52 Original article
Pneumococcal infection among hospitalized Egyptian children Iman H. Draza, Eman F. Halawaa, Ghada Wahbyb, Dalia K. Ismailc and Bassant S. Meligya Departments of aPediatric, bPublic Health and cClinical and Chemical Pathology, Cairo University, Cairo, Egypt Correspondence to Iman H. Draz, Department of Pediatric, Cairo University Pediatric Hospital, El Rasheed st., El Monira, El Sayeda Zeinab, Cairo 11562, Egypt Tel: + 20 115 097 8888; fax: +20 022 364 9281; e-mail: [email protected]
Received 2 March 2015 Accepted 13 April 2015 Journal of the Egyptian Public Health Association 2015, 90:52–57
Aim We aimed to describe the detection rate spectrum of clinical manifestations, and outcome of pneumococcal disease in children younger than 5 years admitted to the largest referral pediatric hospital in Egypt. Materials and methods This was a hospital-based study to detect laboratory-confirmed Streptococcus pneumoniae cases among children younger than 5 years. Data on demographic characteristics, clinical diagnosis, comorbidities, diagnostic tests, antibiotic resistance, and clinical outcome were collected during the study years from 2008 to 2011. Results During the 4-year study period, 22 018 cases younger than 5 years had cultures performed at Cairo University Pediatric Hospital microbiology laboratory. We estimated the annual detection rate of total Streptococcus pneumonia infection to be 54.5/100 000. The incidence of invasive pneumococcal disease (IPD) was half the incidence of non-IPD (18.2 and 36.4/100 000, respectively). Infants of 1 year or younger were statistically more vulnerable to Streptococcus pneumonia infection compared with children between 1 and 5 years of age (annual rate: 110.5/100 000 and 21.6/100 000, respectively). The overall pneumococcal annual case fatality was 33.3% and was higher in IPD (75%) than in non-IPD (12.5%) cases. There was an obviously increasing trend of the pneumococcal detection rate throughout the 4 years of the study (Po0.0001). Conclusion and recommendations Our results confirm the substantial and increasing pneumococcal infection, the emerging of multidrug resistant isolates, and the vulnerability of the younger age group and high-risk population, which calls for a national surveillance to inform policy and decision-making before national wide vaccine introduction. Keywords: Egypt, multi-drug resistance, national surveillance, PCV, pneumococcal infection J Egypt Public Health Assoc 90:52–57 & 2015 Egyptian Public Health Association 0013-2446
Introduction Streptococcus pneumonia is responsible for a wide spectrum of infections in young children, ranging from acute otitis media to sepsis [1]. Noninvasive pneumococcal diseases include bacterial pneumonia, acute otitis media, sinusitis, and, less commonly, surgical wound infection [2]. Invasive pneumococcal diseases (IPD) include bacteremia, sepsis, and meningitis [3]. Pneumococcal disease is a leading cause of child morbidity and mortality worldwide [4]. The WHO estimated the annual pneumococcal mortality among children under 5 years of age to be about one million, most of whom are in developing countries [5]. The reported rates of pediatric IPD per 100 000 ranged from as low as 1.7 (o2 years old) to 4.2 (2–15 years old) in Sweden to a high of 93.5–174 (o2 years old) to 56.2 (o5 years old) in Spain [4]. Adding to the challenge is the steady increase in antimicrobial resistance of S. pneumonia worldwide [6].
national infant immunization programs [3]. Constraints to PCV introduction in low-income and middle-income countries such as Egypt include the high price of new vaccines, competing priorities, limited government budget allocations, lack of data on disease burden – including data on the circulating pneumococcal serotypes in the country – costeffectiveness, and inadequate procurement mechanisms with potential issues for sustainability [7]. Thus, as a step to guide surveillance system development and immunization program in Egypt, we conducted a hospital-based surveillance study, during the period from January 2008 until December 2011, to estimate the annual detection rate of S. pneumoniae infections and identify trends among hospitalized children in Cairo University Specialized Pediatric Hospital, Cairo, Egypt.
Materials and methods Setting
In 2007, the WHO recommended that all countries incorporate pneumococcal conjugate vaccines (PCV) in their 0013-2446 & 2015 Egyptian Public Health Association
This was a hospital-based study to detect laboratoryconfirmed S. pneumoniae cases in Cairo University Specialized DOI: 10.1097/01.EPX.0000465234.31794.b1
Copyright r 2015 Egyptian Public Health Association. Unauthorized reproduction of this article is prohibited.
Pneumococcal infection among children Draz et al.
