(2) Hospital General Dr. Manuel Gea González. México DF, México.
(3) Hospital Español. México DF, México.
(4) Secretaría de Salud. México DF, México.
Objetivo. Conocer la epidemiología de la enfermedad neumocócica invasora (ENI) en un hospital pediátrico y analizar los factores de riesgo relacionados con la mortalidad, la distribución de serotipos y el patrón de susceptibilidad de S. pneumoniae. Material y métodos. Revisión retrospectiva de los casos de ENI en un hospital pediátrico de tercer nivel, entre 1997 y 2004. Resultados. En 156 pacientes la mortalidad fue de 27.5%. Los serotipos de neumococo más frecuentemente relacionados con la mortalidad fueron: 14, 6B, 23F, 6A, 19F y 19A; no hubo relación de mortalidad con la resistencia a antibióticos. El 28.2% mostró resistencia a penicilina y 24.6% a cefotaxima. A través del modelo multivariado, se encontró una relación estadísticamente significativa entre la mortalidad y enfermedad previa (IC 95%; 2.5-18.3; p<0.05). Conclusiones. La mortalidad asociada a la ENI tuvo relación significativa con antecedente de una enfermedad previa y con seis serotipos, cinco incluidos en la vacuna neumocócica conjugada 7-valente.
Objective. To assess the epidemiologic characteristics of invasive pneumococcal diseases (IPD) among a population in a pediatric hospital in Mexico City and analyze mortality-related risk factors, serotype distribution and antibiotic susceptibility related to S.pneumoniae. Material and Methods. We performed a retrospective review of IPD cases at a third level pediatric hospital between 1997-2004. Results. A total of 156 patients were included. The mortality rate was 27.5% and was associated with six pneumococcal serotypes: 14, 6B, 23F, 6A, 19F and 19A. There was no relationship between mortality and antimicrobial susceptibility pattern. A total of 28.2% of isolates were resistant to penicillin and 24.6% were resistant to cefotaxime. A statistically significant relationship was observed between mortality and previous underlying disease (CI 95%; 2.5-18.3; p< 0.05) using a multivariate logistic regression model. Conclusions. Our outcomes show that IPD mortality in our population is closely related to underlying disease and to six serotypes, five of which are included in the 7-valent pneumococcal conjugate vaccine.
The annual incidence of the disease in industrialized countries where the 7-valent pneumococcal conjugate vaccine (PCV7) is not universally administered is 160 cases per 100 000 inhabitants.1 Attack rates are 1-2 per 1000 children for the invasive form of pneumococcal disease, with Streptococcus pneumoniae isolated in children less than 2 years of age.1 Nevertheless, the current Streptococcus pneumoniae disease attack rate, both invasive and non-invasive, is underestimated because the real load is determined by pneumonia and otitis media, conditions that are not regularly reported.8,9 In addition, many invasive infections caused by pneumococcus are bacteremias with no apparent infectious focus.
We performed a retrospective review of patients who had S.pneumoniae isolated in a sterile site [cerebrospinal fluid (CSF), blood, pleural fluid, peritoneal fluid, synovial secretion] from January 1997 to August 2004 and who had no history of vaccination with PCV7, since this vaccine has only been applied since 2007 as part of nationwide vaccinations in Mexico. The protocol was submitted to the Institutional Research Committee and approval of this clinical study was obtained. The following variables were reviewed: age in months, gender, attendance in daycare centers, nutritional status, previous health status, use of beta-lactam antimicrobials within 30 days of condition onset, and isolation. We analyzed the relationship between age (younger than 24 months), previous health status, S. pneumoniae serotype, antimicrobial susceptibility and beta-lactam antimicrobials mortality rate. The mortality risk was the most important variable in the study.
Pneumococcus was identified by standardized microbiological methods. Penicillin and cefotaxime susceptibility tests were conducted with the microdilution method as established by the Clinical and Laboratory Standards Institute (CLSI before NCCLS).20 The serotyping was conducted using Quellung reaction with serum produced by the Statens Institute (Copenhagen, Denmark); the serogroup and serotype were identified according to Danish nomenclature.21 All these procedures were conducted in a specialized reference laboratory for streptococcal disease in the Hospital Infantil de México Federico Gomez, in Mexico City.
