596071
research-article2015
CPJXXX10.1177/0009922815596071Co et alClinical PediatricsClinical Pediatrics
Resident Rounds
In the Cradle of Death: A Rare Case of Intrauterine Herpes Simplex Virus Infection
Clinical Pediatrics 1–3 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0009922815596071 cpj.sagepub.com
Mary Antonette M. Co, MD1, Madhavi Koneru, MD1, Jose Santiago, MD1, Madhava Reddy Beeram, MD1, and Mohammad Nasir Uddin, PhD, FAHA1
Case Report With Hospital Course A Caucasian male infant was delivered vaginally at 34 74 weeks gestation to a 19-year-old mother of 2 who had a primary herpes simplex virus infection at 18 weeks and another probable outbreak at 26 74 weeks. She was treated with acyclovir for 7 days at both occurrences. Suppressive therapy was to be started at 36 weeks. Prenatal ultrasound at 25 17 weeks was unremarkable; however, at 32 72 weeks, prenatal ultrasound showed enlargement of the third ventricles and at 33 72 weeks showed severe ventriculomegaly. The infant was born limp and apneic. Tracheal suctioning was performed for light meconium, but no meconium was obtained. He was eventually intubated for a heart rate less than 100 beats/min and shallow respirations. Apgar scores were obtained at 1, 6, and 7 at 1, 5, and 10 minutes, respectively. Physical examination on admissions showed a preterm infant with minimal to absent spontaneous movement alternating with occasional focal clonic seizures of the right arm and rhythmic jerking movement of all four extremities. Birth weight and length were at the 50th percentile and the head circumference was at the 25th percentile for gestational age. He was normocephalic with open, soft anterior fontanelle. There were multiple raised hypopigmented lesions on his palm, chin, and arm, which resolved after 24 hours. The rest of the physical examination was unremarkable. He was placed under contact isolation. Laboratory samples were taken and the infant was started on ampicillin, gentamicin, and acyclovir. Phenobarbital and levetiracetam were given for the seizures. Initial complete blood count showed a white cell count of 8.7 with 37% neutrophils, 47% lymphocytes, 5% monocytes, and 65% eosinophil. Liver function tests and disseminated intravascular coagulolopathy panel were within normal limits. Blood cultures taken from 2 sites were negative. Antibodies to cytomegalovirus, toxoplasma, and herpes simplex virus type 1 (HSV-1) were negative, and Venereal Disease Research Laboratory was
nonreactive. However, HSV-2 IgG was positive. Examination of the cerebrospinal fluid (CSF) showed 42 white blood cells/mm3, 2430 red blood cells/mm3, protein 772 mg/dL, and glucose 26 mg/dL (serum glucose 96 mg/dL). No organisms were seen on Gram stain. The urine, skin, and CSF polymerase chain reaction (PCR) for HSV-2 were all positive. A chest radiograph was suggestive of mild surfactant deficiency. A cranial ultrasound showed massive ventriculomegaly. A computed tomography scan, performed a few hours after birth to rule out an intracranial bleed, showed marked intracranial abnormality with ventriculomegaly in addition to an extensive area of brain destruction involving the frontal, temporal, and parietal lobes. Both cerebellar hemispheres were small in appearance. Marked atrophy was apparent in the brainstem. Intracranial calcifications were also seen. Magnetic resonance imaging showed similar findings with near complete absence of brain substance, with minimal residual brain identified in the occipital region. Magnetic resonance imaging also showed compensatory marked dilatation of the lateral and third ventricles (Figure 1). A small bilateral cerebellar hemisphere was visible with marked atrophy of the brainstem. Extensive periventricular and parenchymal calcifications were seen. These findings were consistent with toxoplasmosis, others, rubella, cytomegalovirus, and herpes simplex (TORCH) infection, particularly HSV infection based on the history. Ophthalmologic exam revealed chorioretinitis with scarring, necrosis, and hemorrhage and the infant was assessed to have no useful vision in the future.
1
McLane’s Children’s Hospital, Scott & White Healthcare, Temple, TX, USA Corresponding Author: Mohammad Nasir Uddin, Department of Obstetrics and Gynecology, Scott & White Healthcare, C2401 South 31st Street, Room 352, Temple, TX 76508, USA. Email: [email protected]
Downloaded from cpj.sagepub.com at CALIFORNIA STATE UNIV FRESNO on July 26, 2015
2
Clinical Pediatrics
Pathogenesis It starts with inoculation of the virus in the oral, genital, conjunctival mucosa, or break in the skin. It infects the sensory nerve endings and then transports via retrograde axonal flow to the dorsal root ganglia where it remains latent. During periods of stress, the virus travels down the axon to the sensory nerve endings where it replicates. The fetus may be infected transplacentally through the chorionic villi or through retrograde spread through rupture of membrane or even seemingly intact membranes.1
Figure 1. Magnetic resonance imaging of the brain showing compensatory marked dilatation of the lateral and third ventricles.
