








key: cord-303904-8ubm0kig
authors: Verhagen, Lilly M.; Gómez-Castellano, Keyla; Snelders, Eveline; Rivera-Olivero, Ismar; Pocaterra, Leonor; Melchers, Willem J.G.; de Waard, Jacobus H.; Hermans, Peter W.M.
title: Respiratory infections in Eñepa Amerindians are related to malnutrition and Streptococcus pneumoniae carriage
date: 2013-06-22
journal: J Infect
DOI: 10.1016/j.jinf.2013.06.010
sha: 
doc_id: 303904
cord_uid: 8ubm0kig

OBJECTIVES: High acute respiratory tract infection (ARTI) rates are observed in indigenous populations. We assessed the role of viral infections and nasopharyngeal bacterial carriage in ARTIs in Eñepa Amerindians from Venezuela. METHODS: In 40 children aged 0–10 years with ARTIs, healthy nearest-age sibling controls and their mothers the presence of Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydophila pneumoniae/psittachi and 15 respiratory viruses was investigated. RESULTS: S. pneumoniae was the most frequently detected pathogen, with carriage rates of 75% and 38% in children and mothers respectively. In children, S. pneumoniae carriage was associated with ARTI risk in multivariate analysis (OR 14.1, 95% CI 1.4–137.7). Viral infections were not associated with ARTI risk. S. pneumoniae carriage was common in children of all ages while viral co-infections were more frequently present in children under 4 years compared to older children (46% vs. 17%, p < 0.01). An increase of one unit height-for-age Z score (i.e. improved chronic nutritional status) was associated with decreased odds of S. pneumoniae colonization in multivariate analysis (OR 0.66, 95% CI 0.44–0.99). CONCLUSIONS: In Eñepa children high S. pneumoniae carriage rates associated with a poor nutritional status contribute to the development of ARTIs.

Acute respiratory tract infections (ARTIs) are among the leading causes of childhood mortality worldwide, responsible for about two million child deaths annually. 1 Pneumonia rates are especially high in lowincome countries and underlying malnutrition is a major risk factor for pneumonia in children from developing countries. 2 Recent estimates suggest that Streptococcus pneumoniae and Haemophilus influenzae together account for more than 50% of childhood pneumonia deaths each year. 3, 4 Acquisition of nasopharyngeal carriage of these bacteria is an initial step in the process leading to invasive bacterial diseases. 5 The increased ability to simultaneously test for multiple pathogens has highlighted the potential role of co-colonization with multiple respiratory tract bacteria and coinfection with viral infections in progression to disease after colonization. 6e9 In indigenous children ARTIs, in particular acute lower respiratory tract infections (ALRTIs), are more common and associated with higher morbidity than among nonindigenous age-matched counterparts in the same region. In a population-based birth cohort study performed in Australia, pneumonia rates in Aboriginal children were 13.5 times higher than in non-Aboriginal children (95% CI 12.8e14.4). 10 In the United States, The ALRTI-associated hospitalization rate was 3-fold higher for American Indian/Alaska Native children than for the general U.S. population in retrospective analyses. 11, 12 The high prevalence rates of ARTIs, including ALRTIs and acute otitis media (AOM), in Australian and North American native children have been associated with increased carriage of viral and bacterial respiratory tract pathogens compared to non-natives. 13e18 While in Australia, Canada and the U.S. native populations make up only two to four percent of the population, ten percent of the South American population consists of indigenous people. 19e21 There is a lack of health research reports concerning the principal clinical presentations and infectious etiologies of ARTIs in indigenous people from the South American region. 19 The Eñepa (or Panare) Amerindians inhabit the Cedeño Municipality of the Venezuelan state of Bolívar, characterized by a forest-savanna landscape. They live in around 40 isolated communities where they have very little interaction with other indigenous or non-indigenous Venezuelan populations. Pneumococcal vaccinations have not been introduced in this population. We investigated bacterial nasopharyngeal carriage, viral infections and nutritional status in Eñepa Amerindian children aged 0e10 years with and without ARTIs and their mothers.

