetal hydrops, a markedly enlarged placenta, ascites, a large pericardial effusion, an enlarged heart, and a severe elevation of the middle cerebral artery pressure (maximum peak systolic velocity of 130 cm/sec). The mother was admitted for an intrauterine transfusion and the fetus's hematocrit increased from 5.4 to 10.2 g/dL. Despite intrauterine transfucion, the fetus continued to have severe anemia and decelerations. Therefore, it was decided to induce labor. The infant was delivered by vaginal delivery without complications two days after initial presentation. Apgar scores were 0. Fetal examination showed a 1170 gram male infant with the only significant findings being hydrops and focal skin slippage. Case 4 - Figure 1 A 20X photograph of fetal lung (original magnification) Case 4 - Figure 2 A 100X photograph of fetal lung (original magnification) Case 4 - Figure 3 A 20X photograph of placenta (original magnification) Case 4 - Figure 4 A 100X photograph of placenta (original magnification) Case 4 - Figure 5 The abdomen of this 27 week gestation fetus shows skin slippage characteristic of maceration. In addition, the abdomen is distended, a reflextion of edema. Case 4 - Figure 6 This 20X (original magnification) view of the fetal lung demonstrates premature pulmonary tissue, with a suggestion of cells containing intranuclear inclusions. Case 4 - Figure 7 The 40X (original magnification) view reveals erythroid precursors with inclusions. Case 4 - Figure 8 The intranuclear inclusion is seen in an erythroid precursor at a 100X (original magnification) power. Case 4 - Figure 9 Although villous edema is difficult to diagnose during the second trimester, these villi are enlarged, with loose stroma indicative of edema. Even at the 20X (original) magnification, excessive numbers of red blood cell precursors are noted. Case 4 - Figure 10 A 100X (original magnification) view reveals multiple intravascular erythroid precursors. While inclusions are present, they are less completely formed than the inclusions in the pulmonary erythroid series. It is typical for erythroid precursors in the placenta to have less distinct inclusions than those in the lungs. The reason for this is not known. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: The slide represents pulmonary parenchyma from a fetus with parvovirus B19 infection. Typical of fetal lung, the generalized non-aerated pattern is one seen in fetuses who succumb to in utero demise, having never taken a breath to expand the airways. It is not until one views the lung using a 20X lens (original magnification) that the nuclear changes related to parvovirus B19 become apparent. Scattered throughout the parenchyma are single cells with nuclei which appear to either have an eosinophilic inclusion with peripheral displacement of chromatin, or appear vacant. Using a 40X lens, these cells are seen to be present within vessels, most being small capillaries. The characteristic nuclear changes seen in parvovirus B19 infection include a homogeneous, eosinophilic intranuclear inclusion which displaces the chromatin to the edge of the nuclear envelope. Less commonly are cells which appear to have lost the nuclear basophilia, but which has peripheral clumping of chromatin. Differential Diagnoses: The morphology of the intranuclear inclusions can be confused with those of herpes simplex virus (HSV) or varicella zoster virus (VZV). Both of these viruses produce either glassy intranuclear inclusions, which can be reminiscent of parvovirus inclusions, or single eosinophilic intranuclear inclusions with peripheral halo. One can differentiate between HSV/VZV inclusions and parvovirus by the cell type; parvovirus inclusions are only seen in nucleated red blood cells which in a fetus are in circulation or areas of extramedullary hematopoiesis. HSV inclusions are not found in cells of the erythroid series, but rather are common in parenchymal cells. In addition, HSV infection produces areas of necrosis, particularly in the liver, lung, and adrenal gland of the fetus. There is no necrosis in the slide. While VZV inclusions can not be distinguished from HSV, disseminated VZV infection of the fetus is very rare and not primary on the differential diagnosis. Adenovirus can also produce inclusions which are similar in appearance to parvovirus inclusions. However, adenovirus typically causes necrosis, is rare in fetuses, and infection occurs in parenchymal cells and not the erythroid lineage. In the final result, the differential diagnosis of parvovirus B19 infection of the fetus is narrow, as the typical inclusions in a second trimester fetus with hydrops is characteristically parvovirus infection. The histologic diagnosis can be confirmed by immunohistochemistry or in situ hybridization, or even PCR analysis of the tissue. Final Diagnosis: Fetal parvovirus B19 infection Case Discussion: This case represents a pregnancy complicated by second trimester hydrops with fetal demise. The history in this case was also significant for identification of parvovirus in the amniotic fluid. This confirmed the clinical impression, even prior to fetal demise. Intrauterine transfusions can sometimes result in fetal survival, but did not save the fetus in this case. The differential diagnosis of hydrops fetalis includes immune and non-immune hydrops. Immune hydrops is much less prevalent than in previous decades, as mothers mother who are Rh negative receive Rh immune prenatally. This results in sensitization in only 1 of 1000 pregnancies, and even with sensitization the pregnancies are closely followed with typically good fetal outcomes. Immune hydrops may also occur with antibodies other than anti-D, but these are