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    (A) Prevalence of egg patent Schistosoma mansoni infection according to school and altitude. (B) Prevalence of malaria infection according to altitude.

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    Comparison of mean VO2max between Ugandan (study) and Kenyan and Canadian cohorts by gender and age (Canadian and Ugandan data sourced from Leger et al.11 and Bustinduy et al.,2 respectively).

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    (A) Median hemoglobin at baseline and follow-up. (B) Scatter plot of VO2max for follow-up and new participants with median and interquartile range.

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    Conceptual pathway for impaired physical fitness in Schistosoma mansoni infection in children. Note: broken arrows represent relationships described elsewhere.

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Schistosoma mansoni Infection as a Predictor of Low Aerobic Capacity in Ugandan Children

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  • 1 Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom;
  • 2 Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom;
  • 3 Vector Control Division, Ministry of Health, Kampala, Uganda;
  • 4 Lancaster Medical School, Lancaster University, Lancaster, United Kingdom

Using the 20-meter shuttle run test (20mSRT) as a morbidity metric, we assessed whether Schistosoma mansoni infection was associated with decreased aerobic capacity in Ugandan children across a range of altitudes, either at low (∼600 m) or high (∼1,000 m) altitudes. A total of 305 children were recruited from six schools within the Buliisa District, Lake Albert, Uganda. A subset (n = 96) of these had been previously assessed and treated for schistosomiasis ± malaria 2 weeks prior. Fitness scores on the 20mSRT were translated into VO2max using a standardized equation. Unadjusted and multivariable-adjusted analyses were performed using VO2max as the primary outcome. Analysis of fitness scores from 304 children, inclusive of the subset follow-up cohort, revealed a median VO2max of 45.4 mL kg−1 min−1 (interquartile range: 42.9–48.0 mL kg−1 min−1). Children residing at high altitudes demonstrated increased aerobic capacities (46.3 versus 44.8 mL kg−1 min−1, P = 0.031). The prevalence of stunting, wasting, S. mansoni egg patent infection, malaria, giardiasis, anemia, and fecal occult blood were 36.7%, 16.1%, 44.3%, 65.2%, 21.4%, 50.6%, and 41.2%, respectively. Median VO2max was elevated in those previously treated, compared with those newly recruited (46.3 versus 44 mL kg−1 min−1, P < 0.001). Multivariable-adjusted analysis revealed a strong negative association between S. mansoni egg patent infection and VO2max at low altitude (beta coefficient: −3.96, 95% CI: −6.56 to −137, P = 0.004). This is the first study to document a negative association between S. mansoni infection and aerobic capacity at low altitudes using the 20mSRT.

INTRODUCTION

Intestinal schistosomiasis, as caused by infection with Schistosoma mansoni, is an important contributor toward chronic morbidity in African children as measured by various methodologies.110 However, its impact on diminished exercise tolerance is not well explored. By contrast, the functional consequence of Schistosoma haematobium–associated anemia has been assessed by the 20-m shuttle run test (20mSRT) and validated to provide an accurate correlate of aerobic capacity by the VO2max (measured in mL kg−1 min−1).11

The pathophysiological pathway underlying decreased physical fitness in children with either form of schistosomiasis is complex, hinging on immunopathological lesions and generalized inflammatory responses.1214 Anemia is a cause of decreased oxygen carrying capacity and has been associated with both heavy and light Schistosoma infections in childhood.1,2,4,9,1521 The predominant underlying mechanism seems to be anemia of inflammation, involving pro-inflammatory cytokines including tumour necrosis factor (TNF)-alpha and Interleukin-6.2224 Other mechanisms include ulcerative passage of eggs through the intestinal wall, causing extracorporeal blood loss, splenic sequestration, and autoimmune hemolysis.17,25,26

Lake Albert in western Uganda provides the optimum habitat for Biomphalaria snails, the intermediate host for S. mansoni, making it a hub for S. mansoni transmission. Previous studies have identified egg patent S. mansoni infection prevalences of up to 82% among children aged 5–10 years living in the region.27 Since 2004, the control of schistosomiasis-related morbidity in Uganda has been centered on the targeted, periodic distribution of praziquantel therapy to school-aged children older than 4 years and selected “at risk” adult populations.28 Proxy markers of morbidity have since been evaluated, including fecal occult blood, anemia, and fecal calprotectin testing, quality of life questionnaires, biometry, clinical palpation and measurement, portable ultrasonography, and fitness tests.12,29,30

Previous studies investigating the relationship of S. mansoni infection with physical fitness as measured by the 20mSRT have been inconclusive, limited by small sample sizes, and have not compared or incorporated altitudinal effects.7,8 Altitude acclimatization with an associated increase in red blood cell volume may occur at altitudes as low as ∼1,000 m.31 This study aimed to determine whether S. mansoni infection was associated with decreased aerobic capacity in Ugandan children living at low (∼600 m) or high (∼1,000 m) altitudes. It was hypothesized that S. mansoni infection would correlate with decreased aerobic capacity in Ugandan children and that this association would be less pronounced in children living at high altitude.