In August 2011, during the rainy season, five geographically isolated Eñepa communities (Biscochuelo, Colorado, El Guamal, Macanilla, Quebrada seca) were visited for primary health care services. During these visits, all inhabitants were registered. Of the 145 children aged 0e10 years present in the 5 communities at the time of survey, 40 (28%) were diagnosed with an ARTI, including AOM. Nasopharyngeal samples were taken of these children and of 40 nearest-age full sibling controls aged 0e10 years and within 5 years of patient age. When several siblings fulfilled these eligibility criteria, the sibling whose age was nearest to that of the case was included. When no siblings fulfilled these criteria (n Z 3), the nearest-age cousin living in the same household was included as a matched control. Nasopharyngeal samples were also taken of mothers of the included children (n Z 43). As nasopharyngeal samples alone may be insufficient to detect colonization by S. pneumoniae and H. influenzae, 22 oropharyngeal swabs for bacterial isolation were taken as well. Nasopharyngeal samples for bacterial and viral isolation were obtained with a flexible swab (Copan Italia). Oropharyngeal samples were obtained by use of rigid cotton-tipped applicators. Swabs were transported at 4 Ce7 C within 4 h after sampling, in STGG medium 23 for bacterial isolation and in TE (10 mM TriseHCl, 1 mM EDTA, pH 8) for virus isolation, to a À20 C freezer. Within 7 days, swabs were transferred to À70 C where they were stored until microbiological and virological analyses. Physical examinations, including ear examination by pneumatic otoscopy and anthropometric measurements of children and mothers, were performed and documented on a standardized data collection sheet.

ARTIs were classified as upper respiratory tract infection (URTI) or ALRTI. A diagnosis of URTI was made when at least 2 common cold symptoms (fever, rhinorrhea, sore throat, headache, cough, muscle aches) with at least 1 symptom involving the respiratory tract (rhinorrhea, sore throat, cough) in the absence of an increased respiratory rate, chest indrawing, or auscultatory findings such as crepitations or rhonchi, were present.

ALRTIs were classified as follows:

Pneumonia: the presence of (1) a history of cough or difficulty in breathing and (2) chest indrawing or increased respiratory rate (!60 breaths/min for children <2 months of age, !50 breaths/min for children 2e11 months of age, !40 breaths/min for children 1e5 years of age and !30 breaths/min for children 6e10 years of age). 24, 25 Acute bronchitis: productive cough of <3 weeks' duration following a URTI, without wheezing, and no parental history of recurrent wheezing. 25 Acute bronchiolitis: an upper respiratory prodrome followed by wheezing and increased respiratory effort, manifested as tachypnoea or chest indrawing, in children <24 months of age. 25, 26 Acute wheezing: an attack of wheezing preceded by upper respiratory tract symptoms in children !24 months of age, with or without a parental history of recurrent wheezing.

Diagnosis of AOM was based on the combined presence of acute symptoms (fever, irritability, pulling at the ears), at least two signs of middle-ear effusion detected by means of pneumatic otoscopic examination (bulging, decreased or absent mobility, abnormal color or opacity not due to scarring, air-fluid interfaces) and at least one sign of middle-ear inflammation (erythema, increased vascularity over full, bulging or yellow tympanic membrane). 27 A history of breastfeeding was determined by parent's response and defined as breastfeeding at the time of survey in children aged 12 months and breastfeeding during the first year of life in children aged >12 months.

Swabs in STGG were plated on blood and chocolate agar plates and cultured for S. pneumoniae, H. influenzae, Moraxella catarrhalis and Staphylococcus aureus in the laboratory of the 'Instituto de Biomedicina' in Caracas, Venezuela, using standard methods. 28 Virological analysis was performed in the Radboud University Medical Centre in Nijmegen, The Netherlands, using multiplex PCR as previously described. 29 Briefly, respiratory swabs were dissolved in TE and spiked with equine arthritis virus (EAV) as an internal control. 30 DNA/RNA was isolated using the MagNA Pure 96 DNA and Viral NA Small Volume Kit (Roche Diagnostics) and the Viral NA Plasma SV protocol. Realtime multiplex PCR for detection of the atypical bacteria Mycoplasma pneumoniae (MP) and Chlamydophila pneumoniae/psittachi (CP) and for respiratory syncytial virus (RSV), influenza A (FluA), influenza B (FluB), human rhinovirus (HRV), human metapneumovirus (HMPV), parainfluenza 1, 2, 3 and 4 (PIV1-4), human coronaviruses OC43 and 229E (HCoV), enteroviruses (EV), human parechoviruses (HPeV), human bocavirus (HBoV) and human adenoviruses (AdV) was performed on the Roche LightCycler Ò 480 system.

