The Pediatric Infectious Disease Journal • Volume 33, Number 11, November 2014
9. Center for Disease Control and Prevention (CDC). Blastomycosis— Wisconsin, 1986–1995. Morb Mortal Wkly Rep. 1996;45:601–603. 10. Chesney JC, Gourley GR, Peters ME, et al. Pulmonary blastomyco sis in children. Amphotericin B therapy and a review. Am J Dis Child. 1979;133:1134–1139. 11. Smith JG Jr, Harris JS, Conant NF, et al. An epidemic of North American blastomycosis. J Am Med Assoc. 1955;158:641–646. 12. Fanella S, Walkty A, Bridger N, et al. Gastric lavage for the diagnosis of pulmonary blastomycosis in pediatric patients. Pediatr Infect Dis J. 2010;29:1146–1148. 13. Maxson S, Miller SF, Tryka AF, et al. Perinatal blastomycosis: a review. Pediatr Infect Dis J. 1992;11:760–763. 14. Watts EA, Gard PD Jr, Tuthill SW. First reported case of intrauterine transmission of blastomycosis. Pediatr Infect Dis. 1983;2:308–310.
TWO CASES OF NEONATAL HUMAN PARECHOVIRUS 3 ENCEPHALITIS Elena Pariani, PhD,* Laura Pellegrinelli, BS,* Lorenza Pugni, MD,† Paolo Bini, MD,‡ Simona Perniciaro, MD,† Laura Bubba, PhD,* Valeria Primache,* Antonella Amendola, PhD*, Mario Barbarini, MD,‡ Fabio Mosca, MD,† and Sandro Binda, PhD* Abstract: We report 2 neonates with human parechoviruses type 3 encephalitis. Both newborns presented with fever, irritability and seizures. Cerebrospinal fluid analyses were normal, but magnetic resonance imaging revealed white matter damage, suggesting human parechoviruse infection. Human parechoviruses type 3-RNA was detected in cerebrospinal fluid samples and in blood, stool, urine and respiratory samples, indicating the dissemination of the virus. Key Words: neonatal encephalitis, Parechovirus, Parechovirus type 3 Accepted for publication April 30, 2014. From the *Department of Biomedical Sciences for Health; †Neonatal Intensive Care Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan; and ‡Neonatal Intensive Care Unit, General Hospital “Azienda Ospedaliera Sant’Anna”, Como, Italy. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Sandro Binda, PhD, Department of Biomedical Sciences for Health, University of Milan, Via C. Pascal, 36 – 20133 Milan, Italy. E-mail address: [email protected]. Copyright © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/INF.0000000000000412
H
uman parechoviruses (HPeVs) are small, nonenveloped, single-stranded RNA viruses within the Parechovirus genus of the large Picornaviridae family.1 Infections are enteric and often associated with mild gastrointestinal and respiratory symptoms, but severe neonatal diseases including sepsis, meningitis, encephalitis and hepatitis have been described.2 To date, 16 HPeV types have been identified,1 and there is increasing evidence for a specific role of HPeV type 3 (HPeV3) in severe neonatal disease. In particular, HPeV3 has been shown to play an important role in severe neonatal central nervous system infections.2,3 Here, we report 2 cases of neonatal encephalitis caused by HPeV3.