children Hospital (CUSPH), the largest pediatric hospital in Egypt, which provides health services ranging from primary and preventive to tertiary care. It has a capacity of 520 beds, six ICUs, and an average daily flow of 1300 patients. Antibiotic resistance rates were calculated as the sum of intermediately susceptible and resistant S. pneumoniae divided by the total number of S. pneumoniae tested. Annual detection rates were calculated on the basis of sex, age group, and year of diagnosis by dividing the number of confirmed cases by the corresponding hospitalized child population multiplied by 100 000. Mortality rates were calculated in a similar way. Case fatality was calculated by dividing the deaths associated with pneumococcal disease episodes (IPD and non-IPD episodes) by all cases diagnosed (IPD and non-IPD cases, respectively). Target population
All children younger than 5 years, who were admitted to CUSPH from January 2008 to December 2011 with fever (temperature >381C) and/or a possible clinical diagnosis of meningitis, pneumonia, or septicemia were considered for entry into the study. Clinical and demographic data were collected and entered into a standardized database. Case definition
IPD was defined as pneumococcal infection disseminating the S. pneumoniae into a normally sterile body site (to the bloodstream causing bacteremia, the central nervous system causing meningitis, to the pleural fluid causing effusion, or to the pericardial space causing pericardial effusion). Non-IPD included cases with pneumonia confirmed by sputum culture or identification of S. pneumoniae in other body sites (i.e. surgical wound). Clinical diagnosis of pneumonia was made based on the WHO criteria: age range of 2–59 months, a history of cough or difficulty in breathing and tachypnea (for children between 2 and 12 months of age, respiratory rate >50 breaths/min; for children between 12 months and 5 years of age, respiratory rate440 breaths/min), and no chest indrawing or a danger sign of pneumonia. Patients with severe pneumonia had chest indrawing as well, but no signs of very severe disease. Meningitis was defined as having a sudden onset of fever and at least one of the following signs: stiff neck, altered consciousness, bulging fontanelle (for children < 1 year), prostration or lethargy, convulsions, toxic appearance, petechial or purpural rash, or poor sucking and irritability (for children42 months) [8]. A blood culture sample was collected from each patient upon enrollment, before antibiotic administration if possible. Specimens from other sterile sites (bronchoalveolar lavage, nasopharyngeal aspirate, pleural fluid, and cerebrospinal fluid) were collected as per routine medical practice. The blood culture specimens were collected into commercially prepared blood culture bottles [BACTEC Peds Plus/F; Becton Dickinson (Franklin Lakes, New Jersey, USA)]; the bottles were incubated at 351C and were inspected. Other samples were Gram-stained and examined for direct
53
visualization of the typical morphology of S. pneumoniae. All specimens were inoculated on blood and chocolate agar plates and then incubated for 24–48 h at 351C in a candle jar. Sheep blood was only available during the last study year; otherwise, human blood was the only available source of blood for agar. A three times magnifying hand-held lens was used to differentiate S. pneumoniae from viridans streptococci. Further differentiation was made with optochin disk inhibition zone greater than 14 mm (Becton Dikinson). Verification of some optochin-negative S. pneumoniae strains was carried out using the bile solubility test (S. pneumoniae is bile soluble, whereas all other a-hemolytic streptococci are bile resistant) [9]. Antibiotic susceptibility testing was performed with the Kirby-Bauer disk diffusion method on blood agar plates (Oxoid), in accordance with the Clinical and laboratory standard institute (CLSI) guidelines [10]. Benzyl penicillin MIC was determined using E test strips (Biomerieux SA, Marcy L’Etoile, France). Multidrug resistance (MDR) was defined as nonsusceptibility to more than any three different antibiotic groups [11]. Annual detection rates were calculated on the basis of sex, age group, and year of diagnosis by dividing the number of confirmed cases by the corresponding hospitalized child population multiplied by 100 000. Mortality rates were calculated in a similar way. Case fatality was calculated by dividing the deaths associated with pneumococcal disease episodes (IPD and non-IPD episodes) by all cases diagnosed (IPD and non-IPD cases, respectively). Ethical considerations
The study was approved by the local institutional review board of CUSPH. Informed consent was obtained from patients’ caregivers after proper orientation about the study objectives. Anonymity and confidentiality were guaranteed and maintained, and the biological samples were dealt with safely. Statistical analysis
Significant differences between IPD and non-IPD were tested using the w2 or Fisher’s exact tests (as appropriate) for categorical variables. All P values were two-tailed, with a significant P value at 0.05 or less. SPSS software (release 15.0; SPSS Inc., Chicago, Illinois, USA) was used for all statistical analyses.
Results During the period from 2008 through 2011, a total of 22 018 cases younger than 5 years had at least one culture performed at CHSPC microbiology laboratory. We isolated Streptococcus pneumonia (SP) from 12 patients: four IPD and eight non-IPD. The number and percentage of cases identified as IPD were as follows: meningitis one (25%), septicemia one (25%), and pleural effusion two (50%). The number and percentage of cases identified as non-IPD were as follows: pneumonia (7,87.5%) and postoperative wound infection (1,12.5%) (Table 1).
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Journal of the Egyptian Public Health Association
Table 1. Demographic characteristics and outcome of hospitalized children aged younger than 5 years with pneumococcal disease at Cairo University Specialized Pediatric Hospital, Egypt, 2008–2011 IPD [n (%)]
Non-IPD [n (%)]
Total [n (%)]
P-value
Total 4 (33.3) 8 (66.7) 12 NA Sex Male 3 (75) 6 (75) 9 (75) 0.745w Female 1 (25) 2 (25) 3 (25) Age at diagnosis (years) r1 (n = 8140) 4 (100) 5 (62.5) 9 (75) 0.255w 1–5 (n = 13 860) 0 (0) 3 (37.5) 3 (25) Year of diagnosis 2008 (n = 5548) 0 (0) 1 (12.5) 1 (8.3) 0.861z 2009 (n = 5500) 1 (25) 2 (25) 3 (25) 2010 (n = 5586) 0 (0) 2 (25) 2 (16.6) 2011 (n = 4986) 3 (75) 3 (37.5) 6 (50) Comorbidity (congenital heart diseases and/or immune deficiency) Yes 3 (75) 3 (37.5) 6 (50) 0.273 No 1 (25) 5 (62.5) 6 (50) Outcome Recovery 1 (25) 7 (87.5) 8 (66.6) 0.067 Death 3 (75) 1 (12.5) 4 (33.3) IPD, invasive pneumococcal disease. w Fisher’s exact test was used to detect significant differences. z Yates’ correction of the w2-tests was used to detect significant differences.
