Guillain Barré syndrome after combined diphtheria, tetanus, and acellular pertussis (DTaP) vaccine: A rare pediatric case report and review of literature

ABSTRACT

A 20-month-old girl was diagnosed with Guillain – Barré syndrome (GBS) based on progressive muscle weakness, areflexia, and albuminocytologic dissociation of the cerebrospinal fluid. Despite timely and systematic treatment, she eventually became paralyzed. There is a temporal correlation between the girl’s GBS and the DTaP vaccination, but the exact causal relationship between the two is still debatable. Furthermore, we summarized clinical features of other 45 published GBS cases after DTP vaccines (or vaccine substances containing tetanus) through a systematic review. The mean onset age, sex distribution, onset time after vaccination, detection of antiganglioside antibodies, and other basic clinical features of GBS after DTP vaccination (or vaccine substances containing tetanus) were analyzed. The temporal pattern of GBS after vaccination was similar to that of GBS after infection. Herein, we report this rare case of presumptive pediatric GBS after DTaP vaccination and review similar cases to draw the attention of medical personnel to similar events after vaccination. An association between DTP vaccines and GBS has been proposed, and the causal relationship between these two incidents are worthy further exploration. Moreover, surveillance and vigilance for GBS after vaccination are highly recommended.

KEYWORDS:

• Guillain Barré syndrome (GBS)
• diphtheria
• tetanus and pertussis vaccines
• systematic review
• vaccine safety

Introduction

Guillain – Barré syndrome (GBS) is an autoimmune peripheral neuropathy typically characterized by rapidly progressive, essentially symmetric limb weakness and areflexia.^1,2 Approximately 100,000 new GBS cases occur every year worldwide, most commonly in people older than 50 years. Although GBS rarely affects children, it remains the most common cause of acute flaccid paralysis.³ Its incidence is 0.5–2.0 per 100,000 in children (<18 years).¹

GBS is believed to be related to infection, and approximately 2/3 of patients present with preceding gastrointestinal or respiratory infection.^1,2 Many specific pathogens such as Campylobacter jejuni, Haemophilus influenzae, and influenza A virus, have been reported to be associated with GBS.¹ In addition, there have been reports of GBS cases occurring occasionally after vaccination with older versions of rabies, influenza, combined diphtheria, tetanus, pertussis vaccine (DTP), and COVID-19-19 vaccine,^2,4 some of which were reported in The Vaccine Adverse Event Reporting System (VAERS, https://vaers.hhs.gov/data.html).

Here, we describe a rare case of pediatric GBS following combined vaccination for diphtheria, tetanus, and acellular pertussis (DTaP). There have been 35 GBS cases after DTP vaccination among more than 4,000 GBS cases in the VAERS system, but few causalities have been established. Therefore, we reviewed a total of 45 GBS cases (10 cases from the literatures and 35 cases from the VAERS system) after DTP vaccination (or vaccine substances containing tetanus) to analyze their clinical features.

Case presentation

A 20-month-old Chinese girl was admitted with claudication and reduced activity of the right leg having lasted one day accompanied by low-grade fever for three days. She had received a fourth booster dose of DTaP three weeks prior to presentation. The previous three injections had been well tolerated. DTaP vaccination had been administered according to the vaccination schedule of the China Vaccination Committee. The patient had no history of rhinorrhea, rhinorrhea, vomiting, diarrhea, or abdominal pain in the previous month. The fever resolved after routine treatment; however, weakness in her lower limbs progressed.

Initially, the patient’s parents observed a presentation of a limp and weakness in her right leg. Three days after admission, she developed weakness in the other leg and bilateral arms. Neurological examination revealed muscle strength of 3/5 in her upper extremities and 0/5 in her lower extremities on the fourth day of hospitalization. Bilateral deep tendon reflexes were absent in the knees and upper extremities. Subsequently, she presented with dyspnea. Several rounds of magnetic resonance imaging of the brain and the spinal cord revealed no remarkable findings. The cerebrospinal fluid was examined seven days after admission, which displayed cytoalbuminologic dissociation (white blood cell count: 14 × 10⁶/L (normal range: 0–15 × 10⁶/L); protein level: 1.01 g/L (normal range: 0.12–0.60 g/L).