The infant was maintained on low ventilator settings with low resting respiratory rate, periodic breathing, and apneic episodes. He continued to have occasional focal, clonic seizures on the right and rhythmic jerking movements of all 4 extremities despite being placed on phenobarbital, levetiracetam, and midazolam for intractable seizures. Several multidisciplinary care conferences were held involving the parents, extended family members, the primary neonatal intensive care unit team, neurology, infectious disease, and hospice. Taking into consideration all of the findings and results, it was concluded that “No quality of life is expected from this abnormality.” Care was withdrawn on the seventh day of life.
Final Diagnosis Disseminated congenital herpes simplex infection.
Discussion Herpes Simplex Virus Infection Herpes simplex viruses (HSV)-1 and -2 are large, enveloped virions that belong to alphaherpesviridae with an icosahedral nucleocapsid arranged around a linear double-stranded DNA core.3 The glycoprotein IgG provides antigenic specificity and allows the differentiation between HSV-1 and -2.1 The current estimated rate of occurrence of HSV infection in the neonate is approximately 1 in 1500 cases diagnosed annually.2 It is noted that the baseline prevalence of HSV-2 genital infection has increased since 2000. Hence, the severity of cases involving the central nervous system (CNS) and the disseminated type have also increased.1
Periods of Acquisition Intrauterine HSV-2 infection is approximately 5% of all babies with neonatal HSV infection. This is caused by maternal viremia following a primary HSV infection during pregnancy. Survivors of in utero HSV infection may exhibit a triad of cutaneous findings such as scarring, ulceration, and/or manifest as active lesions; eye damage like microophthalmia, retinal dysplasia, optic atrophy, and chorioretinitis; and CNS involvement such as microcephaly, encephalomalacia, hydranencephaly and intracranial calcification.2-4 The factors that influence the transmission of HSV infection in the intrapartum period, which is 85% of all the cases of neonatal infection, includes type of maternal infection, it is subdivided into first episode or primary infection (57% of cases) where antibodies to both HSV-1 and HSV-2 are absent at the time the patient acquires genital HSV due to HSV-1 or HSV-2, type specific antibodies to HSV generally develop within the first 12 weeks after an infection and persists indefinitely; firstepisode nonprimary genital HSV infection occurs in about 25% of cases. This is acquisition of genital HSV-2 with preexisting antibodies to HSV-1, and although rare, is acquisition of HSV-2 with preexisting antibodies to HSV-2. Recurrent genital HSV infection occurs in 2% of cases and is the reactivation of genital HSV in which the HSV type recovered from the lesion is the same type as the antibodies in the serum. The other factors are maternal HSV antibody status, duration of rupture of membrane, integrity of cutaneous barrier (use of scalp electrode), mode of delivery for mothers with vesicular rash in the perineum, and the type of HSV infection. The transmission rate to the neonate at delivery with recurrent infection is lower than the primary or first-episode genital infection.2,4 Postpartum comprises 10% of all cases of HSV infection and is acquired from caretaker of infants who develop an outbreak.2,4 Intrauterine HSV infection is rare and has been reported anecdotally. The timing of acquisition is during
Downloaded from cpj.sagepub.com at CALIFORNIA STATE UNIV FRESNO on July 26, 2015
3
Co et al the first 20 weeks of gestation of a primary infection, which can result in spontaneous abortion, stillbirth, and congenital malformation, particularly hydranencephaly and chorioretinitis. It is also suggested that there should be evidence of infection in the first 48 hours of life, there should be virologic confirmation, other illnesses are excluded, embryogenesis is affected and there is evidence of viral placentitis. In in utero disease, approximately 1 in 300 000 infants is infected via maternal viremia, either from transplacental or ascending infection.1 Marquez et al5 reviewed 24 published cases between 1963 and January 2009, showing the clinical spectrum of intrauterine HSV infection.
