Tropical Medicine and International Health
doi:10.1111/tmi.12234
volume 19 no 2 pp 207–211 february 2014
Effect of azithromycin mass drug administration for trachoma on spleen rates in Gambian children John D. Hart1, Tansy Edwards2, Sarah E. Burr1,3, Emma M. Harding-Esch1,4, Kensuke Takaoka1, Martin J. Holland1, Ansumana Sillah5, David C. W. Mabey1 and Robin L. Bailey1 1 2 3 4 5
Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK MRC Tropical Epidemiology Group, London School of Hygiene and Tropical Medicine, London, UK Disease Control and Elimination Theme, Medical Research Council Unit, Fajara, The Gambia HIV/STI Department, Public Health England, London, UK National Eye Health Programme, Ministry of Health and Social Welfare, Kanifing, The Gambia
Abstract
objective To assess the effect of azithromycin mass drug administration regimens on spleen rates in children aged 0–5 years. methods Clinical assessment of spleen size was carried out during a cluster-randomised trial of azithromycin mass treatment for trachoma elimination in The Gambia. Twenty-four communities received three annual mass treatments with azithromycin, and 24 communities received treatment at baseline only. results At the 30-month follow-up, 3646 children aged 0–5 years had spleen examination and measurement. Palpable splenomegaly was significantly lower in annually treated vs. baseline-only treatment communities and in treated vs. untreated children at 24 months in the annual treatment arm. conclusion The results suggest an effect of azithromycin on spleen rates at the individual level and are most plausibly due to the antimalarial effects of azithromycin. keywords malaria, spleen, splenomegaly, azithromycin, mortality
Introduction Mass drug administration (MDA) with azithromycin is part of the World Health Organization’s (WHO) strategy to eliminate blinding trachoma. Recent evidence suggests that azithromycin MDA may also decrease child mortality (Porco et al. 2009). The mechanisms by which this may occur are unclear although it is likely to be through the broad spectrum of activity of azithromycin on respiratory pathogens, gastrointestinal pathogens and malaria parasites. Several studies have demonstrated the antimalarial effects of azithromycin alone or as combination therapy for malaria treatment or prophylaxis (Taylor et al. 1999; Thriemer et al. 2010), supported by a Cochrane review (van Eijk & Terlouw 2011). Azithromycin MDA for trachoma has been found to reduce Plasmodium falciparum and P. malariae parasitaemia, febrile parasitaemia and splenomegaly (Whitty et al. 1999) as well as malaria symptoms and childhood morbidity (Sadiq et al. 1995). Effects of azithromycin have been demonstrated against the blood stage of P. falciparum (Dahl & Rosenthal
© 2014 John Wiley & Sons Ltd
2007) and on transmission via an impairment of parasite development in the mosquito, in a rodent model (Shimizu et al. 2010). The Gambia has seen a reduction in severe malaria of up to 80% over the past decade, (Ceesay et al. 2008) and, in such a low prevalence setting, it is plausible that a modest antimalarial effect could significantly reduce the human reservoir of malaria, therefore reducing transmission and the incidence of clinical cases. This study aimed to assess the impact of azithromycin MDA on the spleen rate (prevalence of a palpable enlarged spleen), a historical indicator of malaria burden (World Health Organisation 1951). Clinical assessment of spleen size was carried out during a cluster-randomised trial of azithromycin MDA for trachoma elimination in The Gambia, the Partnership for the Rapid Elimination of Trachoma (PRET) trial. Application of PRET study protocols led to 24 communities receiving three annual mass treatments (39 arm) and 24 communities receiving treatment once only at baseline (19 arm; Stare et al. 2011). We aimed to assess the effect of azithromycin MDA regimens on spleen rates in children aged 0–5 years in these communities and consider if any 207
Tropical Medicine and International Health
volume 19 no 2 pp 207–211 february 2014
J. D. Hart et al. Effect of azithromycin mass drug administration
differences could likely be attributed to community or individual treatment.
