Parvovirus b19 infection B08.3

Cossart YE 1975

The human parvovirus B19 (parvovirus of lat. parvum = small; the virus was discovered in 1975 by the Australian virologist Yvonne Cossart in an asymptomatic blood donor. The name B19 comes from the sample of this blood donor, which was labelled with the code "B19") is a linear, unenveloped (like all parvoviruses) single-stranded DNA virus, which belongs to the group of Parvoviridae. Humans are the only known reservoir.

Besides parvoviruses, densoviruses and adeno-associated viruses (AAV) belong to this group. In humans, parvovirus B19 and the probably apathogenic AAV have been detected so far. Parvovirus B19 is the smallest known human pathogenic DNA virus. In addition to linear DNA (5 176 nucleotides), it consists of 2 structural proteins (VP1 and VP2), which form the capsid protein. In addition, the viral DNA codes for two regulatory proteins that perform important tasks in virus replication.

Parvovirus B19 has a pronounced tropism for erythropoietic precursor cells such as burst-forming-units or colony-forming-units which it lytically infects. Here the blood group P antigen acts as a receptor. People who lack the P antigen (phenotypes P1k and p) appear to be resistant to parvovirus infections. Parvovirus B 19 also infects megakaryocytic or myeloid cells, which explains thrombocytopenia and/or neutropenia.

Infectivity exists before the onset of exanthema, but no longer at the exanthema stage. The virus is transmitted exclusively from person to person by droplet infection, but also transplacentally from mother to foetus.

Frequency peaks in school age; seasonal in spring; occasionally epidemics occur in community facilities (e.g. kindergartens). On average, 40 to 60% of the total population have positive immunoglobulin titres, compared to 80% of 50-year-olds.

Within one week after infection, parvoviruses lead to a pronounced viremia with very high virus concentration. The viruses are also present in saliva and urine. This leads to an infection of the erythropoietic precursor cells. These are almost completely lysed, so that in the 2nd week no more reticulocytes are detectable in the peripheral blood. This reticulocytopenia usually leads to a more or less pronounced anaemia about 10 days after infection (Young NS 2006).

The different clinical pictures of the disease are due on the one hand to the aplasia of erythropoiesis and on the other hand to the immunological status of the patient.

In immunocompetent patients, specific, neutralizing IgM antibodies directed against VP1 and VP2 are formed about 10 days after the onset of infection. One week later IgG antibodies are formed. As a result, the virus can usually be eliminated and 25 to 30 days after virus inoculation, haemoglobin levels return to their initial values. In healthy children/adults, parvovirus B-19 infection is completely asymptomatic in 30% of cases. Studies on IgM-positive pregnant women have shown that about 50% of infected women developed neither erythema nor arthralgia. Infection-associated anaemia is also usually mild and often goes unnoticed (Servey JT et al. 2007). In symptomatic immunocompetent infected persons the typical exanthema(erythema infectiosum, also called rubella) appears about 2 weeks after the onset of infection, often accompanied by arthralgia (Vafaie J et al. 2008).

Erythema infectiosum: The erythema infectiosum typically affects pre-school children. It belongs to the 5(6) classic pediatric exanthema diseases (see below). The less itchy anular exanthema, which initially occurs on the cheeks, spares the nose-mouth region (slapped cheek appearance - Katta R 2002). Occasionally, the palms of the hands and the soles of the feet may be affected preferentially(glove-sock syndrome). The exanthema subsides after 1 week. In most cases there is no generalized lymphadenitis.

General symptoms: Cough, headache, fever, loss of appetite, vomiting, diarrhoea and arthralgia may occur, but are not very pronounced.

Rheumatoid course: Infected children suffer from arthralgia or arthritic complaints in about 10% of cases, infected adults in up to 60%. F:w=2:1 Inflammatory arthropathy is usually an acute, symmetrical, peripheral polyarthritis and affects the following groups of joints: metacarpophalangeal joints (75%), proximal interphalangeal joints (75%), knees (65%), wrists (55%) and ankles (40%). The joint symptoms usually subside after a few weeks. Intermittent symptoms lasting for years are rare.

Diseases that may be associated with a parvovirus B19 infection These include:

• Polyarteritis nodosa
• Purpura Beauty Enoch
• Juvenile spring eruption
• Acute generalized exanthematic pustulosis (AGEP)
• Kawasaki Syndrome
• Still's disease
• Systemic lupus erythematosus
• Ulcerative colitis (UC) with Pure Red Cell Aplasia (Isomoto H et al. (2003)

Rare associated diseases: In children, in rare cases of non-B, non-C hepatitis, an association with parvovirus B19 can be established. In adults there are only casuistic reports of parvovirus B19-associated hepatic dysfunctions. Furthermore, there have been isolated reports of cases of parvovirus B19-associated myocarditis and idiopathic thrombocytopenic purpura.