CASE REPORTS CASE 1 A 16-day-old boy, born full term by vaginal delivery without complications, was admitted to the Emergency Department of the Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico in © 2014 Lippincott Williams & Wilkins
Parechovirus 3 Encephalitis
Milan (2012, July) for a 1 day history of hyporeactivity, reduced oral intake, fever and tachypnea. On initial examination, the baby was alert but irritable with a body temperature of 39°C, a respiratory rate of 65 breaths per minute and a heart rate of 170 beats per minute. A pale erythematous rash was present on the trunk and the limbs and abdominal distension was present. Results of the initial physical examination were otherwise normal, with no lung rales, normal tympanic membranes, no bulging of the fontanel or cranial nerve deficits. At admission, routine laboratory tests were normal. Chest radiograph was normal. The febrile and irritable baby with plaintive tears was admitted to the neonatal intensive care unit with an initial diagnosis of bacteremia/viremia. Blood, cerebrospinal fluid (CSF), urine and stool samples were collected for bacterial and viral study. A nasopharyngeal swab was also collected for viral detection. CSF analysis showed no leukocytes, with normal glucose and protein values.4 Empirical antimicrobial therapy (ampicillin and gentamicin) plus acyclovir was started (according to our Unit protocol, acyclovir is commenced when meningoencephalitis is suspected, until herpes simplex virus (HSV) is not excluded as the causative agent). The following day the fever persisted, and the neurologic evaluation showed irritability and generalized hypertonia. On day 3 of hospitalization, the baby had generalized seizures with severe alterations (low voltage) in the electroencephalogram (EEG). Phenobarbital therapy was started and the EEG improved during the following days. Mild lenticulostriate vasculopathy was detected on cranial ultrasonography. Brain magnetic resonance imaging (MRI) done on day 3 of hospitalization showed multiple small focal noncystic areas of increased signal on T1-weighted spin-echo sequences and decreased signal on T2-weighted spin-echo sequences (punctate white matter lesions). On diffusion-weighted imaging, these areas had a restricted diffusion signal. Neuroimaging was suggestive of viral encephalitis. All bacterial cultures of specimens collected at the time of admission were negative. Molecular investigations on blood, CSF, urine, stool samples and nasopharyngeal swab were negative to all considered viruses [ie, herpes simplex virus 1 (HSV1) and 2 (HSV2), cytomegalovirus, human herpesvirus 6, parvovirus B19, enteroviruses, adenovirus, Epstein-Barr virus, BK and JC viruses], but all specimens tested positive for HPeV. Genotyping of HPeV was performed by sequencing VP3/VP1 partial gene5 and indicated the presence of HPeV type 3. To examine the possibility of congenital HPeV infection, the presence of viral RNA was investigated in dried blood spot6 (DBS) that—according to the law—are routinely collected for newborn screening from all neonates within 48–72 hours from birth. DBS collected from case 1 at birth was negative to HPeVRNA. On the basis of examination results, antibiotics and acyclovir were discontinued on day 4 of hospitalization. The patient gradually improved and he was discharged after 2 weeks of hospitalization. Two months later, EEG and MRI were normal, and phenobarbital was stopped. At 18 months of age, head circumference was 48 cm (50–75th percentile), and cognitive and motor developments were normal.
Case 2 A 9-day-old girl, born full term by elective cesarean section without complications, was admitted to the Pediatric Emergency Unit of the General Hospital “Azienda Ospedaliera Sant’Anna” in Como (2013, April) for a 1 day history of plaintive tears, reduced oral intake and fever, in the presence of gastrointestinal symptoms (semiliquid stools). Her 3-year-old sister had had an upper respiratory tract infection in the preceding few days and the father reported a self-resolving episode of diarrhea 3 days before, but their clinical samples were not available for examination. www.pidj.com | 1191
