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Journal of Clinical Microbiology, April 2009, p. 1241-1243, Vol. 47, No. 4
0095-1137/09/$08.00+0     doi:10.1128/JCM.01703-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

CASE REPORT

Human Bocavirus in an Immunocompromised Child Presenting with Severe Diarrhea

Jutte J. C. de Vries,^1,2* Robbert G. M. Bredius,³ Patrick F. van Rheenen,⁴ Frans J. W. Smiers,³ Elisabeth H. Schölvinck,⁴ Ann C. T. M. Vossen,² Eric C. J. Claas,² and Hubert G. M. Niesters¹

Department of Medical Microbiology, Section Clinical Virology, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands,¹ Department of Medical Microbiology, Section Clinical Virology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands,² Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands,³ Department of Pediatrics, University Medical Center Groningen, Groningen, The Netherlands⁴

Received 3 September 2008/ Returned for modification 9 January 2009/ Accepted 28 January 2009

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Human bocavirus (HBoV) is frequently detected in young children with respiratory symptoms. However, the prevalence and pathogenicity of HBoV in immunocompromised patients are largely unknown. This report describes a case of life-threatening hypovolemic shock due to diarrhea associated with disseminated HBoV infection in an immunocompromised child.

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A 9-year-old boy with erythropoietic protoporphyria was admitted to the University Medical Center Groningen, Groningen, The Netherlands. He had undergone orthotopic liver transplantation and allogeneic hematopoietic stem cell transplantation 9 and 4 months prior to admission, respectively. He presented with fever, nausea, vomiting, and diarrhea of 1-day duration. Clinical examination showed a moderately sick boy with a temperature of 39.5°C, tachycardia (pulse rate, 150 beats per min), normal blood pressure, and normal hydration status. Pulmonary examination detected a minor cough and minor rales upon auscultation. Examination of the abdomen revealed hyperperistalsis, no tenderness, and palpable edges of the liver and spleen. Laboratory results showed an elevated C-reactive protein level (51 mg liter^–1; normal, 10 mg liter^–1) and erythrocyte sedimentation rate (106 mm h^–1; normal, 25 mm h^–1) and a normal leukocyte count. The patient had severe therapy-induced lymphopenia (20 CD3⁺ T cells µl^–1; normal range, 700 to 4,200 µl^–1). Liver chemistry test results were stable but elevated due to biliary complications after liver transplantation. Bacterial blood cultures and fecal cultures for Campylobacter, Salmonella, and Shigella spp. and Escherichia coli O157 were negative. PCR analyses of feces for noroviruses (genogroups I and II), adenovirus, parechovirus, enterovirus, and cytomegalovirus and antigen detection assays of feces for rotavirus and astrovirus were all negative. In contrast, feces results were positive for human bocavirus (HBoV) by PCR (threshold cycle [C_T] value in week 49 of 2007, 17) (Fig. 1). The detection of HBoV was performed by real-time PCR amplification of a 138-bp fragment of the NS1 gene (3). Subsequently, high HBoV DNA loads were detected in plasma (5.9 log₁₀ genome copies ml^–1 in week 49) and a nasal swab sample (C_T value in week 49, 13). The nasal swab sample tested negative by PCR for 14 other respiratory viruses, including respiratory syncytial viruses (types A and B), parainfluenza viruses (types 1 to 4), influenza viruses (types A and B), adenovirus, rhinovirus, coronaviruses (229E, OC43, and NL-63), and human metapneumovirus. Plasma was negative for human parvovirus B19 DNA.

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FIG. 1. Plasma HBoV loads and CT values for HBoV in feces and respiratory samples from our immunocompromised patient at different time points. All samples were positive in the time period shown. The plasma HBoV loads are expressed as log10 genome equivalents (copies [c]) per milliliter relative to the WHO international standard for parvovirus B19 DNA for nucleic acid amplification assays (code 99/800; National Institute for Biological Standards and Control, United Kingdom).

In view of the patient's longstanding liver chemistry test abnormalities, a liver biopsy was performed. Damaged bile canaliculi without a ductular inflammatory reaction or infiltrate were seen. Transplant rejection and biliary obstruction were excluded. There was no indication of graft-versus-host disease to explain his diarrheal illness, and the pathological abnormalities were attributed to drug toxicity. The patient received tube feeding and oral rehydration solution to compensate for enteral fluid losses and was discharged upon the request of his mother, with persistent moderate diarrhea. Two days later, the patient was readmitted with hypovolemic shock (10% weight loss) requiring admission to the pediatric intensive care unit. He was comatose (Glasgow coma score, 3), tachycardic (pulse rate, 145 beats min^–1), and tachypneic (respiration rate, 60 breaths min^–1) and had poor, decreased peripheral perfusion (capillary refill rate, 4 to 5 s). Arterial blood gas analysis showed metabolic acidosis (pH 7.20). Respiratory symptoms or infiltrates were absent. The child was rehydrated intravenously and received oxygen. Feces production during hospitalization in the intensive care unit was up to 3 liters day^–1, and feces had a watery and bloody aspect. The HBoV load in plasma (5.5 log₁₀ genome copies ml^–1 in week 50) was comparable to the load at admission in week 49 and was much higher than those in retrospectively tested plasma samples from the months prior to hospitalization (weeks 42 to 48 of 2007) (Fig. 1). Again, no other causative agent (see above description of diagnostics) for the life-threatening diarrhea was found. Furthermore, a Clostridium difficile toxin A/B immunoassay and an immunocard assay were negative. Fecal PCR analyses for parasites Giardia lamblia, Cryptosporidium parvum, Entamoeba histolytica, Encephalitozoon spp., and Enterocytozoon bieneusi were negative, and no worm eggs or cysts were seen. Plasma PCR analyses for adenovirus, cytomegalovirus, and Epstein-Barr virus genomes were negative. After the patient was stabilized, he was further treated with an oral rehydration solution. In week 52, his stools normalized, and 9 days after admission to the intensive care unit, the patient was discharged in good clinical condition. Despite normalized stools, fecal HBoV shedding at a lower level than before (C_T in week 4 of 2008, 25) was seen for approximately 2 months after admission, with still detectable but decreased virus loads in plasma (median, 4 log₁₀ genome copies ml^–1). In the following months, his course was complicated by persistent, uncontrolled varicella-zoster virus reactivation with optic neuritis, which was initially treated with intravenous acyclovir, later combined with intravenous foscarnet and steroids. His immune system recovery was severely delayed (maximal CD3⁺ T-cell count, 100 µl^–1). At that time, the patient died of a combination of largely unexplained multiple organ and bone marrow failures. An autopsy was not performed.

