Disseminated Herpes Simplex Virus-1 in Previously Healthy Child Without Skin Rash: Case report and literature review

TL;DR

A previously healthy 1-year-old child in Saudi Arabia developed severe HSV infection without skin rash and recovered fully after treatment.

Contribution

Reports a rare case of disseminated HSV in an immunocompetent child without skin rash.

Findings

The child presented with febrile illness and altered consciousness, not typical skin rash.

HSV was diagnosed via CSF PCR and positive IgM serology, leading to encephalitis/hepatitis.

The child showed excellent developmental recovery after acyclovir treatment and 1-year follow-up.

Abstract

Disseminated herpes simplex virus (HSV) is a known fatal condition in neonates and immunocompromised patients. However, very few cases have been reported in an immunocompetent host. We report a 1-year-old female child who presented to a children's hospital in Riyadh, Saudi Arabia, in 2022. She was previously healthy and presented with febrile illness associated with decrease conscious level. Upon examination, the patient had markedly elevated liver enzymes. A cerebrospinal fluid (CSF) polymerase chain reaction (PCR) finding of HSV as well as positive HSV IgM serology resulted in a diagnosis of disseminated HSV (encephalitis/hepatitis). She received acyclovir course and during follow-up for 1 year showed excellent developmental outcome.

Tables

Table 1.. Laboratory results for a 1-year-old female child.

Test	At presentation	After 3 weeks	Normal range
ALT in IU/L	1,413	40	4–36
AST in IU/L	2,404	47	15–60
PT in seconds	19	12.8	11–15
INR in seconds	1.5	0.95	0.9–1.1
Paracetamol level at presentation in mcg/mL	4.4		Toxic level >25
HAV, HBV and HCV	Negative		Negative
HSV PCR in CSF	Positive		Negative
HSV IgM in serum	Positive		Negative

Full text

1. Introduction

Herpes simplex virus (HSV) virus is a type of DNA virus that is enveloped and belongs to the Herpesviridae family. HSV can have lifelong effects, although it typically does not result in severe illnesses for individuals with strong immune systems. A recent study conducted in Saudi Arabia revealed that there is a high seroprevalence of HSV among children in the country; 60% of children between the ages of 6–13 years tested positive for the infection.^1^ This percentage is significantly higher than the reported seroprevalence of HSV in the USA (31% for children of the same age range).^2^ Previously reported cases of children with disseminated HSV were mainly in neonates or immunocompromised children and very rarely reported in healthy children. It is important to consider immunodeficiency as there are reported severe HSV infection in cases with interferon pathway defect and other immunodeficiencies.^3^

This report describes the case of a healthy immunocompetent child, who presented with disseminated visceral HSV without skin involvement.

2. Case report

We report a 1-year-old female child who was transferred to a children's hospital in Riyadh, Saudi Arabia, in 2022 due to acute liver injury and suspected viral encephalitis. Prior to her transfer, the child had been in good health with no prior surgical or medical history. She was admitted to the referral hospital after experiencing high-grade fever, poor oral intake and reduced activity for 4 days.

The patient was admitted with a high-grade fever of 39°C and appeared lethargic with decreased activity levels. Skin and mucous membranes showed signs of dehydration but no rash was observed. Neurological examination showed weakness in all extremities, while abdominal examination revealed hepatomegaly 3 cm below the costal margin and diffuse abdominal tenderness with no guarding or rebound tenderness. Cardiovascular and chest examinations were normal. Initial liver function tests revealed markedly elevated liver enzymes (alanine transaminase [ALT] = 1,413 IU/L, aspartate transaminase [AST] = 2,404 IU/L) and a mild derangement (prothrombin time [PT] = 19 seconds [normal range: 11–15 seconds], international normalised ratio [INR] = 1.5 seconds [normal range: 0.9–1.1 seconds]) of the coagulation profile [Table 1]. Complete blood count and renal function were normal. Due to a rapidly declining level of consciousness, the patient was transferred to the paediatric intensive care unit and commenced empirical therapy with cefotaxime, vancomycin and acyclovir.

The tests for viral serology for hepatitis viruses A, B and C were negative, but the cerebrospinal fluid (CSF) polymerase chain reaction (PCR) for HSV-1 and serum HSV IgM antibodies were both positive. Interestingly, despite having received high doses of acetaminophen before presentation, the serum level of the drug at the time of presentation was rather low (4.4 μg/mL). Nonetheless, the patient's condition progressively improved following the commencement of medications, with gradual normalisation of the liver enzymes and clotting profile. By the 20^th^ day of acyclovir therapy, the patient's ALT had reduced to 40 IU/L, AST was 47 IU/L, PT was 12.8 seconds and the INR was 0.95 seconds. By the 21^st^ day of acyclovir therapy, the child had become fully conscious and had resumed premorbid activities. Magnetic resonance imaging (MRI) of the brain and electroencephalogram (EEG) had been performed late in the course of illness. MRI showed pachymeningeal enhancement, however it did not show characteristic HSV features. EEG was abnormal due to generalised background slowing for age which represents mild encephalopathy.