Demographic data and outcome of the cases are shown in Table 2. Almost one-third of the total pneumococcal cases were IPD (33.3%). All IPDs and 75% of non-IPDs were diagnosed before the age of 1 year. We estimate the annual detection rate of total SP infection to be 54.5/ 100 000. The incidence of IPD was half the incidence of non-IPD (18.2 and 36.4/100 000, respectively). We reported a statistically significant male predominance to SP infection – both invasive and non-IPD – with an annual incidence of 157.5/100 000, compared with that in the female population with an incidence of 18.3/100 000. Although statistically nonsignificant, it is worth mentioning that most of the patients with IPD (75%) had an underlying disease and eventually died, whereas 37.5% of non-IPD patients reported a comorbidity and 87.5% had a complete recovery without any complication. Infants younger than 1 year were statistically more common to contract the disease in its two studied forms (IPD and NID) compared with children between 1 and 5 years of age. We recorded their annual rate to be 110.5/ 100 000 compared with 21.6/100 000 for the older age group (Po0.001). The overall pneumococcal annual case fatality was 33.3%; it was higher in IPD (75%) than in non-IPD patients (12.5%). No significant differences were noted between male and female patients. All studied cases had previous antibiotic intake before sample collection. Antibiotic resistances are shown in Table 2. IPD isolates showed 50% resistance to benzyl penicillin with MIC greater than 0.12 mg/ml, 75% resistance to ciprofloxacin, and 25% resistance to erythromycin. All isolates were sensitive to oxacillin, vancomycin, trimethoprim/sulfamethoxazole, doxycycline, and clindamycin, and none were MDR. MDR was detected in three non-IPD isolates that were recovered in
2011. The IPD isolates showing resistance to penicillin and the non-IPD isolates showing resistance to oxacillin, penicillin, erythromycin, and trimethoprim/sulfamethoxazole were also isolated in the year 2011 (Table 3). The annual detection rate among hospitalized children showed a significant peak in 2011 and a lower one in 2009. The two peaks were mainly due to increased detection rate of IPD (no IPD cases in 2008 and 2010). There was an obviously increasing trend of the pneumococcal detection rate during the 4 years of the study (Po0.0001) (Fig. 1). P values were less than 0.0001 for IPD, non-IPD, and total pneumococcal infections (the w2-test with Yates’ correction was used to detect significant differences).
Discussion To our knowledge, this is the first study aiming to identify S. pneumoniae burden in Egyptian children. We estimated the annual incidence of IPD to be 18.2/ 100 000, which is comparable to that recently reported in two studies conducted within the region. One was conducted in the United Arab Emirates and the other in Kingdom of Saudi Arabia; both studies were conducted during the prevaccination era [5,12]. Their rates were 13.6 and 17.4 per 100 000 per year, respectively. Our rates of total pneumococcal disease and non-IPD, however, are less compared with that in the Emirati report (54.5/ 100 000 and 36.4/100 000, compared with 172.5/100 000 and 186.0/100 000 per year, respectively). Internationally, there is huge variability in IPD incidence, not only between developing and developed countries but also within industrialized countries [4]. For example, in children younger than 5 years, IPD incidence in Europe (per 100 000) ranged between 7.6 in Switzerland and 56.2 in Spain [13]. Such variability may be caused by differences in surveillance systems, reporting phase (pre-large-scale vs. post-large-scale vaccination), hospitalization policies, reporting methods, availability of diagnostic techniques, and the use of empirical antibiotic therapies [4]. Infants younger than 1 year were statistically more common to contract the disease in its two studied forms (IPD and NID) compared with children between 1 and 5 years of age (Po0.001). Guided by these results we recommend that future vaccination target the population younger than 1 year. There has been a call for the rapid implementation of PCV7 in developing countries, [14] basically based on the vaccine success in Europe and the USA and the two clinical trials that have demonstrated promising efficacy of PCV9 in developing countries [15,16]. Further studies are needed to reveal how these trials would translate upon practice. The IPD rates of the current study, however, are lower compared with prevaccination incidence reports from the USA (23/100 000) [17]. A few studies have reported IPD
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Pneumococcal infection among children Draz et al.
55
Table 2. Antibiotic sensitivity of 11 resistant pneumococcal cases in children aged younger than 5 years at Cairo University Specialized Pediatric Hospital, Egypt, 2008–2011
Total [n (%)] Sulfamethoxazole–trimethoprim Benzathine penicillin Vancomycin Ceftriaxon Oxacillin Erythromycin Tetracyclin
IPD resistant cases
Non-IPD resistant cases
Total
P-value*
3 (27.3) 0 2 0 0 0 1 0
8 (72.7) 3 2 0 0 2 3 0
11 (100) 3 2 0 0 2 4 0
NA 0.255 0.386 NA NA 0.424 0.665 NA
IPD, invasive pneumococcal disease. *Fisher’s exact test was used to detect significant differences.
