Antecedentes Nacionales

Invasive GBS disease in young infants has a high mortality ratio and significant morbidity in young infants. The meta-analysis by Edmond et al. reported a global mortality for invasive GBS disease to be 9.6%, with case fatality ratios as high as 33% in low income countries like Malawi (Edmond et al., 2012). In this meta-analysis, the case fatality ratio was highest in Africa (22%) compared to Europe (7%) and Americas (11%). In a separate review, Dagnew et al. reported case fatality ratios as high as 60% for invasive GBS disease in low-middle income countries (Dagnew et al., 2012). In South Africa, the case fatality ratio has been reported to be as low as 6% in the Western Cape, (Frigati et al., 2014) but consistently higher (16.9%-17.8%) in Soweto (Madhi et al., 2003, Cutland et al., 2015). In addition, GBS meningitis carries a poorer outcome than sepsis alone, with 4-6 fold higher mortality in low-middle income countries compared to high-income countries (Furyk et al., 2011). The higher mortality in low-middle income countries may be attributed to a number of factors including limited access to resources, resource utilization and quality of care. In contrast, reductions in the mortality attributable to invasive GBS disease in high income countries has largely been due to ready access to antibiotics and the successful

implementation of preventative strategies (Dermer et al., 2004).

In infants surviving invasive GBS disease, neurological sequelae are thought to result from direct damage to the developing brain from GBS meningitis or from cerebral hypo-

perfusion during GBS related septic shock episodes (Law et al., 2005). In addition, GBS precipitates preterm deliveries, which in itself contributes to neurological sequelae. There are limited studies describing the neurological outcomes of infants surviving invasive GBS

disease and GBS meningitis. Of 1037 bacteraemic episodes in neonates with or without meningitis, Chu et al. reported neurological complications in 3.5% of neonates, 41.7% of which were caused by GBS (Chu et al., 2014). A retrospective review of infants with GBS meningitis at hospital discharge between 1998 and 2006 in the USA reported poor

neurological outcomes in 11/50 (22%) survivors of EOD and LOD. Infants had clinical signs such as: hypotonia (n=2), hypertonia (n=9), seizures (n=10), clonus (n=2), dysphagia (n=3), ptosis (n=2), cortical blindness (n=1), hearing loss (n=2) and temperature instability (n=1) (Levent et al., 2010). In a multivariate analysis, seizures before or at presentation was found to be the most useful marker of poor neurological outcome at discharge. These findings were similar to a meta-analysis of eight studies in high income countries which showed that 23% (range: 16-38%) of survivors of neonatal meningitis have moderate to severe neurological impairment (Seale et al., 2014).

The drawback of short-term outcome studies, however, is the failure to recognise infants with mild development delay or learning problems. Consequently, a series of studies have addressed the long-term neurological outcomes from GBS meningitis. Edwards et al. has summarised studies (prior to 1985) reporting on GBS meningitis outcomes: an average fatality of 27% was noted and up to one-third of survivors had neurological sequelae measured at different age time points (Edwards et al., 1985). Table 1.1 further summarises studies reporting on long-term neurological sequelae of GBS meningitis survivors from 1985 onwards (Edwards et al., 1985, Wald et al., 1986, Bedford et al., 2001, Libster et al., 2012). Although studies have used different standards and tools for assessing neurological sequelae, all these studies were carried out in well-resourced high-income countries. Overall, 213 children between 3 and 18 years were evaluated in these four studies, with 95

(45%) displaying neurological sequelae, including 19% with severe sequelae which includes cerebral palsy, severe seizures, visual and auditory impairments.

The high morbidity associated with invasive GBS disease is also coupled with a significant economic burden that is almost double in the first two years of life following invasive disease (Platt et al., 1999, Schroeder et al., 2009). Comparing invasive GBS cases to controls, the main cost drivers were a high level of care and duration of hospitalization. Although long term neurological sequelae have not been assessed in low-middle income countries with limited resources, the heightened cost of treating GBS invasive disease may further exacerbate the poorer outcomes seen in these settings.

Table 1.1: Summary of studies reporting long-term outcomes amongst survivors of Group B Streptococcus meningitis Author date country GBS meningitis; n= Demised; n= Assessed for neurological impairment; n= Ages at follow-up

assessment Neurological impairment

normal mild-moderate severe

Edwards 1985 USA1 (Edwards et al., 1985) 61 13 (21%) 38 3.3-9years (Mean age- 6 years) 19 (50%) 8 (21%)

Unilateral sensorineural deafness (2); borderline mental retardation (2); spastic or

flaccid monoparesis (3); hydrocephalus, arrested (2); seizure disorder, controlled ( 1 );

expressive or receptive speech and language delay (2); porenecephalic cyst (1); mild frontal cortical atrophy (1); deficit in visual

and auditory memory (1).

11 (29%)

Global mental retardation (7); relapse of GBS meningitis (1); uncontrolled seizures (6); cortical blindness (6); microcephalus (3);

hydrocephalus (3); spastic or flaccid quadriparesis (3); central diabetes insipidus

(1); mild mental retardation (3).

Wald 1986 USA (Wald et al., 1986)

74 20 (27%) 34 (Mean age- 3-18years 8.6 years)

9 (26%)

spastic quadriplegia (4); profound mental retardation (8);hemiparesis (1); deafness (4);

cortical blindness (2); seizure disorder (7); hydrocephalus (6). Bedford 2001 UK2 (Bedford et al., 2001) 98 98 5 years 50 (51%) 35 (36%)

Moderate: disability impaired their functioning but attended mainstream schools;

mild neuromotor disabilities; intellectual impairment; moderate sensorineural hearing

loss; mild or moderate visual impairment; epilepsy that was controlled with treatment;

hydrocephalus without complications.

13 (13%)

Unable to attend a mainstream school; severe neuromotor impairment; significant intellectual impairment; severe seizure

disorders; severe visual or auditory impairment. Libster 2012 USA (Libster et al., 2012) 90 5 (6%) 43 3-12 years (Mean age- 6.8 years) 43 (56%) 11 (25%)

Impairment based on Mullen or WIAT-II score (9); grade retention (3); persistent

asymptomatic seizure disorder (3); hydrocephalus with ventriculoperitoneal

shunt (1); loss of terminal digit of right thumb and forefinger (1).

8 (19%)

Profound global developmental delay (8); hydrocephalus (2); cortical visual impairment

(4); bilateral sensorineural deafness (4); cerebral palsy/spasticity (5); persistent

symptomatic seizures (4).