REPORT OF A US PUBLIC-HEALTH SERVICE WORKSHOP ON HYPOTONIC-HYPORESPONSIVE EPISODE (HHE) AFTER PERTUSSIS IMMUNIZATION

Hypotonic-hyporesponsive episode (HHE) is a term used to describe a so mewhat heterogenous group of clinical disorders that have been reporte d primarily in association with whole-cell pertussis vaccination. A 19 91 review by the Institute of Medicine determined that the evidence av ailable was indeed consistent with a causal relation between whole-cel l pertussis-diphtheria-tetanus immunization and HHE, but that the evid ence was insufficient to indicate a causal relationship between HHE an d the subsequent development of permanent neurologic damage. More rece nt data from clinical trials conducted in Europe suggest that HHE also occurs after vaccination with acellular pertussis vaccines. The US Fo od 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 def inition of HHE and to evaluate the general design and feasibility of p ossible studies of HHE using the federal Vaccine Adverse Event Reporti ng System (VAERS), a national passive surveillance system. The goals o f such studies would be to understand better the acute HHE event and t o evaluate the possibility of longterm sequelae. Case Definition. Ther e has been no generally accepted definition of HHE, and a standard def inition would be useful for vaccine safety work and would potentially facilitate interstudy comparisons of the growing number of licensed va ccines containing acellular pertussis components. The workshop defined HHE as an event of sudden onset occurring within 48 hours of immuniza tion, 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 hypor esponsiveness, and 3) pallor or cyanosis or failure to observe or to r ecall skin coloration. HHE is not considered to have occurred if there is a known cause for these signs leg, postictal), if urticaria is pre sent during the event, if normal skin coloration is observed throughou t the episode, or if the child is simply sleeping. This inclusive (sen sitive) case definition will allow investigators, through the techniqu e of stratification according to certain characteristics leg, time fro m vaccination to onset of HHE), to attempt to hone the definition and make it more specific. Refinement of the definition of HHE has been hi ndered by the lack of information on its pathophysiology and by the la ck of pathognomonic signs, symptoms, and diagnostic tests. Another hin drance 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 works hop's HHE definition. Further Study of HHE. Probably the most importan t question about HHE is whether it has any permanent sequelae. The wor kshop assessed the possible contribution VAERS-based studies could mak e to answering this question and found substantial methodologic proble ms; however, ongoing studies in Sweden and The Netherlands have the po tential to provide useful information on this question. The most usefu l contribution of VAERS data would be in a descriptive study of HHE, w ith a possible case-control study of factors that may affect the risk of HHE after vaccination, rather than a study of possible permanent se quelae. The workshop participants felt that a detailed descriptive stu dy of similar to 100 HHE events reported during a 1- to 2-year period could provide a more in-depth description of HHE cases in greater numb ers than has been published previously, but the study would not addres s the issue of long-term sequelae of HHE. Better descriptive data may lead to new hypotheses concerning risk factors, etiology, and pathophy siology 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 questio n 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-bli nd, controlled trial of one whole-cell and three acellular pertussis v accines in Sweden in 1993-1994. In this trial, 101 infants developed H HE after vaccination. Of these children, 100 (1 had left Sweden) were evaluated subsequently at 18 months of age, using routine screening te sts of motor and cognitive development intended to detect moderate to serious developmental problems. All 100 were found to be developing no rmally. At older ages, when more subtle developmental problems are det ectable, comparison of the physical development and neurodevelopment o f 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 comp arison at ages 5 1/2 and 8 1/2 years is being prepared. In The Netherl ands, a case-control study of infants who had HHE reported in 1995 is ongoing. The HHE events were detected through national surveillance li nked to the health care delivery system. Growth, health, and neurodeve lopment are being assessed. Data presented at the workshop concerning children with HHE reported in 1994 indicate that all 101 children foll owed 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 occur rences) after repeat doses of pertussis vaccine. Summary. Despite incr easingly 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 st udy in VAERS and elsewhere of the etiology, pathophysiology, and descr iptive epidemiology of HHE. Ongoing investigations in Sweden and The N etherlands have the potential to expand substantially knowledge of the possibility of long-term sequelae of HHE.