Table 3. The annual detection rate and case fatality of pneumococcal disease among hospitalized children younger than 5 years admitted at Cairo University Specialized Pediatric Hospital, Egypt, 2008–2011
Annual detection rate per 100 000 Overall Sexa Male Female P Age at diagnosis (years)b r1 415 P Year of diagnosisb 2008 (n = 5548) 2009 (n = 5500) 2010 (n = 5586) 2011 (n = 4986) P Case fatality per 100a Overall Sex Male (n = 5720) Female (n = 16280) P Age at diagnosis (years) r1 41–5 P
IPD
Non-IPD
Total
18.2
36.4
54.5
52.5 6.1 o0.0001
105 12.2 o0.0001
157.5 18.3 o0.0001
49.1 0 o0.0001
61.4 21.6 o0.0001
110.5 21.6 o0.0001
0 18.2 0 54.5 o0.0001
18.2 36.4 36.4 54.5 o0.0001
18.2 54.5 36.4 109.1 o0.0001
75
12.5
33.3
66.7 100 0.750
16.7 0 0.750
33.3 33.3 0.745
75 0 NA all IPD cases r1 year
20 0 0.625
44.4 0 0.255
IPD, invasive pneumococcal disease. a The w2-test was used to detect significant differences. b The w2-test with Yates’ correction was used to detect significant differences.
incidence rates from developing countries and all have been considerably higher (range 111–436/100 000 children aged < 5 years) compared with our data [18–20]. S. pneumoniae is a fastidious organism requiring a blood source for proper isolation testing. Human blood is not a recommended substitute for sheep or horse RBCs as a supplement for blood agar, because it results in unsatisfactory bacterial isolation rates [21]. However, many countries with limited resources, including Egypt, commonly rely on utilization of human blood for preparation of microbiological media due to the high cost and lack of suitable environment for raising these animals. The main source of human RBCs is expired blood from hospital blood banks. There was an obviously increasing trend of the pneumococcal detection rate during the 4 years of the study (Po0.0001) reaching a maximum level in 2011. This peak could be explained by either true increasing S.
pneumoniae infection rates or by a better sensitivity of laboratory tests resulting in increased number of cases in this particular year, which could only be unveiled by future studies bearing in mind the use of sheep RBCs in culture media or PCR. The potential coverage of PCVs against colonization strains in the developing world is not as high as in the USA or Western Europe. A recent study in the Middle East region analyzed the carriage state in children and their parents. They reported that only 34.4% of carried S. pneumoniae isolates in children belonged to serotypes included in PCV7 [22]. Although their study focuses on serotypes collected from carriers only and not invasive disease strains, carriage data has been used to estimate IPD using the relative invasive capacity of the different serotypes [23]. Therefore, serotype identification of S. pneumoniae among the
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Journal of the Egyptian Public Health Association
the general population. It was previously demonstrated that, compared with hospital-based studies, more S. pneumoniae cases can be identified through communitybased studies [26,27]. Moreover, in Egypt, as in many parts of the world, antibiotics are readily available without medical prescriptions. Preculture antibiotic use in the early stage of illness could lower the culture positivity rate. For example, in a bacteremia surveillance conducted in Thailand (2005–2006), it was estimated that antibiotic use reduced pneumococcal bacteremia incidence by 39% in children below 5 years of age [28].
annual detection rate per 100,000
Fig. 1.
120 109.1 100 80 54.5
60
54.5 36.4
40 18.2
36.4
20 18.2 0 2007
2008
2009 2010 Years All pneumococcal infection
2011
2012
IPD
Linear (All pneumococcal infection)
Data of the current study may still represent an underestimate for the reasons explained above and the lack of sheep RBC’s in most of the study period.
Non IPD
Annual detection rate of all pneumococcal infection cases (IPD, invasive pneumococcal disease) per 100 000 hospitalized children younger than 5 years by year of diagnosis at Cairo University Specialized Pediatric Hospital, Egypt, 2008–2011.
Egyptian population is recommended and would provide crucial information for future immunization policy. The risk for IPD is highest among individuals who have immunodeficiency, abnormal innate immune response, absent or deficient splenic function (e.g. SCD or congenital or surgical asplenia), or HIV infection [24]. Children with cochlear implants are also at relatively increased risk for pneumococcal meningitis [25]. In our study, underlying conditions significantly contributed to susceptibility for invasive pneumococcal disease, highlighting the vulnerability of the high risk children to this infection. In low-resource countries such as Egypt, little is known about the serotypes or genotypes that are circulating at the population level; thus, the impact of introduction of different types of PCV in the Expanded Program of Immunization cannot be easily predicted based on the experience of introducing PCV in well-resourced countries. Therefore, substantial national laboratory-based surveillance studies are needed to identify the incidence, circulating serotypes, and antibiotic susceptibility of S. pneumoniae among Egyptian pediatric population before PVC large scale introduction. Furthermore, our findings underscore the importance of cost-effectiveness and costefficiency data in guiding vaccine policy and decision making. Meanwhile, guided by our relatively low rates of S. pneumoniae isolation, we recommend giving the vaccine to Egyptian children who are at-risk for severe morbidity and mortality due to S. pneumoniae. However, the current study has few limitations. Being a hospital-based study conducted in a tertiary center, where patients are likely to have more severe S. pneumoniae disease requiring hospitalization, it may not be representative of the whole spectrum of diseases in
Conclusion and recommendations In conclusion, results of the present study confirm the substantial increase in pneumococcal infection, the emerging MDR strains, and the vulnerability of the younger age group and high-risk population, which calls for a national survey to inform policy and decision-making before massive vaccine introduction.
Acknowledgements Conflicts of interest There are no conflicts of interest.