(Hackett 1944). Both graders were blind to treatment allocation.
Methods
Data analysis
Ethics Ethical approval was received from LSHTM and The Gambia Government/MRC Joint Ethics Committee. Written informed consent was obtained from each child’s guardian. PRET study The PRET study design (Stare et al. 2011) and findings (Harding-Esch et al. 2013) have been described previously; only the parts relevant to this spleen rate study are summarised here. The Gambia is divided into census enumeration areas (the clusters in this study) containing approximately 600–800 people, 48 of which were the randomisation units for PRET. All clusters received mass treatment with azithromycin after a baseline census in May/June 2008, just before the rainy season and higher malaria transmission period from June to October. The 24 39 clusters received additional treatments in May/ June 2009 and May/June 2010; the 24 19 clusters received no further treatments. Random number lists were used to select children aged 0–5 years in each cluster for trachoma examination (the primary outcome of the PRET trial). Spleen size examination and measurement was undertaken in children selected at the 30month follow-up in November–December 2010, 6 months or 30 months after the final treatment distribution in 39 and 19 communities, respectively. Figure 1 shows the trial flow with timing of treatments and spleen assessment. Intervention Treatment offered was a single oral dose of azithromycin 20 mg/kg. Height was used as a proxy for weight when treating children. Pregnant women and infants aged less than 6 months were offered tetracycline eye ointment to be taken daily for 6 weeks. Outcome The outcome was a binary measure of palpable (hence enlarged) spleen determined at the 30-month follow-up, defined as a Hackett Score of 1–5. Children were examined by one of two trained physicians, and spleen size scored according to the Hackett spleen grading system 208
Data were entered in Epi Info 7 and analysed using STATA/IC 12.0. Community effects of azithromycin MDA on spleen rate were analysed by intention to treat (ITT). Logistic regression was used to compare spleen rate by arm with and without a priori adjustment for age, sex and district. Likelihood ratio tests were used to assess significance of the association between treatment arm and spleen rate. A sensitivity analysis was conducted on children resident at 24 months to consider a possible individual effect of recent MDA. In this analysis, excluding individuals who were not present in their communities on the evening before treatment, spleen rates were compared by treatment status at 24 months, overall and within the 39 treatment arm. Results Of the 24 clusters per arm, 18 and 17 clusters were included from each of the 19 and 39 arms, respectively. Exclusions were due to unforeseen delays in the ethical approval process. In these 35 clusters, 3689 children aged 0–5 years were examined for trachoma outcomes and 3646 (98.8%) had Hackett spleen grade assessments. Cluster and household level attributes were similar by arm at baseline, at 30 months post-baseline in the 48 PRET clusters and by arm in the 35 assessed study clusters (data not shown). At the 30-month follow-up, of 3646 children aged 0–5 years, 30 (0.8%) had palpable splenomegaly. In ITT analysis, the spleen rate was significantly lower in the 39 arm vs. the 19 arm (P = 0.004, without a priori adjustment, Table 1). After adjustment for age, sex and district, a significant effect remained (OR = 0.35, 95% CI: 0.15– 0.82, P = 0.010). When the adjusted ITT comparison was restricted to the resident population at 24 months to look at community effect of recent treatment (excluding 234 in the 19 arm and 240 in the 39 arm), a similar reduction in the 39 arm remained (OR = 0.33, 95% CI: 0.13–0.84, P = 0.012). In the 39 arm, amongst children eligible for MDA at the 24-month round, 6 months prior to spleen measurement, the children who actually received treatment at 24 months had a lower spleen rate than untreated children (P = 0.04, Table 1). Eligible but untreated children at the 24-month MDA in the 39 arm were younger than untreated children resident at 24 months in the 19 arm and less likely to live in a household with latrine access than children in the 19