The direct detection of the virus is carried out with the polymerase chain reaction (PCR). B19-specific antibodies are determined by ELISA or immunoblot tests. Viremia starts about 4-5 days after virus contact. 2-3 days later 1011 to 1013 virus particles/mL blood are present. IgM antibodies, predominantly against the VP2 capsid proteins, appear on average 10 days after virus contact, usually at the same time as the exanthema. At this time and on the following days, blood and saliva contain 104 to 108 genome equivalents of viral DNA/mL. B19-specific IgM is often no longer detectable as early as 3 weeks after virus contact - at this time, however, patients are still viraemic. Increasing amounts of IgG against the VP1 and VP2 capsid proteins can be determined 14 days after virus contact. They persist for life (Modrow S et al. 2006). IgM and IgG have a partially neutralizing effect and cause a reduction of the viral load. In most cases the pathogens are completely eliminated 3-4 weeks after infection and are no longer detectable in the laboratory.

Inpatients with haemolytic anaemia, regardless of its etiology, the infection of erythropoietic progenitor cells with parvovirus B19 and the associated inhibition of erythropoiesis can lead to a life-threatening aplastic crisis. In these crises, there is a regular drop in Hbs; clinically, the symptoms of anemia are prominent (pure red cells aplasia - Isomoto H et al. 2003; Crabol Y et al. 2013). The development of thrombocytopenia and/or neutropenia is possible. These aplastic crises end self-limiting (due to the formation of specific antibodies) (they settle after 1-2weeks). In patients with haemolytic anaemia, the incidence of parvovirus B19-associated aplastic crises is estimated at 2-5% per year.

Hydrops fetalis: Parvovirus infections can pass transplacentally to the fetus in IgM-positive, IgG-negative pregnant women. 1 - 5% women become infected during pregnancy with a very overwhelming proportion having an uncomplicated pregnancy (Ornoy Asher et al. 2017). Due to the short fetal red blood cell survival time during the first 20 weeks of pregnancy, the infection can lead to severe anemia and hypoxia of the fetus. This may be secondary to severe heart failure with fluid retention. The full picture of infection-associated hydrops fetalis is characterized by ascites, pleural effusions and hydramnios. Often this symptomatology leads to spontaneous abortions. Furthermore, cerebral anomalies and neurological developmental disorders may occur.

Risk of miscarriage: If parvovirus B19 infection occurs in the second half of pregnancy, there is an increased risk of miscarriage (Ornoy Asher et al. 2017).

Immunocompromised patients: In immunocompromised patients, parvovirus B19 can persist and lead to chronic disease (chronic anemia). Courses of up to 10 years have been reported. The following diseases and therapies have been described as predisposing factors: thymic aplasia (Nezelof syndrome), immunodeficiency, acute leukemia, chronic myeloid leukemia, malignant lymphoma, myelodysplastic syndrome, systemic lupus erythematosus, cytostatic therapy, organ transplantation.

Important: the typical erythema infectiosum is completely absent in a proportion of immunosuppressed infected individuals. Specific IgM antibodies may not be detected. This constellation explains the persistence of the virus. In these cases, the diagnosis must be based on direct virus detection in the blood by PCR. In individual cases, chronic parvovirus B19-associated anaemia has also been observed in patients without obvious immunodeficiency. Therapy consists of blood transfusions and the administration of immunoglobulins.

No specific antiviral therapy exists.

The infection can be treated symptomatically with NSAIDs (paracetamol, ibuprofen). Local symptomatic therapy (e.g. lotio alba).

Arthralgias (especially finger, hand, knee and ankle joints) usually subside after 3-4 weeks; rarely persistent arthritis. The therapy is carried out with NSAR

In aplastic crisis, blood component substitution and administration of 7S immunoglobulins (also in patients after organ or KM transplantation)

In case of prenatal infection with danger of fetal hydrops: intrauterine exchange transfusion.

A vaccine against parvovirus-B19 does not exist. Persons with immunodeficiency, chronic anemia as well as pregnant women must be kept away from sick patients!

Fifth disese is one of the 5(6) classic pediatric exanthema diseases:

• Measles ("First disease")
• Scarlet fever ("Second disease")
• Rubella ("Third disease")
• Staphylococcal scarlet fever ("Fourth disease")
• Three-day fever ("Sixth disease")

Obligation to report: According to the German Infection Protection Act (IfSG), there is no nationwide obligation to report parvovirus B19 infections. There is, however, an official obligation to register in Saxony: Obligation to register the names of doctors in case of suspicion, illness or death.

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