Electromyography revealed a significant decrease in the amplitude of motor conduction waves in the bilateral median, tibial, and peroneal nerves. In addition, the frequency of F-waves in the bilateral median and tibial nerves decreased. Electromyography indicated neurogenic damage (axonal damage) in which the proximal nerve roots and motor fibers were severely affected. Serum antibodies against Legionella pneumophila, Mycoplasma pneumonia, Chlamydia pneumonia, adenovirus, influenza A virus, influenza B virus, cytomegalovirus, Epstein – Barr virus, and human immunodeficiency virus tested negative. Oligoclonal banding of the cerebrospinal fluid and serum was also negative. Results of anti-ganglioside (anti-GM1, anti-GM2, anti-GM3, anti-GD1b, anti-GT1b, and anti-GQ1b) antibody testing performed 18 days after admission yielded negative results. Other biochemical and general physical examination results were nonspecific.

After excluding other differential diagnoses such as acute flaccid myelitis, the patient was diagnosed with GBS based on clinical presentation, cytoalbuminological dissociation of the cerebrospinal fluid, and electromyography. The specific GBS subtype was acute motor axonal neuropathy (AMAN). Intravenous immunoglobulin (IVIG) was administered on the third day of admission. She was injected with 1 g/kg (10 g) per day of IVIG for 2 days. The muscle strength of her four extremities was improved after IVIG treatment. Subsequently, she received IVIG at a dose of 1 g/kg (10 g) per day for 2 consecutive days, with the second course administered one week later. This was followed by a maintenance dose of 0.5 g/kg (5 g) per day for 3 consecutive days, given two weeks after the initial treatment. Additionally, gangliosides, mouse nerve growth factor, mecobalamin, and other symptomatic treatments and physical therapy were administered. After systemic therapy, muscle strength in all four extremities was improved, and the patient could grab objects slowly but could not sit or stand on her own. Respiratory function and swallowing were normal. The muscle strength was 2/5 in her bilateral upper limbs, 1/5 in her right lower extremity, and 2/5 in her left lower extremity. The final diagnoses upon discharge were GBS, quadriplegia, and dyskinesia, and the patient was advised to perform rehabilitation exercises at the rehabilitation facility.

In the following three years, the patient was hospitalized intermittently for pulmonary infection, traditional Chinese Medical massage, acupuncture and moxibustion and other rehabilitation treatments. However, her muscle strength showed limited improvement and maintained stable condition. Muscle strength was 3/5 in the upper limbs and 2/5 in both lower extremities. The bilateral deep tendon reflexes were absent in the knees and feet. At the last follow-up, the patient had been diagnosed with GBS (sequelae stage), delayed quadriplegia (severe), muscular atrophy, apraxic osteoporosis, and scoliosis.

Discussion

In this report, we described a 20-month-old girl who presented with progressive muscle weakness, areflexia, and albuminocytologic dissociation, a classical trial of GBS. Neurophysiological examinations were primarily used to indicate the axonal injury or demyelinating damage of nerve fiber, which can support the diagnosis of GBS and discriminate its subtypes.^1,2 The exact electromyography results in our case suggested that there had been severe neurogenic axonal damage that severely affected proximal nerve roots and motor fibers and therefore this GBS case was classified as the AMAN subtype.

The patient did not exhibit prodromal symptoms of respiratory or digestive tract infections within one month prior to the onset of neurological symptoms. Serological and biochemical tests ruled out the presence of common pathogens. The only notable event was the DTaP vaccination three weeks prior to the onset of symptoms. Thus, there was a temporal correlation between the patient’s GBS and the DTaP vaccinations, but the exact causal relationship between the two remains uncertain. To the best of our knowledge, this is a rare reported case of presumptive pediatric GBS following a DTaP vaccination.

GBS is typically considered an aberrant autoimmune response that targets the peripheral nerves and nerve roots. Immune stimulation is thought to play a role in its pathogenesis.^1,2 Therefore, the mechanism of GBS after vaccination or infection is consistent with this theory. Concerns regarding the true relationship between GBS and vaccines or events that occur coincidently after immunization are longstanding.⁵ A meta-analysis showed a statistically significant association between GBS and influenza vaccines.⁶ Yet the relationship between GBS and DTP vaccines (tetanus toxoid-containing vaccines) remains unclear. Some studies have accepted a causal relationship between tetanus toxoid-containing vaccines and GBS.⁷ The exact evidences regarding a relationship between the DTP vaccine and GBS are lacking⁸ although there have been sporadic GBS cases reported after DTP vaccination. Thus, the relationship of GBS associated with DTP vaccines requires further study.² Several sporadic GBS cases following DTP or tetanus toxoid-containing vaccines have been reported, since the first case of demyelinating neuropathy after tetanus vaccination was reported in 1978.^9–13 It is worth noting that in the GBS case reported in 1978,⁹ the patient received three separate injections of tetanus toxoid and developed acute demyelinating polyneuropathy subsequently following each injection. Additionally, there have been reports of cases of MFS, which is a variant of GBS, after DTP vaccination.^14,15 We systematically searched the databases using the keywords “diphtheria, tetanus, pertussis vaccine” or “tetanus toxoid containing vaccines,” “Guillain Barré syndrome” or “GBS” or “Miller Fisher syndrome” in PubMed, Web of science and VAERS for a summary of the clinical and prognosis information regarding the association between DTP vaccines and GBS.