METHODS

Ethics statement and eligibility criteria.

Ethical approval was obtained from the London School of Hygiene & Tropical Medicine (LSHTM) Ethics Committee (LSHTM number 12034), Liverpool School of Tropical Medicine (LSTM) Masters Review Panel (M09-17), and the Vector Control Division, Ministry of Health, Uganda (VCDREC-082). Children were considered eligible for enrollment if they were aged 7–15 years, medically fit, had resided in a S. mansoni–endemic area for at least 2 years, and could provide child assent.

Study setting and population.

This study was carried out in six S. mansoni–endemic schools within the Buliisa District of Lake Albert in western Uganda: Biiso (lat. 41.4199, long. 1.7606), Busingiro (lat. 31.4475, long. 1.7354), Bugoigo Islamic (lat. 31.4122, long. 1.9000), Bugoigo Primary (lat. 31.4167, long. 1.9089), Nyamukuta (lat. 31.4000, long. 1.8683), and Walukuba (lat. 31.3831, long. 1.8425). Epidemiological data previously collected within this region provided a useful foundation and thereby influenced the selection of schools for our study.27,32,33 Buliisa is bordered by Nebbi (north), Masindi (east), Hoima (south), and the Democratic Republic of Congo (west). Biiso and Busingiro lay at altitudes of 1,004 and 1,062 m, respectively. The remainder of the schools lay adjacent to Lake Albert, with an altitude of 616 m. The geographical proximities of the schools to the lake shoreline are < 1 km for Bugoigo and Walukuba, and approximately 9 and 14 km for Biiso and Busingiro, respectively. Egg patent S. mansoni infection prevalences among children aged 5–10 years in the villages of Bugoigo, Walukuba, Biiso, and Busingiro have been previously identified to be 36.7%, 82.0%, 19.7%, and 8.0% respectively.27 No transmission of S. haematobium has been documented on parasitological surveys in the field of study.27,34

The study involved 305 schoolchildren aged 7–15 years. Of the 305 schoolchildren, a total of 96 children from Biiso, Busingiro, and Bugoigo Islamic schools were followed up from 2 weeks prior. The team had performed an identical armory of parasitological diagnostic tests and 20-m shuttle run testing, and had administered praziquantel, albendazole, and, if malaria-positive, artemether–lumefantrine therapy.

The study team comprised members from LSHTM, LSTM, and the Vector Control Division, Ministry of Health, Uganda. Subjects were enrolled following random selection from the P2 to P6 class registers of each school over a 9-day period in June 2017. For each village, community mobilizers assisted with community sensitization before data collection. Three of the six schools sampled had been recently sensitized by the preceding LSTM team. Head teacher consent and written child assent were obtained. The information sheets were translated into the local Alur dialect and distributed. The rationale for the study was explained using a local translator.

Forty to 60 children were sampled per day. The principal investigator, a qualified medical practitioner, assessed each child’s general health before study participation. Each child was assigned a unique study identification number which was written on a wristband to be worn by the child during testing. They were asked a brief series of questions related to their demographics, medical background, and previous praziquantel administration using Open Data Kit software, LSHTM, UK, on a tablet device (http://opendatakit.lshtm.ac.uk/odk/). The frequency of mass drug administration with praziquantel at each school was recorded following head teacher questioning.

Anthropometric assessment.

Assessment for stunting was performed using validated charts based on height-for-age (HFA) Z-score: “stunted” was defined as ≤ 2 to > 3 SD below the mean and “severely stunted” was defined as ≤ 3 SD below the mean.35 Calibrated measurements of weight and height were obtained by trained field-workers using standardized scales and a standardized stadiometer, respectively. The height values obtained were for only a subset of the new participants and were converted to HFA Z-scores according to a standardized reference.36 Body mass index (BMI) was calculated for each child for whom height and weight were obtained and converted to BMI-for-age (BFA) Z-scores according to a standardized reference.36 Results were recorded on the standardized data collection form.

Twenty-meter shuttle run test.

Each participant undertook a 20mSRT.11 The test was performed in the school grounds on a clear and level playing field during school hours to maximize convenience and minimize disruption to the school day program. Six to 12 children were tested at any one time. For every four children, one observer was ascribed to ensure adequate monitoring of their performance. Careful instructions were given using a local translator, and a brief demonstration of the test was performed by the principal investigator before testing. All children were kept well hydrated, and water and sugary snacks were made available.

Materials used included two premeasured 20-m ropes, markers, a microphone, a portable speaker, and a tablet device with a relevant application for the 20mSRT (Bleep Fitness Test; Aspectica Ltd., Bath, Somerset, UK). Colored bibs were worn by the study participants for ease of identification. Each fitness score was then translated into VO2max (mL kg−1 min−1) using a validated reference.11

Field-based parasitological diagnostic testing and treatment.

A single urine specimen was obtained from each child and tested for the presence of urine circulating cathodic antigen (urine-CCA; Rapid Medical Diagnostics, Pretoria, South Africa). Urine-CCA has the advantage of detecting light intensity infections which may be missed using the traditional Kato–Katz technique.37 The test band reaction intensity was semiquantitatively graded as negative (−), trace positive (tr), single positive (+), double positive (++), and triple positive (+++).