© 2014 John Wiley & Sons Ltd
Tropical Medicine and International Health
volume 19 no 2 pp 207–211 february 2014
J. D. Hart et al. Effect of azithromycin mass drug administration
3× treatment arm
1× treatment arm
Clusters = 24
Clusters = 24
All: 16 920 Baseline treatment
Treated: 14 714 (87.0%) 0–5 s: 3640
0–5 s: 3548
Treated: 3239 (89.0%)
Treated: 3088 (87.0%)
All: 15 575 12 month treatment
Treated: 13 683 (87.9%) 0–5 s: 3371 Treated: 2972 (88.2%)
All: 16 412 24 month treatment
Treated: 14 769 (90.0%) 0–5 s: 3483 Treated: 3138 (90.1%)
Clusters: 17 30 month spleen analysis
All: 16 715 Treated: 14 377 (86.0%)
Children (0–5 years) = 1798
All: 15 368 Treated: 0 0–5 s: 3333 Treated: 0
All: 16 077 Treated: 0 0–5 s: 3245 Treated: 0
Clusters: 18 Children (0–5 years) = 1891
19 missing outcome values
24 missing outcome values
Children in analysis = 1779
Children in analysis = 1867
Figure 1 Trial flow showing numbers of individuals treated at each time point and examined for splenomegaly at 30 months.
arm (data not shown); however, the spleen rates were similar in the two groups (Table 1). Discussion This study evaluated the prevalence of a palpable spleen in children aged 0–5 years, aiming to assess the impact of azithromycin MDA on malaria morbidity. Spleen rates were significantly lower in the 39 clusters (last MDA 6 months earlier) than the 19 clusters (MDA 30 months earlier). Furthermore, this reduction appeared to have occurred in children treated 6 months earlier: children not treated at 24 months in 39 clusters had a similar
© 2014 John Wiley & Sons Ltd
prevalence to children in 19 clusters. Caution is needed in this conclusion, as the comparability of untreated groups is susceptible to bias from unknown factors associated with not receiving treatment and related to the outcomes. However, the observation suggests that the reduction in spleen rates results from an effect of recent treatment with azithromycin on individuals, rather than representing a herd, community or reservoir effect. The spleen rates reported here are strikingly low compared with 30–40% in similar areas of The Gambia in the early 1990s (Sadiq et al. 1995). The latest data from surveys in 2008, taking blood films from nearly 8000 individuals across The Gambia, showed prevalence of 209
Tropical Medicine and International Health
volume 19 no 2 pp 207–211 february 2014
J. D. Hart et al. Effect of azithromycin mass drug administration
Table 1 Prevalence of splenomegaly by intention to treat and by treatment received 6 months prior to assessment
Number of clusters randomised Number of clusters in spleen study Number of children aged 0–5 years in spleen study Enlarged spleen, n (%) Unadjusted OR (95% CI), P-value* Adjusted† OR (95% CI), P-value*
All
39 treatment arm
19 treatment arm
48
24
24
35
17
18
3646
1779
1867
30 (0.8)
7 (0.4) 0.32 (0.14–0.74), 0.004
23 (1.2) 1
0.35 (0.15–0.82), 0.010
1
Treated at 24-month treatment round, 6 months prior to assessment ‡
N
Palpable spleen (%)
No Yes Total
2182 1446 3628
26 (1.2) 3 (0.2) 29 (0.8)
Chi-sq P
N
Palpable spleen (%, 95% CI)
0.001
315 1446 1761
3 (1.0, 0.2–2.8) 3 (0.2, 0.04–0.6) 6 (0.1)
Chi-sq P
N
Palpable spleen (%)
Chi-sq P (39 vs. 19)
0.040
1867
23 (1.2)
0.672
1867
23
OR, odds ratio; CI, confidence interval. *P-values from likelihood ratio tests comparing models with and without arm. †Adjusted for sex, age and district. ‡Excludes 18 children eligible for treatment but with unknown treatment status at 24 months.
