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Keywords:

  • hookworm;
  • Necator americanus;
  • Ancylostoma duodenale;
  • anaemia;
  • haemoglobin;
  • anthelmintic treatment
  • ankylostome;
  • Necator americanus;
  • Ankylostome duodenale;
  • anémie;
  • hémoglobine;
  • traitement antihelmintique
  • anquilostoma;
  • Necator americanus;
  • Ancylostoma duodenale;
  • anemia;
  • hemoglobina;
  • tratamiento antihelmíntico

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Objectives  To summarise age- and intensity-stratified associations between human hookworm infection and anaemia and to quantify the impact of treatment with the benzimidazoles, albendazole and mebendazole, on haemoglobin and anaemia in non-pregnant populations.

Methods  Electronic databases (MEDLINE, EMBASE, PubMed) were searched for relevant studies published between 1980 and 2009, regardless of language, and researchers contacted about potential data. Haemoglobin concentration (Hb) was compared between uninfected individuals and individuals harbouring hookworm infections of different intensities, expressed as standardised mean differences (SMD) and 95% confidence intervals (CI). Meta-analysis of randomised control trials (RCTs) investigated the impact of treatment on Hb and anaemia.

Results  Twenty-three cross-sectional studies, six pre- and post-intervention studies and 14 trials were included. Among cross-sectional studies, moderate- and heavy-intensity hookworm infections were associated with lower Hb in school-aged children, while all levels of infection intensity were associated with lower Hb in adults. Among RCTs using albendazole, impact of treatment corresponded to a 1.89 g/l increase (95%CI: 0.13–3.63) in mean Hb while mebendazole had no impact. There was a positive impact of 2.37 g/l (95%CI: 1.33–3.50) on mean Hb when albendazole was co-administered with praziquantel, but no apparent additional benefit of treatment with benzimidazoles combined with iron supplementation. The mean impact of treatment with benzimidazoles alone on moderate anaemia was small (relative risk (RR) 0.87) with a larger effect when combined with praziquantel (RR 0.61).

Conclusions  Anaemia is most strongly associated with moderate and heavy hookworm infection. The impact of anthelmintic treatment is greatest when albendazole is co-administered with praziquantel.

Impact de l’infection à l’ankylostomiase et du déparasitage sur l’anémie dans des populations non-enceintes: une revue systématique

Objectifs:  Résumer les associations entre l’âge/l’intensité stratifié et l’ankylostomiase humaine/l’anémie, et quantifier l’impact du traitement anthelminthique sur l’hémoglobine et l’anémie dans des populations non-enceintes.

Méthodes:  Des bases de données électroniques (MEDLINE, EMBASE, PubMed) ont été recherchées pour des études pertinentes publiées entre 1980 et 2009, indépendamment de la langue, et des chercheurs ont été contactés au sujet de potentielles données. Les concentrations d’hémoglobine (Hb) ont été comparées entre les individus non infectés et ceux avec l’ankylostomiase à des intensités différentes d’infection, exprimées en différences de la moyenne standard (SMD) dans un intervalle de confiance (CI) de 95%. Une méta-analyse d’essais contrôlés randomisés (ECR) a investigué l’impact du traitement sur l’Hb et l’anémie.

Résultats:  23 études transversales, 6 études pré-et post-intervention et 14 essais ont été inclus. les études transversales, des intensités d’ankylostomiase modérées et fortes ont été associées à une baisse d’Hb chez des enfants d’âge scolaire, tandis que tous les niveaux d’intensité d’infection ont été associés à une baisse d’Hb chez des adultes. les ECR ayant utilisé l’albendazole, l’impact du traitement correspondait à une augmentation de 1,89 g/l (IC95%: 0,13-3,63) de la moyenne d’Hb alors que le mébendazole n’avait aucun impact. Il y avait un impact positif de 2,37 g/l (IC95%: 1,33-3,50) sur la moyenne d’Hb lorsque l’albendazole était co-administré avec le praziquantel, mais pas de bénéfice apparent du traitement au benzimidazole combiné avec une supplémentation en fer. L’impact moyen du traitement au benzimidazole seul sur l’anémie modérée était faible (risque relatif (RR): 0,87) avec un effet plus important lorsqu’il était combiné avec le praziquantel (RR: 0,61).

Conclusions: L’anémie est plus fortement associée à l’ankylostomiase modérée et intense. L’impact du traitement anthelminthique est plus grand lorsque l’albendazole est co-administré avec le praziquantel.