In total, 45 GBS (including MFS) cases after administration of DTP vaccines (or tetanus toxoid-containing vaccines) have been reported, of which 35 were from the VAERS system and the remaining 10 were from the literatures. All 45 cases, including the present report, have been summarized in Table 1. The onset age of these 45 GBS cases ranged from 1 month to 72 years old, and 51.1% of them (23/45) were male. All patients with MFS were female. The earliest time from vaccination to the onset of GBS symptoms was immediate and the longest was 4.5 months. Most cases (18/45) occurred approximately 2–5 weeks after vaccination, which is consistent with the temporal pattern of GBS following infection.¹

Table 1. The summary of clinical features of 45 cases of GBS after combined pertussis diphtheria, tetanus vaccine (or vaccine containing tetanus).

Source	Reported year	vaccine	Diagnosis	Age	Sex	Days to onset	Motor symptom	Sensory symptom	Other symptom	Biochemical test. (1. Serum anti-ganglioside antibodies test; 2. Albuminocytologic dissociation.)	Recovered
Literature Case1^Citation9	1978	TT	GBS	42	M	First episode (1962): 3 weeks. Second episode (1971): 2 weeks Third episode (1976): 10 days	First episode: +Second episode: +Third episode: +	First episode: -Second episode: +Third episode: +	-	1. NA. 2. First episode: NA. Second episode: Positive, Protein value: 250 mg/100 ml, without pleocytosis. Third episode: Positive, Protein value: 300 mg/100 ml.	No
Literature Case2^Citation10	1987	TT	GBS	47	M	9	+	+	-	1. NA. 2. Positive, Protein value: 550 mg/dl, without pleocytosis.	No
Literature Case 3^Citation11	1997	TT	GBS	22	M	4	+	+	-	1. NA. 2. Positive, Protein value: 70 mg/dl, 1 white blood cell/ml.	No
Literature Case 4^Citation12	2011	DTP	GBS	40	M	2–3 weeks	+	+	-	1. NA. 2. Positive, Protein value: 790 mg/dl, 1 white blood cell/ml.	No
Literature Case 5^Citation14	2013	DTP	MFS	65	F	21	+	+	-	1. Negative (anti-GQ1b). 2. Positive, Protein value: 83.9 mg/dl, 2 white blood cell/ul.	No
Literature Case 6^Citation13	2014	DT	GBS	61	M	35	+	+	-	1. NA. 2. Positive, Protein value: 148 mg/dl.	No
Literature Case 7^Citation13	2014	DT	GBS	41	M	28	+	+	-	1. NA. 2. Not done.	No
Literature Case 8^Citation13	2014	DT	GBS	72	M	28	+	+	-	1. NA. 2. Negative, Protein value: 28 mg/dl.	No
Literature Case 9^Citation13	2014	DT	GBS	65	M	4 months	+	+	-	1. NA. 2. Positive, Protein value: 46 mg/dl	No
Literature Case 10^Citation15	2019	DTP	MFS	70	F	5	+	+	-	1. High anti-GQ1b antibody (299, Ref range: 0–50). 2. Positive, The specific value was not mentioned.	No
VAERS 0031641–1	1991	DTP	GBS	0.2	F	5	+	-	Pyrexia	unavailable	Yes
VAERS 0049563–1	1993	DTP	GBS	3	M	10	+	-	Pyrexia; Diarrhoea; Rash	unavailable	Yes
VAERS 0049686–1	1993	DTP	GBS	59	M	12	+	+	-	unavailable	No
VAERS 0050081–1	1993	DTP	GBS	2	F	7	+	-	-	unavailable	unknown