The presence of S. mansoni infection was determined by duplicate Kato–Katz thick fecal smears (each 41.7 mg) prepared by trained field technicians in accordance with Katz et al.38 Kato–Katz examination indicates infection with mature, egg-shedding worms. The technique was used to provide further information into the level of egg excretion, which is likely a proxy marker of bowel morbidity in addition to infection. Microscopy with a natural light source was used for infield interpretation on the day of testing. Schistosoma mansoni egg counts and the number of eggs per gram of stool based on the mean of the two specimens were documented. Each fecal specimen was tested for the presence of Giardia duodenalis infection using the Giardia/Cryptosporidium Quik Chek test (TECHLAB®, Inc., Blacksburg, VA), and human hemoglobin and transferrin using the Transferrin/FOB Combo Rapid Test Cassette (Hangzhou AllTest Biotech Co., Ltd., Zhejiang, China).

Capillary blood sampling was used to determine the total hemoglobin level (HemoCue AB, Angelholm, Sweden) and screen for malaria infection (Standard Diagnostics BIOLINE Malaria Ag P.f./Pan, Alere, TM.). Follow-up children were not screened for malaria, given the likelihood of persistent antigenemia following recent testing.

Of the new participants, those who tested positive for schistosomiasis on urine-CCA and/or malaria were administered standardized therapy for schistosomiasis and/or malaria, respectively, in keeping with national guidelines. All participants were administered albendazole therapy. Of the follow-up participants, only those who tested positive for urine-CCA were administered praziquantel therapy, given their recent treatment by the preceding team. No children were identified as being unwell or required referral to the local level 2 health care facility.

Data management and statistical analysis.

All data collected were de-identified, entered into Microsoft Excel (Version 16.13.1; Microsoft Corp., Redmond, WA) or LSHTM Open Data Kit software, and stored on an encrypted universal serial bus (USB) device. Data analysis was performed using STATA 14.2 (StataCorp LLC, College Station, TX) on those for whom 20mSRT data were obtained. Separate analyses of the entire cohort and of the follow-up participants were conducted. Descriptive analyses with stratifications by school and altitude (low: ∼600 m, high: ∼1,000 m) were performed. Wilcoxan rank sum, Kruskal–Wallis, Spearman’s correlation, Chi-squared tests, paired t-test, and analysis of variance (ANOVA) were used to identify differences between schools and altitudes. Linear regression was used to determine the unadjusted associations between independent covariates and the dependent variable, VO2max (continuous). Independent covariates of interest included egg patent S. mansoni infection (dichotomous), malaria infection (dichotomous), fecal occult blood (ordinal), anemia (dichotomous), stunting based on validated charts (dichotomous) and HFA Z-score ≤ 2 SD below the mean (dichotomous), and wasting defined by BFA Z-score ≤ 2 SD below the mean (dichotomous).28,35,36 Anemia was defined according to standardized cutoffs for age: < 11.5 g dL−1 (5–11 year) and < 12.0 g dL−1 (12–14 year), and adjusted for altitude using the equation “Hb (g dL−1) − 0.2 g dL−1” for an altitude approximating 1,000 m.39 Logistic regression was used to examine the unadjusted associations between the aforementioned covariates and dependent variables of fecal occult blood, anemia, and stunting (by validated charts). Multivariable-adjusted linear regression was performed using VO2max as the dependent variable, and multivariable-adjusted logistic regression analyses were undertaken using anemia, fecal occult blood, and stunting each as the dependent variable. Model selection was performed using a stepwise procedure, followed by Akaike’s information criterion (AIC) as the model selection criterion. The model which minimized the AIC was selected. All analyses were stratified by gender and altitude.

RESULTS

Participation.

Six schools within the Buliisa District were consecutively sampled: Biiso (n = 48), Busingiro (n = 46), Bugoigo Islamic (n = 48), Bugoigo Primary (n = 61), Nyamukuta (n = 61), and Walukuba (n = 40). Of 305 children who participated, 304 completed the 20mSRT and were included within the final analysis. Only one child did not complete the 20mSRT because of a minor foot injury. Five children did not provide fecal samples and seven children did not provide urine for testing. Malaria, capillary hemoglobin, and fecal occult blood were limited by resource availability, given the diversion of their use by the local clinic. Of 104 children sampled at baseline, 96 children completed the 20mSRT at follow-up (92.3%) and were included within the final analysis. The main reason for the lack of follow-up was the absence from school on the day of testing (Table 1). The remaining 208 children included within the final analysis were those newly recruited to the study.

