Tropical Medicine and International Health doi:10.1111/tmi.

12835

volume 22 no 4 pp 407–414 april 2017

Nasopharyngeal carriage of respiratory pathogens in Warao

Amerindians: significant relationship with stunting
Lilly M. Verhagen1,2,3, Meyke Hermsen4, Ismar A. Rivera-Olivero1, Mar
ıa Carolina Sisco1,
Marien I. de Jonge2, Peter W. M. Hermans2,* and Jacobus H. de Waard1
1 Laboratorio de Tuberculosis, Universidad Central de Venezuela, Caracas, Venezuela
2 Laboratory of Pediatric Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands
3 Wilhelmina Children’s Hospital Utrecht, Utrecht, The Netherlands
4 Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
*Current address: Janssen – Johnson and Johnson, 2333 CB Leiden, The Netherlands

Abstract objective To assess risk factors for nasopharyngeal carriage of potential pathogens in
geographically isolated Warao Amerindians in Venezuela.
methods In this point prevalence survey, nasopharyngeal swabs were obtained from 1064 Warao
Amerindians: 504 children aged 0–4 years, 227 children aged 5–10 years and 333 caregivers. Written
questionnaires were completed to obtain information on demographics and environmental risk
factors. Anthropometric measurements were performed in children aged 0–4 years.
results Carriage rates of Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae
and Moraxella catarrhalis were 51%, 7%, 1% and 13%, respectively. Crowding index, method of
cooking and tobacco exposure were not associated with increased carriage. In multivariable analysis, an
increase in height-for-age Z score (i.e. improved chronic nutritional status) was associated with
decreased odds of S. pneumoniae colonisation (OR 0.76, 95% CI 0.70–0.83) in children aged 0–4 years.
conclusions Better knowledge of demographic and environmental risk factors facilitates better
understanding of the dynamics of colonisation with respiratory bacteria in an Amerindian population.
Poor chronic nutritional status was associated with increased pathogen carriage in children <5 years
of age. The high rates of stunting generally observed in indigenous children may fuel the acquisition
of respiratory bacteria that can lead to respiratory and invasive disease.

keywords indigenous people, respiratory pathogens, nasopharyngeal colonisation, chronic

malnutrition, risk factors

[12–14]. In Amerindian E~ nepa children (an indigenous

Introduction
Indigenous populations often live in extreme poverty.
Lack of clean drinking water, food and sanitary facilities
renders these populations particularly vulnerable to mal-
nutrition and diseases, resulting in high prevalence rates
of respiratory and other infections [1, 2]. While most
studies on respiratory infections in native children are
conducted in Australian Aboriginals and populations
within the United States [3–6], high rates of respiratory
tract infections are also found in South American indige-
nous populations [7–9]. The high prevalence of respira-
tory infections in native populations is associated with
increased carriage of respiratory tract bacteria compared
with non-natives [4, 10, 11]. Factors that have been
linked to high carriage rates in rural populations are the
lack of in-home running water, a large number of house-
hold or bedroom occupants, and seasonal conditions
tribe in the Venezuelan state of Bol
ıvar), high Streptococ-
cus pneumoniae carriage rates associated with a poor
nutritional status appear to contribute to the burden of
respiratory tract infections [7].
Colonisation is a prerequisite for invasive disease, and
colonised persons can transmit pneumococci to house-
hold and community members through respiratory dro-
plets. While carriage rates of respiratory pathogens such
as S. pneumoniae significantly decrease after 5 years of
age in Western populations [15, 16], high colonisation
rates are observed in children >5 years of age and adults
living in tropical rural areas [7, 13, 17]. This increases
the size of the respiratory pathogen reservoir in these
communities and makes prevention of colonisation with
potential pathogens for people of all ages particularly
important to reduce subsequent respiratory and invasive
infections. Knowledge of risk factors for colonisation