VAERS 0053623–1	1993	DTP	GBS	1.3	F	7	+	-	Pyrexia; Rash	unavailable	No
VAERS 0054010–1	1993	DTP	GBS	5	M	25	NA	NA	NA	unavailable	Yes
VAERS 0054223–1	1993	DTP	GBS	2	F	7	+	-	-	unavailable	missing
VAERS 0060095–1	1994	DTP	GBS	0.3	F	7	+	+	Pyrexia; Pain	unavailable	missing
VAERS 0060688–1	1994	DTP	GBS	0.3	F	6	+	+	Pyrexia; Pain; Anorexia	unavailable	unknown
VAERS 0066280–1	1994	DTP	GBS	0.7	M	17	+	-	Pyrexia; Somnolence	unavailable	missing
VAERS 0066875–1	1994	DTAP	GBS	5	M	20	+	-	Headache	unavailable	unknown
VAERS 0093861–1	1997	DTP	GBS	3	M	18	+	-	Dyspnoea	unavailable	Yes
VAERS 0095162–1	1997	DTaP	GBS	1.3	F	134	+	-	Pain	unavailable	Yes
VAERS 0102972–1	1997	DTaP	GBS	0.4	M	37	+	-	Hypoxia; Malaise	unavailable	missing
VAERS 0111386–1	1998	DTaP	GBS	5	F	1	+	-	Pyrexia; Urticaria	unavailable	unknown
VAERS 0115515–1	1998	DTaP	GBS	6	M	14	+	-	Malaise	unavailable	No
VAERS 0121812–1	1999	DTP	GBS	0.9	M	1	+	-	-	unavailable	missing
VAERS 0126286–1	1999	DTAP	GBS	1.33	F	6	+	-	-	unavailable	No
VAERS 0211307–1	2003	DTAP	GBS	1.4	F	3	+	-	Injection site erythema; injection site swelling	unavailable	Yes
VAERS 0220194–1	2004	DTaP	GBS	4	M	4	+	-	Pain; Tremor	unavailable	unknown
VAERS 0250168–1	2006	DTaP	GBS	4	M	38	+	-	Diarrhoea; back pain	unavailable	Yes
VAERS 0263154–1	2006	DTaP	GBS	0.19	F	1	+	-	Diarrhoea; Erythema	unavailable	Yes
VAERS 0275419–1	2007	DTaP	GBS	4	F	1	+	-	Pyrexia	unavailable	unknown
VAERS 0356046–1	2009	DTaP	GBS	4	F	15	+	-	Fatigue	unavailable	unknown
VAERS 0422015–1	2011	DTaP	GBS	14	F	0	+	-	Dyspnoea	unavailable	No
VAERS 0466144–1	2012	DTaP	GBS	40	M	20	+	+	-	unavailable	Yes
VAERS 0553086–1	2014	DTP	GBS	0.4	F	7	+	-	Dyspnoea	unavailable	No
VAERS 0596954–1	2015	DTap	GBS	1 month	M	Unknown	+	-	Pain; Injection site erythema; Injection site induration	unavailable	Yes
VAERS 0678333–1	2017	DTaP	GBS	0.25	F	10	+	-	Diarrhea;Rash	unavailable	Yes
VAERS 0683662–1	2017	DTaP	GBS	0.3	F	36	+	-	Eryrhema; peripheral swelling	unavailable	Yes
VAERS 0722242–1	2017	DTaP	GBS	53	F	8	+	+	-	unavailable	No
VAERS 0734827–1	2018	DTaP	GBS	1.7	M	19	+	-	Diarrhea; Loss of conscious; somnolence; urticaria	unavailable	Yes
VAERS 1753403–1	2021	DTaP	GBS	1.5	M	12	+	-	Balance disorder	unavailable	No
VAERS 2460856–1	2022	DTaP	GBS	11	F	13	+	+	Unknown	unavailable	No
VAERS 2572960–1	2023	DTaP	GBS	28	F	21	+	-	Headache; Blurred vision	unavailable	No
Present study	2023	DTap	GBS	1.5	F	3 weeks	+	-	Pyrexia	1. Negative. (anti-GM1, anti-GM2, anti-GM3, anti-GD1b, anti-GT1b and anti-GQ1b). 2. Positive, Protein value: 101 mg/dl, 0 white blood cell/ul.	No

Abbreviations: DT, tetanus-diphtheria toxoid; DTP, Combined pertussis, diphtheria, and tetanus vaccine; DTap, Combined pertussis, diphtheria, and acellular tetanus vaccine; F, Female; M, Male; MFS, Miller Fisher syndrome; GBS, Guillain Barré syndrome; NA, not mentioned; VAERS, The Vaccine Adverse Event Reporting System. TT, tetanus toxoid.