Impacto de la infección por anquilostoma y del tratamiento antiparasitario en poblaciones anémicas no embarazadas: revisión sistemática

Objetivos:  Resumir las asociaciones entre la infección por anquilostoma y la anemia, estratificando según la edad y la intensidad, y cuantificar el impacto del tratamiento antihelmíntico sobre la hemoglobina y la anemia en poblaciones no embarazadas.

Métodos:  Se realizaron búsquedas de estudios relevantes publicados entre 1980 y 2009, independientemente del idioma y de los investigadores, en bases de datos electrónicas (MEDLINE, EMBASE, PubMed). Se comparó la concentración de hemoglobina (Hb) entre individuos no infectados e individuos con diferente nivel de anquilostomiasis, expresándolo como la diferencia media estandarizada (DME) e intervalos de confianza del 95% (IC). Mediante un meta-análisis de ensayos controlados aleatorizados (EAC) se investigó el impacto del tratamiento sobre la Hb y la anemia.

Resultados:  Se incluyeron 23 estudios croseccionales, 6 estudios pre- y post-intervención y 14 ensayos. Entre los estudios croseccionales, se encontró una asociación entre infecciones por anquilostoma, moderadas y altas, con una Hb baja en niños en edad escolar, mientras que cualquier nivel de infección estaba asociada con una Hb baja en adultos. Entre los EACs que utilizaban albendazol, el impacto del tratamiento correspondía a un aumento de 1.89 g/l (95%IC: 0.13-3.63) en la Hb media mientras que el mebendazol no tenía ningún impacto. Había un impacto positivo de 2.37 g/l (95%IC: 1.33-3.50 sobre la Hb media cuando se coadministraba el albendazol con prazicuantel, pero no había un beneficio aparente adicional en el tratamiento con benzimidazol más una suplementación con hierro. El impacto medio del tratamiento con benzimidazol solo sobre la anemia moderada era pequeño (riesgo relativo (RR) 0.87) con un mayor efecto cuando se combinaba con praziquantel (RR 0.61).

Conclusiones:  La anemia está fuertemente asociada con una infección moderada y alta con anquilostoma. El impacto del tratamiento antihelmíntico es mayor cuando el albendazol se coadministra con praziquantel.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Hookworms (Necator americanus and Ancylostoma duodenale) reside in the small intestine of infected individuals where they attach themselves to the villi and feed on host blood. Among individuals with inadequate iron intake and high physiological demands, this blood loss can result in anaemia. The link between hookworm and anaemia was first established in the nineteenth century (Perroncito 1880), and during the subsequent 130 years, there have been numerous reviews of the extensive literature in this area (Layrisse & Roche 1964; Miller 1979; Schad & Banwell 1984; Crompton & Stephenson 1990; Crompton & Whitehead 1993; Stoltzfus et al. 1997; Brooker et al. 2004; Hotez et al. 2004). There is a direct relationship between the number of hookworms an individual harbours (the intensity of infection) and the amount of intestinal blood lost attributable to hookworm (Gilles & Williams 1964; Martinez-Torres et al. 1967; Stoltzfus et al. 1996). The clinical consequences of this loss will depend on the host’s underlying iron status as well as the presence of other causes of anaemia (Fleming 2000). Studies indicate that there is some worm burden threshold above which clinically significant anaemia is likely to occur, with the precise threshold dependent on the host’s iron status (Lwambo et al. 1992). As well as influencing morbidity, worm burden is a key determinant of transmission dynamics and hence the rate of reinfection following anthelmintic treatment (Anderson & May 1985). Intensity of infection may also influence the efficacy of treatment (Bennett & Guyatt 2000). It follows therefore that as the intensity of hookworm infection varies considerably between populations, the risk of anaemia attributable to hookworm and the impact of treatment will differ among populations.