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Pneumococcal infection among hospitalized Egyptian children Iman H. Draza, Eman F. Halawaa, Ghada Wahbyb, Dalia K. Ismailc and Bassant S. Meligya Departments of aPediatric, bPublic Health and cClinical and Chemical Pathology, Cairo University, Cairo, Egypt Correspondence to Iman H. Draz, Department of Pediatric, Cairo University Pediatric Hospital, El Rasheed st., El Monira, El Sayeda Zeinab, Cairo 11562, Egypt Tel: + 20 115 097 8888; fax: +20 022 364 9281; e-mail: [email protected]
Received 2 March 2015 Accepted 13 April 2015 Journal of the Egyptian Public Health Association 2015, 90:52–57
Aim We aimed to describe the detection rate spectrum of clinical manifestations, and outcome of pneumococcal disease in children younger than 5 years admitted to the largest referral pediatric hospital in Egypt. Materials and methods This was a hospital-based study to detect laboratory-confirmed Streptococcus pneumoniae cases among children younger than 5 years. Data on demographic characteristics, clinical diagnosis, comorbidities, diagnostic tests, antibiotic resistance, and clinical outcome were collected during the study years from 2008 to 2011. Results During the 4-year study period, 22 018 cases younger than 5 years had cultures performed at Cairo University Pediatric Hospital microbiology laboratory. We estimated the annual detection rate of total Streptococcus pneumonia infection to be 54.5/100 000. The incidence of invasive pneumococcal disease (IPD) was half the incidence of non-IPD (18.2 and 36.4/100 000, respectively). Infants of 1 year or younger were statistically more vulnerable to Streptococcus pneumonia infection compared with children between 1 and 5 years of age (annual rate: 110.5/100 000 and 21.6/100 000, respectively). The overall pneumococcal annual case fatality was 33.3% and was higher in IPD (75%) than in non-IPD (12.5%) cases. There was an obviously increasing trend of the pneumococcal detection rate throughout the 4 years of the study (Po0.0001). Conclusion and recommendations Our results confirm the substantial and increasing pneumococcal infection, the emerging of multidrug resistant isolates, and the vulnerability of the younger age group and high-risk population, which calls for a national surveillance to inform policy and decision-making before national wide vaccine introduction. Keywords: Egypt, multi-drug resistance, national surveillance, PCV, pneumococcal infection J Egypt Public Health Assoc 90:52–57 & 2015 Egyptian Public Health Association 0013-2446
Introduction Streptococcus pneumonia is responsible for a wide spectrum of infections in young children, ranging from acute otitis media to sepsis [1]. Noninvasive pneumococcal diseases include bacterial pneumonia, acute otitis media, sinusitis, and, less commonly, surgical wound infection [2]. Invasive pneumococcal diseases (IPD) include bacteremia, sepsis, and meningitis [3]. Pneumococcal disease is a leading cause of child morbidity and mortality worldwide [4]. The WHO estimated the annual pneumococcal mortality among children under 5 years of age to be about one million, most of whom are in developing countries [5]. The reported rates of pediatric IPD per 100 000 ranged from as low as 1.7 (o2 years old) to 4.2 (2–15 years old) in Sweden to a high of 93.5–174 (o2 years old) to 56.2 (o5 years old) in Spain [4]. Adding to the challenge is the steady increase in antimicrobial resistance of S. pneumonia worldwide [6].
national infant immunization programs [3]. Constraints to PCV introduction in low-income and middle-income countries such as Egypt include the high price of new vaccines, competing priorities, limited government budget allocations, lack of data on disease burden – including data on the circulating pneumococcal serotypes in the country – costeffectiveness, and inadequate procurement mechanisms with potential issues for sustainability [7]. Thus, as a step to guide surveillance system development and immunization program in Egypt, we conducted a hospital-based surveillance study, during the period from January 2008 until December 2011, to estimate the annual detection rate of S. pneumoniae infections and identify trends among hospitalized children in Cairo University Specialized Pediatric Hospital, Cairo, Egypt.
Materials and methods Setting
In 2007, the WHO recommended that all countries incorporate pneumococcal conjugate vaccines (PCV) in their 0013-2446 & 2015 Egyptian Public Health Association
This was a hospital-based study to detect laboratoryconfirmed S. pneumoniae cases in Cairo University Specialized DOI: 10.1097/01.EPX.0000465234.31794.b1
Copyright r 2015 Egyptian Public Health Association. Unauthorized reproduction of this article is prohibited.
Pneumococcal infection among children Draz et al.