Pneumococcal meningitis: any patient with neurologic findings compatible with meningitis and pneumococcal growth in the CSF culture associated with cytochemical abnormalities (low glucose, elevated proteins and increased cellularity with polymorphonuclear predominance). Pneumococcal bacteremia: a positive blood culture in a patient with fever and no localized infectious source. Pneumonia with effusion: a patient with clinical and/or radiological data compatible with pneumonia and/or effusion and positive blood and/or pleural fluid cultures. Pneumococcal peritonitis: isolation of S. pneumoniae in the peritoneal fluid or in blood from a patient with acute peritonitis and/or compatible cytochemical abnormalities of the peritoneal fluid. Pneumococcal septic arthritis: a patient with arthritis and pneumococcus isolated from synovial fluid.
A retrospective review was conducted to assess risk factors associated with mortality. All values are expressed as mean and percentage. Differences between groups were estimated using the X2 test. Progression to death was estimated with a multivariate logistic regression model, considering p<0.05 a statistically significant difference. The logistic regression analysis was performed with the SPSS 12 program.
From January 1997 to August 2004, 156 IPD cases were identified in 156 patients with the following ages: 41% were under 2 years of age and 59% were over 2 years of age, 1.8% were under two months of age, and median age was 24 months with a mean of 45.7 months (range: 1 -170 months).
Ten percent had a history of daycare attendance and 29.4% of those were previously healthy patients.
A total of 30.7% of the patients were previously healthy and 69.3% had an underlying disease. IPD distribution among these can be observed in Figure 1.
The more frequent IPD syndromes in healthy subjects (30.1%) were meningitis (16/156; 10.3%) and complicated pneumonia (15/156; 9.6%), followed by bacteremia without apparent infectious source (13/156; 8.3%). Two patients experienced peritonitis (1.3%) and one patient had arthritis (0.6%). Among patients who had underlying disease (69.9%), the most frequent IPD syndrome was bacteremia without apparent infectious source (37.8%), followed by meningitis (15.4%), pneumonia (7.7%), peritonitis (5.8%) and arthritis (3.2%).
We observed that meningitis and peritonitis were more significant for the group with underlying disease than for the healthy patients (p>0.05) (Table 1).
In our total sample of patients, no statistically significant relationship was found between previous attendance in nurseries or daycare centers and IPD risk; this was also true for previous nutritional status.
Nutritional status at the moment of IPD diagnosis was 45% eutrophic and 55% malnutrition, 13.7% of which had third degree malnutrition according to the Gómez rating scale.23 Of the previously healthy patients, 84.6% had no type of malnutrition, 13.5% of patients experienced first degree malnutrition and 1.9% second degree malnutrition.
A total of 53.6% of the children included in the study had received beta-lactam antibiotics (cephalothin, cephalexin, cefuroxime, ceftriaxone, amoxicillin and/or amoxicillin/clavulanate). A statistically significant relationship was found between the history of previous use of beta-lactam antibiotics and penicillin and third generation cephalosporin resistance (OR 5.4; 95% CI 2.4-16.1; p < 0.05).
The distribution was: occult bacteremia 74/156 (47.5%), mean age 41.1 months; meningitis 40/156 (25.6%), mean age 34.1 months; pneumonia 25/156 (16%), mean age 43.7 months; peritonitis 11/156 (7.1%), mean age 92 months; arthritis 6/156 (3.8%), mean age 42.6 months (Table 1).
A statistically significant relationship was found between meningitis and underlying disease (p>0.05), and we therefore believe that this is why we found so many meningitis cases among children who were over 2 years of age.
The distribution for the nine most frequent serotypes, in decreasing order, was: 23F, 19.5%; 6B, 10.4%; 19F, 9.5%; 6A and 14, 8.5% each; 19A and 9V, 5.5% each; and finally 5 and 11D, 4.9% each.
The five most frequently isolated serotypes in previously healthy children were: 6B, 5.8%; 14, 5.1%; 5, 3.2%; 19F, 3.2% and 4, 2.6%. In children with previous underlying conditions they were: 23F, 18.3%; 6A, 8.5%; 19F, 6.5%; 6B, 4.9%; and 14, 3.7%. We found a statistically significant relationship (p<0.05) between the IPD serotype 23F and underlying disease and previously healthy patients. No statistically significant relationship was found with health status for the remaining serotypes.
Dispersion variables showed a statistically significant relationship (p<0.05) among different serotypes and the type of disease caused.