In 2007, a systematic review of randomised controlled trials (RCTs) investigating the impact of anthelmintic treatment reported an increase in haemoglobin concentration (Hb) of 1.71 g/l after treatment (Gulani et al. 2007). But this review did not distinguish between different helminth species or account for intensity of infection, which may have underestimated the true treatment effect (Awasthi & Bundy 2007); the effect of treatment is likely to be greatest where hookworm is most prevalent and intense. Recent work has quantified hookworm-related anaemia among pregnant women (Brooker et al. 2008). The present work aims to quantify the impact of hookworm infection and anthelmintic treatment using benzimidazoles, albendazole and mebendazole, among non-pregnant populations in hookworm-endemic areas. Specifically, we review available data from cross-sectional studies that investigated the relationship between intensity of hookworm infection and Hb. We also summarise available data from RCTs and pre- and post-intervention observational studies that compared the effects of benzimidazole treatment, either alone or in combination with the anti-schistosomal drug praziquantel, on Hb and anaemia levels. Finally, based on the value of combining deworming with micronutrient supplementation in children, we evaluate the impact of treatment in combination with iron supplementation (Hall 2007).This work contributes to the current reassessment of the global burden of disease (Murray et al. 2007).

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Identification of cross-sectional studies

The bibliographic databases of MEDLINE (http://medline.cos.com/), EMBASE (http://www.embase.com/) and PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) were searched for relevant studies in 2006 and again in April 2009. For analysis of the association between intensity of hookworm infection and anaemia, the following Medical Subject Headings (MSHs) were used to identify relevant studies published between 1980 and 2009: hookworm, Necator americanus, Ancylostoma duodenale, an(a)emia, h(a)emoglobin and h(a)ematocrit. Cross-sectional studies published prior to 1980 were reviewed, but those presenting relevant statistics were found to use different diagnostic test and intensity thresholds, making comparisons with later studies difficult (Beaver 1951; Carr 1926; Chernin 1954). Returned abstracts were reviewed and full texts retrieved if they contained relevant information. References from articles and key reviews were screened for additional studies. Finally, leading researchers in the area and authors of key papers were contacted to ask about unpublished or unindexed data, and this yielded a number of additional studies. Non-English language journals were included in the search, and relevant articles were assessed against the inclusion/exclusion criteria by native speakers. No distinction could be made between the two different hookworm species, Necator americanus and Ancylostoma duodenale, as none of the studies used diagnostic methods able to differentiate species.

The primary outcome for analysis was haemoglobin concentration (Hb) in non-pregnant populations, and our hypothesis was that haemoglobin concentration is associated with the intensity of hookworm infection as assessed by quantitative egg counts, expressed as eggs per gram (epg)/faeces. Abstracted data included the mean Hb, corresponding standard deviation (SD) and number of individuals infected for each category of hookworm infection intensity and were entered into an Excel database. When data were not reported in the preferred format, authors were contacted to request relevant data summaries. Data were stratified by age group (0–4, 5–19 and 20+ years) and category of infection intensity (light, 0–1999 epg; moderate, 2000–3999 epg; heavy, 4000+ epg)) (WHO 2002).

Identification of treatment studies

Treatment studies were identified using the MSHs deworming, anti-helmint(h)ic, anthelmint(h)ic, anthelminth, mebendazole, praziquantel, pyrantel, piperazine, nitazoxanide, levamisole, albendazole, bephenium and niclosamide. Only trials that randomised individuals to treatment with a benzimidazole (BMZ) anthelmintic drug and a control group, either placebo or standard of care, and conducted in hookworm-endemic areas were included. Only studies from 1980 onwards were identified because mebendazole was only introduced to the market in 1975 and albendazole in 1980 and use of these benzimidazoles in public health interventions post-dates 1980 (Horton 2003). Two additional groups of studies were included: (i) RCTs of BMZ combined with praziquantel (PQZ) treatment for schistosomiasis and (ii) RCTs of BMZ treatment combined with iron supplementation. In addition to RCTs, observational studies of the impact of intervention were reviewed. Studies that did not quantify the baseline prevalence of hookworm infection, were conducted in pregnant populations, or used an anthelmintic other than albendazole (ABZ) or mebendazole (MBZ) were excluded as these drugs are not widely used in large-scale treatment programmes. Trials were assessed by recommended criteria as shown in Table S2, but quality was not summarised using a score and incomplete reporting was not followed up with authors. These decisions were based on reported unreliability of scales in assessing quality and on the possibility of introducing bias (Higgins & Green 2009).

Primary outcomes were change in mean Hb and prevalence of anaemia, based on the hypothesis that Hb will differ between intervention and control group in response to anthelmintic treatment. Abstracted data included the baseline prevalence of hookworm infection and anaemia, and the post-treatment relative risk of hookworm infection, prevalence of anaemia, mean Hb and change in Hb in each group, with corresponding SDs. For studies that did not report the prevalence of anaemia, an approximation was made on the basis of the reported mean and standard deviation Hb. The proportion of individuals with Hb below the age-specific thresholds for mild, moderate and severe anaemia was calculated assuming a normal Hb distribution (Sharman 2000; WHO 2008). For studies that evaluated treatment effect at multiple time points, only data from the longest time interval were included in the analysis.