children Hospital (CUSPH), the largest pediatric hospital in Egypt, which provides health services ranging from primary and preventive to tertiary care. It has a capacity of 520 beds, six ICUs, and an average daily flow of 1300 patients. Antibiotic resistance rates were calculated as the sum of intermediately susceptible and resistant S. pneumoniae divided by the total number of S. pneumoniae tested. Annual detection rates were calculated on the basis of sex, age group, and year of diagnosis by dividing the number of confirmed cases by the corresponding hospitalized child population multiplied by 100 000. Mortality rates were calculated in a similar way. Case fatality was calculated by dividing the deaths associated with pneumococcal disease episodes (IPD and non-IPD episodes) by all cases diagnosed (IPD and non-IPD cases, respectively). Target population
All children younger than 5 years, who were admitted to CUSPH from January 2008 to December 2011 with fever (temperature >381C) and/or a possible clinical diagnosis of meningitis, pneumonia, or septicemia were considered for entry into the study. Clinical and demographic data were collected and entered into a standardized database. Case definition
IPD was defined as pneumococcal infection disseminating the S. pneumoniae into a normally sterile body site (to the bloodstream causing bacteremia, the central nervous system causing meningitis, to the pleural fluid causing effusion, or to the pericardial space causing pericardial effusion). Non-IPD included cases with pneumonia confirmed by sputum culture or identification of S. pneumoniae in other body sites (i.e. surgical wound). Clinical diagnosis of pneumonia was made based on the WHO criteria: age range of 2–59 months, a history of cough or difficulty in breathing and tachypnea (for children between 2 and 12 months of age, respiratory rate >50 breaths/min; for children between 12 months and 5 years of age, respiratory rate440 breaths/min), and no chest indrawing or a danger sign of pneumonia. Patients with severe pneumonia had chest indrawing as well, but no signs of very severe disease. Meningitis was defined as having a sudden onset of fever and at least one of the following signs: stiff neck, altered consciousness, bulging fontanelle (for children < 1 year), prostration or lethargy, convulsions, toxic appearance, petechial or purpural rash, or poor sucking and irritability (for children42 months) [8]. A blood culture sample was collected from each patient upon enrollment, before antibiotic administration if possible. Specimens from other sterile sites (bronchoalveolar lavage, nasopharyngeal aspirate, pleural fluid, and cerebrospinal fluid) were collected as per routine medical practice. The blood culture specimens were collected into commercially prepared blood culture bottles [BACTEC Peds Plus/F; Becton Dickinson (Franklin Lakes, New Jersey, USA)]; the bottles were incubated at 351C and were inspected. Other samples were Gram-stained and examined for direct
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visualization of the typical morphology of S. pneumoniae. All specimens were inoculated on blood and chocolate agar plates and then incubated for 24–48 h at 351C in a candle jar. Sheep blood was only available during the last study year; otherwise, human blood was the only available source of blood for agar. A three times magnifying hand-held lens was used to differentiate S. pneumoniae from viridans streptococci. Further differentiation was made with optochin disk inhibition zone greater than 14 mm (Becton Dikinson). Verification of some optochin-negative S. pneumoniae strains was carried out using the bile solubility test (S. pneumoniae is bile soluble, whereas all other a-hemolytic streptococci are bile resistant) [9]. Antibiotic susceptibility testing was performed with the Kirby-Bauer disk diffusion method on blood agar plates (Oxoid), in accordance with the Clinical and laboratory standard institute (CLSI) guidelines [10]. Benzyl penicillin MIC was determined using E test strips (Biomerieux SA, Marcy L’Etoile, France). Multidrug resistance (MDR) was defined as nonsusceptibility to more than any three different antibiotic groups [11]. Annual detection rates were calculated on the basis of sex, age group, and year of diagnosis by dividing the number of confirmed cases by the corresponding hospitalized child population multiplied by 100 000. Mortality rates were calculated in a similar way. Case fatality was calculated by dividing the deaths associated with pneumococcal disease episodes (IPD and non-IPD episodes) by all cases diagnosed (IPD and non-IPD cases, respectively). Ethical considerations
The study was approved by the local institutional review board of CUSPH. Informed consent was obtained from patients’ caregivers after proper orientation about the study objectives. Anonymity and confidentiality were guaranteed and maintained, and the biological samples were dealt with safely. Statistical analysis
Significant differences between IPD and non-IPD were tested using the w2 or Fisher’s exact tests (as appropriate) for categorical variables. All P values were two-tailed, with a significant P value at 0.05 or less. SPSS software (release 15.0; SPSS Inc., Chicago, Illinois, USA) was used for all statistical analyses.
Results During the period from 2008 through 2011, a total of 22 018 cases younger than 5 years had at least one culture performed at CHSPC microbiology laboratory. We isolated Streptococcus pneumonia (SP) from 12 patients: four IPD and eight non-IPD. The number and percentage of cases identified as IPD were as follows: meningitis one (25%), septicemia one (25%), and pleural effusion two (50%). The number and percentage of cases identified as non-IPD were as follows: pneumonia (7,87.5%) and postoperative wound infection (1,12.5%) (Table 1).
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Journal of the Egyptian Public Health Association
Table 1. Demographic characteristics and outcome of hospitalized children aged younger than 5 years with pneumococcal disease at Cairo University Specialized Pediatric Hospital, Egypt, 2008–2011 IPD [n (%)]
Non-IPD [n (%)]
Total [n (%)]
P-value
Total 4 (33.3) 8 (66.7) 12 NA Sex Male 3 (75) 6 (75) 9 (75) 0.745w Female 1 (25) 2 (25) 3 (25) Age at diagnosis (years) r1 (n = 8140) 4 (100) 5 (62.5) 9 (75) 0.255w 1–5 (n = 13 860) 0 (0) 3 (37.5) 3 (25) Year of diagnosis 2008 (n = 5548) 0 (0) 1 (12.5) 1 (8.3) 0.861z 2009 (n = 5500) 1 (25) 2 (25) 3 (25) 2010 (n = 5586) 0 (0) 2 (25) 2 (16.6) 2011 (n = 4986) 3 (75) 3 (37.5) 6 (50) Comorbidity (congenital heart diseases and/or immune deficiency) Yes 3 (75) 3 (37.5) 6 (50) 0.273 No 1 (25) 5 (62.5) 6 (50) Outcome Recovery 1 (25) 7 (87.5) 8 (66.6) 0.067 Death 3 (75) 1 (12.5) 4 (33.3) IPD, invasive pneumococcal disease. w Fisher’s exact test was used to detect significant differences. z Yates’ correction of the w2-tests was used to detect significant differences.