Table 1

Demographic, hematologic, immunochemical, parasitological, and 20-m shuttle run test (20mSRT) findings in villages of the Buliisa District

ParameterTotal (n = 304)Biiso (n = 48)Bugoigo Islamic (n = 48)Bugoigo Primary (n = 61)Busingiro (n = 46)Nyamukuta (n = 61)Walukuba (n = 40)P-value*
Demography
 Median age in years (IQR)11 (10–12.5)11.5 (10–12.5)11 (9–12)11 (10–13)11 (9–12)10 (10–12)12 (10–13)0.091
 % Female (n)49.7 (151/304)50.0 (24/48)50.0 (24/48)49.2 (30/61)47.8 (22/46)50.8 (31/61)50.0 (20/40)1.000
Anthropometry
 Median height in cm (IQR)134 (128.5–140.5)130.5 (126.4–137.5)133.5 (127.7–142.2)135.2 (127.6–141.7)134 (129.6–139)136 (131.0–139.5)140.5 (131.1–145.2)0.186
 % Stunted by HFA Z-score (n)†36.7 (79/215)41.2 (14/34)51.4 (19/37)43.2 (19/44)17.2 (5/29)29.4 (15/51)35.0 (7/20)0.064
 % Stunted by validated charts (n)‡16.7 (49/293)20.8 (10/48)20.5 (9/44)17.2 (10/58)13.3 (6/45)13.8 (8/58)15.0 (6/40)0.333
 % Stunted (n)15.7 (46/293)20.8 (10/48)20.5 (9/44)15.5 (9/58)13.3 (6/45)13.8 (8/58)10.0 (4/40)
 % Severely stunted (n)1.0 (3/293)0.0 (0/48)0.0 (0/44)1.7 (1/58)0.0 (0/45)0.0 (0/58)5.0 (2/40)
 Median BMI (IQR)16.1 (14.8–17.3)14.8 (13.2–16.3)N/A16.0 (14.7–17.2)N/A16.2 (15.2–17.5)N/A0.652
 % Wasted (n11.8 (8/68)0.0 (0/2)N/A11.1 (4/36)N/A13.3 (4/30)N/A0.838
Hematology
 Median hemoglobin in g dL−1 (IQR)12.0 (11.4–12.7)12.0 (11.4–12.6)12.2 (11.4–12.8)11.8 (11.2–12.4)12.1 (11.3–12.8)12.3 (11.5–13)12 (11.5–12.5)0.274
 % Anemic (n)‖¶34.5 (86/249)41.0 (16/39)33.3 (12/36)44 (22/50)35.1 (13/37)21.2 (11/52)34.3 (12/35)0.232
Immunochemical
 % Fecal occult blood test positive41.2 (61/148)46.9 (15/32)44.0 (11/25)32.0 (8/25)27.3 (6/22)48.2 (13/27)47.1 (8/17)0.489
Parasitology
 Schistosomiasis
  % Schistosoma mansoni infection by urine-CCA (n)#80.5 (231/287)82.6 (38/46)75.0 (33/44)87.7 (50/57)79.1 (34/43)79.0 (45/57)77.5 (31/40)0.663
  % Egg patent S. mansoni infection (n)**44.3 (127/288)39.1 (18/46)36.4 (16/44)46.6 (27/58)35.7 (15/42)45.8 (27/59)61.5 (24/39)0.163
  Mean epg (95% confidence interval)**449.5 (330.1–568.9)215.2 (108.1)568.6 (156.2–981.1)430.4 (170.9–690.0)505.8 (202.6–809.1)505.8 (202.6–809.1)656.3 (284.5–1,028.1)0.241
  Schistosoma mansoni intensity**
  % Negative (n)55.9 (161/288)60.9 (28/46)63.6 (28/44)53.5 (31/58)64.3 (27/42)54.2 (32/59)38.5 (15/39)
  % Light (n)10.1 (29/288)4.4 (2/46)9.1 (4/44)13.8 (8/58)7.1 (3/42)10.2 (6/59)15.4 (6/39)
  % Medium (n)11.8 (34/288)13.0 (6/46)6.8 (3/44)8.6 (5/58)14.3 (6/42)13.6 (8/59)15.4 (6/39)
  % Heavy (n)22.2 (64/288)21.7 (10/46)20.5 (9/44)24.1 (14/58)14.3 (6/42)22.0 (13/59)30.8 (12/39)
 Malaria
  % Malaria (n)††65.2 (122/187)88.9 (24/27)82.6 (19/23)65.9 (29/44)63.0 (17/27)43.2 (16/37)58.6 (17/29)0.003
  % Plasmodium falciparum (n)65.2 (122/187)88.4 (24/27)82.6 (19/23)65.9 (29/44)63.0 (17/27)43.2 (16/37)58.6 (17/29)0.008
  % Mixed (n)11.2 (21/187)18.5 (5/27)8.7 (2/23)15.9 (7/44)7.4 (2/27)8.1 (3/37)6.9 (2/29)0.648
 Giardiasis
  % Giardia duodenalis infection (n)‡‡21.4 (63/294)14.9 (7/47)14.9 (7/47)18.6 (11/59)25 (11/44)23.3 (14/60)35.1 (13/37)0.193
20mSRT
 Median VO2max in mL kg−1 min−1 (IQR)45.4 (42.9–48.0)45.7 (43.9–47.9)46.0 (43.6–48.9)45.4 (43.0–47.5)47.0 (42.9–49.5)45.4 (43.8–47.5)42.1 (40.8–45.0)< 0.001
 Males47.5 (43.9–49.0)47.5 (45.5–49.2)48.4 (45.9–50.4)46.3 (44.8–49)48.0 (46.4–50.0)47.25 (43.8–49.7)43.2 (41.7–46.4)0.005
 Females43.9 (41.5–46.3)44.6 (42.9–45.7)43.9 (41.8–46)43.9 (41.5–47.0)43.9 (42.9–47.5)44.8 (42.9–46.3)41.5 (39.9–43.8)0.100

BMI = body mass index; CCA = circulating cathodic antigen; epg = eggs per gram; HFA = height-for-age; IQR = interquartile range.