Data analysis

The difference in Hb among different intensity categories was expressed as pool estimates of standardised mean difference (SMD) based on a meta-analysis using a DerSimonian and Laird random effects model. All P values are from two-tailed tests of significance where alpha is equal to 0.05.

The impact of treatment was assessed using two approaches. First, for RCTs and observational studies, the impact of treatment on the prevalence of anaemia was expressed as a relative risk (RR) and mean impact summarised. Second, for RCTs, a DerSimonian and Laird random effects meta-analysis was conducted to provide pooled estimates of the effect of treatment on Hb, and a metaregression was used to identify sources of variation between studies. The analysis was stratified by co-administration of PQZ in the intervention arm. This design was justified by the lack of an equivalent intervention in the control arm of these trials and their incomparability to those specifically evaluating the impact of BMZ treatment. SMDs were transformed into g/l using a mean of the SDs of included studies. Linear regression analysis was used to summarise relative risk of mild and moderate anaemia and identify potential determinants of anaemia impact. Study characteristics that were investigated in the modelling process included: age category, WHO region, intervention, baseline prevalence and intensity of hookworm infection, mean Hb at baseline, dosage schedule and follow-up period. Sensitivity analysis identified the Stephenson et al. (1993) study as responsible for significant variation in the results, and this study was therefore excluded from further analysis on the basis that participants were restricted to those with heavier infections.

Heterogeneity between studies was assessed by an I2 test, with values greater than 50% representing significant heterogeneity, and a sensitivity analysis and preliminary metaregression identified potential sources of variation. Results were displayed as forest plots. Publication bias was investigated by the construction of funnel plots and by the Egger and Begg statistical tests. Analysis was performed using the ‘metan’ and related functions in STATA version 10 (College Station, TX).

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Associations between hookworm intensity and haemoglobin

The search identified 423 citations, from which 117 unique and potentially relevant articles were retrieved. Of these, 48 were determined to be eligible and 14 had suitable cross-sectional data, including 11 surveys among school-aged children and seven among non-pregnant adults1. In addition, unpublished data were available for nine studies. Eighteen studies were conducted in Africa, one in South Asia, four in Southeast Asia and one in Latin America. Survey characteristics are described in Table S1. For all populations, prevalence estimates for hookworm infection ranged from 0.3 to 96%, with 12.5% of the surveys having a mean intensity of infection >1000 epg and eight studies having no individuals with infection intensity >2000 epg. Prevalence of anaemia (110 g/l or 120 g/l threshold) ranged between 4.5 and 90%.

Figure 1 presents the difference in Hb between school-aged children uninfected and those harbouring different levels of infection intensity. There was no evidence for a difference in Hb between uninfected and lightly infected children (SMD −0.04, 95%Confidence interval [CI]: −0.11 to 0.03) (Figure 1a), but there was evidence for a difference between uninfected children and moderately (SMD −0.32, 95% CI −0.46 to −0.18) or heavily (SMD −0.64, 95% CI −0.84 to −0.45) infected children (Figure 1b). There was significant heterogeneity in differences between studies but that could not be explained by any single study. However, a higher baseline prevalence of anaemia was weakly associated with lower Hb in lightly or moderately infected children compared to uninfected children (= 0.06), suggesting that children with poor underlying iron status may be more likely to suffer the consequences of light hookworm infection than those with better nutritional status. There was some evidence of non-symmetry in the funnel plot of uninfected children compared to those with a moderate infection and weak evidence of publication bias using the Egger’s test but not Begg’s test.

image

Figure 1.  Forest plot of the difference in haemoglobin concentration (Hb) among school-aged children (a) uninfected with hookworm and children with a light (1–1999 eggs/gram) hookworm infection and (b) uninfected with hookworm and children with a heavy (4000+ eggs/gram) hookworm infection. Standardised mean difference less than zero indicates lower Hb levels in children harbouring infections compared to uninfected children. The area of the shaded box represents the contribution (or weight) assigned to the estimate of effect from each study (centre point). The diamond represents the overall pooled estimates of the effect of hookworm infection on Hb. Study ID refer to references in Table S1.