HBoV is a newly identified human pathogen classified in the family Parvoviridae (3). The virus is frequently found in young children with respiratory symptoms, with detection rates of up to 19%. Coinfection with other respiratory viruses is frequent (occurring in up to 78% of cases) (2, 6, 8, 16). Clinical findings associated with HBoV include rhinorrhea, coughing, and fever, as well as diarrhea.

This report describes a disseminated HBoV infection in a pediatric immunocompromised patient who developed diarrhea with life-threatening hypovolemia. Respiratory symptoms were mild. No coinfection with another viral, bacterial, or parasitic pathogen was found, leaving HBoV as the only association with the gastrointestinal symptoms. High HBoV loads in plasma and feces correlated in time with severe gastrointestinal symptoms, whereas lower HBoV loads correlated with the recovery from the diarrheal illness. Prolonged shedding of HBoV in normalized stools from this severely lymphopenic child was observed, as has been described previously for other respiratory and gastrointestinal viruses in immunocompromised patients.

Only a few data about HBoV in immunocompromised patients have been published (Table 1). Several large respiratory disease surveys briefly describe HBoV detection in immunosuppressed adults and children (4, 7, 13, 14, 18). Furthermore, a few case reports on the detection of HBoV in immunocompromised patients have been published (9, 10, 11, 17). Kainulainen et al. (9) reported an HBoV infection and hepatitis in a child with T-cell immunodeficiency. Kupfer et al. (11) described a case of severe pneumonia associated with HBoV in an adult patient with non-Hodgkin's lymphoma. Koskenvuo et al. (10) reported HBoV detection in respiratory samples from three pediatric leukemia patients (ages 2 to 4 years) with respiratory symptoms, fever with diarrhea, and recurrent febrile episodes, respectively. No fecal sample from the patient with gastrointestinal symptoms was available. Schenk et al. (17) described a 4-year-old child with disseminated HBoV infection who suffered from severe respiratory symptoms and diarrhea after hematopoietic stem cell transplantation. HBoV was detected in respiratory samples, plasma, and feces. Prolonged fecal shedding (lasting for more than 1 month) was detected, as in our patient. However, life-threatening diarrhea as a major presentation of HBoV infection with very limited respiratory symptoms, as seen in our patient, has not been described before.

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TABLE 1. Clinical features of immunocompromised patients with HBoV infection and sources of isolated HBoV described in the English language literature

Unlike human parvovirus B19, bovine and canine bocaviruses are frequently associated with enteritis in young animals. However, the role of HBoV in gastroenteritis in humans remains unclear and has been investigated in a number of studies with immunocompetent patients. In a large respiratory disease survey, diarrhea was reported in 16% of HBoV-positive patients (4). In another survey, HBoV was detected in 14 (45%) of 31 fecal samples from children with HBoV-positive respiratory samples (15). HBoV has been detected in 2 to 9% of fecal samples (n, 527 to 1,435) from children with gastroenteritis (1, 12, 19). Coinfection with other intestinal pathogens was found in 21 to 58% of these cases. Recently, the results of large uncontrolled and controlled studies by Yu et al. (20) and Cheng et al. (5) did not support a causative role for HBoV as a gastroenteritis agent in children hospitalized with diarrhea, despite frequent fecal HBoV detection. Thus, HBoV is frequently detected in feces but its association with gastrointestinal infection is less clear. In our immunocompromised patient, the high level of HBoV detected in feces may suggest HBoV replication in the gastrointestinal tract.

In summary, we describe an immunocompromised child with severe diarrhea associated with HBoV infection. It would be relevant to include HBoV detection in the diagnostic approach for immunocompromised patients presenting with diarrhea in order to find out further details of the role of this virus in causing gastrointestinal disease.

 
We thank Aloys Kroes (Department of Medical Microbiology, Section Clinical Virology, LUMC) for critical reading of the manuscript.

 
* Corresponding author. Mailing address: Department of Medical Microbiology, Section Clinical Virology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Phone: 31 71 526 5242. Fax: 31 71 526 6981. E-mail: jjcdevries{at}lumc.nl

Published ahead of print on 4 February 2009.

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Journal of Clinical Microbiology, April 2009, p. 1241-1243, Vol. 47, No. 4
0095-1137/09/$08.00+0     doi:10.1128/JCM.01703-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by de Vries, J. J. C. Articles by Niesters, H. G. M. Search for Related Content PubMed PubMed Citation Articles by de Vries, J. J. C. Articles by Niesters, H. G. M.