malaria parasitaemia in the dry season to be 0.6%, 1.3% and 1.8% in children aged
doi:10.1111/tmi.12234
volume 19 no 2 pp 207–211 february 2014
Effect of azithromycin mass drug administration for trachoma on spleen rates in Gambian children John D. Hart1, Tansy Edwards2, Sarah E. Burr1,3, Emma M. Harding-Esch1,4, Kensuke Takaoka1, Martin J. Holland1, Ansumana Sillah5, David C. W. Mabey1 and Robin L. Bailey1 1 2 3 4 5
Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, UK MRC Tropical Epidemiology Group, London School of Hygiene and Tropical Medicine, London, UK Disease Control and Elimination Theme, Medical Research Council Unit, Fajara, The Gambia HIV/STI Department, Public Health England, London, UK National Eye Health Programme, Ministry of Health and Social Welfare, Kanifing, The Gambia
Abstract
objective To assess the effect of azithromycin mass drug administration regimens on spleen rates in children aged 0–5 years. methods Clinical assessment of spleen size was carried out during a cluster-randomised trial of azithromycin mass treatment for trachoma elimination in The Gambia. Twenty-four communities received three annual mass treatments with azithromycin, and 24 communities received treatment at baseline only. results At the 30-month follow-up, 3646 children aged 0–5 years had spleen examination and measurement. Palpable splenomegaly was significantly lower in annually treated vs. baseline-only treatment communities and in treated vs. untreated children at 24 months in the annual treatment arm. conclusion The results suggest an effect of azithromycin on spleen rates at the individual level and are most plausibly due to the antimalarial effects of azithromycin. keywords malaria, spleen, splenomegaly, azithromycin, mortality
Introduction Mass drug administration (MDA) with azithromycin is part of the World Health Organization’s (WHO) strategy to eliminate blinding trachoma. Recent evidence suggests that azithromycin MDA may also decrease child mortality (Porco et al. 2009). The mechanisms by which this may occur are unclear although it is likely to be through the broad spectrum of activity of azithromycin on respiratory pathogens, gastrointestinal pathogens and malaria parasites. Several studies have demonstrated the antimalarial effects of azithromycin alone or as combination therapy for malaria treatment or prophylaxis (Taylor et al. 1999; Thriemer et al. 2010), supported by a Cochrane review (van Eijk & Terlouw 2011). Azithromycin MDA for trachoma has been found to reduce Plasmodium falciparum and P. malariae parasitaemia, febrile parasitaemia and splenomegaly (Whitty et al. 1999) as well as malaria symptoms and childhood morbidity (Sadiq et al. 1995). Effects of azithromycin have been demonstrated against the blood stage of P. falciparum (Dahl & Rosenthal
© 2014 John Wiley & Sons Ltd
2007) and on transmission via an impairment of parasite development in the mosquito, in a rodent model (Shimizu et al. 2010). The Gambia has seen a reduction in severe malaria of up to 80% over the past decade, (Ceesay et al. 2008) and, in such a low prevalence setting, it is plausible that a modest antimalarial effect could significantly reduce the human reservoir of malaria, therefore reducing transmission and the incidence of clinical cases. This study aimed to assess the impact of azithromycin MDA on the spleen rate (prevalence of a palpable enlarged spleen), a historical indicator of malaria burden (World Health Organisation 1951). Clinical assessment of spleen size was carried out during a cluster-randomised trial of azithromycin MDA for trachoma elimination in The Gambia, the Partnership for the Rapid Elimination of Trachoma (PRET) trial. Application of PRET study protocols led to 24 communities receiving three annual mass treatments (39 arm) and 24 communities receiving treatment once only at baseline (19 arm; Stare et al. 2011). We aimed to assess the effect of azithromycin MDA regimens on spleen rates in children aged 0–5 years in these communities and consider if any 207
Tropical Medicine and International Health
volume 19 no 2 pp 207–211 february 2014
J. D. Hart et al. Effect of azithromycin mass drug administration
differences could likely be attributed to community or individual treatment.