* Significance of differences among the villages by Kruskal–Wallis or Chi-squared analysis, and paired t-test or ANOVA. Statistically significant differences (P ≤ 0.05) indicated in bold.

† As defined by HFA Z-scores ≤ 2 SD below mean.36

‡ According to validated stunting charts based on HFA Z-score: “stunted” (≤ 2 to > 3 SD below mean) and “severely stunted” (≤ 3 SD below mean).35

§ As defined by BMI-for-age Z-scores ≤ 2 SD below mean.36

‖ Hemoglobin adjusted for altitude.39

¶ As per standardized hemoglobin cutoffs for age: < 11.5 g dL−1 (5–11 years) and < 12.0 g dL−1 (12–14 years).

# As per urine-CCA testing.

** As per dual Kato–Katz examination. Intensity defined by epg: 1–99 = light, 100–399 = medium, and ≥ 400 = heavy.28

†† As per malaria rapid diagnostic testing.

‡‡ As per Giardia/Cryptosporidium Quik Chek test.

Descriptive analyses.

The age, gender, and parasitology distributions were similar between schools, with the exception of malaria (P = 0.003, Table 1, Figure 1). The prevalence of S. mansoni may have been confounded by the variable distances of the schools from the lake. The prevalence of Plasmodium falciparum malaria was significantly higher at 1,000 m than at 600 m altitudes (P = 0.015, Table 2, Figure 1). Prevalence of S. mansoni by urine-CCA was highest (80.5%), followed by P. falciparum (65.2%), S. mansoni by egg patency (44.3%), and G. duodenalis infection (21.3%). All of the schools studied had received mass drug administration with praziquantel within the preceding 12 months. Overall, 34.5% of children were classified as anemic (n = 86/249) and 41.2% of children had fecal occult blood in the stool. There were no differences in the prevalence of anemia or fecal occult blood and median hemoglobin between schools (Table 1).

Figure 1.
Figure 1.

(A) Prevalence of egg patent Schistosoma mansoni infection according to school and altitude. (B) Prevalence of malaria infection according to altitude.

Citation: The American Journal of Tropical Medicine and Hygiene 100, 6; 10.4269/ajtmh.18-0922

Table 2

Linear regression models with VO2max as the outcome

Unadjusted analysisMultivariable-adjusted analysis
Coefficient95% CIP-valueCoefficient95% CIP-value
Schistosoma mansoni egg patent infection*−1.279−2.199−0.3600.007−4.191−6.312−2.070< 0.001
Fecal occult blood−1.181−0.7670.4040.5420.404−0.5331.3420.392
Malaria†0.142−1.0571.3410.815−0.811−2.8241.2030.424
Stunting‡−0.534−1.6500.5830.348−0.615−2.9341.7040.598
Anemia§−0.650−1.6630.3630.2080.364−1.5952.3230.711

Statistically significant differences (P ≤ 0.05) indicated in bold.

* As per dual Kato–Katz examination.

† As per malaria rapid diagnostic testing.

‡ According to validated stunting charts based on height-for-age Z-score ≤ 2 SD below mean.35

§ As per standardized hemoglobin cutoffs for age: < 11.5 g dL−1 (5–11 years) and < 12.0 g dL−1 (12–14 years). Hemoglobin adjusted for altitude.39 For multivariable-adjusted analysis, n = 68. P-value = 0.009. R2 = 0.2142. Adjusted R2 = 0.1508. Akaike’s information criterion = 373.447.

Anthropometrics and nutritional status.

Acute and chronic malnutrition were identified within all schools. Overall, 36.7% of children were stunted according to a HFA Z-score ≤ 2 SD below the mean (n = 79/215) and 16.7% were stunted according to validated charts (n = 49/293). Of the latter, 1% were severely stunted based on a HFA score ≤ 3 SD below the mean (n = 3/293, Table 1).

Performance in the 20mSRT.

Careful instructions and a test demonstration were provided before shuttle run testing. Overall, the 20mSRT was well understood with very few false starts and trips observed. If either occurred, a rest period was provided and testing was recommenced. Overall, the median VO2max was 45.4 mL kg−1 min−1 (interquartile range [IQR]: 42.9–48 mL kg−1 min−1) with higher values obtained by males than females (47.5 versus 43.9 mL kg−1 min−1, P < 0.001, Table 1). Those children living at high altitude demonstrated a higher median VO2max than those residing at low altitude (46.3 versus 44.8 mL kg−1 min−1, P = 0.031, Supplemental Table 1).