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Among adults, there was evidence for progressively lower Hb among individuals lightly infected (SMD −0.15, 95% CI −0.29 to −0.00) (Figure 2a), moderately infected (SMD −0.47, 95% CI −0.77 to -.17) and heavily infected (SMD −0.93, 95% CI −1.43 to −0.44) relative to those uninfected (Figure 2b). There was evidence of heterogeneity of effect that could be explained by specific studies in each infection strata which, when excluded, altered the SMD (in parenthesis): Brooker et al. (2007a), the only study in Latin America (SMD −0.21, 95% CI −0.30 to −0.11); Latham et al. (1982) among Kenya male road workers in Kenya (SMD −0.36, 95% CI −0.53 to −0.19); and Olsen et al. (1998) in a highly malaria endemic area (SMD −0.71, 95% CI −1.07 to 0.34). No evidence of publication bias was detected in any of the other age group or intensity strata.

image

Figure 2.  Forest plot of the difference in haemoglobin concentration (Hb) among non-pregnant adults (a) uninfected with hookworm and adults with a light (1–1999 eggs/gram) hookworm infection and (b) uninfected with hookworm and adults with a heavy (4000+ eggs/gram) hookworm infection. Standardised mean difference less than zero indicates lower Hb levels in adults harbouring infections compared to uninfected adults. The area of the shaded box represents the contribution (or weight) assigned to the estimate of effect from each study (centre point). The diamond represents the overall pooled estimates of the effect of hookworm infection on Hb. Study ID refer to references in Table S1.

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Impact of anthelmintic treatment

Of the 31 studies identified, 14 RCTs met the criteria for inclusion, of which 10 evaluated the effects of either ABZ or MBZ treatment alone (Table 1), four evaluated ABZ treatment with PQZ (Table 2), and five evaluated treatment in combination with iron supplementation (Table 3). In addition, six observational studies were included (Tables 1–3). The majority of studies were conducted in Africa (75%), predominantly in East Africa, used ABZ (85%), and were conducted among school-aged children (75%) (Table 4). Of the RCTs, most studies were individually randomised (79%) and double blind (77%), while seven used a factorial study design to evaluate deworming in combination with iron supplementation. The mean follow-up period for all studies was 3.8 months. Marked variation in the prevalence of hookworm and anaemia (using different thresholds) existed between studies.

Table 1.   Anthelmintic intervention studies investigating the impact of albendazole (ABZ) or mebendazole (MBZ) on anaemia outcomes in non-pregnant populations
Site & yearInterventionAge (years)Study duration (months)Parasite prevalenceHw mean intensity (epg)RR of Hw infection*Prevalence of anaemia & mean Hb ± SDOutcome measureHb impact†Anaemia impact: RRAnaemia prevalence, mean Hb ± SD or change in Hb (SE)‡N§Reported data or normal approx.¶
InterventionControl
  1. Hw, hookworm; Al, Ascaris lumbricoides; Tt, Trichuris trichiura; SD, standard deviation; SE, standard error; NR, not reported; RR, relative risk.

  2. *The reduction in the prevalence of hookworm infection at the time of follow-up (intervention group/control group).

  3. †The difference in mean Hb or mean change in Hb between intervention and control groups at follow-up.

  4. ‡Mean Hb in g/l.

  5. §Number in treatment group at follow-up.

  6. ¶Approximation of the prevalence of anaemia, assuming Hb concentrations to be normally distributed around the reported mean, with the reported SD.

  7. **Stephenson et al. 1990, 1993 include men only, Gilgen et al. 2001 includes women only.

  8. ††Mean Hb is estimated from baseline Hb and change in Hb and assumed to have the same SD as at baseline.

  9. ‡‡At follow-up, some of control group were treated.

  10. §§Change in Hb was estimated as the difference in reported pre-intervention and post-intervention Hb levels.

  11. ¶¶Standard error estimated from t-test.

  12. ***The adjusted odds ratio (age, baseline Hb, fever, Plasmodium falciparum) followed the same trend as crude RR.

  13. †††Includes children infected with either Hw or Schistosoma haematobium.

  14. ‡‡‡Geometric mean.