Anthropometric measurements were transformed into weight-for-height, height-for-age, and body mass index (BMI)-for-age Z scores based on WHO standard reference populations 31,32 using WHO anthro software. 33 Children under 5 years of age with weight-for-height or height-for-age Z scores < -2 standard deviations (SD) were defined as malnourished. Children aged 5e10 years with BMI-for-age or height-for-age Z scores < -2 SD were defined as malnourished. Weight-for-height and BMI-for-age Z scores are indicators of wasting (acute malnutrition) in respectively children under 5 years and those aged 5 years and above. The height-for-age Z score is an indicator for grading stunting (chronic malnutrition) in children of all ages. 34e36 Mothers with a BMI <18.5 were classified as malnourished. 37 

Before the start of the survey, meetings were held with village elders and members of the communities to explain to them in Spanish and/or in their native language the nature and objectives of the study. Children were included on the basis of written informed consent from parents. Mothers also provided written informed consent. The ethical committee of the Instituto de Biomedicina (Comité de Bioética, Estado portador nasofaríngeo de S. pneumoniae en adultos y niños de la poblaci on indígena Panare y relaci on con neumonía-CB-2011-07) and the Regional Health Services approved the study protocol.

The Mc Nemar test was used to assess the association of viral and bacterial pathogens with ARTI univariately. For univariate analysis of the association of continuous variables with ARTI the paired Student's t test or nonparametric Wilcoxon signed rank test was used, depending on whether or not the variables were normally distributed (KolmogoroveSmirnov's test, p > 0.05). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by means of multivariate conditional logistic regression analysis. Those pathogens and variables associated with ARTI with a p-value 0.20 in univariate analyses were entered into the multivariate model. Sex and indicators of nutritional status (weight-for-height, BMI-for-age and height-for-age Z scores) were retained in the multivariate model, irrespective of their p-values in univariate analysis.

Determinants of viral infection and bacterial colonization were identified univariately using Chi-square test or Fisher's exact test, as appropriate, for categorical variables. For continuous variables, the unpaired Student's t test or nonparametric ManneWhitney's test was used depending on whether or not the variables were normally distributed (KolmogoroveSmirnov's test, p > 0.05). Variables associated with S. pneumoniae colonization with a p-value 0.20 in univariate analysis were entered into a multivariate logistic regression model. Age, sex and indicators of nutritional status were retained in the multivariate model, irrespective of their p-values in univariate analysis.

Statistical significance was set at p < 0.05. The SPSS program for Windows version 20.0 (SPSS Inc, Chicago, IL) was used for statistical analyses.

Samples for viral and bacterial analyses were taken in 79/80 children (99%). Of the 43 included mothers, samples for bacterial analyses were taken in 42 mothers (98%), while swabs for viral analyses were taken in all mothers.

Most of the 40 cases were classified as having ALRTI (58%, n Z 23), further differentiated as pneumonia (15%, n Z 6), acute bronchitis (33%, n Z 13), acute bronchiolitis (3%, n Z 1) and acute wheezing (8%, n Z 3). Eleven children (28%) were classified as URTI. Twenty-one children (53%) were diagnosed with AOM, of which 18 were unilateral and three were bilateral. Fifteen (71%) of the children with an AOM were also diagnosed with an ARTI at the time of the survey. Characteristics of cases and controls are shown in Table 1 . Cases were significantly more often malnourished compared to controls (83% vs. 58%, p Z 0.013). In particular indicators of acute malnutrition, i.e. weight-for-height and BMI-for-age Z scores, were lower in cases compared to controls ( Table 1) .

