Among the immunocompetent, infections with parvovirus B19 (B19V) and human bocavirus (HBoV) 1 range clinically from asymptomatic to severe, while following allogeneic hematopoietic SCT (HSCT) B19V can cause a persistent severe illness. The epidemiology and clinical impact of HBoV1 and the other emerging parvovirus 4 (PARV4) among immunocompromised patients have not been established. To determine the occurrence and clinical spectrum of B19V, PARV4 and HBoV1 infections, we performed a longitudinal molecular surveillance among 53 allogeneic HSCT recipients for pre- and post-HSCT DNAemias of these parvoviruses. Quantitative real-time PCR showed B19V DNA in sera of 16 (30%) patients, at mean levels of 4.6 × 103, 9.9 × 107, 1.1 × 1010 and 1.6 × 102 B19V DNA copies/mL pre-HSCT (9/53), and at 1 (6/53), 2 (4/53) and 3 months (1/25) post HSCT, respectively. However, no clinical manifestation correlated with the presence of B19V viremia. All B19V sequences were of genotype 1. None of the sera investigated contained PARV4 or HBoV1 DNAs. Our data demonstrate B19V viremia to be frequent among pediatric allogeneic HSCT recipients, yet without apparent clinical correlates. PARV4 or HBoV1 viremias were not seen in these immunocompromised patients.
Infections not only by opportunistic pathogens but also by community-acquired respiratory viruses can cause severe illness in immunocompromised hosts following allogeneic hematopoietic SCT (HSCT). Virus detection is of key importance in early diagnosis among these patients.1, 2, 3
Only a few years ago parvovirus B19 (B19V) was the only known member of Parvoviridae causing illness in humans.4 Since then the emerging parvoviruses, parvovirus 4 (PARV4) and human bocavirus 1 (HBoV1), have also been shown to infect humans.5, 6 The epidemiology and clinical impact of HBoV1 and the other emerging PARV4 among immunocompromised patients have not been fully established.
Three genotypes of B19V exist, 1–3, of which genotype 1 is the most prevalent.7, 8 Approximately half of 15-year-old adolescents and up to 80% of adult blood donors are B19V IgG seropositive.9 It causes a self-limiting aplasia of erythroid progenitor cells, followed by erythema infectiosum (fifth disease) and/or arthralgia. Allogeneic HSCT patients are at a particular risk for B19V infection, which may lead to severe, persistent and usually nonspecific illness.10, 11, 12, 13 A few studies address the incidence and clinical spectrum of B19V infections among HSCT patients; however, large prospective studies among the pediatric population are lacking. B19V infections can be severe after allogeneic HSCT and in addition to aplastic crises14 cause pneumonia10 and multiorgan failure.11 B19V can have a clinical impact also in non-transplanted patients with hematologic malignancy.15 Although specific antiviral therapy is not available, i.v. Ig results in clinical improvement in most cases. However, relapses occur in up to 25% of immunocompromised patients.1
HBoV1 is increasingly recognized as a cause of respiratory infection worldwide; it has been estimated to be among the four most prevalent viruses along with respiratory syncytial, rhino- and adenoviruses in children hospitalized for respiratory disease.16, 17, 18, 19, 20, 21 HBoV1 genomes have also been observed in stool among 0–13% of patients with or without gastroenteritis22 and in 0–44% of respiratory samples from individuals with non-infectious illnesses.23, 24 Serodiagnosis or HBoV1 DNA detection in serum therefore provides more reliable diagnosis of acute HBoV1 infection.21, 25, 26, 27, 28 The role of HBoV1 among the immunosuppressed is poorly understood. Tozer et al.29 observed that among 229 whole blood samples collected over 18 months from immunocompromised children (n=31) 2.6% were HBoV1 DNA positive. One patient, however, accounted for three (50%) of the findings. HBoV1 infections have also been reported among pediatric leukemia and immunocompromised patients.30, 31, 32 One disclosed a child with disseminated bocavirus infection shortly after allogeneic HSCT.33 The clinical manifestations were fever, rhinorrhea, cough, diarrhea and hypoxia, and the virus occurred in high quantities in plasma, nasopharyngeal aspirates and stool. Fecal shedding was present for several weeks after clinical resolution. No data are available on antiviral therapy of HBoV1 infection.