© 2017 John Wiley & Sons Ltd 407

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L. M. Verhagen et al. Respiratory carriage in Warao Amerindians

provides starting points for community-based interven- and 4–6 years of age; and the measles, mumps, rubella
tions aimed at reduction in colonisation and disease rates, vaccine is given at 12 months and 4–6 years of age.
such as vaccination programmes and interventions with a Furthermore, the schedule includes yellow fever vaccina-
behavioural or educational component aimed at achieving tion at 12 months of age; H. influenzae type b (Hib) vac-
lifestyle or environmental sanitary interventions. cination at 2, 4 and 6 months of age with a booster dosis
Venezuela harbours >20 indigenous populations. The at 15–18 months; and rotavirus vaccination at 2 and
Warao people are the second-largest Amerindian popula- 4 months. Hepatitis B vaccination is given at birth, 2, 4
tion in Venezuela. They reside in wooden houses along and 6 months of age. Immunisation coverage rates are
the Orinoco Delta, an area of approximately low: only 27% of children < 5 years of age are fully
40 000 km2, where the Orinoco River spreads out in immunised with the classical EPI vaccines (BCG, DTP,
many distributaries towards the Atlantic Ocean. A cross- polio and MMR), and 18% is fully vaccinated with the
sectional interview-based survey that included 668 Warao additional vaccines [9].
women from 97 geographically spread communities All children <5 years of age present in the included com-
showed that an estimated one-third of Warao children munities were approached for this study. Included children
dies during childhood. Over 95% of these deaths occur were subjected to a physical examination including anthro-
in children under 5 years of age. Caregivers reported res- pometric measurements and, if indicated, lung ausculta-
piratory tract infections/pneumonia as the cause of death tion. For each included child <5 years of age, one sibling
in 18% of all cases [18]. Pathogen-specific incidence rates aged 5–10 years and the primary caregiver (typically the
of respiratory infections are not available for the Warao mother) were also asked to participate. Standardised ques-
population due to the lack of epidemiological and medi- tionnaires were conducted with primary caregivers.
cal monitoring. Immunisation coverage in the Orinoco
Delta is poor, largely due to the inaccessibility of the area Table 1 Characteristics of the study population (n = 1064)
[9]. Age categories, n (%)
The identification of risk factors for carriage is impor- 0–4 years 504 (48)
tant to understand the transmission patterns of respira- 5–10 years 227 (21)
tory pathogens in families and communities and identify 13–62 years (caregivers) 333 (31)
potential preventative measures. In this study, we investi- Gender per age category, n (%)
0–4 years
gated environmental factors and undernutrition as poten-
M 249 (49)
tial risk factors for nasopharyngeal carriage of potential F 255 (51)
pathogens in Warao Amerindian children and adults. 5–10 years*
M 108 (48)
F 114 (50)
Methods 13–62 years
M 4 (1)
Study population F 329 (99)
Nasopharyngeal colonisation present, n (%)
This study is an observational, cross-sectional survey of Streptococcus pneumoniae
nasopharyngeal colonisation in nine geographically 0–4 years 366 (73)
spread Warao villages in Antonio Diaz, the largest of 5–10 years 124 (55)
four municipalities in the Orinoco Delta. These popula- 13–62 years 50 (15)
tions are relatively isolated; Warao villages in this munic- Haemophilus influenzae
0–4 years 6 (1)
ipality are only accessible by boat. Nasopharyngeal
5–10 years 4 (2)
swabs (Copan Italia, Br
ecia, Italy) were taken as part of 13–62 years 2 (0.6)
a pre-vaccination survey before the first introduction of Staphylococcus aureus
the 13-valent pneumococcal conjugate vaccine [19]. Thus, 0–4 years 28 (6)
pneumococcal conjugate vaccines had not been intro- 5–10 years 23 (10)
duced in the Orinoco Delta at the time of this survey. 13–62 years 26 (8)
Routine vaccination programmes are carried out by vac- Moraxella catarrhalis
0–4 years 113 (22)
cination teams. The vaccination schedule includes the
5–10 years 14 (6)
WHO Expanded Program on Immunisation (EPI). The 13–62 years 7 (2)
Bacille Calmette Gu
erin vaccine is administered at birth;
diphtheria, tetanus, pertussis, and polio vaccines at 2, 4 *Numbers do not add up to 100% due to missing data (n = 5,
and 6 months of age with booster doses at 15–18 months 2%).