Viral or atypical bacterial pathogens were detected in 24/ 79 (30%) of the children. The most commonly identified viruses were HRV (10%), EV (6%), FluA H1N1 (6%), and HBoV (3%). AdV, HMPV and RSV were all detected in 1% of the children. Of the atypical bacterial pathogens, CP was detected in 1 child (1%); MP was not detected. In three mothers a viral infection was detected, either FluA H1N1, HRV or HBOV. No children or mothers were infected with more than one virus. Fifty-nine children (75%) were colonized with S. pneumoniae, 17 (22%) were colonized with H. influenzae, 17 (22%) were colonized with S. aureus and 22 (28%) were colonized with M. catarrhalis. Nasopharyngeal colonization rates of all four bacteria in children of different ages were approximately equal ( Table 2 ). For mothers, colonization rates were lower but still considerable; respectively 38%, 2%, 12% and 2% for S. pneumoniae, H. influenzae, S. aureus and M. catarrhalis. Thirty-two children (41%) and one mother (2%) were colonized with multiple bacterial pathogens. In 12% of the children and in 81% of the mothers that were colonized with S. pneumoniae, pneumococci were detected only in the oropharyngeal sample and not in the nasopharyngeal sample. In contrast, no H. influenzae was isolated from the oropharyngeal sample alone.

S. pneumoniae carriage rates were significantly higher in cases compared to controls (90% vs. 59%, p < 0.01). In contrast, M. catarrhalis was less often detected in cases compared to controls, but this was not statistically significant (18% vs. 36%, p Z 0.14). Colonization with H. influenzae or S. aureus was not significantly associated with ARTI (p Z 1.0 and p Z 0.58 respectively). None of the detected viral infections showed a significant association with ARTI with p-values varying from p Z 0.38 to p Z 0.73. In multivariate conditional logistic regression analyses, S. pneumoniae colonization was a significant determinant of ARTI risk (OR 14.1, 95% CI 1.4e137.7). Furthermore, the indicator of acute malnutrition (weight-for-height and BMI-for-age Z score in respectively children under 5 years of age and those aged 5 years and above) was associated with ARTI in multivariate analysis: an increase of one unit Z score (i.e. improved acute nutritional status) was significantly 

As the prevalence of S. pneumoniae colonization was high in both children and mothers, we determined factors associated with carriage in both groups (Table 3) . No significant differences in sex or number of people living in the household between S. pneumoniae colonized and non-colonized children were seen. Also, age was not significantly correlated with S. pneumoniae colonization. Children colonized by S. pneumoniae were significantly more often malnourished than non-colonized children (76% vs. 50%, p Z 0.027). In particular the indicator of chronic malnutrition, height-forage Z score, was lower in children colonized with S. pneumoniae compared to non-colonized children (À2.08 vs. À1.03, p Z 0.056). In multivariate analysis including all variables with a p 0.20 an increase of one unit Z score of heightfor-age (i.e. improved chronic nutritional status) was significantly associated with decreased odds of S. pneumoniae colonization (OR 0.66, 95% CI 0.44e0.99). The absence of a statistically significant relationship between age and S. pneumoniae colonization was observed in both cases and controls. Of the cases aged 0e5 years 92% was colonized by S. pneumoniae while 78% of cases aged 6e10 years were S. pneumoniae positive (p Z 0.30). In controls, S. pneumoniae was observed in 70% of children aged 0e5 years vs. 50% of children aged 6e10 years (p Z 0.23).

Children with a viral infection were younger than children without a viral infection, but this was not statistically significant (3.3 vs. 4.5 years, p Z 0.090). Sex and indicators of nutritional status were not significantly associated with detection of a respiratory virus.

In mothers, S. pneumoniae colonization was significantly associated with a lower mean BMI (20.9 vs. 23.4, p Z 0.049 in colonized vs. non-colonized mothers, Table 3 ). Furthermore, the median number of people living in the household was significantly lower in mothers colonized with S. pneumoniae compared to mothers not colonized with S. pneumoniae (4.5 vs. 5, p Z 0.041). S. pneumoniae colonization rates in mothers of control children were not significantly different from rates observed in mothers of cases (36% vs. 46%, p Z 0.72).