Conclusion An HSV infection during the early trimester of pregnancy can pose serious problems to the offspring. The health profession should have a high index of suspicion in monitoring and treating infection aggressively. An educational campaign, especially toward teenagers, should be undertaken since the incidence in this age group is increasing. Author Contributions MAMC wrote the manuscript. MK, JS, MRB and MNU provided guidance and edited the manuscript.
Declaration of Conflicting Interests
Diagnosis Viral culture is the definitive diagnostic test. However, it takes several days for the results to be available. PCR amplification is more sensitive than a viral culture. It has a sensitivity of 75% to 100% and specificity of 71% to 100%. It is the preferred method to document CNS involvement and serves as adjunct to the HSV surface culture. Generally, the serologic test has no role in the diagnosis of neonatal HSV disease. It can identify past infection but it cannot identify the site of HSV infection.2,3
Treatment The treatment is acyclovir 60 mg/kg/d divided into 3 doses (20 mg/kg/dse) intravenously. The duration of treatment is 21 days for disseminated or CNS infection and 14 days for skin, eyes, mucous membrane disease. A repeat lumbar puncture should be done at the end of the treatment for CNS HSV infection, and treatment is to be continued until the CSF PCR is negative.6 With the utilization of acyclovir 60 mg/kg/d for 21 days, the mortality rate was reduced from 85% to 29% for the disseminated type and 50% to 4% for the CNS disease.4,6
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Kimberlin DW. Neonatal herpes simplex infection. Clin Microbiol Rev. 2004;17:1-13. 2. Kimberlin DW, Lin CY, Jacobs RF, et al. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics. 2001;108:230-238. 3. Kimberlin DW, Baley J. Guidance on management of asymptomatic neonates born to women with active genital herpes lesions. Pediatrics. 2013;131:383-386. 4. Kimberlin DW. Herpes simplex virus infections of the newborn. Semin Perinatol. 2007;31:19-25. 5. Marquez L, Levy ML, Munoz FM, Palazza DL. A report of three cases and review of intrauterine herpes simplex virus infection. Pediatr Infect Dis J. 2011;30:153-157. 6. Pinninti SG, Kimberlin DW. Neonatal herpes simplex virus infections. Pediatr Clin North Am. 2013;60:351-365.
Downloaded from cpj.sagepub.com at CALIFORNIA STATE UNIV FRESNO on July 26, 2015
research-article2015
CPJXXX10.1177/0009922815596071Co et alClinical PediatricsClinical Pediatrics
Resident Rounds
In the Cradle of Death: A Rare Case of Intrauterine Herpes Simplex Virus Infection
Clinical Pediatrics 1–3 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/0009922815596071 cpj.sagepub.com
Mary Antonette M. Co, MD1, Madhavi Koneru, MD1, Jose Santiago, MD1, Madhava Reddy Beeram, MD1, and Mohammad Nasir Uddin, PhD, FAHA1
Case Report With Hospital Course A Caucasian male infant was delivered vaginally at 34 74 weeks gestation to a 19-year-old mother of 2 who had a primary herpes simplex virus infection at 18 weeks and another probable outbreak at 26 74 weeks. She was treated with acyclovir for 7 days at both occurrences. Suppressive therapy was to be started at 36 weeks. Prenatal ultrasound at 25 17 weeks was unremarkable; however, at 32 72 weeks, prenatal ultrasound showed enlargement of the third ventricles and at 33 72 weeks showed severe ventriculomegaly. The infant was born limp and apneic. Tracheal suctioning was performed for light meconium, but no meconium was obtained. He was eventually intubated for a heart rate less than 100 beats/min and shallow respirations. Apgar scores were obtained at 1, 6, and 7 at 1, 5, and 10 minutes, respectively. Physical examination on admissions showed a preterm infant with minimal to absent spontaneous movement alternating with occasional focal clonic seizures of the right arm and rhythmic jerking movement of all four extremities. Birth weight and length were at the 50th percentile and the head circumference was at the 25th percentile for gestational age. He was normocephalic with open, soft anterior fontanelle. There were multiple raised hypopigmented lesions