408 © 2017 John Wiley & Sons Ltd

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L. M. Verhagen et al. Respiratory carriage in Warao Amerindians

Laboratory analyses factors of carriage with rates of S. pneumoniae, M. catar-

Swabs were stored in STGG medium for a maximum of
3 days at 4 °C before storage at 20 °C for a maximum
of 4 weeks and, subsequently, 70 °C until analysis [20].
Swabs were plated on blood and chocolate agar plates in
the laboratory of the Instituto de Biomedicina in Caracas.
Isolates were identified as S. pneumoniae, H. influenzae,
M. catarrhalis or S. aureus using standard microbiological
methods [21].
Anthropometric measurements
Height (cm) and weight (kg) were measured as previously
described in children under 5 years of age [9]. Anthro-
pometric measurements were transformed into weight-
for-height (WHZ, i.e. wasting) and height-for-age (HAZ,
i.e. stunting) Z scores based on WHO standard reference
populations [22].
Ethical aspects
Families were included on the basis of written informed
consent from primary caregivers. The ethical committee of
the Instituto de Biomedicina, the Delta Amacuro Indige-
nous Health Office (Servicio de Atenci
on y Orientaci

on al
Ind
ıgena), as well as community leaders (consejos comu-
nales) of each included community approved the study.
Statistical analysis
Descriptive statistics and regression analysis were per-
formed to determine the relationship of known risk
rhalis and S. aureus colonisation. Characteristics of H.
influenzae colonisation were not assessed because of low
carriage prevalence (1%). For children aged <5 years, the
association between nutritional status and carriage preva-
lence was also assessed. Generalised estimating equations
(GEEs) were used to fit univariate and multivariable
logistic regression models, accounting for community
clustering. In multivariable analysis, we adjusted for all
factors summed up in Table 2 and, for the assessment of
the association between nutritional status and carriage,
also for the presence of a respiratory infection (i.e. upper
or lower respiratory tract infection or otitis media). A P-
value <0.05 was considered statistically significant. IBM
SPSS Statistics V22 for Windows (SPSS Inc, Chicago, IL,
USA) was used for all statistical analysis.
Results
We obtained 1064 nasopharyngeal samples. This
included 333 caregivers, 227 children aged 5–10 years
and 504 children aged 0–4 years. A total of 66 families
(16.5%) within the studied communities did not partici-
pate. Characteristics of the study population are shown
in Table 1. Most primary caregivers were female, corre-
sponding with the traditional role of women as the domi-
nant person in taking care of the children in Warao
families.
The median total number of people in the households
was seven (IQR 6–10), and houses had a median of two
rooms (IQR 1–3). The median crowding index (no. of
people/no. of rooms) was 4 (IQR 3–7).

100 72.8 69.6

52.5
27.2
17.7
13.6 11.9
8.4 10.1
10 7.3 6.3 7.3
3.9
2.8
% 2.1
1.3
0.9 0.9
1 0.7
0.5

0.1
0-

3-

6-

11

≥3
2

10

-3

1
ye

ye

ye
0
ye
ar

ar

ye

ar
ar
s

ar

s
s

Streptococcus pneumoniae Haemophilus influenzae Staphylococcus aureus Moraxella catarrhalis

Figure 1 Nasopharyngeal carriage of respiratory pathogens in different age groups.