The Pediatric Infectious Disease Journal • Volume 33, Number 11, November 2014
Pariani et al
At admission, the neonate was alert but irritable with a body temperature of 39.4°C; the respiratory rate and the heart rate were normal for age (50 breaths per minute and 150 beats per minute, respectively). Results of initial physical examination were otherwise normal, with no rash or petechiae, no lung rales, normal tympanic membranes, no bulging of the fontanel, or cranial nerve deficits. Routine laboratory analysis and urinalysis were normal; chest radiograph was normal. Blood, urine, stool samples and a nasopharyngeal swab were collected for bacterial and viral identification. The neonate was admitted to the neonatal intensive care unit with a diagnosis of suspected infection and intravenous antimicrobial therapy (ampicillin and netilmicin) was started. Two hours after her admission, the baby had a convulsive episode characterized by myoclonic seizures and staring, with no alterations of vital signs. The occurrence of other seizure episodes with recurrent apneas required intubation and assisted ventilation. Anticonvulsant therapy (phenobarbital plus phenytoin) was commenced, but the baby continued to have seizures requiring control by mydazolam. A lumbar puncture was performed, and biochemical analysis of the CSF showed no leukocytes and normal glucose and protein. Intravenous acyclovir (according to Unit protocol) was administered. EEG showed repeated events of specific activity, especially in the left hemisphere and also contra laterally. Brain MRI T2-weighted spin-echo axial section showed punctate white matter lesions suggestive of petechial hemorrhages. Diffusion-weighted imaging revealed diffuse excessive high signal intensity. This distinctive pattern of white matter involvement was noteworthy, and these abnormalities extended into the subcortical white matter and involved the entire fiber tracts, corpus callosum, optic radiation and posterior thalamus. During the first week of hospitalization, the clinical condition of the neonate was characterized by severe hypotension and it was necessary to undertake therapy with dopamine up to a dose of 7.5 mcg/kg/ min, followed by oliguria and hyponatremia up to 126 mmol/L. Bacterial cultures of specimens collected at the time of admission were negative. Viral investigations on CSF, blood, nasopharyngeal swab, urine and stool samples resulted negative for all investigated pathogens (HSV1, HSV2, cytomegalovirus, human herpesvirus 6, parvovirus B19, enteroviruses, adenovirus, Epstein-Barr virus, BK and JC viruses), but all tested positive for HPeV type 3. DBS collected from case 2 at birth was negative for HPeV-RNA. At that point, acyclovir was stopped. The patient gradually improved and she was discharged on day 27: maintenance therapy with phenobarbital was recommended. At discharge, the child had no neurobehavioral abnormalities in motor, postural and behavioral skills. The child was inserted into a clinical and instrumental follow-up program to define her long-term prognosis. Twelve months later, the child presented microcephaly [head circumference was 35 cm at birth (50–75th percentile), 37 cm (< 3rd percentile) at 3 month, and 43 cm (
9. Center for Disease Control and Prevention (CDC). Blastomycosis— Wisconsin, 1986–1995. Morb Mortal Wkly Rep. 1996;45:601–603. 10. Chesney JC, Gourley GR, Peters ME, et al. Pulmonary blastomyco sis in children. Amphotericin B therapy and a review. Am J Dis Child. 1979;133:1134–1139. 11. Smith JG Jr, Harris JS, Conant NF, et al. An epidemic of North American blastomycosis. J Am Med Assoc. 1955;158:641–646. 12. Fanella S, Walkty A, Bridger N, et al. Gastric lavage for the diagnosis of pulmonary blastomycosis in pediatric patients. Pediatr Infect Dis J. 2010;29:1146–1148. 13. Maxson S, Miller SF, Tryka AF, et al. Perinatal blastomycosis: a review. Pediatr Infect Dis J. 1992;11:760–763. 14. Watts EA, Gard PD Jr, Tuthill SW. First reported case of intrauterine transmission of blastomycosis. Pediatr Infect Dis. 1983;2:308–310.
