Pneumococcal meningitis in Cuban children and adolescents: A fifteen years follow up

Pneumococcal meningitis still remains a serious global threat for children and adolescents. The aim of this study was to assess main epidemiological features of Pneumococcal meningitis, some risks for fatality and major pneumococcal serogroup/serotypes and their potential coverage by the available pneumococcal conjugate vaccines. An observational study of 569 confirmed cases (1998-2012) was completed based on surveillance system. Incidence, case-fatality rate and seasonality were estimated. Association of different variables related with dead was assessed by using Relative Risk and its 95% confidence interval with p<0.05 considered as significant. A common protocol was used for the isolation and identification of Streptococcus pneumoniae. Overall incidence reached 1.3 per 105 population, with annual variations. Infants showed the highest incidence (10.7 per/105 population) especially at 4th, 2nd and 6th month of age. Seasonality was confirmed in January-March. Overall case-fatality rate reached 23.2% with highest figures in infants. Delayed hospitalization (≥24 hours) showed association (p>0.05) in 6-11, 12-14 and 1519 years old (Relative Risk=3.61, 3.00 and 3.16 respectively). Proportion of S. pneumoniae isolates covered by commercial pneumococcal conjugate vaccines ranked 53.0-71.4%. Pneumococcal meningitis affects predominantly infants and is particularly lethal in Cuba. Seasonal increase occurs in winter. Hospitalization ≥24 hours may contribute to increase fatality. Main S. pneumoniae serogroups/serotypes circulating among Cuban children and adolescents are included in commercial pneumococcal conjugated vaccines. We emphasize the importance of continuous nationwide surveillance to achieve more comprehensive insights into pneumococcal epidemiology as well as their contribution to the assessment of future immunization strategies.


Introduction
Pneumococcal infections remain a major cause of severe disease in childhood worldwide.The World Health Organization has reported (2007) that most frequent clinical presentations are acute otitis media, bacteraemia, pneumonia, and meningitis, affecting in particular the young children.Globally, Pneumococcal meningitis (Pnm) is the most severe cause of communityacquired bacterial meningitis (CABM) in children aged less than 5 years as declared by Parent et al., (2005).According to Ispahani et al., (2004), the survivors have the highest incidence of sequel among all meningitis.The rising incidence of decreased susceptibility to penicillin and third generation cephalosporins among pneumococci, is also a cause of concern as MacMaster et al., (2002) mentioned.The advent of pneumococcal vaccines provided a potential way of preventing pneumococcal infections effectively.Available pneumococcal conjugate vaccines can induce protection in children aged 2 months and are well-tolerated, decreasing considerably the incidence after their introduction as showed different studies by Clarke (2006), Tsai et al., (2008) and Hsu et al., (2009) Pérez et al., (2010).The purpose of this paper was to describe the main epidemiological features of Pnm in children and adolescents, to assess the association of timely hospitalization with mortality, as well as to determine major serogroups and serotypes of S. pneumoniae responsible for community-acquired meningitis and their potential coverage by the available pneumococcal conjugate vaccines.

Methods
This observational study was based on CABM surveillance data from January 1 st , 1998 to December 31 st , 2012 including 569 Pnm reported cases (compatible clinical picture and the identification of S. pneumoniae directly from cerebrospinal fluid or blood) in Cuban children and adolescents, considering the date of the symptoms onset.The annual incidence was calculated as the number of cases per/10 5 population by using Cuba Census annual population estimates from the Office for National Statistics in Cuba adjusted for age.Case-fatality rate (CFR) was calculated as the fatalities per 100 cases.Seasonal variations were estimated by using Holt-Winters multiplicative test, considering seasonality when observing an increase above the trend of the cases monthly average value.For the purpose of this research it was defined the delayed hospitalization when "the time elapsed between the symptoms onset and the hospitalization was equal or greater than 24 hours", considering that Public Health System implemented in Cuba since 1959, is based on nationwide free and universal health service for every citizen, allowing a prompt hospitalization and high quality medical assistance (Perez et al., 1999).The association between delayed hospitalization and death was estimated through the Relative Risk (RR) and its 95% confidence interval (95% CI) with p<0.05 considered as significant, using either a Chisquared Test or Fisher's Exact Test as appropriate.
The National Reference Laboratory at Institute Pedro Kourí (NRL-IPK) was responsible for the confirmation of S. pneumoniae isolates submitted from the hospitals, following the standard procedure proposed by World Health Organization (2003).For capsular serotyping, it was applied the swelling capsule reaction (Quellung reaction) by using Pneumotest reactive (Staten Serum Institute, Denmark) as recommended by the Pan American Health Organization and the National Health Institute of Colombia (2004).The present study was approved by the Scientific Board at the IPK, but did not require approval from an Ethics Committee because the Cuban Ministry of Public Health is the governmental organization responsible for the collection of infectious disease notifications, hospital discharge records and population or laboratory surveillance.The management of these data for public health purposes does not require a patient's informed consent nor does it require any authorization regarding privacy laws in Cuba.For database analysis we used Excel 2007, EpiInfo 3.4 and Epidat 3.1 software.

Results
Throughout the study it was reported 569 cases of Pnm, for an annual average of nearly 37 cases and a mean age of 3.4 years old (Data not shown).Overall incidence was 1.3 per 10 5 population.Infants showed the highest incidence (10.7 per/10 5 population), followed by children 1-5 years old (2.2 per/10 5 population).The rates in older children and adolescents remained below 1.0, ranking 0.3-0.5 per/10 5 population (Table 1).