© 2017 John Wiley & Sons Ltd 409

 410
Table 2 Univariate and multivariable analyses of factors associated with nasopharyngeal carriage of potential pathogens in 1064* Venezuelan Warao people

S. pneumoniae univariate multivariable S. aureus univariate multivariable M. catarrhalis univariate multivariable

Characteristic n (%) % carrier P-value OR (95% CI) % carrier P-value OR (95% CI) % carrier P-value OR (95% CI)

Sex
Tropical Medicine and International Health

Male 361 (44) 67 <0.01 1 6 0.29 1 17 <0.01 1

Female 698 (66) 43 0.97 (0.81–1.2) 8 1.27 (0.70–2.3) 11 1.1 (0.78–1.7)
Age (years)
0–4 504 (47) 73 <0.01 0.90 (0.89–0.92)# 6 0.11 1.0 (0.99–1.0)# 22 <0.01 0.87 (0.83–0.91)#
5–10 227 (21) 55 10 6
13–62 333 (31) 15 8 2
Cooking method
Woodsmoke 894 (85) 52 0.31 1 8 0.50 1 12 0.65 1
Gas 160 (15) 45 0.79 (0.48–1.3) 6 0.57 (0.23–1.4) 14 1.1 (0.52–2.3)
L. M. Verhagen et al. Respiratory carriage in Warao Amerindians

Wall status of house

Without 319 (30) 54 0.34 1 3 <0.01 1 12 0.51 1
walls
With walls 739 (70) 50 0.85 (0.59–1.2) 9 2.8 (1.3–6.1) 13 1.1 (0.73–1.8)
Tobacco smoke exposure in household
No 564 (54) 50 0.47 1 6 0.6 1 12 0.90 1
Yes 491 (46) 52 1.2 (0.80–1.7) 8 1.3 (0.56–3.1) 13 1.1 (0.57–2.0)
Crowding (no. of people/no. of rooms in the house)
<5 549 (52) 48 0.31 1.0 (0.97–1.1)# 9 0.07 0.96 (0.86–1.1)# 14 0.79 1.0 (0.92–1.1)#
≥5 511 (48) 54 6 12

*For some characteristics, there were missing values (maximum n = 10 per characteristic); therefore, not all numbers in the second column add up to 1064.
#These variables were evaluated as continuous variables in univariate and multivariable analysis. This number reflects the change in odds of carrying the specific patho-
gen for every extra person/child < 5 years in the household or for every increase of 1 year of age.

© 2017 John Wiley & Sons Ltd

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L. M. Verhagen et al. Respiratory carriage in Warao Amerindians

Risk factors for colonisation with potential pathogens

0.96 (0.82–1.1)*

0.92 (0.81–1.1)*

*These variables were evaluated as continuous variables in univariate and multivariable analysis. This number reflects the change in odds of carrying the specific patho-
OR (95% CI)
multivariable
The overall carrier rate of respiratory pathogens was 57%;
22% of caregivers, 63% of children aged 5–10 years and
78% of children aged <5 years were colonised with at least
one pathogen. Overall carriage rates were 51% for S. pneu-
moniae, 7% for S. aureus, 1% for H. influenzae and 13%

univariate
for M. catarrhalis. Carriage rates of S. pneumoniae and M.

P-value

0.049
catarrhalis were highest in children aged <5 years (Figure 1,

0.25
Table 1), and this was statistically significant in multivari-
able analysis (Table 2). Carriage rates in children aged

M. catarrhalis
0–2 years (n = 283) were not significantly different from

% carrier
those aged 3–5 years (n = 286) for all four pathogens.
No association was found for sex in multivariable anal-

28
19

33
22
ysis. Crowding index, method of cooking and tobacco
exposure were not associated with increased carriage,

Table 3 Univariate and multivariable analyses of HAZ and WHZ scores in Venezuelan Warao children < 5 years of age

0.91 (0.57–1.5)*

0.95 (0.72–1.3)*
while S. aureus carriage was more often observed in

OR (95% CI)
multivariable
houses with walls in multivariable analysis.

Nutritional status
More than one-third (38%) of included children suffered

univariate
from chronic malnutrition, that is HAZ < 2 SD. The

P-value
prevalence of wasting (WAZ < 2 SD) was much lower

0.68

0.08
(5%). Stunted children had higher rates of both S. pneumo-
niae and M. catarrhalis carriage than non-stunted children
% carrier
S. aureus

(57% vs. 43% and 53% vs. 47%, respectively). In multi-

variable analysis (Table 3), higher HAZ scores (i.e. an

4
6

8
5
improved chronic nutritional status) were indeed associ-
ated with lower odds of S. pneumoniae colonisation (OR 0.76 (0.70–0.83)*

1.1 (0.91–1.3)*
0.76, 95% CI 0.70–0.83). For wasting, no significant asso-
OR (95% CI)
multivariable

ciations with carriage rates were observed, possibly due to

the lower number of children suffering from wasting.

