Introduction

Whooping cough, also known as pertussis, is an acute infection of the respiratory tract that is charac terized by the presence of a paroxysmal cough for at least two weeks, respiratory stridor or posttussive vo miting¹. The main etiological agent is the Bordetella pertussis, although other species of Bordetella, such as B. parapertussis, B. bronchiseptica and B. holmesii have also been associated with sporadic cases and outbreaks of this disease^2,3.

The first vaccines for whooping cough were appro ved in the United States, 1914, and were formed of B. pertussis inactivated whole-cells (wP) by heat and/or chemical agents. Then, in the 1940s, wP formulations were in included in combined vaccines that contai ned tetanus (T) and diphtheria toxoids (D)⁴. Notably, DTwP combined vaccines showed to be highly immu nogenic and protective against B. pertussis, however, the pertussis component was associated, commonly, with adverse effects such as irritability, fever and erythema, and less frequently, seizures and hypotonic-hyporesponsive episodes (HHE)⁵. The HHE is a severe adverse effect that is characterized by the clinical triad of sudden muscle flaccidity, a lower response to stimulus and a change in the skin coloration (paleness or cyanosis)⁶.

Despite of the massive vaccination of the popula tion with DTwP Vaccines the occurrence of whooping cough plunged^7,8, concern about adverse effects led to developing acellular anti-pertussis vaccines (aP) com posed of one or more purified antigens (pertussis toxin, filamentous hemagglutinin, pertactin and fimbriae) in the 1970s and 1980s. DTaP vaccines were less reactogenic than vaccines with wP and they are, currently, included in the vaccination programs of many de veloped countries^9,10. In fact, the rates of incidence of HHE after the administration of DTaP vaccines (from 4 to 140 episodes per 100,000 children) are lower than DTwP vaccines (from 36 to 250 episodes per 100,000 children)⁶. However, despite the availability of anti pertussis vaccines and the wide vaccination coverage, it has been reported that in some countries, including Chile, there has been an increase in the incidence and mortality due to whooping cough, especially in chil dren under 6 months^2,7,11,12,13. Even though that the re asons for the re-emergence of the disease are complex and can vary in each country, the short duration of the protection and the probable lower impact of the aP vaccines on the infection and transmission seem to have an important role¹⁴, which is currently a topic of stu dy and discussion^15,16. In this epidemiological scenario, whooping cough remains a public health problem and one of the most common vaccine-preventable diseases, both in developed and developing western countries^8,17.

The vaccination for pertussis started, in Chile (1955), with a combined vaccine of wP and diphtheria (DP). Significantly, as in other countries, the intro duction and massive administration of anti-pertussis vaccines led to a significant reduction in the incidence of whooping cough, in comparison with the pre-vacci nation period. Later, between 1975 and 2006 a DTwP vaccine was administered and in 2007, the National Immunization Program (NIP) included the combined DTwP-HB-Hib vaccine⁸. After the change of immuni zation schedule of anti-pertussis vaccination in 2012, the current NIP administrates three dosis DTwP-HB-Hib vaccine at 2nd, 4th, 6th months with the first booster injection at the 18th month and two additional booster injections of acellular anti-pertussis vaccine with reduced-antigen content (Tdpa), which were are administrated to scholars of primary education (first and fourth of basic elementary education)^18,19.

After the change of immunization schedule of anti pertussis vaccination in 2012, the current NIP admi nistrates three dosis DTwP-HB-Hib vaccine at 2nd, 4th, 6th months with the first booster injection at the 18th month and two additional booster injections of acellular anti-pertussis vaccine with reduced-antigen content (Tdpa), which are administrated to scholars of primary education (first and fourth of basic elemen tary education)^18,19. In addition, as of May 2017 prema ture newborn younger than 37 weeks of gestation must receive a vaccination schedule at the 2nd, 4th, 6th and 18th month with a hexavalent combined vaccine (di phtheria, tetanus, acellular pertussis, hepatitis B, inactivated polio and Haemophilus influenzae type B b)²⁰.

On the other hand, regarding the safety of the va ccines for whooping cough available in Chile, there is only one study carried out by Abarca et al²¹, where the adverse effects of two formulations DTwP used as a booster during 2005 were evaluated. In this study, the most common adverse effect was high fever, while more severe adverse effects such as HHE and encepha lopathy were not present.

In addition, it is important to mention that in the country, every adverse event following immunization (AEFI) must be notified to the Pharmacovigilance Sub Department of the Public Health Institute (SDFV) by an AEFI questionnaire. The notification can be made by an assistance center, emergency services or immu nization clinics. Later, the SDFV, the NIP and the Re gional Ministerial Secretary of Health (SEREMI) carry out the evaluation, research, and tracking of the noti fied AEFI²².

The objective of this study is to report a case of HHE after the administration of the pentavalent com bined vaccine with diphtheria, tetanus, acellular per tussis, hepatitis B and Haemophilus influenzae type B (DTwP-HB-Hib) which is included in the NIP of Chi le, in order to spread this infrequent complication of benign evolution, auto-limited and non-recurrent.

Clinical Case

A 6-month old infant, with a history of allergies to cow’s milk protein and a vaccination schedule up-to-date according to the NIP schedule (without evidence of previous adverse effects). After 3 hours of the ad ministration of the third dose of DTwP-HB-Hib, the patient assisted to Pediatric Emergency Service, due to a medical symptom: sudden loss of consciousness for less than 1 minute, hyporeactivity, muscle flaccidity, general paleness and perioral cyanosis. The parents also reported clonic movements and eye deviation.