Out of 40 S. pneumoniae isolated in CSF (meningitis), 61% were penicillin-susceptible and 39% were penicillin resistant. In the case of cefotaxime, 65.4% susceptible isolates were found and 34.6% were resistant (3.8% with intermediate susceptibility and 30.8% resistant). The most frequent serotypes that were penicillin resistant, in decreasing order, were: 14 (28%) 19F, 6B and 23F (16% each), 15C (8%) and 6B (14.2%). Cefotaxime non-susceptible serotypes were: 23F (33.3%), 19F, 14 and 6B (22.2%, each).
Out of 116 non-meningitis isolates of S. pneumoniae, 83.5% were penicillin-susceptible and 16.5% were penicillin resistant (12.2% with intermediate susceptibility and 4.3% were highly resistant). The most frequent serotypes that were penicillin resistant, in decreasing order, were: 6B (31.6%), 14, 23F and 19F (15.8% each), 9V (10.4%), 3 and 5 (5.3% each).
In the case of cefotaxime, 90 susceptible isolates were found (77.6%) and 26 (22.4%) were resistant (71.8% with intermediate susceptibility and 28.2% resistant). Cefotaxime non-susceptible serotypes were: 23F (33.4%), 19F (23.1%), 14 (15.3%) 6B (10.3%), 9V (7.7%), 19A (7.7%) and 18A (2.6%).
A total of 61 isolates of S. pneumoniae in patients with a history of beta-lactam therapy were resistant as follows: 51 (31.1%) to penicillin, 17 (10.4%) to cefotaxime and 11 (6.7%) to other beta-lactam.
A statistically significant relationship was found between serotypes 23F, 19F, 14 and 6B and non-susceptibility to penicillin and cefotaxime (Figure 2). No statistically significant relationship was found in the remaining serotypes with regard to non-susceptibility to these antimicrobial agents.
Overall mortality was 27.5% (43/156); 81.4% had an underlying disease and 18.6% was previously healthy. A statistically significant relationship was found between mortality and underlying disease (OR 5.4; 95% CI 2.5-18.3; p < 0.05) (Table II). Patients with IPD who correlated with a greater mortality risk had bacteremia and meningitis (OR 2.3; 95% CI 0.9 -6) (Table III). Of the isolates from patients who died, 40.8% were non-penicillin-susceptible and 18.6% were non-cefotaxime-susceptible. No statistically significant relationship was found between antimicrobial susceptibility and mortality.
Serotypes more highly related to mortality were: 14(16.7%), 6B(16.7%), 23F(14.6%), 6A (12.5%), 19F(6.3%), 19A(6.3%), 9V (4.1%), 18C (4.1%) and 10A (4.1%) (p< 0.005).
In the present study, we analyzed 156 S. pneumoniae isolates in 6 years, we found 27 serotypes, 59% are including in PCV7, 68.6% in PCV10, and 81.4% in PCV13.
The most frequent serotypes isolated in this group were: 23F (20.5%), 6A (10.9%), 19F (10.3%), 6B (9%), 14 (9%), 9V (5.6%), 19A (5.6%), 5 (5.1%), and 11D (5.1%). These results are different than those of the SIREVA study, in which they included 8 993 S. pneumoniae serotype isolates from 10 Latin American countries (including Mexico).
Compared to the Mexican SIREVA study during a similar period (2000-2005),10 we found that only 41% of our children was younger than 2 years of age, as opposed to 77.8%. Said difference may be related to the kind of patients in the study (our patients were from only one Mexico City reference hospital and 68.9% had underlying disease). Nevertheless, we must be cautious when trying to make a comparison with our results, since geographical contrasts can result in some variations among the different serotypes. Whereas we present data from 156 cases of S. pneumoniae isolated from invasive pneumococcal disease in a single concentration hospital in Mexico City, the SIREVA data is based on 728 cases from different cities in Mexico.
Regarding gender, in this study, similar to other studies,8,9,28,33 we found more male cases (1:1-5), but we didn't find statistic association between genders from both age groups and the mortality risk.
Since most (62.5%) mortality-related serotypes are included in the serotypes contained in the PCV7, they could be prevented by the vaccination.
Of the isolated serotypes in patients who died due to IPD, 62.5% are included in PCV7, 66.7% are included in the 10-valent pneumococcal conjugate vaccine (PCV10), and 85.4% in the 13-valent pneumococal conjugate vaccine (PCV13).