Randomised-controlled trials
Kenya (Stephenson et al. 1990)ABZ (400 mg) single dose 6–12 **1.6Hw = 91.0 Al = 39.0 Tt = 94.062290.567% (<120 g/l) 113 ± 12Mean†† Change <115 g/l <100 g/l <70 g/l 0.0 +2.00.88 0.62 0.12110 ± 11.9 −4.0 (1.8) 66.3% 20.0% 0.0%106 ± 13.2 −6.0 (1.8) 75.2% 32.5% 0.3% 18Data Data Approximation Approximation Approximation
Kenya, 1989 (Stephenson et al. 1993)ABZ (600 mg) single dose 7–13 **4Hw = 96.2 Al = 41.5 Tt = 98.133520.4447% (<120 g/l) 120 ± 9.6Mean Change <115 g/l <100 g/l+5.0 +4.00.65 0.40119 ± 10.4 −2.0 (1.2) 35.0% 3.4%114 ± 10.2 −6.0 (1.0) 53.9% 8.5% 27Data Data Approximation Approximation
Kenya, 1990 (Adams et al. 1994)ABZ (400 mg) triple dose 5–101.7Hw = 92.7 Al = 29.1 Tt = 83.648730.0109 ± 14Mean Change <115 g/l <100 g/l <70 g/l+2.0 +1.00.94 0.81 0.46108 ± 12.2 −1.6 (1.9) 71.7% 25.6% 0.1106 ± 12.5 −2.6 (1.6) 78.8% 34.5% 0.3 28Data Data Approximation Approximation Approximation
Tanzania, 1994 (Stoltzfus et al. 1998)MBZ (500 mg) single dose thrice-yearly 6–1612Hw = 93.3 Al = 74.2 Tt = 96.1 450‡‡‡0.7563% (<110 g/l) 105 ± 12Mean†† Change <110 g/l <100 g/l−0.6 +1.41.15 1.33116.7 ± 13 +12.7(1.7) 33.2% 9.9%117.3 ± 12 +11.3 (1.7) 28.9% 7.5%970Data Data (adjusted) Data Approximation
North India, 1995 (Awasthi & Bundy 2000)‡‡ABZ (600 mg) single dose, every 6 months. 1.5–3.524Hw = 3.6 Al = 11.7NRNR91% (<110 g/l) 95 ± 9Mean Change§§ <110 g/l <100 g/l 0.0  0.01.00 1.0096.7 ± 6.6 +1.7 96.8 66.696.7 ± 6.5 +1.7 96.8 66.6610Data Data Approximation Approximation
Benin, (Dossa et al. 2001)ABZ (200 mg) triple dose at 0,1 month. 3–510Hw = 13 Al = 38 Tt = 47 286‡‡‡0.23 (3 months.)76% (<110 g/l) 99.8 ± 11Mean Change <110 g/l <100 g/l 0.0 +4.01.06 0.85106 ± 10 + 8 (2.1) 65.5% 27.4%106 ± 13 + 5 (2.1) 62.1% 32.2% 38Data Data Approximation Approximation
Bangladesh (Gilgen et al. 2001)ABZ (400 mg) single dose at 0 and 12 weeks14–66**5.5Hw = 74.4 Al = 47.6 Tt = 56.8 57.7‡‡‡NR86% (<120 g/l) 97.8Mean Change§§,¶¶+3.9 +2.2 100.6 +2.0 (1.6)96.7 −0.2 (1.4)143Data Data
Tanzania (Stolzfus et al. 2004)***MBZ(500 mg) single dose every 3 months0.5–512Hw = 31.3 Al = 31.3 Tt = 47.75.6‡‡‡0.7494% (<110 g/l) 91 ± 12Mean Change <110 g/l: <30 months >30 months <90 g/l: <30 months >30 months <70 g/l:+1.0 +1.00.98 1.01 0.71 1.34 1.09100±16 +9 71.4% 73.2% 25.7% 15.5% 5.7%99±16 +8 87.3% 71.2% 36.6% 13.6% 5.0%220 220  35  71  35  71 106Combined data Combined data Data Data Data Data Data
Viet Nam, 2005 (Le Huong et al. 2007)MBZ (500 mg) single dose at 0, 3 months6–86Hw = 9.3 Al = 68.3 Tt = 68.3 Mostly ‘light’0.6888% (<115 g/l) 108.1 ± 6.2Mean†† Change <115 g/l−0.1 −0.80.78123.1 ± 6.9 +14.6 (1.0) 15.2%123.2 ± 6.2 +15.4 (0.92) 19.5% 79Data Data Data
Viet Nam, 2007 (Nga et al. 2009) ABZ (400 mg) single dose6–84Hw = 5.1 Al = 66.0 Tt = 62.6Mostly ‘light’1.224% (<115 g/l) 119.6 ± 7.3Mean Change§§ <115 g/l <100 g/l−0.2 +1.21.05 0.37119.9 ± 7 +1.0 20.5% 0.2%120.1 ± 8 −0.2 19.5% 0.6%117Data Data Data Approximation
Observational studies          BaselineFollow-up  
Tanzania, 1997 (Bhargava et al. 2003)ABZ (400 mg) triple dose at 0, 12 weeks5–183,15Hw = 100423NR67%††† (<120 g/l) 111.2±16.4Mean <115 g/l <100 g/l+9.30.56 0.21120.5 ± 12.6 33.1% 5.2%111.2 ± 16.4 59.2% 24.7% 56Data Approximation Approximation
Table 2.   Anthelmintic intervention studies investigating the impact of albendazole (ABZ) or mebendazole (MBZ) combined with praziquantel (PQZ) on anaemia outcomes in non-pregnant populations
Site & yearIntervention*Age (years)Study duration (months)Parasite prevalenceHw mean intensity (epg)RR of Hw infection†Prevalence of anaemia & mean Hb ± SDOutcome measureHb impact‡Anaemia impactAnaemia prevalence, mean Hb ± SD or change in Hb (SE)§NReported data or normal approx.**
InterventionControl
  1. Hw, hookworm; Al, Ascaris lumbricoides; Tt, Trichuris trichiura; SD, standard deviation; SE, standard error; NR, not reported; RR, relative risk.