There were no significant associations between bacterial colonization in mothers and children. S. pneumoniae was more often detected in mothers of children colonized by S. pneumoniae than in mothers of children not colonized by S. pneumoniae, but this was not statistically significant (39% vs. 20%, p Z 0.098, Table 3 ).

The effect of the co-occurrence of bacteria and viruses on the risk of ARTI was investigated by dividing the data according to whether at least one vs. no bacterial pathogen was detected. This showed no significant difference in the prevalence of a viral infection in addition to bacterial colonization between cases and controls (31% vs. 26%, p Z 0.80). Children that suffered from a viral infection in addition to colonization with a bacterial pathogen were significantly younger than children in which a bacterial pathogen alone, without viral co-infection, was detected (3.4 years vs. 4.8 years, p Z 0.043). Of the children younger than 4 years of age with bacterial colonization 46% suffered from a viral co-infection compared to 17% of the children aged 4e10 years (p < 0.01).

In Eñepa Amerindian children, acute malnutrition and S. pneumoniae colonization were significantly associated with the presence of an ARTI in multivariate analysis. S. pneumoniae carriage rates were high in children up to 10 years of age and chronic malnutrition was significantly associated with an increased risk for S. pneumoniae colonization. A viral infection in addition to colonization by respiratory tract bacteria occurred significantly more often in children under 4 years of age. To our knowledge, this is the first report describing the detection of both respiratory viruses and bacteria in South American indigenous children.

In caseecontrol studies performed in Vietnam, Turkey and Greenland a significant association of S. pneumoniae colonization with ARTIs was also observed. 7, 38, 39 In healthy children, S. pneumoniae carriage rates observed in studies performed in industrialized areas before the introduction of pneumococcal vaccines decrease from 30% to 40% in the first 5 years of life to below 20% in children aged 6e10 years. 40e42 In a study performed in another Venezuelan Amerindian population, the Warao people, S. pneumoniae carriage rates in children under 2 years of age were higher compared to carriage rates in children older than 2 years of age (50% vs. 25%). 43 However, in other tropical rural areas S. pneumoniae carriage rates up to 40% have been observed in healthy children between 5 and 10 years of age. 44e46 We observed a S. pneumoniae carriage rate of 50% in healthy controls older than 5 years of age. The high S. pneumoniae colonization rate in Eñepa Amerindians increases the size of the pneumococcal reservoir in these communities. As in these populations approximately half of the population is less than 15 years of age, those children aged 5e10 years represent a sizeable fraction of the total population and one that is likely to interact frequently with young children who are most susceptible to the development of disease after nasopharyngeal colonization. 5 Carriage rates of S. pneumoniae in Eñepa mothers were extremely high (38%) compared to the carriage rates of 7%e 9% that are observed in mothers and other close adult contacts in cross-sectional studies from industrialized as well as rural areas. 45e47 A previously performed study in the Eñepa Amerindian population during the dry season showed a prevalence of S. pneumoniae colonization in mothers of children under 5 years of age of only 11%. 48 This suggests that the high prevalence observed in our study was due to seasonal influences. Longitudinal studies have demonstrated seasonal variations in the rate of pneumococcal colonization and rainy season has been identified as a significant risk factor for S. pneumoniae carriage in children and adults. 16, 44, 49, 50 However, the prevalence of S. pneumoniae colonization observed in healthy Eñepa children under 5 years of age in the previous study (69%) was similar to the rate we observed in healthy controls up to 5 years of age (70%). Another possible explanation for the high carriage rate in mothers in our study is the observation that in 81% of the S. pneumoniae positive mothers, pneumococci were only isolated from the oropharyngeal sample. In the previously performed study, oropharyngeal samples were not taken. 48 The percentage of S. pneumoniae positive children in which S. pneumoniae was isolated from the oropharyngeal sample alone was lower (12%). The importance of oropharyngeal sampling for detection of S. pneumoniae and H. influenzae in children and mothers was previously demonstrated by Greenberg et al. 22 However, in contrast to their findings, in our study no H. influenzae was isolated from the oropharyngeal sample alone. This might be due to the high number of children with ARTI in our study, as H. influenzae detection in the nasopharyngeal swab increased during illness in the study of Greenberg et al. 22 We did not study the molecular characteristics of identified pathogens. As HRV was the viral infection with the highest prevalence in our study population, it would be of interest to perform phylogenetic analysis of the HRV strains circulating in this population in order to compare the strains detected in this area with published HRV sequences from other parts of the world. 51 Respiratory viruses were, however, not significantly associated with ARTIs in our study. S. pneumoniae carriage was significantly associated with ARTIs in our study and further characterization of S. pneumoniae isolates by serotyping, molecular typing and susceptibility testing is recommendable to obtain insight into resistance patterns and pneumococcal vaccination coverage in this population.

