The impact of Parvovirus B19 on hereditary haemolytic anaemias.

Abstract

Parvovirus B19 is a small single-stranded DNA virus, generally causing an asymptomatic infection in 25–50% of the general population. Seropositivity increases with age (15% in preschool children, 50% in young adults and 85% in the elderly), and transmission most commonly is horizontally by respiratory secretions, but also vertically from mother to foetus during pregnancy. The most clinically relevant cellular receptor of parvovirus B19 is the globoside or P antigen, which is present on several cell types, particularly erythrocytes and haematopoietic precursors. Since its discovery more than 40 years ago, parvovirus B19 has been associated with several diseases. Erythema infectiosum (‘fifth disease’) is the most common and self-limiting clinical manifestation of acute parvovirus B19 infection in immunocompetent hosts. However, chronic forms of parvovirus B19 infection are increasingly described in immunocompromised patients, such as those with haematologic cancers, autoimmune diseases and solid organ transplant recipients.1-3 The most prevalent clinical form of chronic parvovirus B19 infection is pure red-cell aplasia, characterized by recurrent anaemia with reticulocytopenia, which may be serious and life-threatening. In addition, chronic parvovirus B19 infection includes also myocarditis, dilated cardiomyopathy and chronic arthritis, due to a tropism of the virus for myocytes and synovial tissues. Parvovirus B19 infection in haemoglobinopathies has been already investigated and recently reviewed.4 In beta-thalassaemia, positivity for parvovirus B19 IgG, IgM and DNA is reported in up to 81%, 40% and 15% of cases, respectively. In sickle cell disease (SCD), seropositivity was less prevalent (IgG varied 37–66%, IgM 3–30%) while the DNA detection rate was greater (4–54%). In both thalassaemia and SCD, acute parvovirus B19 can cause transient but potentially severe aplastic crises. In SCD, this can be complicated by acute splenic and hepatic sequestration and acute chest syndrome. Less is known about other hereditary haemolytic anaemias, which are a heterogeneous group of conditions including defects of erythrocyte membrane proteins, red-cell enzymes and defective erythropoiesis. They are characterized by variable degrees of anaemia and haemolysis, increased erythrocyte turnover, splenomegaly, jaundice, biliary lithiasis and iron overload. The typical examples of membrane defects are hereditary spherocytosis (HS), hereditary elliptocytosis and the group of hereditary stomatocytoses. Glucose-6-phosphate dehydrogenase (G6PD) and pyruvate kinase (PK) are the most common enzyme deficiencies, and congenital dyserythropietic anaemia type II is the best-studied form of defective erytropoiesis. These rare diseases are sometimes difficult to diagnose due to their variable phenotype and the need of specialized work-up and genetic testing. In HS, several case reports showed that parvovirus B19 can induce a severe aplastic crisis, sometimes as the first manifestation of an undiagnosed disease.5-7 Moreover, parvovirus B19 infection can be associated with other severe complications, including myocarditis, glomerulopathy or microangiopathy, encephalopathy and haemophagocytic lymphohistiocytosis.8-10 In G6PD deficiency, acute parvovirus B19 infection causing a transient aplastic crisis has been reported as presentation of a previously unknown disease, and a chronic infection has been misinterpreted as a Diamond-Blackfan anaemia.11, 12 In PK deficiency, aplastic crises are reported during the clinical course of the disease or as its initial manifestation, often complicating the differential diagnosis. They are characterized by an abrupt onset of profound anaemia with reticulocytopenia, generally requiring blood transfusions, and sometimes by pancytopenia, again challenging the diagnosis.13 The paper by Mahmoud I. Elbadry14 offers a comprehensive evaluation of parvovirus B19 infection in a large cohort of 244 patients with different types of hereditary haemolytic anaemias (HHA), namely beta-thalassaemia, SCD, HS and G6PD deficiency. From February 2018 to February 2020 all patients admitted with haemolytic symptoms at the Shoag and Assiut University Hospitals in Egypt were simultaneously screened for HHA and parvovirus B19 infection; positive patients underwent an extensive clinical, laboratory and radiological evaluation of organ damage and a long follow-up (12–32 months). Of note, 67 of the 244 patients (27%) were previously undiagnosed and received a first diagnosis of HHA at admission for an acute event during the study period, highlighting that early diagnosis is still difficult for rare haematological disorders if screening of newborns is not in place, and frequently occurs during emergency admissions.15 Acute symptomatic parvovirus B19 infection was diagnosed in 33 of the 244 patients (13·5%). All patients presented with cytopenia (pancytopenia 27, bicytopenia 6); fever and musculoskeletal pain were also common, but interestingly clinical manifestations differed according to age and disease type. Adolescents most commonly had lymphadenopathy, while adults more frequently had acute kidney injury (AKI) and severe pancytopenia. General symptoms (skin rash and lymphadenopathy) and extreme direct hyperbilirubinaemia (EDHB) were more frequent in patients with HS, and AKI was more common in patients with HS and SCD compared to those with thalassaemia. One death occurred due to multiorgan failure (AKI, acute hepatitis, respiratory failure, encephalopathy) in a patient with SCD with vaso-occlusive crisis. Compared to previous reports on single disease cases, this large cohort shows that 82% of the HHA with parvovirus B19 infection presented with multiple organ impairment such as AKI, acute hepatitis, EDHB and neurological sequelae, as well as the widely known transient bone marrow failure. Interestingly, transient EDHB occurred only in patients with HS and resolved with steroid therapy and plasma exchange. The authors describe in depth the overall clinical phenotypes of parvovirus B19 in their cohort but also present clinical management and evolution of particular cases according to organ involvement. Their detailed experience can guide other clinicians in the routine approach to patients with HHA and parvovirus B19 infection in their settings and prompt an increased awareness for multiple organ complications of parvovirus B19, especially in patients with HS and SCD.