Among 45 GBS cases, 68.8% (31/45) of patients were children. The mean onset age of all 31 pediatric GBS was about 2.72 years old, ranging from 1 month to 14 years old. Among these pediatric GBS, most (26/31, 83.8%) were aged ≤4 years old, which is similar with a Chinese study that the incidence of the GBS peaked in children aged 1–4 years.¹⁶ It is reported that¹⁷ children with GBS was more common in male, while 58% (18/31) of pediatric GBS was female in our reviewed cases. The clinical symptoms of GBS vary remarkably, and young age children with GBS often present with nonspecific clinical features which may lead to misdiagnosis and delayed diagnosis.¹⁸ Almost all children with GBS cases presented with motor dysfunction, while sensory dysfunction symptoms were infrequent. This phenomenon may be due to the limited ability of infants and young children to articulate their symptoms accurately. Other clinical manifestations encompass fever, diarrhea, pain, rash, and hypoxia, and so on (Table 1). Among these, 8 cases presented with fever, and 5 cases were accompanied by diarrhea. Previous studies have shown that 70–80% of pediatric GBS cases present with pain.¹⁹ In this study, six pediatric patients had clinical manifestations of pain. Although the majority of GBS patients can achieve complete recovery, severe disability and death can also occur.¹⁹ Remarkably, only 11 pediatric GBS cases achieved full recovery in this study.

Regarding relevant laboratory examinations, the examination of cerebrospinal fluid (CSF), electrophysiological examination, and test of anti-ganglioside antibodies are considered highly informative. However, specific and detailed laboratory test results were only available for 10 GBS cases from the literature. Conversely, the remaining 35 GBS cases from the VAERS System lacked these essential details. Out of the 10 cases with available data, 8 patients (8/10) tested positive for albuminocytologic dissociation, 1 tested negative, and 1 case was not tested. The detailed laboratory examinations of those 10 GBS cases from the literature are summarized in Table 1.

Anti-ganglioside antibodies are the only disease-specific autoantibodies generally recognized in patients with GBS.²⁰ Serum antiganglioside antibodies can be detected in up to 60% of patients with GBS during the acute clinical phase.²¹ Importantly, anti-ganglioside antibody is linked to specific GBS variants, and anti-GM1 and anti-GQ1b antibodies have been associated with pure motor function in patients with GBS and MFS, respectively. Anti-GT1a antibodies are associated with the pharyngocervical-brachial variant of GBS.²² The pathogen-induced production of antibodies against peripheral nerve components (especially gangliosides) provoked by the pathogen is believed to play an important role in the pathogenesis.² On the other hand, antiganglioside antibodies have been detected in individuals vaccinated with Pandemrix.²³ Therefore, GBS after vaccination may exhibit an immunological pattern similar to that of GBS following an infection. However, among 45 GBS cases, antibodies against gangliosides were only positive in one patient (1/45), negative in one patient (1/45), and not mentioned in the remaining 43 GBS patients. Testing for antibodies against gangliosides in the present study was negative which was unfavorable to the GBS diagnosis.

Conclusion

To the best of our knowledge, this is a rare case of presumptive pediatric GBS following DTaP vaccination in China. We report this rare presumptive pediatric case of GBS to draw the attention of medical personnel to similar events after vaccination. The serious consequence of GBS following vaccination usually involves concerns regarding vaccine safety and subsequent civil compensation issues. However, the causal relationship between vaccines and GBS remains difficult to clarify. Second, we reviewed all 45 GBS cases after the DTP vaccines (or tetanus toxoid-containing vaccines) reported in the literature and VAERS system. GBS cases after vaccination were consistent with the temporal pattern of GBS following infection. We also analyzed the onset time after vaccination, preceding symptoms, the detection rate of antiganglioside antibodies and other basic clinical presentations of GBS after DTP vaccination (or tetanus toxoid-containing vaccines) to further investigate the association between GBS and DTP vaccination. Testing for antiganglioside antibodies in GBS should be taken seriously as they can both confirm clinical suspicion and suggest the pathogenic mechanism of GBS.

There are several limitations in the present study. Firstly, although we consider the clinical data to strongly support the diagnosis of GBS, we recognize that GBS is a diagnosis of exclusion and that the absence of anti-gangliosideganglioside antibodies weakens the attribution. Secondly, the attribution of causality to the antecedent DTaP injection depends largely on timing and the failure to identify another known trigger, but we recognize that a trigger is not clearly identified for most cases of GBS. Lastly, the VAERS system, as a passive reporting system, lacks both denominator data as well as comprehensive systemic clinical information including essential laboratory test results which affects the collection of clinical data in this report.

Ethical approval

All data and sample collections were handled in strict accordance with the ethical guidelines of the Tongji Medical College, Huazhong University of Science and Technology.

Patient consent for publication

Informed consent was obtained from the patient’s relatives for the publication of this case report.

Acknowledgments

We would like to thank Editage (www.editage.cn) for English language editing.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request https://vaers.hhs.gov/data.html.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.