To improve comparability of vaccine safety data, the Hypotonic-Hyporesponsive Episode (HHE) Working Group has developed a case definition and guidelines for HHE applicable in study settings with different availability of resources, in health care settings that differ by availability of and access to health care, and in different geographic regions.
The definition and guidelines were developed through group consensus and are grounded on both expert opinion and a systematic literature review related to the assessment of HHE as an adverse event following immunization and to the diagnosis of HHE in humans. The only published structured work put into the development of a case definition for HHE resulted from a US public health service workshop on HHE after pertussis immunization [1]. This definition has served as the basis for consensus formation within the working group.
1.1. Background on HHE
HHE is characterized by sudden onset of reduced muscle tone, hyporesponsiveness and change of skin color (paleness or cyanosis). It has been referred to by various terms including “shock”, “shock like syndrome”, “collapse” and “collapse reaction”. The diversity of terms and case descriptions used rendered interpretation and comparison of data on the occurrence, pathophysiology, and consequences of HHE difficult.
HHE has been documented to occur after administration of diphtheria, tetanus, Haemophilus influenzae type B, and hepatitis B vaccines, but most reports of HHE follow pertussis component vaccines [1], [2]. HHE has been observed more frequently following whole-cell pertussis vaccines than following acellular pertussis vaccines [3], [4], [5], [6], [7]. The reported rates (per 100,000 doses) following whole-cell and acellular pertussis vaccines may vary from 36 to 250 episodes and 4 to 140 episodes, respectively [3], [4], [5], [6], [7], [8], [9]. The wide variation in incidence of HHE following immunization probably reflects the various case definitions and case ascertainments rather than the inherent properties of different vaccines. For example, the reported incidence of HHE after DTPw vaccines varies greatly [3]. HHE has been observed more commonly after the primary immunization series and particularly after the first dose [2], [6], [10], [11]. Whether this is an effect of the age of the vaccinee or a true immunologic phenomenon (or a combination of both) remains to be elucidated [12].
A slight predominance (53%) of HHE among females was demonstrated in reports to the Vaccine Adverse Event Reporting System (VAERS) in the United States [13]. In contrast, a slight prominence among male was observed in the enhanced surveillance program in The Netherlands [14].
The median time to onset of symptoms after immunization is 3–4 h but ranges from immediately to 48 h postimmunization [2], [10], [15], [16]. Of 203 cases presenting within 5 min following immunization, only 8.5% were <24 months of age, whereas 66.7% of those older than 24 months had such an early onset [16]. Fever is associated with HHE in up to one third of cases [10], [16]. The median duration of symptoms is 6–30 min, but parents may report the time to full recovery as being up to 10 days [10], [17].
Apart from the clinical triad of symptoms, there are no further investigations (e.g. laboratory examinations) helpful in confirming the diagnosis of HHE. Data from a small case series indicate that blood pressure is normal at the time of presentation [15]. Leukocytosis due to neutrophilia is observed in children with or without HHE following immunization [18], [19]. There is no evidence of significant changes in insulin or glucose levels [13], [15].
Studies reporting on the follow-up of HHE relying on parental reporting and neurodevelopmental testing demonstrated HHE to be a self-limiting event without long-term sequelae [11], [15], [16], [21].
The pathogenesis of HHE is unknown and has been poorly studied given the constraints of investigating a condition that is rare and results in transient symptoms. The pathogenesis of HHE is likely to be multifactorial and may result from factors both idiosyncratic to the child and inherent in the vaccine.