uncommon. The diagnosis can be confirmed by measuring the antibody titer in the mother's serum. Non-immune hydrops has a much wider differential and broadly includes chromosomal disorders, malformations, storage disorders, anemia from a variety of causes, and infection. A karyotype and ultrasound examination will afford a diagnosis in most of the cases which have malformations as the etiology. As the onset of hydrops in the current case was proximate to the time of death, a chromosomal analysis was not yet available. Intrauterine infections may be associated with hydrops fetalis, presumably because they cause anemia. In addition, anemia alone may result in high output failure and hydrops. Alpha- thalassemia, when containing deletion of all four alpha chain alleles, presents in the third trimester with hydrops fetalis. Parvovirus B19 infection is the most common cause of infection associated fetal hydrops, although other causes include syphilis, CMV, or HSV infection. Even without the test result of the amniotic fluid revealing parvovirus B19, this case provides a classic representation of this entity. It typically presents in the second trimester with hydrops fetalis and anemia. The placenta was large and pale, consistent with fetal anemia, and erythroblastosis was identified. The mother often has school aged children who bring the infection home, and typically the mother has an asymptomatic infection, as in this case. Review of the Literature/Treatment Options: Parvovirus B19 is the cause of "fifth disease", a typical childhood illness that causes a characteristic "slapped cheek" rash followed by a linear-reticular rash over the extremities and often associated with arthralgias and sometimes fever. Children are less likely to have arthralgias than adults; however, even in the case of adult infection, 50% of patients are asymptomatic. Immunocompetent patients have self-limited infections. In the immunocompromised, and rarely in persons who are immunocompetent, parvovirus infection can prolonged with chronic arthralgias and anemia. Patients who are highly dependent on effective erythropoiesis, such as fetuses or patient with sickle cell disease, may become profoundly anemic because the virus causes lysis of erythroid precursors secondary to infection. The virus attaches to the P1 antigen, which is present on erythroid precursors, megakaryocytes, and endothelial cells. While some patients with parvovirus infection have thrombocytopenia, the greatest effect of infection is anemia. Even patients who are immunocompetent develop slight anemia, which goes undiagnosed, during the course of parvovirus viremia. Parvovirus B19 is the cause of aplastic crisis in patients with sickle cell disease or other disorder of hemoglobin production. Because patients with chronic anemia are dependent on rapid and effective production of red blood cell precursors, infection of the precursors by parvovirus B19 causes severe drop in circulating red blood cells. The anemia is hypoplastic, and can be diagnosed by serum serology or blood PCR for parvovirus B19. A bone marrow biopsy will show depletion of red blood cell precursors which, when present, contain characteristic viral inclusions. These inclusions are not seen in nucleated red blood cells from the bone marrow aspirate. Infected erythroid precursors are enlarged and have faintly visible intranuclear inclusions. While parvovirus B19 infection typically produces a hypoplastic anemia, in the face of immunodeficiency, such as HIV infection, there can be erythroid hyperplasia with large numbers of precursors in the bone marrow that have intranuclear inclusions. Parvovirus infection occurs in pregnant women at a rate of about 3%, and less than 10% of pregnancies complicated by maternal parvovirus B19 infection result in fetal demise. Many fetuses who have been infected in utero spontaneously recover, and there is a consensus that if the mother becomes infected during the first trimester, there is a higher rate of fetal loss than if she becomes infected later in gestation. The diagnosis of parvovirus infection during pregnancy may be done by several means. Maternal serologic evaluation reveals an IgM serologic response occurs by approximately 10 days following infection, and persists for several weeks. Polymerase chain reaction amplification can detect the viremia in the mother, which is present for about a week. Fetal infection can be diagnosed by PCR analysis of the amniotic fluid or, less commonly, umbilical blood sampling. Treatment of fetal infection begins with expectant monitoring. If a pregnant woman is diagnosed with parvovirus infection, serial ultrasound examinations will be performed. Testing of the fetal middle cerebral artery is the most sensitive, non-invasive test to detect anemia. If anemia is present, an intrauterine transfusion can be performed, and is generally repeated at 14 day intervals until fetal anemia resolves. Conclusion(s): This case is a classic example of fetal demise secondary to parvovirus B19 infection. The characteristic pathologic features are fetal hydrops, enlarged and pale placenta, and intranuclear inclusions in the erythroid series on a background of erythroblastosis. References: Al-Khan A, Caligiuri A, Apuzzio J. Parvovirus B-19 infection during pregnancy. Infect Dis Obstet Gynecol 2003;11:175-9. Bellini C, Hennekam RCM, Fulcheri E, et al. Etiology of nonimmune hydrops fetalis: a systematic review. Am J Med Genet. 2008;149A:844-51. Brennand J and Cameron A. Fetal anaemia: diagnosis and management. Best Pract Res Clin Obstet Cynaecol. 2007;22 (1):15-29. Rogers BB. Parvovirus B19: twenty-five years in perspective. Pediatr Develop Pathol. 1999;2:296-315.