Discussion
univariate
P-value

Warao Amerindian children living in geographically isolated

<0.01*

0.75

communities have high rates of respiratory tract infections

and a high prevalence of nasopharyngeal colonisation with
gen for every increase of 1 unit HAZ/WHZ.

respiratory pathogens. Pneumococcal colonisation rates in

S. pneumoniae

this population were highest in young children (73%) and

% carrier

much higher than in non-indigenous children of the same

age group from Caracas, the capital city of Venezuela
< 2 SD 193 (38) 81
≥ 2 SD 311 (62) 68

79
≥ 2 SD 480 (95) 72

(27%) [23]. Over half of the children aged 5–10 years

Weight-for-height Z score

(55%) carried S. pneumoniae, and caregivers still showed

Height-for-age Z score

24 (5)

considerable colonisation prevalence rates (15%). In con-

n (%)

trast, industrialised childhood populations show prevalence

Nutritional status

peaks of S. pneumoniae at much younger ages [15, 16, 24].

< 2 SD

Table 4 compares colonisation rates from population stud-

ies performed in developing areas with prevalence rates in
industrialised areas. The high carriage rates in older children
and adults in developing areas lead to an increased

© 2017 John Wiley & Sons Ltd 411


Tropical Medicine and International Health
L. M. Verhagen et al. Respiratory carriage in Warao Amerindians
Table 4 Nasopharyngeal carriage rates of S. pneumoniae in developing areas and industrialised areas in various age groups
Developing areas
Warao Alaskan
Amerindians Natives [12] Rural Kenyans
pre-PCV post-PCV [13] pre-PCV
Age (years) 0–4 5–10 13–62 0–4 5–9 >10 0–4 5–9
S. pneumoniae 73 55 15 65 62 22 57 41
(%)
pneumococcal reservoir in indigenous populations fuelling
respiratory and invasive disease.
We evaluated risk factors for colonisation and found that
increased prevalence of S. pneumoniae carriage in children
under 5 years of age is independently associated with poor
chronic nutritional status. This observation is consistent
with a previously performed case–control study in another
indigenous population in Venezuela, the E~ nepa Amerindi-
ans, also showing increased carriage rates in chronically mal-
nourished children [7]. Recently, we demonstrated that
stunted Warao children up to 5 years of age had higher anti-
body responses after a primary series of 13-valent pneumo-
coccal conjugate (catch-up) vaccination [25]. It is possible
that increased carriage with pneumococci in stunted children
induces strong immunological priming. Malnourished chil-
dren show a cytokine response pattern that is skewed
towards a T helper-2 response with high levels of
immunoglobulins [26]. Repeated or prolonged episodes of
colonisation and disease in chronically malnourished chil-
dren may further increase the level of immunoglobulins in
general [27] and/or post-vaccination [25]. An enhanced
immune responses to a pneumococcal conjugate vaccine was
observed in children with increased exposure to pneumo-
cocci [28]. However, it has previously been noted that
nasopharyngeal colonisation prior to pneumococcal vaccina-
tion in early infancy is associated with hyporesponsiveness
to the specific colonising serotypes [29–31]. As stunting rates
are higher in children aged 2–5 years compared with those
under 2 years of age [9], the effect of chronic malnutrition
on pneumococcal colonisation and boosting of immune
responses may only become visible with increasing age.
Surprisingly, in contrast to other studies [32–34], we did
not observe an association between nasopharyngeal carriage
of potential pathogens and tobacco smoke exposure in the
household. In a large survey including >1700 children
attending day care centres or schools in Italy, no association
between passive smoking and carriage of S. pneumoniae, H.
influenza or M. catarrhalis was observed either [35]. Possi-
bly, this was related to the fact that children included in this
study did not spend the majority of their time inside the
home, reducing potential exposure time. Most smokers in
412
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volume 22 no 4 pp 407–414 april 2017
Industrialised areas
Australian Israel Sweden
Aboriginals [14] [39] [40] England [41]
post-PCV pre-PCV pre-PCV pre-PCV
>10 2–4 5–12 >12 0–6 >18 0–6 >18 2–4 5–20 >20
9 82 64 26 53 4 40 2 48 21 8
the Warao population are older men who sit together smok-
ing their pipes during the day. Warao children generally
play outside during the day and spend little time in their
houses, which might explain the absence of an association
between in-house smoke exposure and carriage rates.
The Warao people in this study lived in severely crowded
conditions, with a median of four people per room. In Abo-
riginal children in Australia, crowding was an important
risk factor for carriage of S. pneumoniae, while S. aureus
carriage risk was not associated with crowding indices. The
increased risk of pneumococcal carriage was, however,
attenuated by living in a larger house [36]. Warao houses
are generally large, which may explain why an association
between crowding and colonisation was not observed in our
study population despite the high crowding index. We did
not measure the surface area of the houses of participants. If
there is a large variety in surface area of the rooms, the
crowding index (number of people per room) may not be
the optimal measure of actual crowding. However, Warao
houses generally resemble each other in surface area of the
rooms, and the index in our study is commonly used [12,
37]. A link between household crowding and colonisation
with respiratory pathogens has been observed in many other
populations [12, 37, 38]. Another explanation for the lack
of this link in our study may be that Warao people generally
have a nomadic lifestyle. Warao families tend to move from
one place to another, and many families migrate each year
temporarily from their village to small settlements to culti-
vate crops. The crowding index at the moment of inclusion
in this study may thus not reflect the overall crowding expo-
sure of participants. Finally, as Warao children usually
spend most of the day outside their houses and young chil-
dren are the greatest transmitters of pneumococci, the
crowding index presented in this study may not be an accu-
rate reflection of the degree of physical contact that
enhances pneumococcal transmission.
A limitation of our study was its cross-sectional design.
Longitudinal studies are needed to determine whether
malnutrition is a risk factor for carriage and/or whether
carriage affects growth. Studies in which nutritional and
colonisation status are measured at multiple time points
© 2017 John Wiley & Sons Ltd