PARV4 is a human parvovirus first detected in the plasma of an individual with an acute HIV infection-like illness.6 Three genotypes of PARV4 have been identified, two of them in Europe and one in Africa.6, 34, 35, 36 The viral DNA has been shown to persist in lymphoid and some other tissues.37, 38, 39, 40, 41 The virus is most frequently detected in persons with a history of i.v. drug use or as co-infections with other parenterally transmitted viruses, such as HIV or hepatitis C and B.37, 42, 43, 44, 45 Viremia seems to accompany acute PARV4 infection, and the viral DNA has been demonstrated also in blood products, indicating a risk for parenteral transmission.34, 39, 42, 43 The seroprevalence in Northern Europe reaches 78% among HIV-positive i.v. drug users, but is negligible among non-users.42, 44 In all, the epidemiology and clinical implications of PARV4 are still under evaluation.46, 47
The aim of this study was to determine the occurrence and clinical associations of B19V, PARV4 and HBoV1 viremias among pediatric patients immunocompromised due to allogeneic HSCT.
Materials and methods
The retrospective study included all 53 pediatric (of 195) patients (Table 1) with a hematologic malignancy, who underwent allogeneic HSCT and had serum samples collected at least pre-, 1 and 2 months post HSCT at the Division of Hematology-Oncology and Stem Cell Transplantation, Children’s Hospital, University of Helsinki, Finland, between 1997 and 2006. The time from the primary diagnosis to HSCT ranged from 0.3 to 6.5 years, with a mean of 1.7 years. The patient files were studied and demographics and details of infectious symptoms reviewed.
The study material consisted of a total of 184 sera collected from the 53 patients and stored at −70 °C until analysis. The time points of interest were pre-HSCT and 1, 2 and 3 months post HSCT until discharge or death.
Extraction of viral DNA
DNA was extracted from 100 μL of serum by using the QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany) according to the manufacturer’s protocol.
Because of the high sensitivity of PCR, strict precautions, including the use of separate rooms, aerosol-resistant tips and disposable racks, were employed to avoid false-positive results.48 In each PCR run, water and plasmids containing the respective viral genomes served as negative and positive controls, respectively. For all PCRs 5 μL of the sample DNA extract was applied per 20-μL reaction.
For an initial qualitative PCR for B19V genotypes 1–3, a 248-base-pair fragment of the B19 VP1 gene was amplified and the results confirmed by Southern hybridization.49 To further solidify the results and to quantify the DNA, all positive samples were re-examined by a commercial quantitative PCR (qPCR) detecting all the three genotypes of B19V50 (Artus Parvo B19 LC PCR Kit; Qiagen). The criterion for a positive B19V PCR result was positivity by both the methods.
For HBoV1 a real-time quantitative PCR assay targeting the NP1 gene of HBoV1 was applied as described20, 51 with a Stratagene Mx3005P instrument (Agilent Technologies, Santa Clara, CA, USA). For standardization of quantification, a plasmid pST2 (GenBank accession DQ000496) containing the HBoV1 NP1 gene was used in serial dilutions covering a range of 7 logs.
For PARV4-DNA detection a multiplex quantitative PCR was applied, which identifies and quantifies all three PARV4 genotypes currently known.52 This quantitative PCR has been thoroughly evaluated with both plasmids and patient samples containing the three genotypes. The analytical sensitivity, determined with PARV4 plasmids serially diluted in purified human DNA or buffer alone, was 20 copies per reaction for each of the three genotypes.
Data were analyzed by using Statistical Package for Social Science (SPSS version 19). The Mann–Whitney U-test was used to compare the nonparametric data. The Fisher’s exact and χ2 tests were used to compare the frequency of qualitative variables. P-values <0.05 were considered statistically significant.
The study was approved by the Ethics Committee of the Medical Faculty of the Turku University. Also, the Health Care Supervision Centre granted their permission for the analysis.
