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View PB19 based on electron microscopy data

Abstract

Parvovirus B19 (PB19) is an important human pathogen that results in a wide spectrum of clinical outcomes, from mild, self-limiting erythema infectiosum in immunocompetent children and arthralgia in adults to lethal cytopenia in immunocompromised patients and intrauterine fetal death. However, there have been few reports of PB19 infection in neonates or young infants (aged 28–90 days), and no previous reports contained descriptions of PB19 infection as a cause of sepsislike syndrome in this age group. We report a case of sepsislike syndrome caused by PB19 infection in a 56-day-old infant whose mother had polyarthralgia at the time of his admission. PB19 infection was diagnosed on the basis of positive polymerase chain reaction results for PB19 DNA in the serum and cerebrospinal fluid. Positive immunoglobulin M and negative immunoglobulin G for PB19 suggested acute infection. He was admitted to the ICU because of poor peripheral circulation, but fully recovered without antibiotic administration. After excluding other possible pathogens, PB19 should be suspected as a cause of sepsislike syndrome in young infants, especially those who have close contact with PB19-infected individuals.

Abbreviations:
CSF — cerebrospinal fluid
IgG — immunoglobulin G
IgM — immunoglobulin M
PB19 — parvovirus B19
PCR — polymerase chain reaction
SIRS — systemic inflammatory response syndrome

Parvovirus B19 (PB19) infection is common in childhood, but its clinical manifestations vary considerably in relation to patient age and immunologic status. PB19 infection typically presents as erythema infectiosum in healthy, immunocompetent school-aged children. Arthralgia is the most common manifestation in adults, particularly in women. PB19 can cause fetal hydrops when mothers develop intrauterine infections. Less common manifestations of PB19 infection in neonates and young infants (aged 28–90 days) include meningitis, hepatitis, leukoerythroblastosis, transient myeloproliferation, encephalitis, and hemophagocytic lymphohistiocytosis. However, PB19 infection in this population is rare, and no researchers of previous reports described PB19 infection as a cause of sepsislike syndrome in neonates or young infants. Herein, we report a case of sepsislike syndrome caused by PB19 infection in a young infant.

Case Presentation

A term 56-day-old boy with a birth weight of 3072 g was admitted to our hospital in January 2016 because of high fever and poor sucking. Perinatal history was unremarkable. He had close contact with sick family members who had clinical symptoms of PB19 infections, namely a 12-year-old cousin and 8-year-old cousin with erythema infectiosum 10 and 6 days before our patient’s admission, respectively. In addition, his mother reported systemic joint pain, a sign of PB19 infection, on the day of his admission. However, they were not tested for PB19-specific antibodies or viral DNA by immunoassay or quantitative polymerase chain reaction (PCR) assay.

In the emergency department, his vital signs were as follows: body temperature, 39.0°C; pulse rate, 210 beats per minute; blood pressure, 95/45 mm Hg; and respiratory rate, 45 breaths per minute. Peripheral oxygen saturation was 97% in room air. Physical examination revealed significant abdominal distension. Capillary refilling time was prolonged (up to 5 seconds), and his extremities were cold. He had no bulging anterior fontanelle, rash, petechiae, vesicular lesions, hepatosplenomegaly, or abnormal neurologic signs.

Laboratory findings on admission were a white blood cell count of 3.1 × 109/L (normal range: 6.0–14.0 × 109/L), hemoglobin of 97 g/L (normal range: 98–116 g/L), mean corpuscular volume of 88 fL (normal range: 72–88 fL), reticulocyte count of 3.0% (normal range: 0.1%–2.9%), and a platelet count of 218 × 109/L (normal range: 84–478 × 109/L). A blood smear revealed no evidence of atypical lymphocytes or abnormal red blood cell morphology. Biochemistry testing revealed an aspartate aminotransferase level of 57 U/L (normal range: 22–63 U/L), an alanine aminotransferase level of 38 U/L (normal range: 12–45 U/L), lactate dehydrogenase of 237 U/L (normal range: 170–580 U/L), total bilirubin level of 0.94 mg/dL (normal range: <1.0 mg/dL), and a C-reactive protein level of 21.9 nmol/L (normal range: 7.6–150.5 nmol/L). No abnormal findings were observed in cerebrospinal fluid (CSF) or urine.

The patient did not present with any obvious source of fever on admission. He was critically ill with poor circulation and was admitted to an ICU. Bacterial infection was excluded on the basis of negative results for blood, urine, and CSF cultures. Real-time reverse transcription PCR was used to test serum and CSF samples for herpes simplex virus, enteroviruses, human parechoviruses, and adenovirus, but all tests yielded negative results.

As stated above, the boy had close contact with family members with erythema infectiosum. His mother developed rash on her extremities a few days after she developed arthritis. Because we suspected an outbreak of PB19 among his family members, PB19 was considered as a possible cause of his condition. PB19 DNA was detected in serum and CSF on admission, when he presented with symptoms of sepsislike syndrome, and viral load was high on real-time PCR (1.6 × 1010 copies/mL in serum and 1.6 × 107 copies/mL in CSF). Sequence analysis of the NS1-VP1 overlapping region (from nt 1765 to nt 2672) of PB19 showed genotype 1A. The presence of positive immunoglobulin M (IgM) results and negative immunoglobulin G (IgG) results indicated acute infection. Ultimately, sepsislike syndrome due to PB19 infection was diagnosed.

