Hypotonic-hyporesponsive episodes after administration of hexavalent DTP-based combination vaccine: A description of 12 cases

ABSTRACT

Hypotonic-hyporesponsive (HHE) episodes are known and recognized phenomena, which typically occur within 48 hours of immunisation..Our aim is to describe 12 cases of HHE brought to the Center of Pediatric Sleep Medicine, with attention to the clinical features of the episode and their follow-up. Medical charts of infants visited between 2005–2015 were reviewed. Twelve infants showed a HHE using HHE using Brighton Collaboration Criteria. All infants received a Hexavalent diphtheria -tetanus -pertussis acellular component -hepatitis B-,inactivated poliovirus- Haemophilus influenzae type-b conjugate vaccine. Five out of 12 were brought to Emergency Department, where 2 were symptomatic (one was hyporeactive, the other had fever). No infant died during the episode, or the follow-up, nor developed neurological disease after subsequent vaccinations. HHE are confirmed as benign events, even after administration of hexavalent vaccination, devoid of negative neuropsychomotor outcome.

KEYWORDS:

• emergency department
• hexavalent
• HHE
• infant
• vaccination
• vagal reaction

Introduction

A hypotonic-hyporesponsive episode (HHE) is defined as the sudden onset of hypotonia, hyporesponsiveness, and pallor or cyanosis that occurs within 48 hours after childhood immunizations.^1,2 This syndrome has been primarily associated with pertussis-containing vaccines administered to children <2 y of age, and has been estimated to occur once every 1750 diphtheria-tetanus-pertussis (DTwP) vaccinations.³ However, various case reports and epidemiological studies showed a HHE's temporal association with several other vaccinations.^4-6

However, data regarding HHE are mainly deduced by Vaccine Adverse Event Reporting Systems (VAERS).^2,3

Our aim is to describe 12 cases of HHE defined using the Brighton Collaboration HHE Working Group guidelines⁷ brought to our attention, using out clinical records.

Methods

The present study was performed at the Center for Pediatric Sleep Medicine and Sudden Infant Death Syndrome (SIDS) of Regina Margherita Children's Hospital of Turin, Italy. The Center also offers sleep studies and consultation for infants admitted for a syncopal episode to a pediatric ward or to an Emergency Department anywhere in the Region. During history collection, parents of the patients are asked about events and minor symptoms preceding the episode including recent episodes of fever, illness, medication, immunization, sleep deprivation, or change in daily life routine.⁸ In the case of recent vaccination, immunization data are recorded.

Medical charts of infants visited between January 1, 2005-December 31, 2015 were reviewed; patients were included if and only they presented an HHE as defined by Brighton Collaboration HHE Working Group guidelines⁷ after a vaccination,

Data pertaining clinical features of the episode, parents' intervention and decision to bring the infant to Emergency Department (ED), clinical evaluation at ED arrival and infants progress' during admission were collected using Center database, which collects medical recording of the infants.

Fever was defined using the Brighton Collaboration Fever Working group guidelines.⁹

All the evaluated patients undergo 24 hours cardiorespiratory recording of chest wall movements by thoracic impedance, electrocardiogram, heart rate, oxygen saturation and pulse wave by a Masimo oximeter with an averaging mode of 6 seconds.

All patients were followed-up to assess recurrence of HHE and outcome (death and neurological disorders) by retrospective chart review. This was made possible by the fact that, as a standard policy of the Center, all patients are visited 2 months after the first admission to assess their condition. If the patient did not attend, staff physicians checked their condition by phone. If any problems occur, patients are followed-up until the end of clinical problems, and this leads to their being followed-up even for more than 3 months.

Unreported death can be excluded as the Center provides an active surveillance of sudden unexpected infant death in the range 0– 2 y in the whole Region.¹⁰

Results

Twelve infants showed a HHE as defined by Brighton criteria (Table 1). Of these, one infant had been admitted to a Pediatric Division 2 months before for a suspect absence seizure, not confirmed successively; another infant had previously presented episodes of hypotonia and pallor in concomitance with temperature increase and underwent 24 hour cardiorespiratory monitoring, which showed no alteration. Both episodes occurred independently of immunization.

Table 1. Classification of HHE and demographical features of the infants.