Tropical Medicine and International Health
L. M. Verhagen et al. Respiratory carriage in Warao Amerindians
are also needed to determine whether chronic malnutri-
tion is associated with persistent colonisation and/or an
increased rate of carriage acquisition. Our observation
that there was no significant difference in colonisation
rates between Warao children aged 0–2 and 3–5 years
while the latter age group is more severely affected by
chronic malnutrition suggests that chronic undernourish-
ment may promote persistent colonisation. However, this
hypothesis, and its underlying immunological mecha-
nisms, is best studied in a prospective design.
Conclusion
Our study shows that high respiratory pathogen carriage
rates in young Warao Amerindian children were signifi-
cantly associated with poor nutritional status. Longitudi-
nal studies are needed to determine whether malnutrition
is a risk factor for carriage or whether carriage affects
growth. In addition to programmes focusing on the pre-
vention of acute malnutrition during disease episodes,
targeting chronic malnutrition may directly affect coloni-
sation with disease-causing pathogens.
Acknowledgements
We thank all participants and field workers involved in the
recruitment and sampling of children and adults, in partic-
ular the medical students of the Escuela de Medicina Jos
e
Maria Vargas of the Universidad Central de Venezuela and
Thor K€ uchler, Marcella Overeem and Stephan Kraai. We
also thank Jochem Burghouts and Mailis Maes for facilita-
tion of study logistics as well as the personnel of the Labo-
ratorio de Tuberculosis, Instituto de Biomedicina, for
technical support. Our work was funded by Pfizer Vene-
zuela and the Fundacion para la Investigaci
on en Micobac-
terias, Caracas, Venezuela. The funders had no role in
study design, data collection and analysis, decision to pub-
lish or preparation of the manuscript.
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