Varicella zoster in sudden infant death

Abstract

A 2-month-old girl with normal development and no previous physical illnesses was resuscitated having been found lifeless on her back at home. On admission to Paediatric Intensive Care, she had severe metabolic disturbance, associated with an extremely troubling neurological signs. She died 2 hours later. A full body CT scan did not reveal injury and her parents declined an autopsy. Peripheral blood and cerebrospinal fluid samples were sterile. However, a broad-range PCR coupled with electrospray-ionisation mass spectrometry onto the PLEX-ID automat of peripheral blood revealed the presence of varicella zoster virus. There was a specific viral load in whole blood of 20 542 copies/ml. It is presumed that Varicella myocarditis was the likely cause of death. Our case illustrates the potential usefulness of a broad range PCR strategy in determining infectious causes of death in sudden infant death. Varicella is a potential cause of sudden infant death.

Background

The ‘triple risk’ hypothesis for sudden infant death syndrome (SIDS) has implicated pathological vulnerability, the level of development of the child and an unsafe sleeping environment.^{1 2} The most frequent pathologies associated with SIDS are intentional and non-intentional physical injury, metabolic and cardiac abnormalities and bacterial and viral infection with or without an association with background risk factors. This wide-ranging list of diagnoses makes a positive identification of the exact cause of death difficult. The interaction between several different causes and/or environmental factors can further complicate diagnosis.

Chicken pox is a frequent childhood infection caused by the alphaherpesvirus varicella zoster virus (VZV). Neonates who have not been protected by maternal antibody transfer are at risk of severe complications including fulminant pulmonary and hepatic manifestations.³ In childhood, contact between infected individuals and children is not discouraged as severe complications, which may include cardiac manifestations, are rare.^4–7

We present a case of a fatality in a 2-month-old child with ventricular fibrillation who was infected with VZV.

Case presentation

A 2-month-old infant girl drank a bottle of milk in the evening and was put to bed on her back with a low grade fever (38°C). Later that evening, her parents found her lifeless lying on her back and called the paramedic service while starting cardiopulmonary resuscitation (CPR).

A paramedical ambulance arrived, a rhythm ECG tracing showed asystole and CPR was continued with bag-and-mask ventilation. A second ambulance with a Consultant was dispatched from the paediatric intensive care unit (PICU) which arrived 25 min later. The rhythm on arrival of the PICU team was asystole with very occasional broad complex ventricular extrasystoles. Tracheal intubation was performed, an intraosseous needle was inserted into a tibia and 100 µg of epinephrine followed by 100 µg and 1 mg was injected. CPR continued and transport was started to the nearest PICU. A brief medical history revealed a normal term-delivery, followed by normal growth and development with no previous illnesses. The infant has not yet received her first vaccinations. There were no external signs of injury or skin lesions. Subsequent questioning of the parents revealed that the child had been in contact with several other children with active chicken pox during the preceding days/weeks.

During transport, the ventricular asystoles became increasingly frequent before transformation to ventricular fibrillation. A 40J biphasic shock was applied in the ambulance prior to arrival in PICU. No change in rhythm was noted.

In PICU, a second 40J biphasic shock was applied with no change in rhythm noted (see figure 1). Conversion to sinus rhythm to broad complex bradycardia occurred spontaneously during the preparation of an amiodarone infusion. The time from discovery of the child and return to spontaneous circulation (ROSC) was 2 hours 20 min with an unknown period of no-flow preceding.

Figure 1.

ECG strip of ventricular fibrillation on arrival in paediatric intensive care.

Further clinical examination in PICU did not reveal signs of injury, purpura or other skin lesions. The child was unconscious without sedation with fixed, dilated and unreactive pupils. No other abnormal physical signs were detected.

An adrenaline infusion was started at 5µ/kg/min accompanied by infusions of calcium gluconate, magnesium sulfate and a fluid bolus of 20 mL/kg of 0.9% saline administered.

Investigations

On admission to PICU, an arterial blood gas sample showed a pH of 6.52 with a PCO₂ of 67, base excess of −34, bicarbonates<5 mmol/L, dextrose 22 mmol/L and lactates 27 mmol/L. Further blood biochemistry and haematology revealed a sodium of 135 mmol/L, potassium 10.5 mmol/L, protein 50 g/L, calcium 2.96 mmol/L, C reactive protein <10 mg/L, procalcitonin 0.1 µg/L, ASAT 1229 UI/L and haemoglobin of 9.3 g/L and white cells 31 900/mm³.

A 12-lead ECG and cardiac ultrasound and ECG were performed; the former showed a normal QT interval and the latter revealed a structurally normal heart with very poor contractility and a pericardial effusion. Cranial Doppler ultrasound showed severe cranial hypertension with a systolic velocity of 9 cm/s.

Peripheral blood samples were taken for bacterial analysis. A postmortem lumbar puncture did not reveal signs of meningeal inflammation. Both haemoculture and culture of cerebrospinal fluids were sterile. A postmortem cardiac puncture was performed and 5 mL of pericardial fluid and 5 mL of blood withdrawn for virological analysis. A whole body CT scan did not reveal evidence of injury.