on his palm, chin, and arm, which resolved after 24 hours. The rest of the physical examination was unremarkable. He was placed under contact isolation. Laboratory samples were taken and the infant was started on ampicillin, gentamicin, and acyclovir. Phenobarbital and levetiracetam were given for the seizures. Initial complete blood count showed a white cell count of 8.7 with 37% neutrophils, 47% lymphocytes, 5% monocytes, and 65% eosinophil. Liver function tests and disseminated intravascular coagulolopathy panel were within normal limits. Blood cultures taken from 2 sites were negative. Antibodies to cytomegalovirus, toxoplasma, and herpes simplex virus type 1 (HSV-1) were negative, and Venereal Disease Research Laboratory was
nonreactive. However, HSV-2 IgG was positive. Examination of the cerebrospinal fluid (CSF) showed 42 white blood cells/mm3, 2430 red blood cells/mm3, protein 772 mg/dL, and glucose 26 mg/dL (serum glucose 96 mg/dL). No organisms were seen on Gram stain. The urine, skin, and CSF polymerase chain reaction (PCR) for HSV-2 were all positive. A chest radiograph was suggestive of mild surfactant deficiency. A cranial ultrasound showed massive ventriculomegaly. A computed tomography scan, performed a few hours after birth to rule out an intracranial bleed, showed marked intracranial abnormality with ventriculomegaly in addition to an extensive area of brain destruction involving the frontal, temporal, and parietal lobes. Both cerebellar hemispheres were small in appearance. Marked atrophy was apparent in the brainstem. Intracranial calcifications were also seen. Magnetic resonance imaging showed similar findings with near complete absence of brain substance, with minimal residual brain identified in the occipital region. Magnetic resonance imaging also showed compensatory marked dilatation of the lateral and third ventricles (Figure 1). A small bilateral cerebellar hemisphere was visible with marked atrophy of the brainstem. Extensive periventricular and parenchymal calcifications were seen. These findings were consistent with toxoplasmosis, others, rubella, cytomegalovirus, and herpes simplex (TORCH) infection, particularly HSV infection based on the history. Ophthalmologic exam revealed chorioretinitis with scarring, necrosis, and hemorrhage and the infant was assessed to have no useful vision in the future.
1
McLane’s Children’s Hospital, Scott & White Healthcare, Temple, TX, USA Corresponding Author: Mohammad Nasir Uddin, Department of Obstetrics and Gynecology, Scott & White Healthcare, C2401 South 31st Street, Room 352, Temple, TX 76508, USA. Email: [email protected]
Downloaded from cpj.sagepub.com at CALIFORNIA STATE UNIV FRESNO on July 26, 2015
2
Clinical Pediatrics
Pathogenesis It starts with inoculation of the virus in the oral, genital, conjunctival mucosa, or break in the skin. It infects the sensory nerve endings and then transports via retrograde axonal flow to the dorsal root ganglia where it remains latent. During periods of stress, the virus travels down the axon to the sensory nerve endings where it replicates. The fetus may be infected transplacentally through the chorionic villi or through retrograde spread through rupture of membrane or even seemingly intact membranes.1
Figure 1. Magnetic resonance imaging of the brain showing compensatory marked dilatation of the lateral and third ventricles.
The infant was maintained on low ventilator settings with low resting respiratory rate, periodic breathing, and apneic episodes. He continued to have occasional focal, clonic seizures on the right and rhythmic jerking movements of all 4 extremities despite being placed on phenobarbital, levetiracetam, and midazolam for intractable seizures. Several multidisciplinary care conferences were held involving the parents, extended family members, the primary neonatal intensive care unit team, neurology, infectious disease, and hospice. Taking into consideration all of the findings and results, it was concluded that “No quality of life is expected from this abnormality.” Care was withdrawn on the seventh day of life.
Final Diagnosis Disseminated congenital herpes simplex infection.
