Neonatal herpes simplex presenting as a zosteriform eruption

  1. Elizabeth Anderson 1,
  2. Emma Johns 2,
  3. Joseph Conlon 3 , 4 and
  4. Ezzeldin Saleh 5
  1. 1 Internal Medicine, Southern Illinois University School of Medicine, Springfield, Illinois, USA
  2. 2 Department of Pediatrics, Southern Illinois University School of Medicine, Springfield, Illinois, USA
  3. 3 Department of Pediatrics and Department of Dermatology, Southern Illinois University School of Medicine, Springfield, Illinois, USA
  4. 4 Department of Pediatrics, Springfield Clinic, Springfield, Illinois, USA
  5. 5 Pediatrics-Infectious Diseases, Southern Illinois University School of Medicine, Springfield, Illinois, USA
  1. Correspondence to Dr Ezzeldin Saleh; esaleh84@siumed.edu

Publication history

Accepted:11 Jan 2023
First published:19 Jan 2023
Online issue publication:19 Jan 2023

Case reports

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Abstract

Herpes simplex virus (HSV) infection in newborn infants is a potentially devastating disease leading to death and disability. Skin, eye and mouth (SEM) infections account for approximately half of the cases in the USA. The appearance of skin findings often guides clinicians towards early diagnosis of HSV infection, prompt interventions and life-saving management; however, less than half of neonates with proven disease present with characteristic vesicular lesions. Furthermore, if SEM infections are not treated promptly, there is significant risk of progression to central nervous system and disseminated disease. We present a case of HSV-2 infection in a neonate with an atypical zosteriform eruption on day 3 of life. This case demonstrates that neonatal HSV can unusually present in a zosteriform rash. By elucidating this unique presentation, we highlight atypical HSV skin presentation and emphasise on the importance of earlier diagnosis and antiviral treatment to prevent the associated morbidity and mortality.

Background

Worldwide, neonatal herpes simplex virus (HSV) cases are estimated to be around 10 per 100 000 live births, or about 14 000 cases annually.1 In the USA, incidence has been increasing with a recent estimate of approximately 1 in 2000 live births.2 The mode of transmission in neonates varies, as neonatal herpes can be acquired in utero (5%), perinatally (85%) and postnatally (10%).3 In clinical practice, neonatal HSV infection may be classified by manifestations in the skin, eyes and mouth (SEM), central nervous system (CNS) or disseminated infection. Initial presentation of almost all infected newborns occurs in the first 4 weeks of life, with some cases occurring up to 6 weeks of age. Disseminated disease and SEM present between the first and second week, while CNS disease usually presents later between the second and third week of life.2 Infants with disseminated infection may present with sepsis syndrome, severe liver dysfunction, consumptive coagulopathy, viral pneumonia with involvement of visceral organs and multiple organs including the brain, larynx, trachea, oesophagus, stomach, lower gastrointestinal tract, spleen, kidneys, adrenals, pancreas and heart.4 5 CNS disease may manifest as meningoencephalitis with cerebrospinal fluid (CSF) abnormalities, irritability, seizures or poor feeding.2 4 5 Skin can be affected in both disseminated and CNS disease.2 4 5

The appearance of skin findings often guides clinicians towards early diagnosis of HSV infection and leads to prompt intervention and life-saving management. The SEM form of infection accounts for approximately 45% of the cases in the USA. SEM presents as vesicular lesions in majority of cases (80%), keratoconjunctivitis when the eye is involved or ulcers when infection is confined to the mouth.6 7 Localised vesicular lesions classically appear clustered with an erythematous base and carry significant risk of progression to CNS or disseminated disease if not treated promptly. We present a case of HSV-2 infection in a neonate with an atypical cutaneous manifestation of a zosteriform eruption noted on day 3 of life. Further characterisation of the dermatological variation in neonatal herpes will decrease time to treatment and increase favourable outcomes. Given the variability in presentation and gravity of disease progression, a high index of suspicion should be used to diagnose and treat neonatal HSV infections.