We investigated potential bacterial and viral infections by using a broad-range PCR coupled with electrospray-ionisation mass spectrometry (PCR-ESI-MS) onto the PLEX-ID automat (Abbott Molecular, Des Plaines, Illinois, USA). This system facilitates microbial identification using a standardised broad-range PCR to amplify target regions and high-resolution MS to determine the base composition of the amplicons across multiple loci.⁸ Dedicated nucleic acid extractions from blood were made using a magnetic-bead-based method with the PLEX-ID SP instrument (extractor) and PLEX-ID FH instrument (fluid handler). Amplification was performed with the PLEX-ID Viral IC Spectrum and BAC Spectrum SF and Fungal Spectrum assays (Abbott Molecular).

The results of the broad fungal spectrum and BAC Spectrum SF assays were negative and the PLEX-ID Viral IC Spectrum assay identified VZV in the child’s blood. VZV detection was further confirmed using a specific real time PCR assay with a load in whole blood of 20 542 copies/mL (RealStar VZV PCR Kit—Altona Diagnostics).

The infant’s serum tested negative for the presence of VZV-specific IgG antibody.

Differential diagnosis

Our case showed no evidence of structural anomaly from the cardiac ultrasound, long QT syndrome was excluded by the ECG performed in PICU, there was no physical injury demonstrated by the whole body scan and there was no connection with a hazardous sleeping environment. Medium chain acetyl-CoA enzyme dehydrogenase deficiency can be ruled out by the negative Guthrie test. Cerebrospinal fluid culture, bacterial and other virological studies, with the exception of VZV, were also all negative.

The general risk factors for Sudden Infant Death Syndrome, such as teenage motherhood, low birth weight, maternal smoking and parental alcohol consumption were all absent.

Treatment

In the light of the prolonged period of no-flow and low-flow, detrimental biological investigations and troubling neurological examination, a decision was made, with the approval of the parents, not to resuscitate if an episode of fibrillation and/or low flow occurred.

Outcome and follow-up

The infant died following a further episode of bradycardia/asystole 2 hours after admission. The very poor neurological prognosis ruled out connection to a source of extracorporeal membranous oxygenation.

An autopsy request was refused by the parents, as is acceptable under French law. Two PICU Consultants saw the parents when the full results were available.

Discussion

The diagnosis of fulminant VZV carditis is the likely, but not certain, cause of death. The diagnosis is suggested by the presence a very strong virological signal of VZV, ventricular fibrillation plausibly linked to VZV myocardial involvement and the absence of passive immunity derived from the mother. Nevertheless, there are two caveats to this hypothesis.

The first caveat is that the ventricular fibrillation could have been caused by the reoxygenation of an ischaemic myocardium and is unrelated to varicella myocarditis. The absence of a postmortem examination means that we were unfortunately unable to conduct immunohistochemical analyses of the myocardium to rule out this hypothesis. However, cardiac complications of VZV are known to include myocarditis, which have been associated with arrhythmias, pericarditis and pericardial effusion and circulatory failure.^4–6 Ventricular fibrillation has previously been described in children with VZV. One case has noted that VZV may have a specificity for the cardiac conduction system.⁷

The second caveat is the absence of pustules. Nonetheless, a case of pneumonitis and brainstem encephalitis VZV in an immunocompetent adult without cutaneous manifestations shows that deep tissue involvement is possible in VZV without skin rash.⁹

The Herpes viruses, Epstein Barr virus, Cytomegalovirus and herpesvirus-6, have previously been associated with sudden infant death but not VZV.¹⁰ The infant’s mother had been infected by VZV during her childhood, so the infection occurred in the period between decreasing maternally transferred passive immunity and increasing host resistance. The predictors of neonatal antibody titre are gestational age at birth and maternal antibody titre.¹¹ Protective passive immunity from the mother was absent in the infant’s blood.

The PlexID system (also known as IRIDICA) has been proven to be able to rapidly detect a large panel of pathogens.^{8 12} Despite its recent market withdrawal,¹³ our case highlights the usefulness of PCR broad detection of infectious agents, which has previously been established in ICU.¹⁴

An epidemiological study in Japan has estimated the frequency of VT/pVF in out-of-hospital cardiac arrest at the time of arrival of a paramedic team in a large cohort of infants to be 3.4%.¹⁵ The frequency of survival following cardiac arrest is 6.1% at 1 month for cases with a cardiac origin and 8.9% with a non-cardiac origin.¹⁵ The detrimental features of our case that mitigate against survival in our case are prolonged asystole,¹⁶ the absence of ROSC before arrival at hospital and arrest rhythm being asystole.¹⁷

There is no recommendation regarding the age at which it is safe to allow exposure of infants to chicken pox. Our case highlights the potential risk for infants where maternal antibody is no longer protective. We also highlight the usefulness of the Plex-ID test to screen for virological infections in causes of sudden infant death when autopsy results are unavailable.

Learning points.

• Broad-range PCR coupled with electrospray-ionisation mass spectrometry is a valuable tool in sudden infant death in screening for pathogens when autopsy is not undertaken.

• Varicella infection should be added to the list of possible causes of sudden infant deaths.