Rotavirus infection beyond the gut

Figures & data

Figure 1 The “iceberg” model of RV infection proposal: AGE and diarrhea are just the most obvious and frequent clinical picture of the pathology by RV.

Notes: Systemic viral spreading occurs and might produce several other extraintestinal manifestations such as seizures in the CNS (Table 1). Moreover, RV infection may be a trigger for the development of autoimmune pathology in individuals with a specific genetic background through a proposed mechanism of immune tolerance breakdown at early ages.

Abbreviations: AGE, acute gastroenteritis; CNS, central nervous system; RV, rotavirus.

Table 1 Extraintestinal manifestations of RV infection.

1. Infectious/extraintestinal symptoms/diseases
Neurological symptoms
	Benign afebrile convulsionsa
	Febrile convulsions
	Other seizures (febrile or afebrile)
	Epilepsy
	Acute encephalitis
	Acute cerebellitis
	Encephalopathy (with specific white matter pattern on magnetic resonance)
	Transient acute flaccid paralysis
	Opsoclonus-myoclonus syndrome
Neonatal complications
	Neonatal necrotizing enterocolitis
	Cystic periventricular leukomalacia
Splenic lesions (transient or recurrent)
Acute arthritis
Pneumonia
Acute hemorrhagic infantile edema
Systemic inflammatory response
Cutaneous vasculitis
Rhabdomyolysis
Pancreatitis
Hemophagocytic lymphohistiocytosis
Reye or Reye-like syndrome
Disseminated intravascular coagulation
Hepatitis
Myocarditis
2. Autoimmune diseases
Diabetes mellitus
Celiac disease
Opsoclonus-myoclonus syndrome
Myasthenia gravisb
Uveitisb

Notes:

a Most frequent extraintestinal presentation described in the literature.

b Based only on experimental/animal models. The list shows clinical entities different to diarrhea that have been reported or suggested to be related to RV infection, (1) or triggered by RV infection in susceptible subjects (2). These symptoms can be present alone or in combination, with or without diarrhea. See text for further explanations. Adapted from J Infect, 72 Suppl, Rivero-Calle I, Gómez-Rial J, Martinón-Torres F, Systemic features of rotavirus infection, S98–S105, copyright 2016, with permission from Elsevier.²

Abbreviation: RV, rotavirus.

Figure 2 Data from different studies indicating the relation existing between RV vaccination coverage and seizures/convulsions expressed as RRs and their 95% CI.

Notes: RR values below one suggest a heterologous effect or an unforeseen direct effect of the RV vaccine that would favor a lower incidence of seizures/convulsions in the child population. ^aPayne et al⁴ first-ever seizures; ^bPayne et al⁴ all seizures; ^cPardo-Seco et al³ (AKS) in year 2007; ^dPardo-Seco et al³ AKS in year 2010; ^ePardo-Seco et al³ convulsions in year 2007; ^fPardo-Seco et al³ convulsions in year 2012; ^gSheridan et al⁷² any emergency department presentation; ^hSheridan et al⁷² any hospital admission; ⁱSheridan et al⁷² first emergency department presentation; ^jSheridan et al⁷² first hospital admission; ^kPringle et al⁷³ seizure rates; ^lOrrico-Sánchez et al³⁸ vaccine coverage 1%–19%; ^mOrrico-Sánchez et al³⁸ vaccine coverage 20%–39%; ⁿOrrico-Sánchez et al³⁸ vaccine coverage >39; °Burke et al⁷⁴ full vaccination; ^pBurke et al⁷⁴ partially vaccinated; Unpublished data AKS and RV vaccination coverage 1%–14%; Unpublished data AKS and RV vaccination coverage 15%–29%; Unpublished data AKS and RV vaccination coverage >29%; Unpublished data convulsions and RV vaccination coverage 1%–14%; Unpublished data convulsions and RV vaccination coverage 15%–29%; Unpublished data convulsions and RV vaccination coverage >29%.

Abbreviations: AKS, all kinds of seizures; RV, rotavirus.

Figure 3 Interactions in RV pathology: host, microbiota and RV.

Notes: Host background includes genetics through expression of histo-blood groups in epithelia, glycomics with the importance of sugars for RV interaction with host cells, and the IFN pathway, key in immune host defense. Intestinal microbiota composition and metagenome influence the course of RV infection through interactions between commensal microbial flora and pathogen. RV proteins (VP4 and VP7) determined by G and P genotypes and enterotoxin NSP1 play an important role in RV attachment, cell internalization and pathogeny. Overall, effectiveness of RV vaccines may be influenced by all these elements.

Abbreviations: IFN, interferon; RV, rotavirus; NSP1, nonstructural protein1.

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