TWO CASES OF NEONATAL HUMAN PARECHOVIRUS 3 ENCEPHALITIS Elena Pariani, PhD,* Laura Pellegrinelli, BS,* Lorenza Pugni, MD,† Paolo Bini, MD,‡ Simona Perniciaro, MD,† Laura Bubba, PhD,* Valeria Primache,* Antonella Amendola, PhD*, Mario Barbarini, MD,‡ Fabio Mosca, MD,† and Sandro Binda, PhD* Abstract: We report 2 neonates with human parechoviruses type 3 encephalitis. Both newborns presented with fever, irritability and seizures. Cerebrospinal fluid analyses were normal, but magnetic resonance imaging revealed white matter damage, suggesting human parechoviruse infection. Human parechoviruses type 3-RNA was detected in cerebrospinal fluid samples and in blood, stool, urine and respiratory samples, indicating the dissemination of the virus. Key Words: neonatal encephalitis, Parechovirus, Parechovirus type 3 Accepted for publication April 30, 2014. From the *Department of Biomedical Sciences for Health; †Neonatal Intensive Care Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, University of Milan, Milan; and ‡Neonatal Intensive Care Unit, General Hospital “Azienda Ospedaliera Sant’Anna”, Como, Italy. The authors have no funding or conflicts of interest to disclose. Address for correspondence: Sandro Binda, PhD, Department of Biomedical Sciences for Health, University of Milan, Via C. Pascal, 36 – 20133 Milan, Italy. E-mail address: [email protected]. Copyright © 2014 by Lippincott Williams & Wilkins DOI: 10.1097/INF.0000000000000412
H
uman parechoviruses (HPeVs) are small, nonenveloped, single-stranded RNA viruses within the Parechovirus genus of the large Picornaviridae family.1 Infections are enteric and often associated with mild gastrointestinal and respiratory symptoms, but severe neonatal diseases including sepsis, meningitis, encephalitis and hepatitis have been described.2 To date, 16 HPeV types have been identified,1 and there is increasing evidence for a specific role of HPeV type 3 (HPeV3) in severe neonatal disease. In particular, HPeV3 has been shown to play an important role in severe neonatal central nervous system infections.2,3 Here, we report 2 cases of neonatal encephalitis caused by HPeV3.
CASE REPORTS CASE 1 A 16-day-old boy, born full term by vaginal delivery without complications, was admitted to the Emergency Department of the Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico in © 2014 Lippincott Williams & Wilkins
Parechovirus 3 Encephalitis
Milan (2012, July) for a 1 day history of hyporeactivity, reduced oral intake, fever and tachypnea. On initial examination, the baby was alert but irritable with a body temperature of 39°C, a respiratory rate of 65 breaths per minute and a heart rate of 170 beats per minute. A pale erythematous rash was present on the trunk and the limbs and abdominal distension was present. Results of the initial physical examination were otherwise normal, with no lung rales, normal tympanic membranes, no bulging of the fontanel or cranial nerve deficits. At admission, routine laboratory tests were normal. Chest radiograph was normal. The febrile and irritable baby with plaintive tears was admitted to the neonatal intensive care unit with an initial diagnosis of bacteremia/viremia. Blood, cerebrospinal fluid (CSF), urine and stool samples were collected for bacterial and viral study. A nasopharyngeal swab was also collected for viral detection. CSF analysis showed no leukocytes, with normal glucose and protein values.4 Empirical antimicrobial therapy (ampicillin and gentamicin) plus acyclovir was started (according to our Unit protocol, acyclovir is commenced when meningoencephalitis is suspected, until herpes simplex virus (HSV) is not excluded as the causative agent). The following day the fever persisted, and the neurologic evaluation showed irritability and generalized hypertonia. On day 3 of hospitalization, the baby had generalized seizures with severe alterations (low voltage) in the electroencephalogram (EEG). Phenobarbital therapy was started and the EEG improved during the following days. Mild lenticulostriate vasculopathy was detected on cranial ultrasonography. Brain magnetic resonance imaging (MRI) done on day 3 of hospitalization showed multiple small focal noncystic areas of increased signal on T1-weighted spin-echo sequences and decreased signal on T2-weighted spin-echo sequences (punctate white matter lesions). On diffusion-weighted imaging, these areas had a restricted diffusion signal. Neuroimaging was suggestive of viral encephalitis. All bacterial cultures of specimens collected at the time of admission were negative. Molecular investigations on blood, CSF, urine, stool samples and nasopharyngeal swab were negative to all considered viruses [ie, herpes simplex virus 1 (HSV1) and 2 (HSV2), cytomegalovirus, human herpesvirus 6, parvovirus B19, enteroviruses, adenovirus, Epstein-Barr virus, BK and JC viruses], but all specimens tested positive for HPeV. Genotyping of HPeV was performed by sequencing VP3/VP1 partial gene5 and indicated the presence of HPeV type 3. To examine the possibility of congenital HPeV infection, the presence of viral RNA was investigated in dried blood spot6 (DBS) that—according to the law—are routinely collected for newborn screening from all neonates within 48–72 hours from birth. DBS collected from case 1 at birth was negative to HPeVRNA. On the basis of examination results, antibiotics and acyclovir were discontinued on day 4 of hospitalization. The patient gradually improved and he was discharged after 2 weeks of hospitalization. Two months later, EEG and MRI were normal, and phenobarbital was stopped. At 18 months of age, head circumference was 48 cm (50–75th percentile), and cognitive and motor developments were normal.