When compared with a Canadian cohort, males demonstrated lower VO2max for all ages.11 Females demonstrated a lower VO2max up until the age of 12 years, after which an upward trend was observed. Figure 2 illustrates the differences between the Canadian and study cohorts by age and gender, and incorporates data from a Kenyan cohort for comparison.2 Outliers at the ages of 7 years (n = 3) and 15 years (n = 3) were excluded (Supplemental Table 3).

Figure 2.
Figure 2.

Comparison of mean VO2max between Ugandan (study) and Kenyan and Canadian cohorts by gender and age (Canadian and Ugandan data sourced from Leger et al.11 and Bustinduy et al.,2 respectively).

Citation: The American Journal of Tropical Medicine and Hygiene 100, 6; 10.4269/ajtmh.18-0922

Associations between infection, nutritional status, and aerobic capacity.

Unadjusted and multivariable-adjusted analyses examining VO2max as an outcome were performed using linear regression. Covariates studied included S. mansoni egg patent infection, fecal occult blood, malaria, and stunting (based on validated charts). The analyses were stratified by gender because of the differences in aerobic capacity between males and females (Supplemental Table 3), and by altitude for the purposes of this study. Model selection was performed using a stepwise procedure, followed by AIC as the model selection criterion. The model with the lowest AIC was selected. Tables 2 and 3 and Supplemental Table 4 summarize these findings.

Table 3

Linear regression models with VO2max as the outcome, stratified by altitude

Unadjusted analysisMultivariable-adjusted analysis
Coefficient95% CIP- valueCoefficient95% CIP-value
Schistosoma mansoni egg patent infection*
 Low altitude1.2992.3890.2080.0203.9626.5561.3680.004
 High altitude−0.971−2.7120.7700.2710.452−5.1026.0070.866
Fecal occult blood
 Low altitude−0.610−1.3490.1280.104−0.226−1.3620.9110.690
 High altitude0.592−0.3331.5180.2050.694−1.0942.4820.424
Malaria†
 Low altitude−0.938−2.3200.4440.182−2.121−4.3900.1480.066
 High altitude2.8320.4945.1700.0195.5240.08410.9640.047
Stunting‡
 Low altitude−0.448−1.7490.8530.498−0.126−2.7152.4630.922
 High altitude−0.719−2.8751.4380.510−0.842−6.2304.5470.746
Anemia§
 Low altitude−0.924−2.1450.2970.1370.891−1.4183.2010.440
 High altitude−0.326−2.0761.4240.711−1.834−5.3841.7170.291

AIC = Akaike’s information criterion. Statistically significant differences (P ≤ 0.05) indicated in bold.

* As per dual Kato–Katz examination.

† As per malaria rapid diagnostic testing.

‡ According to validated stunting charts based on height-for-age Z-score ≤ 2 SD below mean.35

§ As per standardized hemoglobin cutoffs for age: < 11.5 g dL−1 (5–11 years) and < 12.0 g dL−1 (12–14 years). Hemoglobin adjusted for altitude.39 For multivariable-adjusted analysis, low altitude: n = 45. P-value = 0.022. R2 = 0.277. Adjusted R2 = 0.184. AIC = 246.900. High altitude: n = 23. P-value = 0.202. R2 = 0.326. Adjusted R2 = 0.128. AIC = 125.111.

On unadjusted analysis, S. mansoni egg patent infection was a negative predictor of VO2max (Coeff: −1.28, 95% CI: −2.20 to 0.36, P = 0.007). Increasing S. mansoni intensity of infection correlated with decreasing VO2max (Coeff: −0.496, 95% CI: −0.862 to −0.132, P < 0.05). No other covariates demonstrated significant associations with VO2max. The correlation between S. mansoni egg patent infection and VO2max remained when adjusted for the presence of fecal occult blood, malaria, stunting (based on validated charts), and anemia (Coeff: −4.91, 95% CI: −6.31 to 2.07, P < 0.001, Table 2). Similarly, for girls, S. mansoni egg patent infection was associated with VO2max on unadjusted (Coeff: −1.91, 95% CI: −3.12 to −0.70, P = 0.002) and multivariable-adjusted (Coeff: −5.04, 95% CI: −8.80 to −1.28, P = 0.011) analyses (Supplemental Table 4). For boys, no significant correlations with VO2max were identified. For schools residing at low altitudes, S. mansoni egg patent infection negatively correlated with VO2max on both unadjusted (Coeff: −1.30, 95% CI: −2.39 to −0.21, P = 0.02) and multivariable-adjusted (Coeff: −3.96, 95% CI: −6.56 to −1.368, P = 0.004) analyses. For schools residing at high altitude, malaria infection positively correlated with VO2max on both unadjusted (Coeff: 2.83, 95% CI: 0.49–5.17, P = 0.019) and multivariable-adjusted (Coeff: 5.52, 95% CI: 0.08–10.96, P = 0.047) analyses (Table 3).