Case	Level of HHE	Vaccine	Age (days)	Sex	Gestational Age	Birth weight (g)	Weight at the time of the visit (g)
1	1	Hexavalent	60	Male	38	n.a.	6015
2	2	Hexavalent	90	Male	n.a.	n.a.	5600
3	3	Hexavalent	140	Male	38	n.a.	7020
4	2	Hexavalent and pneumococcical conjugate	80	Male	36	2340	6000
5	1	Hexavalent	120	Male	34	2350	6670
6	1	Hexavalent	105	Male	39	3220	n.a.
7	1	Hexavalent and pneumococcical conjugate	75	Male	40	3290	7790
8	2	Hexavalent	330	Female	39	3050	9900
9	1	Hexavalent	75	Male	39	3130	5620
10	1	Hexavalent	130	Male	40	3660	5620
11	1	Hexavalent and meningococcical group C conjugate	60	Male	39	4240	6880
12	1	Hexavalent and pneumococcical conjugate and meningococcical group C conjugate	136	Female	39	3780	7480

n.a.: data not available

Two infants out of the 12 were born preterm. Ten out of 12 were male.

Time between the vaccination and the HHE and duration of the event, as reported by parents, are shown in Tables 2 and 3 respectively. In 7 cases out of 12, the episode resolved within 5 minutes. Only one infant showed an HHE in the waiting room 5 minutes after vaccination. After mild stimulation by medical personnel, he normalized and was kept in observation for one hour before returning home. In past medical history, the infant had had a rhinitis 2 weeks before, treated with βmethasone.

Table 2. Timing between HHE and vaccination.

Timing	n/N*	Level of HHE
<1h	1 /12	1
1–2h	1/12	1
2–3h	1/12	1
5–6h	1/12	1
6–7h	1/12	2
10–11h	2/12	1 and 3
13–14 h	1 /12	1
36–37 h	1/12	1
Day 3 (49–72H)	2 /12**	1 and 2

For one infant it was not possible to determinate the timing between vaccination and HHE, which occurred within 12–24 hours from vaccine administration.

* n/N: number of events/number of cases.

** One infant out of the 2 presented fever for the 24 hours after vaccination, but was hypothermic at the time of the episode.

Table 3. Duration of the HHE.

Duration (min)	n/N*	Level
<1	2/12***	1 and 2
1-<2	1/12	1
2 -<3	1/12	1
4-<5	3/12	1 (2) and 2(1)
9-<10	3/12	1 (2) and 2 (1)
14-<15	1/12	I
59–60	1/12	3

* n/N: number of events/number of cases

** One out of the 2 infants presented hyporeactivity for 12 hours, but hypotonia and pallor immediately resolved.

Interestingly, at the time of the event 4 infants also showed sweating; one of them had fever (38°C), other 2 were reported hypotermic. One of these had had temperature up to 38–39 °C just one day after immunization and presented the HHE 70 hours later (Table 3).

For 7 infants it was the first administration, for 4 the second, for one the third and last of the immunization schedule. All the infants had received a hexavalent Diphtheria -Tetanus -Pertussis acellular component -Hepatitis B-,inactivated Poliovirus- Haemophilus influenzae type b conjugate vaccine (Infantrix Hexa, GlaxoSmithKline). In addition to hexavalent, 4 patients were also administered other vaccines: one with meningococcical conjugate group C (Menjugate, Novartis), 2 with pneumococcical conjugate (Prevenar 13, Pfizer) and one with meningococcical conjugate group C and pneumococcical conjugate (Menjugate and Prevenar 13).

For those we had lot number (7 out of 12), we found that 2 infants were administered hexavalent from the same lot; however, one of them also received anti-pneumococcical vaccination too.

During the episode, all patients were held by parents to stimulate them; one was also turned upside down, shaken, and received back-blows.

Five out of 12 were brought to ED where 2 were symptomatic: one presented hyporeactivity, and the other had an increase in body temperature (37.9 °C). While in the ED, Capillary Blood Gas Analysis (CBA) was performed on 3 infants resulting normal in each case.

Four infants out of 5 were admitted to a Paediatric Ward (length of stay 4.5 ± 2.69 days); the infant with the temperature increase was discharged 2 hours later, as he normalized with paracetamol administration and temperature decrease. All the infants admitted underwent electrocardiogram, resulted always normal, and blood examination (complete blood count and basic metabolic panel). One case showed a slight increase in blood ammonia (49 mcm/L, normal value <32 mcm/L). This infant also underwent complete metabolic panel examination, reactive C protein evaluation, neurological consultation, cerebral and abdominal ultrasound, all resulted normal. The blood ammonia value normalized during the follow-up period, in which the infant showed normal neuropsychomotor development.