Demographic data and outcome of the cases are shown in Table 2. Almost one-third of the total pneumococcal cases were IPD (33.3%). All IPDs and 75% of non-IPDs were diagnosed before the age of 1 year. We estimate the annual detection rate of total SP infection to be 54.5/ 100 000. The incidence of IPD was half the incidence of non-IPD (18.2 and 36.4/100 000, respectively). We reported a statistically significant male predominance to SP infection – both invasive and non-IPD – with an annual incidence of 157.5/100 000, compared with that in the female population with an incidence of 18.3/100 000. Although statistically nonsignificant, it is worth mentioning that most of the patients with IPD (75%) had an underlying disease and eventually died, whereas 37.5% of non-IPD patients reported a comorbidity and 87.5% had a complete recovery without any complication. Infants younger than 1 year were statistically more common to contract the disease in its two studied forms (IPD and NID) compared with children between 1 and 5 years of age. We recorded their annual rate to be 110.5/ 100 000 compared with 21.6/100 000 for the older age group (Po0.001). The overall pneumococcal annual case fatality was 33.3%; it was higher in IPD (75%) than in non-IPD patients (12.5%). No significant differences were noted between male and female patients. All studied cases had previous antibiotic intake before sample collection. Antibiotic resistances are shown in Table 2. IPD isolates showed 50% resistance to benzyl penicillin with MIC greater than 0.12 mg/ml, 75% resistance to ciprofloxacin, and 25% resistance to erythromycin. All isolates were sensitive to oxacillin, vancomycin, trimethoprim/sulfamethoxazole, doxycycline, and clindamycin, and none were MDR. MDR was detected in three non-IPD isolates that were recovered in
2011. The IPD isolates showing resistance to penicillin and the non-IPD isolates showing resistance to oxacillin, penicillin, erythromycin, and trimethoprim/sulfamethoxazole were also isolated in the year 2011 (Table 3). The annual detection rate among hospitalized children showed a significant peak in 2011 and a lower one in 2009. The two peaks were mainly due to increased detection rate of IPD (no IPD cases in 2008 and 2010). There was an obviously increasing trend of the pneumococcal detection rate during the 4 years of the study (Po0.0001) (Fig. 1). P values were less than 0.0001 for IPD, non-IPD, and total pneumococcal infections (the w2-test with Yates’ correction was used to detect significant differences).
Discussion To our knowledge, this is the first study aiming to identify S. pneumoniae burden in Egyptian children. We estimated the annual incidence of IPD to be 18.2/ 100 000, which is comparable to that recently reported in two studies conducted within the region. One was conducted in the United Arab Emirates and the other in Kingdom of Saudi Arabia; both studies were conducted during the prevaccination era [5,12]. Their rates were 13.6 and 17.4 per 100 000 per year, respectively. Our rates of total pneumococcal disease and non-IPD, however, are less compared with that in the Emirati report (54.5/ 100 000 and 36.4/100 000, compared with 172.5/100 000 and 186.0/100 000 per year, respectively). Internationally, there is huge variability in IPD incidence, not only between developing and developed countries but also within industrialized countries [4]. For example, in children younger than 5 years, IPD incidence in Europe (per 100 000) ranged between 7.6 in Switzerland and 56.2 in Spain [13]. Such variability may be caused by differences in surveillance systems, reporting phase (pre-large-scale vs. post-large-scale vaccination), hospitalization policies, reporting methods, availability of diagnostic techniques, and the use of empirical antibiotic therapies [4]. Infants younger than 1 year were statistically more common to contract the disease in its two studied forms (IPD and NID) compared with children between 1 and 5 years of age (Po0.001). Guided by these results we recommend that future vaccination target the population younger than 1 year. There has been a call for the rapid implementation of PCV7 in developing countries, [14] basically based on the vaccine success in Europe and the USA and the two clinical trials that have demonstrated promising efficacy of PCV9 in developing countries [15,16]. Further studies are needed to reveal how these trials would translate upon practice. The IPD rates of the current study, however, are lower compared with prevaccination incidence reports from the USA (23/100 000) [17]. A few studies have reported IPD
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Pneumococcal infection among children Draz et al.
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Table 2. Antibiotic sensitivity of 11 resistant pneumococcal cases in children aged younger than 5 years at Cairo University Specialized Pediatric Hospital, Egypt, 2008–2011
Total [n (%)] Sulfamethoxazole–trimethoprim Benzathine penicillin Vancomycin Ceftriaxon Oxacillin Erythromycin Tetracyclin
IPD resistant cases
Non-IPD resistant cases
Total
P-value*
3 (27.3) 0 2 0 0 0 1 0
8 (72.7) 3 2 0 0 2 3 0
11 (100) 3 2 0 0 2 4 0
NA 0.255 0.386 NA NA 0.424 0.665 NA
IPD, invasive pneumococcal disease. *Fisher’s exact test was used to detect significant differences.