(Hackett 1944). Both graders were blind to treatment allocation.
Methods
Data analysis
Ethics Ethical approval was received from LSHTM and The Gambia Government/MRC Joint Ethics Committee. Written informed consent was obtained from each child’s guardian. PRET study The PRET study design (Stare et al. 2011) and findings (Harding-Esch et al. 2013) have been described previously; only the parts relevant to this spleen rate study are summarised here. The Gambia is divided into census enumeration areas (the clusters in this study) containing approximately 600–800 people, 48 of which were the randomisation units for PRET. All clusters received mass treatment with azithromycin after a baseline census in May/June 2008, just before the rainy season and higher malaria transmission period from June to October. The 24 39 clusters received additional treatments in May/ June 2009 and May/June 2010; the 24 19 clusters received no further treatments. Random number lists were used to select children aged 0–5 years in each cluster for trachoma examination (the primary outcome of the PRET trial). Spleen size examination and measurement was undertaken in children selected at the 30month follow-up in November–December 2010, 6 months or 30 months after the final treatment distribution in 39 and 19 communities, respectively. Figure 1 shows the trial flow with timing of treatments and spleen assessment. Intervention Treatment offered was a single oral dose of azithromycin 20 mg/kg. Height was used as a proxy for weight when treating children. Pregnant women and infants aged less than 6 months were offered tetracycline eye ointment to be taken daily for 6 weeks. Outcome The outcome was a binary measure of palpable (hence enlarged) spleen determined at the 30-month follow-up, defined as a Hackett Score of 1–5. Children were examined by one of two trained physicians, and spleen size scored according to the Hackett spleen grading system 208
Data were entered in Epi Info 7 and analysed using STATA/IC 12.0. Community effects of azithromycin MDA on spleen rate were analysed by intention to treat (ITT). Logistic regression was used to compare spleen rate by arm with and without a priori adjustment for age, sex and district. Likelihood ratio tests were used to assess significance of the association between treatment arm and spleen rate. A sensitivity analysis was conducted on children resident at 24 months to consider a possible individual effect of recent MDA. In this analysis, excluding individuals who were not present in their communities on the evening before treatment, spleen rates were compared by treatment status at 24 months, overall and within the 39 treatment arm. Results Of the 24 clusters per arm, 18 and 17 clusters were included from each of the 19 and 39 arms, respectively. Exclusions were due to unforeseen delays in the ethical approval process. In these 35 clusters, 3689 children aged 0–5 years were examined for trachoma outcomes and 3646 (98.8%) had Hackett spleen grade assessments. Cluster and household level attributes were similar by arm at baseline, at 30 months post-baseline in the 48 PRET clusters and by arm in the 35 assessed study clusters (data not shown). At the 30-month follow-up, of 3646 children aged 0–5 years, 30 (0.8%) had palpable splenomegaly. In ITT analysis, the spleen rate was significantly lower in the 39 arm vs. the 19 arm (P = 0.004, without a priori adjustment, Table 1). After adjustment for age, sex and district, a significant effect remained (OR = 0.35, 95% CI: 0.15– 0.82, P = 0.010). When the adjusted ITT comparison was restricted to the resident population at 24 months to look at community effect of recent treatment (excluding 234 in the 19 arm and 240 in the 39 arm), a similar reduction in the 39 arm remained (OR = 0.33, 95% CI: 0.13–0.84, P = 0.012). In the 39 arm, amongst children eligible for MDA at the 24-month round, 6 months prior to spleen measurement, the children who actually received treatment at 24 months had a lower spleen rate than untreated children (P = 0.04, Table 1). Eligible but untreated children at the 24-month MDA in the 39 arm were younger than untreated children resident at 24 months in the 19 arm and less likely to live in a household with latrine access than children in the 19