The other 7 infants were referred to the Center by the family's pediatrician. In 3 cases parents checked the temperature at the end of the episode and found fever (38, 38.5, 38.6 °C respectively). Two out of 3 were administred paracetamol by parents: one after the temperature assessment, one before the episode as suggested by the vaccinal center personnel. Another infant received paracetamol from their parents due to inconsolable crying. Six out of 7 performed ECG and resulted normal.

In 11 cases, 24 hours cardiorespiratory recording, performed after the vaccine administration (between 2 and 21 d after the HHE, mean 9 days), did not show any pathological findings.

Interruption of the immunization schedule was recommended in 10 cases (removed 2 months later for 7 infants, 3 months later for one infant, one month later for one infant and at 6 months for the remaining one).

No infant died during the follow-up period, nor developed neuro-psychomotor impairment; no patient presented recurrence of the episode (in 2 cases, patient condition was assessed by phone call with parents). Only one patient did not complete the immunization schedule after HHE.

Discussion

While most works published on HHE start from VAERS,^3,5 we describe cases evaluated by our Center, which routinely performs a standardized collection of information with an accurate history collection and physical examination, evaluates previous clinical recording and performs instrumental examinations: all infants underwent 24 h cardiorespiratory recording, with no abnormality found.

Our findings are in line with the previously published literature ^1-7 regarding the benignity of the episodes, as they mostly resolved briefly and all the infants returned to the pre-vaccination status with no alteration in neuropsychomotor development.

All the cases reported received a Hexavalent vaccine with acellular pertussis components. The first studies published described HHE following a whole-cell pertussis vaccine^1-3; a Cochrane review¹¹ showed that the risk of hypotonic-hyporesponsive episodes was significantly lower in acellular vaccine recipients compared with those immunised with whole-cell vaccines. Our cohort did not allow us to make a comparison between the 2 vaccines, but seems to confirm that the cellular pertussis components are not the only factor involved in HHE.

Ten out of 12 patients were males; literature available showed no predominance of sex in HHE after a DTP vaccination. Has HHE following hexavalent administration another undiscovered pathogenesis, which makes males more susceptible? This could be the case in other phenomena involving immune response with male predominance without apparent explication (for instance, meningitis or pneumonia¹²). The theme is relevant and a meta-analysis protocol has recently been assessed to investigate the influence of gender on immunogenicity, reactogenicity and efficacy of vaccines in children.¹³

Obviously, no causal relationship can be assessed by our work. Many hypotheses have been postulated¹⁴ about pathogenesis of HHE; activation of inflammatory pathway could play a role,^3,7 eventually eliciting autonomous nervous system activity. Recent works show how autonomous nervous system can be influenced by inflammation and vice versa.¹⁵ There is no evidence that HHE is the unequivocal result of autonomic nervous dysfunction, but in some infants inflammation could elicit an increase in autonomous nervous system reactivity, which may produce the symptoms observed. It is known that some infants can have a paroxysmal vagal over activity¹⁶; furthermore, the Brighton Collaboration HHE Working Group, despite referring that the pathogenesis of HHE remains unknown, states that “A vasovagal-syncope is clinically defined by the same triad of diagnostic signs but usually occurs in an older age group:” a vasovagal-syncope is a typical manifestation of autonomic system hyper reactivity, so it seems that, simply basing on the clinical features, an association between the 2 systems may be supposed.

In conclusion, our study, focused on clinical evaluation, showed that HHEs can occur after hexavalent vaccination as well and are confirmed as benign events.

Abbreviations

ED	=	Emergency Department
HHE	=	Hypotonic Hyporesponsive Episode
VAERS	=	Vaccine Adverse Event Reporting Systems

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Author contributions

Alessandro Vigo conceptualized and designed the study, wrote the manuscript and approved the final manuscript as submitted.

Giulia Costagliola and Elisa Ferrero were involved in the acquisition and the analysis of the data, wrote the manuscript and approved the final manuscript as submitted.

Silvia Noce was involved in the acquisition and the analysis of the data, wrote the article and approved the final manuscript as submitted.

Acknowledgments

We would like to thank for their kind collaboration the referents for the Active Surveillance on Sudden Death 0–2 years Network of Regione Piemonte, Italy.