Table 3. Summary of the evidence on the relation between ZIKV infection and adverse autoimmune outcomes.
Evidence is displayed for each dimension of the causality framework and for each question. Zika virus (ZIKV); Dengue virus (DENV); Guillain-Barré syndrome (GBS); immune-mediated idiopathic thrombocytopaenia purpura (ITP). NA, not applicable; evidence about analogous conditions was not searched systematically; the dimension of consistency used information in items included for all other causality dimensions. the baseline review (BR), Update 1 (U1).
| Question | BR, N | U1, N | Summary |
|---|---|---|---|
| Temporality | |||
| 1.1a | 9 | 17 | Expansion of the evidence. Additional case reports and case series were identified that confirmed that
ZIKV infection preceded adverse autoimmune outcomes 3, 5, 6, 95– 102, 103– 108. |
| 1.1b | 9 | 4 | Expansion of the evidence that on the population level ZIKV precedes GBS or ITP 103, 109– 111. |
| 1.2 | 7 | 14 | Expansion of evidence that the interval between exposure to ZIKV and occurrence of symptoms is
typical for para- or post-infectious autoimmune-mediated disorders 5, 6, 95– 102, 103– 106, 112. |
| Biological plausibility | |||
| 2.1 | 3 | 0 | No additional evidence was identified that ZIKV epitopes mimic host antigens (molecular mimicry). |
| 2.2 | 1 | 0 | No additional evidence was identified that ZIKV infection leads to an increased in detectable
autoreactive immune cells or autoreactive antibodies. |
| 2.3 | 0 | 0 | There is no evidence on other biologically plausible mechanisms of ZIKV infection leading to GBS/ITP. |
| Strength of association | |||
| 3.1 | 1 | 0 | No additional evidence was identified on the association between Zika infection and GBS/ITP at the
individual level. |
| 3.2 | 2 | 4 | Expansion of evidence. GBS incidence increased in several regions, during the same time ZIKV was
circulating 103, 109– 111. |
| Exclusion of alternatives | |||
| 4.1 | 7 | 9 | Confirmation of the evidence where other infections were assessed. However, often previous DENV
infection was reported, and not excluded 4– 6, 95, 98, 101, 103, 104, 111. |
| 4.2 | 0 | 1 | Expansion on the evidence where vaccines were excluded 5. |
| 4.3 | 0 | 5 | Expansion on the evidence where other systemic illnesses were excluded 4– 6, 95, 99, 112. |
| 4.4 | 0 | 2 | Expansion on the evidence where medication, drugs or other chemicals was excluded 99, 112. |
| Cessation | |||
| 5.1 | 0 | 0 | No relevant studies identified that intentional removal or prevention of ZIKV infection in individuals
leads to a reduction in cases with GBS/ITP. |
| 5.2 | 0 | 0 | No relevant studies identified that intentional removal or prevention of ZIKV infection at population level
leads to a reduction in cases with GBS/ITP. |
| 5.3 | 6 | 2 | Expansion. Additionally, in Venezuela and the Dominican Republic, it was shown that GBS cases
decreased with a decrease in reported ZIKV cases 103, 111. |
| Dose-response | |||
| 6.1 | 0 | 0 | No relevant studies identified that the risk and the clinical severity of GBS/ITP are associated with viral
titres. |
| Animal experiments | |||
| 7.1 | 0 | 0 | No relevant studies identified where the inoculation of animals with ZIKV leads to an autoimmune
reaction resulting in peripheral neuropathy or thrombocytopenia. |
| 7.2 | 0 | 0 | No relevant studies identified that other animal experiments support the association of ZIKV infection
and GBS/ITP. |
| Analogy | |||
| 8.1 | NA | NA | No additional studies identified that other flaviviruses or arboviruses cause GBS/ITP. |
| 8.2 | NA | NA | No additional studies identified that other pathogens cause GBS/ITP. |
| 8.3 | NA | NA | No additional studies identified that explain which pathogen or host factors facilitate the development
of GBS/ITP. |
| Specificity | |||
| 9.1 | 0 | 0 | No relevant studies identified that pathological findings in cases with GBS/ITP are specific for ZIKV
infection. |
| Question | v1, N | v2, N | Summary |
| Consistency | |||
| 10.1 | NA | NA | Confirmation that the association between ZIKV cases and cases with GBS is consistently found
across different geographical regions. |
| 10.2 | NA | NA | Confirmation that the association between ZIKV cases and cases with GBS is consistently found
across different populations/subpopulations. |
| 10.3 | NA | NA | No additional studies identified that the association between ZIKV cases and cases with GBS/ITP is
consistently found across different ZIKV lineages/strains. |
| 10.4 | NA | NA | Confirmation that the association between ZIKV cases and cases with GBS is consistently found
across different study designs. |