Guillain-Barré syndrome associated with Zika virus infection in the Americas: a bibliometric study

Dear Editor:

We conducted an extensive bibliometric study into cohorts of patients with Guillain-Barré syndrome (GBS) associated with Zika virus infection. We searched numerous databases including Scopus, Medline/PubMed, Web of Science, Science Direct, Scielo, and Imbiomed.

We selected studies conducted in the Americas and grouped them by country and cohort size; evaluated the methodology used to identify infectious agents (selecting those that screened for Zika virus as a primary objective and other agents [viruses and bacteria] as a secondary objective); and analysed the percentage of patients testing positive for Zika virus, global or average incidence, and the nerve conduction findings reported. We excluded case reports, series of fewer than 5 cases, and cohort studies not reporting serology findings for Zika virus.

We identified 22 studies analysing cohorts of patients with GBS associated with Zika virus infection, published between 2014 and 2017; cohort size varied between studies. Brazil and Colombia had the most studies published (4 and 6, respectively), followed by Puerto Rico and Mexico (3 each), and Venezuela, Jamaica, Grenada, and Martinique (one study each). We found 2 multicentre studies, with participants from different Central and South American countries (Table 1).

Table 1.

Main cohort studies conducted in the Americas.

Year/country	No. patients	Serology panel used	No. patients positive for Zika	Percentage patients with Zika	EMG findings	Authors
2014–2016, Brazil	57	Zika	57	100	NR	Ferreira et al.^1
2015, Brazil	41	Zika, dengue	0	0	AMAN	Styczynski et al.^2
2015, Brazil	38	Zika, dengue, chikungunya	18	47	AIDP	Dourado et al.^3
2017, Brazil	35	Zika, HIV, HSV, hepatitis, CMV, syphilis, chickenpox, EBV	27	77	AIDP	Da Silva et al.^4
2015–2016, Barranquilla, Colombia	47	Zika, dengue, HIV, CMV, Campylobacter (serum), syphilis, hepatitis, Leptospira	21	45	AIDP	Salinas et al.^5
2015–2016, Cúcuta, Colombia	19	Zika	1	5	AMAN	Arias et al.^6
2016, Colombia	68	Zika, dengue 1-4	17	25	AIDP	Parra et al.^7
2016, Sucre, Colombia	23	Zika	16	70	NR	Villamil-Gómez et al.^8
2017, Colombia	21	Zika, dengue, chikungunya	20	95	AIDP	Villa et al.^9
2017, Cúcuta, Colombia	20	Zika, dengue, chikungunya	20	100	AIDP	Uncini et al.^10
2016, Puerto Rico	56	Zika	34	61	AIDP	Dirlikov et al.^11
2016, Puerto Rico	43	Zika, dengue	5	12	NR	González et al.^12
2016, Puerto Rico	36	Zika	19	53	AIDP	Luciano et al.^13
2016–2017, Mexico	34	Zika, dengue, chikungunya, TORCH, Campylobacter (rectal swab RT-PCR), HSV/enterovirus (CSF)	2	6	AIDP	Del Carpio et al.^14
2016, Mexico	8	Zika, dengue, chikungunya	0	0	AIDP	Del Carpio et al.^15
2017, Mexico	7	Zika, dengue, chikungunya, HIV, TORCH, hepatitis B/C, Brucella, Salmonella, Campylobacter (rectal swab RT-PCR), HSV/enterovirus (CSF)	0	0	AIDP	Del Carpio et al.^16
2016, Martinique	30	Zika	23	77	AIDP	Rozé et al.^17
2015–2016, Venezuela	30	Zika	22	73	AMSAN	Navas et al.^18
2016, Jamaica	21	Zika, dengue, chikungunya	2	9	AIDP	Ali et al.^19
2015–2016, Multicentre Latin America	49	Zika, dengue, HIV, CMV, hepatitis, EBV, chikungunya, herpes, Campylobacter (serum), Mycoplasma	10	20	AIDP	Ugarte et al.^20
2015, Multicentre Latin America	24	Zika, dengue, chikungunya, rubella, measles, parvovirus	3	12	NR	Cardoso et al.^21
2016, Grenada	9	Zika, dengue, chikungunya, West Nile virus, yellow fever, Japanese encephalitis	4	44	NR	Brenciaglia et al.^22
Average incidence				42	AIDP

AMAN: acute motor axonal neuropathy; AMSAN: acute motor-sensory axonal neuropathy; AIDP: acute inflammatory demyelinating polyneuropathy; CMV: cytomegalovirus; CSF: cerebrospinal fluid; EBV: Epstein-Bar virus; EMG: electromyography; HIV: human immunodeficiency virus; HSV: herpes simplex virus; NR: not reported; RT-PCR: reverse transcription polymerase chain reaction; TORCH: panel of toxoplasmosis, other, rubella, cytomegalovirus, herpes simplex virus.

Two studies, conducted in Brazil and Colombia, reported Zika virus positivity in every patient with GBS; another found no case of Zika virus infection among the 41 patients studied. Incidence varied in the remaining studies.

Incidence rates were lower in Central America and the Caribbean, but the majority of studies reported rates above 50%; in North America and specifically Mexico, the incidence of positive results dropped considerably, with no association found between GBS and Zika virus infection.

The average rate of Zika virus infection in the cohorts of patients with GBS was 42%.

A meta-analysis including 3 large South American studies estimated the prevalence of GBS associated with Zika virus at 1.23%.²³

In terms of the neurophysiological patterns reported, 12 studies reported acute inflammatory demyelinating polyneuropathy (AIDP), 2 (from Brazil and Colombia) reported acute motor axonal neuropathy (AMAN), and one (Venezuela) reported acute motor-sensory axonal neuropathy (AMSAN).

The serology tests performed vary between studies: 7 only tested for Zika virus, 5 studied the 3 main arboviruses (Zika, dengue, and chikungunya), and 3 studied Zika and dengue viruses only; others additionally searched for other viruses and bacteria, with Campylobacter and the TORCH panel (toxoplasma, other, rubella, cytomegalovirus, and herpes simplex) being the most frequent.

The association between Zika virus infection and GBS is variable, even between studies conducted within the same geographical region; we are therefore unable to reliably establish a causal relationship. As the Zika outbreak spread towards Central America and the Caribbean, incidence of Zika virus infection among patients with GBS decreased, approaching zero in North America.

The predominant neurophysiological pattern was AIDP. AIDP is the most frequent pattern in infectious processes and the predominant type observed in Europe and North America, whereas AMAN is usually more frequent in Mexico and Central and South America; this was not the case in these cohorts. AMSAN was predominant in a study conducted in Venezuela; this pattern has not previously been reported in the region.²⁴

In conclusion, there is a need for additional clinico-epidemiological studies following a uniform protocol that may be applied and reproduced in any population; this would include testing for known pathogens of significant incidence (e.g., Campylobacter); major neurotropic arboviruses such as dengue, Zika, and chikungunya viruses; the TORCH panel; enteroviruses; and West Nile virus, among others.