Associations between infection, anemia, fecal occult blood, and nutritional status.

Logistic regression was used to explore the association between fecal occult blood, anemia, and stunting with infection status, with each covariate being recorded as dichotomous variables. Schistosoma mansoni egg patent infection positively correlated with fecal occult blood (OR: 0.04, 95% CI: 4.01–20.37, P < 0.05). Schistosoma mansoni egg patent infection was positively associated with anemia on unadjusted analysis (OR: 1.85, 95% CI: 1.08–3.15, P = 0.02), as was fecal occult blood (OR: 1.51, 95% CI: 1.11–2.07, P = 0.01). Multivariable-adjusted analysis revealed fecal occult blood to be the only positive predictor of anemia (OR: 1.96, 95% CI: 1.11–3.43, P = 0.02, Supplemental Figure 1).

Logistic regression was also used to analyze stunting (based on validated charts) as an outcome. Schistosoma mansoni egg patent infection positively correlated with stunting (OR: 2.49, 95% CI: 1.30–4.77, P = 0.01) on unadjusted analysis; however, this association did not remain when adjusted for the presence of fecal occult blood, malaria, and anemia (OR: 0.75, 95% CI: 0.17–3.39, P = 0.71, Supplemental Table 5, Supplemental Figure 1).

Comparison between baseline and follow-up.

The prevalence of egg patent S. mansoni infection was similar at baseline and follow-up (20.8% versus 25.0%, P = 0.053). Median hemoglobin was significantly higher at follow-up (10.7 versus 10.2 g dL−1, P < 0.001, Figure 2). Similarly, the prevalence of anemia was lower at follow-up (69.3% versus 72.9%, P = 0.001), particularly for those residing at low altitude. There was no difference in the prevalence of fecal occult blood between the two time-points (22.9% versus 31%, P = 0.584, Supplemental Table 2).

In those residing at low altitude, median VO2max declined between baseline and follow-up (47.0 versus 48.7 mL kg−1 min−1, P < 0.001); however, it remained similar between the two time-points in those residing at high altitude (46.3 versus 46.3 mL kg−1 min−1, P = 0.349, Supplemental Table 2). Median VO2max was higher in those who had been treated 2 weeks prior at baseline, compared with those who were newly recruited to the study (46.3 mL kg−1 min−1, IQR: 44.6–49.7 mL kg−1 min−1 versus 44 mL kg−1 min−1, IQR: 42.1–47.5 mL kg−1 min−1, P < 0.001, Figure 3).

Figure 3.
Figure 3.

(A) Median hemoglobin at baseline and follow-up. (B) Scatter plot of VO2max for follow-up and new participants with median and interquartile range.

Citation: The American Journal of Tropical Medicine and Hygiene 100, 6; 10.4269/ajtmh.18-0922

DISCUSSION

Chronic childhood morbidity secondary to S. mansoni infection has been previously overshadowed by a lack of feasible morbidity metrics adaptable to the pediatric population living within resource-poor settings. This study has shown that S. mansoni egg patent infection is associated with decreased aerobic capacity in Ugandan schoolchildren, with lower aerobic capacities seen in Ugandan than Canadian children. The 20mSRT proved to be a feasible and easily implementable tool that may be harnessed for the identification of S. mansoni–related morbidity within the school setting.

Negative correlations between all S. mansoni infection intensities and VO2max were found in our study, highlighting the important contribution of light-intensity infections to S. mansoni–related morbidity.3,4 These findings were based on the traditional Kato–Katz method which can miss up to 20–40% of active infections.40 However, in the presence of infections of moderate–high intensity as was predominantly the case in this study, both urine-CCA and parasitological examination maintain high levels of accuracy.41

The pathway between S. mansoni infection and decreased aerobic capacity is multifactorial and complex. Anemia is a known downstream effector of S. mansoni infection and has been shown to be associated with decreased aerobic capacity.2 Fecal occult blood is a proxy marker of intestinal inflammation and mechanism for anemia in S. mansoni infection.26,29,42 Schistosoma mansoni egg patent infection and fecal occult blood both positively correlated with anemia in our study. Furthermore, S. mansoni egg patent infection was linked with stunting; another known pathway for anemia causation in S. mansoni infection.2 Figure 4 integrates the findings of this study with current knowledge to suggest a potential, albeit-simplified, pathophysiological basis for reduced physical fitness in children living in S. mansoni–endemic areas.

Figure 4.
Figure 4.

Conceptual pathway for impaired physical fitness in Schistosoma mansoni infection in children. Note: broken arrows represent relationships described elsewhere.