Table 3. The annual detection rate and case fatality of pneumococcal disease among hospitalized children younger than 5 years admitted at Cairo University Specialized Pediatric Hospital, Egypt, 2008–2011
Annual detection rate per 100 000 Overall Sexa Male Female P Age at diagnosis (years)b r1 415 P Year of diagnosisb 2008 (n = 5548) 2009 (n = 5500) 2010 (n = 5586) 2011 (n = 4986) P Case fatality per 100a Overall Sex Male (n = 5720) Female (n = 16280) P Age at diagnosis (years) r1 41–5 P
IPD
Non-IPD
Total
18.2
36.4
54.5
52.5 6.1 o0.0001
105 12.2 o0.0001
157.5 18.3 o0.0001
49.1 0 o0.0001
61.4 21.6 o0.0001
110.5 21.6 o0.0001
0 18.2 0 54.5 o0.0001
18.2 36.4 36.4 54.5 o0.0001
18.2 54.5 36.4 109.1 o0.0001
75
12.5
33.3
66.7 100 0.750
16.7 0 0.750
33.3 33.3 0.745
75 0 NA all IPD cases r1 year
20 0 0.625
44.4 0 0.255
IPD, invasive pneumococcal disease. a The w2-test was used to detect significant differences. b The w2-test with Yates’ correction was used to detect significant differences.
incidence rates from developing countries and all have been considerably higher (range 111–436/100 000 children aged < 5 years) compared with our data [18–20]. S. pneumoniae is a fastidious organism requiring a blood source for proper isolation testing. Human blood is not a recommended substitute for sheep or horse RBCs as a supplement for blood agar, because it results in unsatisfactory bacterial isolation rates [21]. However, many countries with limited resources, including Egypt, commonly rely on utilization of human blood for preparation of microbiological media due to the high cost and lack of suitable environment for raising these animals. The main source of human RBCs is expired blood from hospital blood banks. There was an obviously increasing trend of the pneumococcal detection rate during the 4 years of the study (Po0.0001) reaching a maximum level in 2011. This peak could be explained by either true increasing S.
pneumoniae infection rates or by a better sensitivity of laboratory tests resulting in increased number of cases in this particular year, which could only be unveiled by future studies bearing in mind the use of sheep RBCs in culture media or PCR. The potential coverage of PCVs against colonization strains in the developing world is not as high as in the USA or Western Europe. A recent study in the Middle East region analyzed the carriage state in children and their parents. They reported that only 34.4% of carried S. pneumoniae isolates in children belonged to serotypes included in PCV7 [22]. Although their study focuses on serotypes collected from carriers only and not invasive disease strains, carriage data has been used to estimate IPD using the relative invasive capacity of the different serotypes [23]. Therefore, serotype identification of S. pneumoniae among the
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Journal of the Egyptian Public Health Association
the general population. It was previously demonstrated that, compared with hospital-based studies, more S. pneumoniae cases can be identified through communitybased studies [26,27]. Moreover, in Egypt, as in many parts of the world, antibiotics are readily available without medical prescriptions. Preculture antibiotic use in the early stage of illness could lower the culture positivity rate. For example, in a bacteremia surveillance conducted in Thailand (2005–2006), it was estimated that antibiotic use reduced pneumococcal bacteremia incidence by 39% in children below 5 years of age [28].
annual detection rate per 100,000
Fig. 1.
120 109.1 100 80 54.5
60
54.5 36.4
40 18.2
36.4
20 18.2 0 2007
2008
2009 2010 Years All pneumococcal infection
2011
2012
IPD
Linear (All pneumococcal infection)
Data of the current study may still represent an underestimate for the reasons explained above and the lack of sheep RBC’s in most of the study period.
Non IPD
Annual detection rate of all pneumococcal infection cases (IPD, invasive pneumococcal disease) per 100 000 hospitalized children younger than 5 years by year of diagnosis at Cairo University Specialized Pediatric Hospital, Egypt, 2008–2011.
Egyptian population is recommended and would provide crucial information for future immunization policy. The risk for IPD is highest among individuals who have immunodeficiency, abnormal innate immune response, absent or deficient splenic function (e.g. SCD or congenital or surgical asplenia), or HIV infection [24]. Children with cochlear implants are also at relatively increased risk for pneumococcal meningitis [25]. In our study, underlying conditions significantly contributed to susceptibility for invasive pneumococcal disease, highlighting the vulnerability of the high risk children to this infection. In low-resource countries such as Egypt, little is known about the serotypes or genotypes that are circulating at the population level; thus, the impact of introduction of different types of PCV in the Expanded Program of Immunization cannot be easily predicted based on the experience of introducing PCV in well-resourced countries. Therefore, substantial national laboratory-based surveillance studies are needed to identify the incidence, circulating serotypes, and antibiotic susceptibility of S. pneumoniae among Egyptian pediatric population before PVC large scale introduction. Furthermore, our findings underscore the importance of cost-effectiveness and costefficiency data in guiding vaccine policy and decision making. Meanwhile, guided by our relatively low rates of S. pneumoniae isolation, we recommend giving the vaccine to Egyptian children who are at-risk for severe morbidity and mortality due to S. pneumoniae. However, the current study has few limitations. Being a hospital-based study conducted in a tertiary center, where patients are likely to have more severe S. pneumoniae disease requiring hospitalization, it may not be representative of the whole spectrum of diseases in
Conclusion and recommendations In conclusion, results of the present study confirm the substantial increase in pneumococcal infection, the emerging MDR strains, and the vulnerability of the younger age group and high-risk population, which calls for a national survey to inform policy and decision-making before massive vaccine introduction.
Acknowledgements Conflicts of interest There are no conflicts of interest.
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