Discussion Herpes Simplex Virus Infection Herpes simplex viruses (HSV)-1 and -2 are large, enveloped virions that belong to alphaherpesviridae with an icosahedral nucleocapsid arranged around a linear double-stranded DNA core.3 The glycoprotein IgG provides antigenic specificity and allows the differentiation between HSV-1 and -2.1 The current estimated rate of occurrence of HSV infection in the neonate is approximately 1 in 1500 cases diagnosed annually.2 It is noted that the baseline prevalence of HSV-2 genital infection has increased since 2000. Hence, the severity of cases involving the central nervous system (CNS) and the disseminated type have also increased.1
Periods of Acquisition Intrauterine HSV-2 infection is approximately 5% of all babies with neonatal HSV infection. This is caused by maternal viremia following a primary HSV infection during pregnancy. Survivors of in utero HSV infection may exhibit a triad of cutaneous findings such as scarring, ulceration, and/or manifest as active lesions; eye damage like microophthalmia, retinal dysplasia, optic atrophy, and chorioretinitis; and CNS involvement such as microcephaly, encephalomalacia, hydranencephaly and intracranial calcification.2-4 The factors that influence the transmission of HSV infection in the intrapartum period, which is 85% of all the cases of neonatal infection, includes type of maternal infection, it is subdivided into first episode or primary infection (57% of cases) where antibodies to both HSV-1 and HSV-2 are absent at the time the patient acquires genital HSV due to HSV-1 or HSV-2, type specific antibodies to HSV generally develop within the first 12 weeks after an infection and persists indefinitely; firstepisode nonprimary genital HSV infection occurs in about 25% of cases. This is acquisition of genital HSV-2 with preexisting antibodies to HSV-1, and although rare, is acquisition of HSV-2 with preexisting antibodies to HSV-2. Recurrent genital HSV infection occurs in 2% of cases and is the reactivation of genital HSV in which the HSV type recovered from the lesion is the same type as the antibodies in the serum. The other factors are maternal HSV antibody status, duration of rupture of membrane, integrity of cutaneous barrier (use of scalp electrode), mode of delivery for mothers with vesicular rash in the perineum, and the type of HSV infection. The transmission rate to the neonate at delivery with recurrent infection is lower than the primary or first-episode genital infection.2,4 Postpartum comprises 10% of all cases of HSV infection and is acquired from caretaker of infants who develop an outbreak.2,4 Intrauterine HSV infection is rare and has been reported anecdotally. The timing of acquisition is during
Downloaded from cpj.sagepub.com at CALIFORNIA STATE UNIV FRESNO on July 26, 2015
3
Co et al the first 20 weeks of gestation of a primary infection, which can result in spontaneous abortion, stillbirth, and congenital malformation, particularly hydranencephaly and chorioretinitis. It is also suggested that there should be evidence of infection in the first 48 hours of life, there should be virologic confirmation, other illnesses are excluded, embryogenesis is affected and there is evidence of viral placentitis. In in utero disease, approximately 1 in 300 000 infants is infected via maternal viremia, either from transplacental or ascending infection.1 Marquez et al5 reviewed 24 published cases between 1963 and January 2009, showing the clinical spectrum of intrauterine HSV infection.
Conclusion An HSV infection during the early trimester of pregnancy can pose serious problems to the offspring. The health profession should have a high index of suspicion in monitoring and treating infection aggressively. An educational campaign, especially toward teenagers, should be undertaken since the incidence in this age group is increasing. Author Contributions MAMC wrote the manuscript. MK, JS, MRB and MNU provided guidance and edited the manuscript.
Declaration of Conflicting Interests
Diagnosis Viral culture is the definitive diagnostic test. However, it takes several days for the results to be available. PCR amplification is more sensitive than a viral culture. It has a sensitivity of 75% to 100% and specificity of 71% to 100%. It is the preferred method to document CNS involvement and serves as adjunct to the HSV surface culture. Generally, the serologic test has no role in the diagnosis of neonatal HSV disease. It can identify past infection but it cannot identify the site of HSV infection.2,3
Treatment The treatment is acyclovir 60 mg/kg/d divided into 3 doses (20 mg/kg/dse) intravenously. The duration of treatment is 21 days for disseminated or CNS infection and 14 days for skin, eyes, mucous membrane disease. A repeat lumbar puncture should be done at the end of the treatment for CNS HSV infection, and treatment is to be continued until the CSF PCR is negative.6 With the utilization of acyclovir 60 mg/kg/d for 21 days, the mortality rate was reduced from 85% to 29% for the disseminated type and 50% to 4% for the CNS disease.4,6
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Kimberlin DW. Neonatal herpes simplex infection. Clin Microbiol Rev. 2004;17:1-13. 2. Kimberlin DW, Lin CY, Jacobs RF, et al. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics. 2001;108:230-238. 3. Kimberlin DW, Baley J. Guidance on management of asymptomatic neonates born to women with active genital herpes lesions. Pediatrics. 2013;131:383-386. 4. Kimberlin DW. Herpes simplex virus infections of the newborn. Semin Perinatol. 2007;31:19-25. 5. Marquez L, Levy ML, Munoz FM, Palazza DL. A report of three cases and review of intrauterine herpes simplex virus infection. Pediatr Infect Dis J. 2011;30:153-157. 6. Pinninti SG, Kimberlin DW. Neonatal herpes simplex virus infections. Pediatr Clin North Am. 2013;60:351-365.
Downloaded from cpj.sagepub.com at CALIFORNIA STATE UNIV FRESNO on July 26, 2015