During hospitalization, fever persisted for 2 days but resolved with supportive care. He was well enough to be transferred from the ICU to the pediatric ward on hospital day 2 and was discharged from the hospital on day 6 without sequelae. At the time of discharge, white blood cell count (13.2 × 109/L; normal range: 6.0–14.0 × 109/L) and platelet count (532 × 109/L; normal range: 84–478 × 109/L) had improved, and hemoglobin level (90 g/L, normal range: 98–116 g/L) was close to normal range. No additional measurement of viral load was performed during his hospitalization. Findings of a 2-month follow-up examination were all normal.

Written informed consent was obtained from his parents, and they were informed that the case would be submitted for publication as a case report.

Discussion

This is the first case report of a young infant (aged 28–90 days) with a sepsislike illness caused by PB19. This age group is susceptible to numerous pathogens; thus, when bacterial infection is ruled out, viral etiologies should be considered, including herpes simplex virus, enterovirus, human parechoviruses, and adenovirus. We diagnosed PB19 infection after real-time PCR detection of PB19 in serum and CSF samples and exclusion of other possible pathogens.

PB19 DNA viral load in serum was extremely high (>1.0 × 1010 copies/mL) in our patient. Researchers of a previous study reported that PB19 DNA viral load in the serum was high (median: 7.63 × 106 genomes/mL; range: 4.48 × 103–8.31 × 106) among patients with acute erythema infectiosum. The researchers of that report also found that PB19 DNA viral load in serum during the acute phase of aplastic crisis in chronic hemolytic anemia was extremely high (range: 1.0 × 1010–1.0 × 1013). The extremely high viral load in our patient suggests that PB19 infection was the cause of severe sepsislike syndrome. The patient had leukopenia at admission, which suggests the possibility of viral infection, including PB19 infection, as a cause. However, leukopenia was not reported by researchers in previous case studies of young infants (aged 28–90 days) with PB19 infection. Therefore, it is uncertain whether leukopenia is a characteristic of PB19 infection in young infants.

The prevalence of antibodies against PB19 in pregnant women was reported to be 55.4% in Japan, which is similar to prevalences reported in other countries (30%–50%), including the Netherlands, Denmark, and the United States. Therefore, approximately half of neonates and young infants are at risk for primary PB19 infection in Japan. However, sepsislike syndrome in young infants has not been reported. A possible explanation for the lack of such reports is that young infants with PB19 infection might not present with rash, which is the most common sign of PB19 infection in children. A literature search revealed only 7 cases of PB19 infection confirmed by positive anti-PB19 IgM and/or PB19 DNA by PCR of serum or CSF in young infants (Table 1). The clinical presentations included fever, poor feeding, and vomiting; rash was observed in only 1 patient. Although the number of reported cases is small, existing data suggest that PB19 infection can present without rash in young infants. Therefore, many pediatricians might not consider PB19 as the pathogen responsible for sepsislike syndrome presenting in a young infant. A second reason for the lack of previous reports is that, for viral diagnosis of sepsis in neonates and young infants, we usually test for herpes viruses, enteroviruses, and parechoviruses, but not for PB19.

A review of the clinical records for 11 infants aged 3 to 11 months who were confirmed to be infected with PB19 by positive IgM and/or PB19 DNA revealed that no patient had presented with sepsis or sepsislike syndrome. One patient with dilated cardiomyopathy caused by PB19 met the definition of systemic inflammatory response syndrome (SIRS). He had a respiratory rate of 56 breaths per minute and a temperature of 39°C, and sepsis was thus diagnosed. Four cases did not meet the definition of SIRS, and the reports of the remaining 6 cases had no clinical information on SIRS diagnosis. Therefore, existing evidence is insufficient for determining how often sepsis or sepsislike syndrome develops in infants. A previous report showed that ∼55% of pathogens responsible for infantile sepsis could not be identified even after thorough investigation. PB19 might be a possible pathogen in such cases. In addition, we suspected that PB19 might be the pathogen responsible for sepsislike syndrome in the present patient because he had close contact with family members who had developed erythema infectiosum. Obtaining a history of sick contacts can be helpful for identifying the pathogen in cases without an apparent source.

Conclusions

We reported a case of sepsislike syndrome caused by PB19 infection in a young infant. After excluding other possible pathogens, PB19 should be considered as a cause of sepsislike syndrome in this age group, especially when infants have close contact with PB19-infected individuals. Serological testing for PB19 (IgM and IgG antibodies) should be the first assessment. If serological testing cannot exclude PB19 infection, PCR testing for PB19 should be performed in suspected cases. Obtaining a history of sick contacts was also essential in identifying PB19 as the cause of sepsislike syndrome in our patient.

Based on information from the American Academy of Pediatrics.