Case presentation

A female infant was born at 28+4 weeks’ gestation by vaginal delivery to a multiparous (gravid 5 and parous 2) mother in her late 20s following preterm labour. The mother had premature rupture of membranes for 5 days prior to delivery and was treated with latency antibiotics and steroids. Her prenatal laboratory studies for syphilis, hepatitis B, HIV, gonorrhoea and chlamydia were all negative. However, she was rubella non-immune although reportedly has had received adequate vaccination. She has never been diagnosed with HSV infection or had active genital lesions, and no known history of fever, rashes or viral illnesses during this pregnancy.

The infant was born with APGAR scores of 8 and 9 at 1 and 5 min, respectively. She was appropriate-for-gestational age with birth weight of 1190 g, length of 36.5 cm and head circumference of 26.5 cm (all above 50th centile). She required continuous positive airway pressure in the delivery room. She was admitted to the neonatal intensive care unit for further evaluation and management of respiratory distress. Ampicillin and gentamicin were started as empirical antibiotics after sepsis evaluation was initiated, however, were discontinued after blood cultures were negative.

Three days after delivery, one white pustule with an erythematous base was noted on the infant’s left side (figure 1). The rash quickly evolved, spreading down the left flank onto the abdomen with periumbilical involvement. A skin and soft tissue infection was initially suspected. Bacterial cultures from the pustule and blood cultures were obtained, and ceftazidime, oxacillin, vancomycin and topical bacitracin were initiated. Four days later (7 days after delivery), the rash became vesicular. Physical examination revealed many 2–3 mm vesicles on erythematous bases in a band-like distribution on the patient’s left flank and abdomen (figures 2 and 3).

Figure 1

Day 3, one white pustule with an erythematous base on left posterior flank.

Figure 2

Day 7, many 2–3 mm vesicles on erythematous bases in a band-like distribution on the patient’s left flank and abdomen.

Figure 3

Rash appearance on day 7 of life.

Investigations

Initial white cell count (WCC) immediate to delivery was 9.2 x 109/L; however, after the pustular presentation of the rash, her WCC was 16 x 109/L. There was no evidence of liver dysfunction, kidney dysfunction or electrolytes abnormalities. CSF analysis revealed 0.006 x109/L WCC, 0.001x 1012/L red blood cell/mm3, protein 145 mg/dL and glucose 44 mg/dL. Blood and skin lesion bacterial cultures were negative. CSF gram stain and bacterial culture were negative. CSF meningitis–encephalitis panel PCR (including HSV and varicella zoster virus (VZV)) was negative. HSV PCR testing of vesicular lesion and a surface swab of the patient’s eyes, nose, throat and rectum were both positive for HSV-2. The blood HSV DNA PCR identified HSV-2 with viral load of 56 434 copies/mL. Ophthalmology eye examination was normal, and repeated head ultrasound studies were also normal. Paediatric infectious disease and paediatric dermatology were consulted.

Differential diagnosis

At initial presentation of the lone pustule, a bacterial skin infection was considered. This was higher on the differential due to maternal preterm premature rupture of membranes. Blood and lesion cultures were obtained at that time to rule out bacterial infection. Additionally, empirical intravenous antibiotics and topical bacitracin were initiated for broad bacterial coverage.

However, on day 7, when the rash appeared vesicular on physical examination, VZV and HSV infections were highest on the differential. Due to the zosteriform presentation of the lesion, VZV was the initial diagnostic hypothesis. At that time, surface swabs on eyes, mouth, nose, and rectum and skin lesions, in addition to blood and CSF specimens, were obtained for PCR testing for HSV in addition to PCR testing for VZV from skin lesion swab. Rare congenital blistering conditions such as epidermolysis bullosa, incontinentia pigmenti and congenital erosive and vesicular dermatosis were considered. However, these diseases were not consistent with the overall clinical picture and remained as less likely differentials pending further evaluation.

Treatment

The patient was started on empirical intravenous acyclovir 20 mg/kg per dose three times a day while awaiting laboratory results. There was no evidence of disseminated HSV; however, given the prematurity, severity of presentation and delayed diagnosis, intravenous acyclovir was given for 21 days and transitioned to long-term oral acyclovir suppression therapy given at 300 mg/m2 per dose three times a day.

Outcome and follow-up

The patient continued on long-term oral acyclovir suppression therapy which is planned to continue until 1 year of age. At the patient’s 9-month follow-up, she had one recurrence episode a month earlier that resolved within 3 days. She continues to have adequate growth and normal expected developmental milestones.