The sera were collected from the 53 pediatric patients receiving allogeneic HSCT within a 10-year period (years 1997–2006). The pre-transplant sample and samples taken at 1 and 2 months post HSCT were collected from all the patients, while only 25 samples taken at 3 months were available. The mean point of discharge was 78 days (median 64, range 30–188) post HSCT. Among the deceased, the time from HSCT to death (n=23, 43%), ranged from 0.2 to 5.6 years (mean 1.4). Two patients died within the first 3 months.
One or more serum samples were B19V PCR positive in 30% (16/53) of the patients (Table 2), all of genotype 1. In four patients two samples were positive, once with negative sample in between. Altogether 11% (20/184) serum samples were B19V PCR positive; at pre-HSCT 17% (9/53), and at one 11% (6/53), two 8% (4/53), and three 4% (1/25) months post HSCT. The viral loads ranged from 2.9 × 101 to 1.9 × 108/mL (mean 4.6 × 103/mL) at pre-HSCT, 6.3 × 101–5.9 × 108/mL (mean 9.9 × 107/mL) at 1, 9.0 × 101–4.4 × 1010/mL (mean 1.1 × 1010/mL) at 2 and 1.6 × 102/mL at 3 months post HSCT, respectively.
During 1997–2001 an HSCT was performed on 28 patients in the study group, of whom 46% (13/28) had at least one B19V-positive serum sample, but after 2001 only 12% (3/25) of samples were B19V positive (odds ratio 6.4, P=0.008; Fisher’s exact test). In total, only three patients had B19V DNA levels exceeding 104/mL and one exceeding 1010/mL; these patients were clinically indistinguishable.
In all, no clinical manifestation showed a significant correlation with the presence of B19V viremia (Table 2). In particular, the durations of neutropenia, thrombocytopenia or anemia during the first 100 days post HSCT did not differ between those with or without B19V viremia. Also, the proportions of patients requiring red cells beyond the first 100 days post HSCT were similar.
No PARV4 or HBoV1 DNA was detected in the serum of any of the cases pre- or post-transplant.
The key finding in our study was that among pediatric patients with hematologic malignancy and an allogeneic HSCT, B19V viremia is frequently detectable. The prevalence of B19V PCR positivity among our children was 30%. This is in agreement with the occurrences (22–27%) reported for children with malignancies.53, 54 However, compared to two reports in which the recipients remained B19V PCR negative for 6–12 months post HSCT (allogeneic),55, 56 our genoprevalence rate appears markedly higher.
Soliman et al.54 found B19V PCR-positive pediatric oncology patients to have a significantly higher frequency of unexplained anemia and red cell transfusions, and a longer hospital stay than PCR-negative patients. Lindblom et al.15 found children with ALL and B19V viremia to develop cytopenia, leading to reduced treatment intensity and complicated course. However, in that retrospective study the infection was clinically apparent in only one patient out of 18. A recent review identified 98 solid organ and hematopoietic transplanted patients (24 with an allogeneic HSCT) with symptomatic B19V infection after transplantation. The authors concluded the predominant manifestation to be refractory anemia, a complication occurring commonly after transplantation along with other cytopenias.57 It has been reported that B19V DNA may be detectable by PCR for extended periods of up to years in bone marrow and even serum.58 Donor-derived nosocomial infection has also been described (blood products; stem cells).1, 59 The infection has been seen in association with other post-transplant complications, such as allograft dysfunction, hepatitis, myocarditis and glomerulonephritis, and post-transplant mortality directly attributable to B19V has been estimated at 3%.10, 57 B19V exanthema can also mimic cutaneous acute GVHD (aGVHD).12, 60 In our study none of the patients with B19V viremia had any specific signs or suspicion of B19V infection. Neither retrospectively did any clinical manifestation (including anemia) correlate significantly with the B19V viremia. However, many symptoms common after HSCT (fever, exanthema and anemia) resemble the symptoms of B19V infection, but as surveillance is not routine, the frequency of B19V infections might have been underestimated.