Citation: The American Journal of Tropical Medicine and Hygiene 100, 6; 10.4269/ajtmh.18-0922

Previous studies have demonstrated a reduction in anemia, nutrition-related morbidity, and fecal occult blood, and an increase in physical performance following praziquantel therapy.18,23,29,33,43,44 A reassuring decline in the prevalence of anemia was noted in the follow-up cohort after treatment for schistosomiasis at baseline. Furthermore, higher aerobic capacities were seen in those who had been recently treated, compared with those who were newly recruited to the study, emphasizing the reversibility of functional morbidities. It is important to note, however, that disentangling chronic morbidity and the effects of interventions in low-resource settings is a challenging task. Chronic morbidity is confounded by polyparasitic infections, nutritional deficiencies, and numerous other factors, such as socioeconomic status and food scarcity, which were unable to be accounted for within the constraints of this study.35,45,46

Those children residing at high altitude exhibited higher aerobic capacities than those residing at low altitude. In the former, S. mansoni infection did not have a negative effect on aerobic capacity. With increasing altitude, barometric pressure and atmospheric partial pressure of oxygen decline, resulting in an increase in erythropoietin production. This occurs via the release of hypoxia-inducible factor alpha. Erythropoietin stimulates the bone marrow to increase iron turnover and production of nucleated red blood cells, thereby increasing red blood cell mass.4749 These adaptations may transpire at altitudes as low as ∼1,000 m.31 Such acclimatization may have dampened the deleterious effect of S. mansoni infection on aerobic capacity in the children living at a higher altitude.

This study has several limitations. The small sample size achievable within the time frame has limited the strength of the inferences one can make from the findings, particularly with regard to baseline and follow-up cohorts. Nevertheless, the sample size calculation performed at the outset was achieved, and these findings provide a robust indication for further investigation into the pathway linking S. mansoni infection with physical fitness in children living in S. mansoni–endemic areas. In addition, testing resource availability was limited because of the unforeseen need of the local clinic to use the resources for medical indications. No specific method for ensuring the children reached their maximal aerobic capacity was used. Such methods are usually time-consuming and cumbersome, and were therefore purposely avoided as a means of maintaining the external validity of the 20mSRT as a school-based morbidity metric. The time period between baseline and follow-up testing was brief, limiting the speculations one could make with regard to outcomes following previous exposure to infection and treatment.

Areas requiring further investigation include 1) the development of more rigorous diagnostic tests capable of detecting light infections and demonstrating antigenic cure, thereby illustrating treatment efficacy; 2) the innovation and application of feasible morbidity metrics with the ability to identify sequelae of S. mansoni infections of all intensities; 3) the degree of impact of various altitudes on VO2max and interplay of these associations with parasitic infections and anemia; and 4) extended baseline–follow-up comparisons to delineate the effects of treatment on physical fitness within S. mansoni–endemic areas at different altitudes.

This is the first study to document a relationship between S. mansoni infection and decreased aerobic capacity at high and low altitudes. Altitude acclimatization may be partially protective of this effect. Although the cause of impaired physical performance is multifactorial, this study provides evidence to support the important contribution that S. mansoni infection has toward childhood morbidity. The lower aerobic capacities seen in the Ugandan children than in Kenyan and Canadian children emphasize the inherent need for morbidity assessment in children residing within S. mansoni–endemic areas. Furthermore, a recent malacological survey identified schistosomiasis transmission in regions with an altitude beyond 1,400 m, indicating the need for the geographical expansion of morbidity assessment.34,50,51 Widespread deployment of the 20mSRT throughout school settings represents a promising means by which schistosomiasis-related childhood morbidity may be rapidly detected and managed appropriately within these areas.

Supplementary Files

Acknowledgments:

We would like to acknowledge the field-workers from the Vector Control Division and their tireless efforts to complete every task to an exceptional standard. We are indebted with much gratitude to the Liverpool School of Tropical Medicine for their collaboration and generosity with their equipment and data. Finally, we thank the Ugandan people for their boundless warmth, hospitality, and enthusiasm throughout the entire project.

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Author Notes

Address correspondence to Amaya L. Bustinduy, Department of Clinical Research, London School of Hygiene & Tropical Medicine, Keppel Street, London, UK WC1E 7HT. E-mail: ama.bustinduy@lshtm.ac.uk

Financial support: The London School of Tropical Medicine & Hygiene (bench fees), The Liverpool School of Tropical Medicine (bench fees) and the Medical Research Council (nested within project with code ITCRZJ44).

Authors’ addresses: Courtney Smith and Amaya L. Bustinduy, Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom, E-mails: courtney.bree@live.com and amaya.bustinduy@lshtm.ac.uk. Georgia McLachlan, Hajri Al Shehri, E. James LaCourse, and J. Russell Stothard, Parasitology Department, Liverpool School of Tropical Medicine, Liverpool, United Kingdom, E-mails: george.mac11@btinternet.com, hajri.alshehri@lstmed.ac.uk, james.lacourse@lstmed.ac.uk, and russell.stothard@lstmed.ac.uk. Moses Adriko, Moses Arinaitwe, Aaron Atuhaire, and Edridah Muheki Tukahebwa, Vector Control Division, Ministry of Health, Kampala, Uganda, E-mails: adrikomoses@gmail.com, moses0772359814@gmail.com, aaronatuhaire@gmail.com, and edmuheki@gmail.com. Michelle Stanton, Lancaster Medical School, Lancaster University, Lancaster, United Kingdom, E-mail: michelle.stanton@lancaster.ac.uk.

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