Discussion
Results from this study need to be interpreted considering some potential limitations.As occurs in many developing and transitional countries, microbiological identification of the causative microorganism in hospitals was not always possible to achieve, owing to laboratory practices, lack of supplies and/or diagnostic methods, as well as to previous antibiotic therapy.For this reason, the true number of Pnm cases might be slightly higher than reported by surveillance.
However, our study has several important strengths.First, this report represents one of the largest, longest and deepest epidemiological studies of Pnm in children and adolescents registered in Cuba so far.Second, it was based on a nationwide surveillance which was "useful and proficient providing and synthesizing critical and multidisciplinary information, fulfilling all suitable surveillance system attributes" (Perez et al, 2010, p.4), guaranteeing reliability of data.Finally, our research was performed in a geographically well-defined population where medical care for every citizen is nationwide, with total and free access to medical assistance, vaccination, and other health requirements.
S. pneumoniae have been identified as the major and most lethal agent causing bacterial meningitis in many region of the world, mainly in infants, as reported by the World Health Organization (2003), Jeena (2006) and Zaidi et al (2009).The extensive 15-year surveillance in Cuba identified incidence rates similar to those reported in high income countries by Jeena (2006), Vergison et al (2006), Theodoridou et al (2007) and Tsai et al (2008), but lower than those declared by Mwangi et al (2002) and Zaidi et al (2009) in less-developed and transitional countries.Cases in infants during neonatal period were only a few.Beyond this period, the age distribution was analogous to those reported by Ispahani et al (2004).However, the decrease of incidence observed in Cuba, where pneumococcal vaccination has not been implemented to date, is complex to be elucidated only by means of the available surveillance data.Similarly, Pérez et al (2010) has reported an overall decrease of CABM in Cuba, probably as a result of prior nationwide massive and high coverage vaccinations, improvements in prevention and control of this group of diseases after the implementation of the National Prevention and Control Program for Neurological Infectious Syndrome, as well as the continuous development of public health and other social benefits accessible to the population.On the other hand, it could not be totally discarded the coincidence during the analyzed period of a low incidence phase as a part of a larger cyclic variation of disease (periodical long-lasting oscillations), but the available data do not allow to fully confirm this assumption.
After the use of H. influenzae type b conjugate vaccine targeted to children under 2 years old, Dickinson et al (2001) reported a sharp decline of meningitis caused by this pathogen during 1999.
Simultaneously, Pnm increased appreciably from 1999 to 2000 (much more evident in infants), with a slow decrease onward.Explanation of this spiky increase may be multifarious.Most likely, the significant reduction of Hib after conjugate vaccination may have opened a niche for pneumococci, increasing their carriage in population, and therefore the exposure and likelihood to infection and disease as Auranen et  Perez et al (2010) previously mentioned that mortality may depend on some factors: careseeking behaviour in the population, referral practices to hospitals, opportune diagnose, timely and quality of care, underlying conditions on the host and the virulence of the strains.Adequate management of Pnm certainly requires timely hospitalization and treatment.Delay in treatment may increase the risk of an unfavorable outcome as declared by Radetsky (1992).With the criteria accepted for this study, association of delayed hospitalization with fatal outcome was more evident in older children and adolescents, although no statistical significance was found, perhaps because the small number of cases in these groups.Influence of underlying conditions, as reported by Bingen et al (2008), poor and untimely recognition of symptoms (by patients or relatives), extremely virulent strains and other factors might explain these results but will require additional studies to better define.
S. pneumoniae serotype distribution may vary according to geographic region in accordance with previous results of Hausdorf, Siber and Paradiso (2001).In a research study by Gabastou et al (2008), serotypes 14, 6B, 1, 5, 19F and 18C are the most frequent reported in Latin America and the Caribbean region; all are included in 7-valent, 10-valent and 13-valent pneumococcal conjugated vaccines.Lagos et al (2008) in Chile identified serotypes 1 and 5 as the common cause of meningitis.Results in the present study reveal that serogroups/serotypes are coincident with some circulating in the region.Therefore, the use of available pneumococcal conjugated vaccines may induce a decrease of Pnm (and other clinical presentations of pneumococcal disease), preventing fatality, disability and neurological sequel particularly among children and adolescents.
In Cuba it has not been implemented vaccination against S. pneumoniae on a national scale until now, because of economical reasons.Introduction of a suitable pneumococcal conjugate vaccine in the future will reduce significantly the incidence of pneumococcal infections.At that time, the existing epidemiological and microbiological data will be essential as a baseline to compare further changes in behavior of the disease, the circulating serogroups/serotypes, as well as the impact of vaccination.

Conclusion
Meningitis caused by S. pneumoniae affects mostly the infants and is particularly lethal in Cuba.Seasonal increase occurs in dry and cold months.Delayed hospitalization contributes to increase fatality.Main S. pneumoniae serogroups/serotypes circulating in Cuban children and adolescents are included in commercial pneumococcal conjugated vaccines.We emphasize the importance of continuous nationwide surveillance to achieve more comprehensive insights into pneumococcal epidemiology as well as their contribution to the assessment of future immunization strategies.