Carriage rates of S. pneumoniae in children included in our study were significantly increased in chronically malnourished children. Due to the caseecontrol study design, it was unknown whether chronic malnutrition is a risk factor for S. pneumoniae colonization or whether S. pneumoniae carriage affects growth leading to growth deficits and chronic malnutrition. In a longitudinal study including South Indian infants, S. pneumoniae carriage was significantly associated with increased odds of chronic malnutrition (OR 3.1, 95% CI 1.3e7.4), suggesting that S. pneumoniae colonization affects growth. 52 In Bangladesh, immunization of infants with a pneumococcal conjugate vaccine (PCV7) was independently associated with an increase in height-for-age. 53 Acute malnutrition was significantly associated with ARTI risk in our study. A significant relationship between acute malnutrition and respiratory tract infections has also been observed in other studies and undernutrition, either acute or chronic, negatively affects disease outcome. 1,54e56 While bacterial colonization was not associated with the age of the child in our study, children with viral-bacterial co-occurrence were significantly younger than children with bacterial colonization alone. A mixed nasopharyngeal flora containing respiratory viruses and bacteria was also significantly more often observed in children under 4 years of age compared to children aged 5e8 years in Greenland. 39 Interestingly, we did not observe a significant association of respiratory viral infections with ARTI risk. In studies performed in developed countries, viruses have been identified as the potential etiological cause in more than half of the ARTI cases. 57, 58 It is important to know the relative contributions of viruses and bacteria to the burden of ARTI and AOM in different populations to ensure appropriate population-specific case management and preventive strategies, including vaccination.

Conclusions from the present study must be tempered by an appreciation of limitations. As we matched cases with sibling controls, we may underestimate the effect of factors related to residence and household exposure. An example of a factor related to residence that has been associated with ARTIs is exposure to biomass smoke. 55, 59 Larger crosssectional studies are needed to examine the associations between household-related factors and ARTI risk. Additionally, the magnitude of the associations between demographic and nutritional variables and S. pneumoniae colonization in our study may differ from the effect magnitude in the general population as our study population was not a representative sample of the general population of Eñepa Amerindian children due to the caseecontrol study design. Finally, confidence intervals of the OR determined in multivariate analyses of factors associated with ARTI and S. pneumoniae colonization were wide due to the small sample size of our study. Rural areas are generally difficult to reach during the winter season due to heavy rain falls, limiting possibilities for field workers and researchers. The communities included in our study were very isolated communities that could be reached only after several hours of walking through an undulating forest-savanna area as heavy rains had flooded area roads. As most respiratory viruses circulate in the rainy season, 60,61 this is the preferred period for research focusing on the correlation of respiratory tract bacteria with viral infections.

In conclusion, our study shows that high S. pneumoniae carriage rates in Eñepa Amerindian children up to 10 years of age are a risk factor for ARTI while viral infections were not significantly associated with ARTI risk. These data highlight the need for the further investigation of relative contributions of viruses and bacteria to the burden of ARTI in South American indigenous children, taking into consideration population-specific epidemiological and anthropometric characteristics.

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The authors thank the participating families and the field workers involved in the recruitment of participants, in particular the medical students of the Escuela de Medicina José María Vargas of the Universidad Central de Venezuela.This work was partly supported by 'Integrated Microsystems for Biosensing (3E-01), FES0901:FES HTSM', a project of NanoNextNL, a micro and nanotechnology consortium of the Government of the Netherlands and 130 partners. Additionally, the study was funded by the Fundacion para la Investigaci on en Micobacterias (FUNDAIM), Caracas, Venezuela.