At the moment of admission to the emergency service, the patient had skin paleness, slight cyanotic tone on the lips, and coldness in the extremities with good reactivity and vigorous cry. The patient was also afebrile, hemodynamically stable, without respiratory distress and hypoglycemia. In the face of a possible case of seizures, samples for a blood count, bioche mical profile, venous blood gases, plasma electrolytes, C-reactive protein and hepatic profile were required. After 30 minutes of monitoring, the patient recovered the skin tone with warm extremities, a firm pulse and a normal capillary nail refill test.

Two hours after the admission, there was no cli nical deterioration, the infant showed a recovery of the muscular tone, normal reactivity to stimulus and a better tissue perfusion, with a normal physical and neurological exam.

The HHE diagnosis was considered, due to the nor mal results of the clinical tests and electroencephalo gram, and the record of the patient vaccinated with a combined vaccine DTwP-HB-Hib.

The patient was discharged after 24 hours of mo nitoring. The family was notified of the boosters with an acellular anti-pertussis vaccine as a preventive mea sure. The immunization clinic, where the infant recei ved the vaccine, was notified of the HHE, who later reported the case to the SDFV through an AEFI ques tionnaire. Lastly, in the first and sixth month after the discharge, the patient was monitored via phone, the fa mily reported that the infant did not show any sequelae related to HHE.

Discussion

Despite the unquestionable success of the vaccina tion, the safety of vaccines is an issue of public interest that is becoming increasingly important²³. Thus, the monitoring and identifications of adverse effects sup posedly attributable to vaccination must be a priority in the public health of each country.

HHEs are infrequent adverse reactions after infant vaccinations, mostly associated with whole-cell anti pertussis vaccines. However, there are some reports of HHE due to acellular anti-pertussis vaccines²³, di phtheria, tetanus, hepatitis B, polio and Haemophilus influenzae type b²⁴. In general, the major incidence of these episodes can be observed after the administration of the first dose of vaccine and the time range, in which the symptoms show up, goes from the administration to 48 hours. Additionally, it is an auto-limited event that does not leave sequelae on a long-term basis. The HHE phathophysiological mechanism has not been established yet, but it is probable that many factors con tribute to it, such as idiosyncratic/immunological from the children and inherent to the vaccine.

On the other hand, it is important to point out that the diagnosis of this clinical condition is difficult be cause: (i) its short duration, most of the times we base based on the description of the parents, (ii) a possible confusion with other similar clinical symptoms and (iii) the lack of laboratory tests that confirm this con dition. In addition, it has been reported, historically, in the literature as shock, fainting or syndromes simi lar to fainting, consequently, the various descriptions of the condition have complicated interpretation and comparison of reports about its occurrence and consequences^6,24,26. Therefore, to facilitate an early diagnosis of HHE and its notifications, it is important that the doctor and the sanitary staff are familiarized with a standard description of of this AEFI⁶.

In this sense, the definition established by the Work Group for HHE from the “Brighton Collaboration”⁶ has been the first international effort to elaborate a global consensus about this clinical condition, which is now used in many countries^24,25,26. Since the clinical triad of hypotonicity, hyporeactivity and cyanosis is not always present in the HHE, the definition given by the “Brighton Collaboration” includes the level of diag nostic certainty according to the presence or absence of these clinical symptoms (Table 1). Also, during the differential diagnose the vasovagal syncope and atonic seizures of short duration must be considered. The va sovagal syncope is defined by the same clinical-triad, but it appears in a different age group (children older than 10 years), while atonic seizures are characterized more by hypotonicity than hyporeactivity, and there is no cyanosis. It must be rejected if the symptoms are caused by intoxication, septicemia or if the patient is just sleeping⁶.

Table 1 Definition of HHE with levels of diagnostic certainty established by the "Brighton Collaboration". 

Thus, considering the HHE definition by the “Brighton Collaboration”, this report corresponds to an HHE case with level 1 of diagnostic certainty. Authors consider that the classifications of these adverse effects and the proper notification to the corres ponding authorities (SDFV) significantly contribute to the vigilance of the safety of authorized vaccines. These notifications also contribute to the execution of epide miologic studies that can be a guide in policy-making by authorities of public health.

Conclusion

A classic HHE case is reported, with the classic triad of hypotonicity, hyporeactivity, and cyanosis due to a vaccine combined with wP. It is essential that the pe diatrician and the medical staff educate families about HHE since these events might discourage infant vaccination, especially taking into account the emergence of anti-vaccination movements that discuss this topic in mass media without the proper scientific support. Du ring the orientations, the topic to be discussed is that it is an entity of benign evolution, auto-limited and non recurrent, thus the vaccination on children schedule can be continued by administrating formulations that contain acellular anti-pertussis components as precau tion measures.

Ethical Responsibilities

Human Beings and animals protection: Disclosure the authors state that the procedures were followed ac cording to the Declaration of Helsinki and the World Medical Association regarding human experimenta tion developed for the medical community.

Data confidentiality: The authors state that they have followed the protocols of their Center and Local regu lations on the publication of patient data.

Rights to privacy and informed consent: The authors have obtained the informed consent of the patients and/or subjects referred to in the article. This docu ment is in the possession of the correspondence author.

Financial Disclosure: Authors state that no economic support has been asso ciated with the present study.

Conflicts of Interest: Authors declare no conflict of interest regarding the present study.

Acknowledgments: We gratefully acknowledge Drs. Roberto Vidal, Miguel O’Ryan, José Manuel Caballero and nurse Patricia Ceballos Olivares for their critical reading of the manus cript.