B19V transmission occurs most commonly via aerosols or respiratory secretions, but virus-containing blood products can also be a source of transmission.61 In Finland, at the Red Cross Blood Service all blood donations have been screened by PCR for B19V since April 2002. As cellular products with DNA levels below 104 IU/mL are rarely infectious, the European Pharmacopoeia stipulates that the B19V concentration in pooled blood should not exceed 104 IU/mL. However, it has been recommended to screen plasmas by minipool testing, to supply immunosuppressed patients with B19V-negative blood components.62
In our study B19V viremia occurred mostly (81%, 13/16) among patients transplanted prior to 2002, that is, before blood product screening. Yet, were B19V in this context transmitted via blood components, it should have been present also in the Finnish adult allogeneic HSCT study.55 The clinical importance of transfusion-transmitted infections is still controversial and reports scarce.9 Yet, B19V infections among the immunocompromised might be underdiagnosed because of mildness or habituality of symptoms. Our results point to the importance of blood product screening for B19V DNA; after the onset of screening only three B19V viremias ensued in this cohort.
Susceptibility to an infection may depend on the presence or absence of neutralizing antibodies. Immunosuppression decreases the ability of the transplant patients to produce neutralizing antibodies.63 In a review by Eid et al.57 many of the transplant patients did not possess specific IgM at the onset of clinical disease, while almost all had B19V viremia.
PARV4 or HBoV1 viremias were not demonstrable in this group of immunocompromised patients. The absence of PARV4 in these immunocompromised patients is in agreement with the recent study by Tolfvenstam et al. and with the previous studies reporting PARV4 appearing to be primarily blood-borne in Northern Europe, but could possibly also reflect a lower prevalence in Northern Europe.38, 41, 42, 43, 44, 47 It has been found among infants in West Africa with no evidence of parenteral exposure.35, 36
Children and infants are ubiquitously infected by HBoV1, leading to respiratory illnesses. The incidence of serologically verified acute HBoV1 infections has been shown to be highest during the second year of life, and short-term viremia has also been found to be an excellent marker of an acute HBoV1 infection.21, 27, 28, 64 Studies of nasopharyngeal samples have shown persistence of HBoV1 DNA for several months.65, 66, 67, 68 HBoV1 seroprevalence ranges from 25% in infants younger than 1 year to 93% and 100% in children of 3(ref. 28) to 7(ref. 27 ) years of age, respectively. The causative role of HBoV1 in clinical manifestations other than respiratory diseases remains to be assessed.64 Accurate diagnosis requires antibody analysis or PCR of serum; PCR of nasopharyngeal samples alone is insufficient.27 In our study all serum samples investigated were HBoV1 PCR negative. With a median age of 6 years, most of our patients had probably been infected by HBoV1 previously. Other reasons for PCR negativity may be the short duration of HBoV1 viremia, as well as the fact that these children may not have had respiratory infections due to their separation from other children (especially day-care) during the chemotherapy and HSCT.66
In this study the incidences of B19V, PARV4 and HBoV1 viremias were evaluated using quantitative real-time PCR techniques in a pediatric HSCT cohort. One-third of the patients were PCR positive for B19V without correlation with clinical symptoms (including anemia). However, the symptoms were long-lasting and diffuse and could not be related to a specific time point. None of the children had HBoV1 or PARV4 DNA in serum. Our results suggest that in Northern Europe infections by B19V, HBoV1 or PARV4 rarely complicate pediatric HSCT.
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This work was supported by grants from the Foundation for Pediatric Research, the Nona and Kullervo Väre Foundation, the University of Helsinki Research Fund, and the Turku University Foundation, the Sigrid Jusélius Foundation, the Finnish Medical Foundation (FLS), and the Academy of Finland (Grant No. 1257964).
The authors declare no conflict of interest.
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Rahiala, J., Koskenvuo, M., Norja, P. et al. Human parvoviruses B19, PARV4 and bocavirus in pediatric patients with allogeneic hematopoietic SCT. Bone Marrow Transplant 48, 1308–1312 (2013). https://doi.org/10.1038/bmt.2013.63
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- parvovirus 4
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Parvovirus B19 infection in adult patients after allogeneic stem cell transplantation: our experience of five cases and literature review
Bone Marrow Transplantation (2019)
Community-Acquired Respiratory Viruses in Transplant Patients: Diversity, Impact, Unmet Clinical Needs
Clinical Microbiology Reviews (2019)
The impact of alternative donor types on viral infections in pediatric hematopoietic stem cell transplantation
Pediatric Transplantation (2018)