Discussion

We searched PubMed and Embase for cases of neonatal HSV presenting as zosteriform eruption. We limited our search to English language with no timeline restrictions. A few studies have highlighted HSV zosteriform presentation in older children.8–10 However, our review focused on cases presented in the neonatal period.

Typically, in neonatal HSV, skin involvement commonly presents as classic eruption of grouped vesicular lesions; however, approximately one-third of neonates with disseminated disease or CNS involvement will not have skin lesions at the time of presentation.2 Rarely, in neonates, HSV skin lesions can present as an atypical zosteriform eruption as illustrated by our case. Summaries of zosteriform neonatal HSV reported cases are presented in table 1. There were six case reports describing seven cases. All cases were girls except for one case where sex was not specified. Four (57%) of the infants were preterm and half of them presented with lesions at birth, indicating a likely intrauterine infection. In general, infants with intrauterine HSV infection present with lesions at birth and have a wide variation of atypical dermatological lesions including bullae, erosions, ulcerations, pustules, plaques, macules, areas of denudation, scars and hyperpigmentation and hypopigmentation.11 12 In our case, the patient presented on day 3 of life; however, because of prolonged rupture of membranes for 4 days, it is possible that HSV infection occurred at an earlier time before delivery via ascending infection from the cervix allowing for time for viral replication and spread. Furthermore, our patient prematurity is a risk factor for severe disease, and this in part may explain the severity and the atypical presentation.

Table 1

A summary of the reported cases of neonatal herpes simplex presenting as a zosteriform eruption

Author
(year)		 Maternal HSV history/serology Gestation (weeks) Age at presentation Appearance and distribution of cutaneous lesions HSV subtype Diagnostic test Clinical outcome
Music et al (1971)20 No known history
HSV IgG positive		 Term
Female		 Day 10 Small blisters beside umbilicus
On day 12, vesicles and vesicopustules on an erythematous base from the periumbilical region along the 10th thoracic dermatome toward the back. Grouped vesicles on left foot		 HSV-2 Immunostaining of skin lesion 3 recurrences in first 4 months
Rabalais et al (1991)21
(1)		 No known history 33
Female		 At birth Denuded areas on torso, right upper arm and left leg. An area of denuded skin extended in the T4 dermatome on the right side from the midline posteriorly to the midline anteriorly
On day 16 vesicles on hands and feet		 HSV-2 Viral culture skin lesion
HSV IgM		 Recurrence at 6 weeks. Severe neurodevelopmental delay and cutaneous scarring at 1-year follow-up
(2) Genital HSV-2 before delivery
HSV recurrence 1 week before delivery		 28
Female		 At birth Band of denuded skin in the left T9 dermatome, extending from the midline posteriorly to the midline anteriorly; two 5 mm, crusted, round lesions on left leg and left upper arm HSV-2 Viral culture skin lesion
HSV IgM		 3 recurrences while hospitalised
Severe neurological impairment
Goel
(1992)22		 Not reported 32
Female		 Day 4 Zosteriform vesicular rash on the lower abdomen Not reported Not reported Not reported
Cliff et al
(1997)23		 No known history
IgG positive for HSV-2		 32
Female		 At birth Area of ‘denuded skin’ on left side of the chest extending to back
Zosteriform flaccid vesicles at T3–T5		 HSV-2 Viral culture skin lesion No recurrence by 1 year
Del Boz et al
(2008)24		 Recurrent vaginal burning and redness 40
Not reported		 Day 11 Umbilicated vesicles and pustules with erythematous bases in metameric configuration on the right-hand side HSV-1 PCR skin lesion
HSV IgM		 Not reported
Drumm et al
(2018)25		 No known history
IgG positive for HSV-2		 37 4/7
Female		 At birth Erythematous erosions and scarred thin plaques with crust in T1–T3 distribution
On day 7 developed vesiculopustular lesions		 HSV-2 PCR and
immunostaining of skin lesion		 Follow-up at 29 days: re-epithelialisation of erosions, post-inflammatory hyperpigmentation
Present case No known history 28 4/7
Female		 Day 3 White pustule with erythematous base
On day 7 developed 2–3 mm vesicles on erythematous bases in a band-like distribution on the left flank and abdomen		 HSV-2 PCR skin lesion
Serum PCR		 Recurrence at 9 months

  • HSV, herpes simplex virus.