Case 2 A 9-day-old girl, born full term by elective cesarean section without complications, was admitted to the Pediatric Emergency Unit of the General Hospital “Azienda Ospedaliera Sant’Anna” in Como (2013, April) for a 1 day history of plaintive tears, reduced oral intake and fever, in the presence of gastrointestinal symptoms (semiliquid stools). Her 3-year-old sister had had an upper respiratory tract infection in the preceding few days and the father reported a self-resolving episode of diarrhea 3 days before, but their clinical samples were not available for examination. www.pidj.com | 1191
The Pediatric Infectious Disease Journal • Volume 33, Number 11, November 2014
Pariani et al
At admission, the neonate was alert but irritable with a body temperature of 39.4°C; the respiratory rate and the heart rate were normal for age (50 breaths per minute and 150 beats per minute, respectively). Results of initial physical examination were otherwise normal, with no rash or petechiae, no lung rales, normal tympanic membranes, no bulging of the fontanel, or cranial nerve deficits. Routine laboratory analysis and urinalysis were normal; chest radiograph was normal. Blood, urine, stool samples and a nasopharyngeal swab were collected for bacterial and viral identification. The neonate was admitted to the neonatal intensive care unit with a diagnosis of suspected infection and intravenous antimicrobial therapy (ampicillin and netilmicin) was started. Two hours after her admission, the baby had a convulsive episode characterized by myoclonic seizures and staring, with no alterations of vital signs. The occurrence of other seizure episodes with recurrent apneas required intubation and assisted ventilation. Anticonvulsant therapy (phenobarbital plus phenytoin) was commenced, but the baby continued to have seizures requiring control by mydazolam. A lumbar puncture was performed, and biochemical analysis of the CSF showed no leukocytes and normal glucose and protein. Intravenous acyclovir (according to Unit protocol) was administered. EEG showed repeated events of specific activity, especially in the left hemisphere and also contra laterally. Brain MRI T2-weighted spin-echo axial section showed punctate white matter lesions suggestive of petechial hemorrhages. Diffusion-weighted imaging revealed diffuse excessive high signal intensity. This distinctive pattern of white matter involvement was noteworthy, and these abnormalities extended into the subcortical white matter and involved the entire fiber tracts, corpus callosum, optic radiation and posterior thalamus. During the first week of hospitalization, the clinical condition of the neonate was characterized by severe hypotension and it was necessary to undertake therapy with dopamine up to a dose of 7.5 mcg/kg/ min, followed by oliguria and hyponatremia up to 126 mmol/L. Bacterial cultures of specimens collected at the time of admission were negative. Viral investigations on CSF, blood, nasopharyngeal swab, urine and stool samples resulted negative for all investigated pathogens (HSV1, HSV2, cytomegalovirus, human herpesvirus 6, parvovirus B19, enteroviruses, adenovirus, Epstein-Barr virus, BK and JC viruses), but all tested positive for HPeV type 3. DBS collected from case 2 at birth was negative for HPeV-RNA. At that point, acyclovir was stopped. The patient gradually improved and she was discharged on day 27: maintenance therapy with phenobarbital was recommended. At discharge, the child had no neurobehavioral abnormalities in motor, postural and behavioral skills. The child was inserted into a clinical and instrumental follow-up program to define her long-term prognosis. Twelve months later, the child presented microcephaly [head circumference was 35 cm at birth (50–75th percentile), 37 cm (< 3rd percentile) at 3 month, and 43 cm (
