Report of a US Public Health Service Workshop on Hypotonic–Hyporesponsive Episode (HHE) After Pertussis Immunization
Authors: Braun M. Miles , Terracciano Gina , Salive Marcel E. , Blumberg Dean A. , Vermeer-de Bondt Patricia E. , Heijbel Harald , Evans Geoffrey , Patriarca Peter A. , Ellenberg Susan S. 
Published: August 2004

Hypotonic–hyporesponsive episode (HHE) is a term used to describe a somewhat heterogenous group of clinical disorders that have been reported primarily in association with whole-cell pertussis vaccination. A 1991 review by the Institute of Medicine determined that the evidence available was indeed consistent with a causal relation between whole-cell pertussis-diphtheria-tetanus immunization and HHE, but that the evidence was insufficient to indicate a causal relationship between HHE and the subsequent development of permanent neurologic damage. More recent data from clinical trials conducted in Europe suggest that HHE also occurs after vaccination with acellular pertussis vaccines.The US Food and Drug Administration, in collaboration with the US Public Health Service, sponsored a workshop on HHE in Rockville, Maryland, on June 19, 1997. The primary goals of the workshop were to develop a case definition of HHE and to evaluate the general design and feasibility of possible studies of HHE using the federal Vaccine Adverse Event Reporting System (VAERS), a national passive surveillance system. The goals of such studies would be to understand better the acute HHE event and to evaluate the possibility of long-term sequelae.Case Definition. There has been no generally accepted definition of HHE, and a standard definition would be useful for vaccine safety work and would potentially facilitate interstudy comparisons of the growing number of licensed vaccines containing acellular pertussis components.The workshop defined HHE as an event of sudden onset occurring within 48 hours of immunization, with duration of the episode ranging from 1 minute to 48 hours, in children younger than 10 years of age. All of the following must be present: 1) limpness or hypotonia, 2) reduced responsiveness or hyporesponsiveness, and 3) pallor or cyanosis or failure to observe or to recall skin coloration. HHE is not considered to have occurred if there is a known cause for these signs (eg, postictal), if urticaria is present during the event, if normal skin coloration is observed throughout the episode, or if the child is simply sleeping.This inclusive (sensitive) case definition will allow investigators, through the technique of stratification according to certain characteristics (eg, time from vaccination to onset of HHE), to attempt to hone the definition and make it more specific. Refinement of the definition of HHE has been hindered by the lack of information on its pathophysiology and by the lack of pathognomonic signs, symptoms, and diagnostic tests. Another hindrance is that by the time the child presents for medical evaluation, the signs of HHE often have normalized. Moreover, different mechanisms may be involved in different individuals whose events meet this workshop's HHE definition.Further Study of HHE. Probably the most important question about HHE is whether it has any permanent sequelae. The workshop assessed the possible contribution VAERS-based studies could make to answering this question and found substantial methodologic problems; however, ongoing studies in Sweden and The Netherlands have the potential to provide useful information on this question. The most useful contribution of VAERS data would be in a descriptive study of HHE, with a possible case–control study of factors that may affect the risk of HHE after vaccination, rather than a study of possible permanent sequelae.The workshop participants felt that a detailed descriptive study of ∼100 HHE events reported during a 1- to 2-year period could provide a more in-depth description of HHE cases in greater numbers than has been published previously, but the study would not address the issue of long-term sequelae of HHE. Better descriptive data may lead to new hypotheses concerning risk factors, etiology, and pathophysiology of HHE that might be evaluated further by studying subsequent cases and controls from VAERS or from other sources, depending on the hypotheses being tested.Workshop participants agreed that the question of possible long-term sequelae of HHE may currently be best answered in studies being conducted outside of the United States. A cohort of 82 892 infants was enrolled in the Stockholm II randomized, double-blind, controlled trial of one whole-cell and three acellular pertussis vaccines in Sweden in 1993–1994. In this trial, 101 infants developed HHE after vaccination. Of these children, 100 (1 had left Sweden) were evaluated subsequently at 18 months of age, using routine screening tests of motor and cognitive development intended to detect moderate to serious developmental problems. All 100 were found to be developing normally. At older ages, when more subtle developmental problems are detectable, comparison of the physical development and neurodevelopment of these children with a sample of trial participants without a history of HHE should be feasible. A protocol for a study to make such a comparison at ages 5½ and 8½ years is being prepared.In The Netherlands, a case–control study of infants who had HHE reported in 1995 is ongoing. The HHE events were detected through national surveillance linked to the health care delivery system. Growth, health, and neurodevelopment are being assessed. Data presented at the workshop concerning children with HHE reported in 1994 indicate that all 101 children followed during the second year of life (mean age, 1.5 years) were in good health and developing normally. An interesting finding of this follow-up study was the low rate of recurrent collapse (subsequent HHE occurrences) after repeat doses of pertussis vaccine.Summary. Despite increasingly widespread use of acellular pertussis vaccine in infants, HHE will continue to occur. The HHE definition proposed by this workshop should facilitate interstudy comparisons of HHE incidence among in the growing number of vaccines containing acellular pertussis components and perhaps of other vaccines as well. This definition also may aid study in VAERS and elsewhere of the etiology, pathophysiology, and descriptive epidemiology of HHE. Ongoing investigations in Sweden and The Netherlands have the potential to expand substantially knowledge of the possibility of long-term sequelae of HHE.