Regarding antibiotic susceptibility, 74.2% of the penicillin resistant serotypes are included in PCV7, 77.1% would be covered by PCV10 and 93.4% by PCV13. Of the cefotaxime resistant serotypes, 71.8% are covered by PCV7, 78.9% by the experimental PCV10 and 91.7% by the experimental PCV13.
The results we are reporting are based on experience in a third level pediatric hospital, thus they may not reflect IPD epidemiological behavior throughout the country or its relationship with prevalent serotypes. It is therefore critical to create surveillance programs to generate nationwide data before the universal application of conjugate vaccines, which are already in process in Mexico.
Invasive pneumococcal disease in Mexican children in a third level hospital is a significant cause of morbidity and mortality since it is a sizeable disease among children with previous underlying disease. The key to the control of this disease is the introduction of conjugate vaccines that are effective in children under 2 years of age, those with the greatest IPD incidence. In Mexico, the recent universal introduction of PCV7 addresses this problem.
1. Centers of Disease Control and Prevention. Prevention of pneumococcal disease. Recommendations of the Advisory Committee on Immunization Practice (ACIP). MMWR Morb Mortal Wkly Rep 1997;46 (RR-8):1-24.
2. Centers of Disease Control and Prevention. Preventing pneumococcal disease among infants and young children: recommendations of the Advisory Committee on Inmunization Practices (ACIP). MMWR 2000;49 (RR-09):1-35.
3. Syriopoulou V, Daikos GL, Soulis K, et al. Epidemiology of invasive childhood pneumococcal infections in Greece. Acta Pediatr Suppl 2000;89:30-34.
4. Bedford H, de Louvois J, Halket S, Peckham C, Hurley R, Harvey D. Meningitis in infancy in England and Wales: followup at age 5 years. BMJ 2001;323:533-536.
5. Yu VL, Chiou CC, Feldman C, Ortqvist A, Rello J, Morris AJ, et al. An international prospective study of pneumococcal bacteremia, correlation with in vitro resistance, antibiotics administered, and clinical outcome. Clin Infect Dis 2003;37:230-237.
6. Levine OS, Farley M, Harrison LH, Lefkowitz L, McGeer A, Schuchat A. Risk factors for invasive pneumococcal disease in children: a population–based case-control study in North America. Pediatrics 1999;103:E28.
7. Rückinger S, von Kries R, Siedler A, van der Linden M. Association of serotype of Streptococcus pneumoniae with risk of severe and fatal outcome. Pediatr Infect Dis J 2009;28:118-122.
8. Turner RB, Lande AE, Chase P, Hilton N, Weinberg D. Pneumonia in Pediatrics outpatients: cause and clinical manifestations. J Pediatr 1987; 111:194-200.
9. Lee GM, Harper MB. Risk of bacteremia for febrile young children in the post-Haemophilus influenzae type b era. Arch Pediatr Adolesc Med 1998; 152:624-628.
10. Castañeda E, Agudelo IC, Regueira M, Corso A, de Cueto Brandileone MC, et al. Laboratory–based surveillance of Streptococcus pneumoniae invasive disease in children in 10 Latin American countries: a SIREVA II project, 2000-2005. Pediatr Infec Dis J 2009;28;e265-e270.
11. Center for Disease Control and Prevention (CDC). Progress in introduction of pneumococcal conjugate vaccine worldwide, 2000-2008. MMWR Morb Mortal Wkly Rep 2008;57(42):1148-1151.
12. Butler JC, Hofmann J, Cetron MS, Elliott JA, Facklam RR, Breiman RF. The continued emergence of drug-resistant Streptococcus pneumoniae in the United States: An update from the Centers for Disease Control and Prevention´s Pneumococcal Sentinel Surveillance System. J Infect Dis 1996; 174(5):986-993.
13. Appelbaum PC. Resistance among Streptococcus pneumoniae: implications for drug selection. Clin Infect Dis 2002;34:1613-1620.
14. Hortal M, Lovgren M, de la Hoz F, Agudelo CI, Brandileone MC, Camou T et al. Antibiotic resistance in Streptococcus pneumoniae in six Latin American countries: 1993-1999. Surveillance Microb Drug Resist 2001;7: 391-401.
15. Eskola J, Black S, Shinefield H. Pneumococcal conjugated vaccines. In Plotkin SA, Orstein WA, eds. Vaccine 4th ed Philadelphia WB Saunders. 2004: 539-524.
16. Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR., et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern Californi Kaiser Permanente Vaccine Study Center Group. Pediatr Infect Dis J 2000;19:187-195.