The atypical skin presentation obscures recognition of neonatal HSV and makes timely diagnosis more difficult with subsequent treatment delay. If not recognised and treated, SEM disease can progress to disseminated and CNS disease in 80% of cases.5 Therefore, high clinical suspicion is required and the threshold for evaluation for HSV should be low in neonates presenting with atypical skin lesions due to the broad array of dermatological presentations in neonatal HSV and the severity of disease if allowed to progress. Most infants (up to 80%) are born to women who are asymptomatic for genital HSV infection during pregnancy and at the time of delivery, with maternal subclinical genital HSV infection evident only if HSV PCR from vaginal secretions is obtained.13 14 Therefore, absence of maternal history of HSV infection or lack of genital herpetic lesions at delivery does not preclude the diagnosis of neonatal HSV.2 This is consistent with our review of four out of seven mothers who reported no history of HSV infection. Routine serological screening for HSV infection in asymptomatic individuals including pregnant persons is not recommended due to the high false positive test results and the associated potential psychosocial harm.15 16 Molecular diagnosis by PCR has revolutionised testing and facilitated rapid diagnosis of HSV infection. When neonatal HSV is suspected, specimens from skin lesions, surface swab (eyes, mouth, nose, axilla and rectum), blood and CSF should be sent for HSV DNA PCR testing.

In our case, due to concern for a bacterial infection at initial presentation, HSV was not suspected, and the infant was not treated with acyclovir until 3 days later when the bacterial workup was negative and the patient’s skin eruption evolved to zosteriform pattern. At this time, our patient has no known neurological sequelae; however, prompt antiviral treatment is critical to prevent morbidity and mortality. Prior to antiviral therapy use for treatment of neonatal HSV disease, mortality from disseminated HSV disease and CNS disease was 85% and 50%, respectively.17 Treatment should be started as soon as neonatal HSV diagnosis is suspected. The current recommended treatment for neonatal HSV is acyclovir given intravenously at 60 mg per kg per day in three divided doses (20 mg/kg/dose).2 18 The duration of therapy is 14 days for SEM disease and 21 days for CNS or disseminated disease. In infants with CNS involvement, CSF HSV PCR should be obtained near the end of 21 days’ therapy and acyclovir should be continued until CSF PCR is undetectable. Topical antiviral therapy may be added in HSV eye disease with an ophthalmologist involved in the management. After completing parenteral therapy for acute neonatal HSV disease (regardless of the clinical classification), patients should be transitioned to suppressive doses of oral acyclovir administered at 300 mg per m2 surface area per dose, three times a day for 6 months.2 14 Studies have shown that if patients experience three or more recurrences in the first 6 months of life, they are at significantly higher risk of developing neurological dysfunction.19

This case report demonstrates that neonatal HSV can present in a zosteriform rash, although uncommon. Zosteriform lesions in the neonate should increase clinical suspicion for HSV infection and decrease the threshold for HSV evaluation. By further elucidating this presentation, we hope that earlier diagnosis and optimal antiviral treatment will be achieved to prevent the morbidity and mortality of neonatal HSV. Early use of intravenous acyclovir when neonatal HSV diagnosis is suspected is crucial to prevent the progression of localised cutaneous disease and therefore, decrease the morbidity and mortality associated with HSV disease.

Learning points

  • Neonatal herpes simplex virus (HSV) infection can uncommonly present with zosteriform eruptions.

  • High index of suspicion is important for early diagnosis and initiation of acyclovir to avoid complications.

  • PCR testing is a crucial test that facilitates rapid diagnosis of HSV infection.

Ethics statements

Patient consent for publication

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Acknowledgments

The authors would like to acknowledge the contribution of the neonatology team at Southern Illinois University School of Medicine and the staff of the Neonatal Intensive Care Unit, St John’s Children’s Hospital, Springfield, Illinois, USA for management of this patient.

Footnotes

  • Presented at The case was presented at the Southern Illinois University School of Medicine 32nd annual trainee’s research symposium.

  • Contributors EA and EJ drafted the initial manuscript and table, collected pertinent data, and reviewed and revised the manuscript. ES provided figures. EA, EJ and ES performed the relevant literature search and review. ES and JC reviewed and revised the manuscript. ES and JC contributed to case management. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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