The patient was subsequently discharged and an out-patient follow-up at the clinic was scheduled. After a year of follow-up, the patient was doing fine and her developmental milestones were appropriate for her age. It is worth mentioning that immune investigations were not done as immunodeficiency was not suspected.

3. Discussion

It is worth noting that HSV is not commonly associated with acute liver failure in children. Only 2% of viral-related acute liver failure cases in the general population are caused by HSV; these cases often have a poor outcome.^4^ A study conducted in Saudi Arabia that reviewed the viral causes of hepatitis in children did not find any cases of HSV-related hepatitis, with hepatitis A virus being the most common aetiology.^5^ Moreover, research has shown that over 70% of adults with HSV-related liver failure were immune-compromised and less than half of the affected cases had skin manifestations.^6^ Interestingly, the current index case did not exhibit any cutaneous manifestation.

Most of the previously reported cases of disseminated HSV infection were among neonates and immunocompromised children.^7^ Disseminated HSV is likely second to viremia as demonstrated in viral blood culture in one study.^8^ It has significant mortality.^910^ Data is sparse on the occurrence of disseminated or visceral HSV among previously healthy children beyond the neonatal period. An old study reported severe non-neonatal HSV infection in 93 children; the majority had measles or malnutrion.^11^

Other reported cases have varying manifestations but generally had good outcomes. Very few cases have been documented in the literature where healthy children suffer from acute liver failure and encephalitis. For instance, a 5-year-old was reported to have acute liver failure and encephalitis in addition to renal failure and disseminated intravascular coagulopathy, which was not present in the current case.^12^ Similarly, a 9-year-old had hepatitis, herpetic rashes and fever, but had relatively lower liver enzymes (ALT and AST were approximately 300 IU) and no clotting issues.^13^ Another 9-year-old had herpetic stomatitis and liver transaminases as high as the current index case, with ALT peaking at 2,400 IU and AST at 4,000 IU.^14^

It has been observed in the literature that children diagnosed with HSV hepatitis have shown positive outcomes upon initiation of acyclovir treatment, unlike adults who suffer from HSV-associated acute liver failure. A previous review indicated that many adults with HSV acute liver failure succumbed to the disease or underwent liver transplantation. Additionally, the review inferred that a significant proportion of 74% of cases of HSV-related liver failure were identified through autopsy.^6^

The current patient also had HSV encephalitis, which is a more common form of disseminated/visceral HSV in affected children and this generally responds favourably to intravenous acyclovir but long term sequalae have been frequently reported.^15^ The diagnosis of HSV encephalitis may be relatively more straightforward, due to the characteristic features of viral encephalitis on CSF analysis and the widespread availability of PCR.

Although, viral causes of acute liver failure, including HSV, should be proactively investigated in children with fever and features of hepatic dysfunction, another important consideration in such children is acetaminophen toxicity. The current index case had received high doses of acetaminophen before presentation, however, the serum level of the drug at the time of presentation was rather low (4.4 μg/mL) and, the identification of CSF fluid PCR for HSV-1 and serum HSV IgM antibodies in the current patient makes HSV infection the more plausible diagnosis.

Disseminated HSV is a treatable condition, following the prompt commencement of acyclovir. Hence, it is suggested that routine workup for HSV should be done in children with acute liver failure of unknown etiology and acyclovir therapy should be initiated early. This has the potential to reduce the need for liver transplantation and preserve liver function in affected children.

4. Conclusion

This case report highlights the occurrence of disseminated HSV infection in a previously healthy immunocompetent child without cutaneous involvement. This case is significant because HSV is not commonly associated with acute liver failure in children, and most reported cases of disseminated HSV infection are in neonates or immunocompromised individuals. The prompt initiation of acyclovir therapy led to the gradual normalisation of liver enzymes and clotting profile, as well as the improvement the overall patient's condition. This emphasises the importance of considering HSV as a potential aetiology in children presenting with acute liver failure of unknown origin. Further research and awareness are needed to enhance the routine evaluation and early recognition of HSV in such cases, which has the potential to prevent the need for liver transplantation and preserve liver function in affected children.

Ethics Statement

Informed consent was obtained from the parents of the patient for publication purposes while ensuring the strict confidentiality of the patient's identity. Institutional ethical approval was obtained (FWA00018774).

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Authors' Contribution

IAA, AA, ASA and FA were responsible for writing the manuscript. AA and MA revised the manuscript. All authors approved the final version of the manuscript.