© 2014 John Wiley & Sons Ltd
Tropical Medicine and International Health
volume 19 no 2 pp 207–211 february 2014
J. D. Hart et al. Effect of azithromycin mass drug administration
3× treatment arm
1× treatment arm
Clusters = 24
Clusters = 24
All: 16 920 Baseline treatment
Treated: 14 714 (87.0%) 0–5 s: 3640
0–5 s: 3548
Treated: 3239 (89.0%)
Treated: 3088 (87.0%)
All: 15 575 12 month treatment
Treated: 13 683 (87.9%) 0–5 s: 3371 Treated: 2972 (88.2%)
All: 16 412 24 month treatment
Treated: 14 769 (90.0%) 0–5 s: 3483 Treated: 3138 (90.1%)
Clusters: 17 30 month spleen analysis
All: 16 715 Treated: 14 377 (86.0%)
Children (0–5 years) = 1798
All: 15 368 Treated: 0 0–5 s: 3333 Treated: 0
All: 16 077 Treated: 0 0–5 s: 3245 Treated: 0
Clusters: 18 Children (0–5 years) = 1891
19 missing outcome values
24 missing outcome values
Children in analysis = 1779
Children in analysis = 1867
Figure 1 Trial flow showing numbers of individuals treated at each time point and examined for splenomegaly at 30 months.
arm (data not shown); however, the spleen rates were similar in the two groups (Table 1). Discussion This study evaluated the prevalence of a palpable spleen in children aged 0–5 years, aiming to assess the impact of azithromycin MDA on malaria morbidity. Spleen rates were significantly lower in the 39 clusters (last MDA 6 months earlier) than the 19 clusters (MDA 30 months earlier). Furthermore, this reduction appeared to have occurred in children treated 6 months earlier: children not treated at 24 months in 39 clusters had a similar
© 2014 John Wiley & Sons Ltd
prevalence to children in 19 clusters. Caution is needed in this conclusion, as the comparability of untreated groups is susceptible to bias from unknown factors associated with not receiving treatment and related to the outcomes. However, the observation suggests that the reduction in spleen rates results from an effect of recent treatment with azithromycin on individuals, rather than representing a herd, community or reservoir effect. The spleen rates reported here are strikingly low compared with 30–40% in similar areas of The Gambia in the early 1990s (Sadiq et al. 1995). The latest data from surveys in 2008, taking blood films from nearly 8000 individuals across The Gambia, showed prevalence of 209
Tropical Medicine and International Health
volume 19 no 2 pp 207–211 february 2014
J. D. Hart et al. Effect of azithromycin mass drug administration
Table 1 Prevalence of splenomegaly by intention to treat and by treatment received 6 months prior to assessment
Number of clusters randomised Number of clusters in spleen study Number of children aged 0–5 years in spleen study Enlarged spleen, n (%) Unadjusted OR (95% CI), P-value* Adjusted† OR (95% CI), P-value*
All
39 treatment arm
19 treatment arm
48
24
24
35
17
18
3646
1779
1867
30 (0.8)
7 (0.4) 0.32 (0.14–0.74), 0.004
23 (1.2) 1
0.35 (0.15–0.82), 0.010
1
Treated at 24-month treatment round, 6 months prior to assessment ‡
N
Palpable spleen (%)
No Yes Total
2182 1446 3628
26 (1.2) 3 (0.2) 29 (0.8)
Chi-sq P
N
Palpable spleen (%, 95% CI)
0.001
315 1446 1761
3 (1.0, 0.2–2.8) 3 (0.2, 0.04–0.6) 6 (0.1)
Chi-sq P
N
Palpable spleen (%)
Chi-sq P (39 vs. 19)
0.040
1867
23 (1.2)
0.672
1867
23
OR, odds ratio; CI, confidence interval. *P-values from likelihood ratio tests comparing models with and without arm. †Adjusted for sex, age and district. ‡Excludes 18 children eligible for treatment but with unknown treatment status at 24 months.
malaria parasitaemia in the dry season to be 0.6%, 1.3% and 1.8% in children aged