  2. *PQZ administered by WHO praziquantel dose pole (40 mg/kg).

  3. †The reduction in the prevalence of hookworm infection at the time of follow-up (intervention group/control group).

  4. ‡The difference in mean Hb or mean change in Hb between intervention and control groups at follow-up.

  5. §Mean Hb in g/l.

  6. ¶Number in treatment group at follow-up.

  7. **Approximation of the prevalence of anaemia, assuming Hb concentrations to be normally distributed around the reported mean, with the reported SD.

  8. ††Mean Hb is estimated from baseline Hb and change in Hb and assumed to have the same SD as at baseline.

  9. ‡‡Geometric mean.

Randomised-controlled trials (combined with praziquantel (PQZ); placebo in control group)
Tanzania, 1994 (Beasley et al. 1999)ABZ (400 mg) single dose PQZ7–12 3.5Al = 49.1 Hw = 92.9 Tt = 68.2 Pf = 74.1 Sh = 10020450.6349% (<110 g/l) 110 ± 10.1 Mean Change <110 g/l <100 g/l+2.0 +2.40.85 0.60109 ± 9.0 −1.1 (.7) 53% 15.9%107 ± 11.1 −3.5 (.7) 62% 26.4%127Data Data Data Approximation
South Africa, 1996 (Taylor et al. 2001)ABZ (400 mg) triple dose at 0, 6 months PQZ6–1512Hw = 59.4 Pf = 5.1 Sm = 0LightNR34% (<120 g/l) 125.3Mean†† Change+2.1 +2.0 121.6 −3.8 (1.6)119.5 −5.8 (1.2) 34Data Data
Kenya, 2003 (Friis et al. 2003)ABZ (600 mg) single dose PQZ9–18 8Hw = 51.9 Al = 14.0 Tt = 48.1 Pf = 59.5 Sm = 72.859‡‡NR40% (age/sex specific) 123.7 ± 12.7Mean†† Change <115 g/l <100 g/l +3.9 +3.10.31 0.62 132.7 ± 12.7 +8.6 (0.9) 4.0% 0.6%128.8 ± 12.3 +5.5 (1.1) 13.1% 1.0%187Data Data Approximation Approximation
Côte d’Ivoire, 2007 (Rohner et al. 2010)ABZ (400 mg) single dose at 0, 3 months PQZ6–14 6Hw = 51.4 Al = 1.4 Tt = 2.9 Pf = 57.7107.8‡‡0.3870% (<115 or 120 g/l) 110.8 ± 9.0Mean Change <115 g/l <100 g/+2.9 +2.70.80 0.62109.6 ± 9.2 −1.2 (1.0) 70.6% 14.8%106.7 ± 9.4 −3.9 (1.1) 87.8% 23.8% 60Data Data Data Approximation
Observational studies          BaselineFollow-up  
Tanzania, 1996 (Guyatt et al. 2001)ABZ (400 mg) single dose PQZ8–1410, 15Hw = 61 Sh = 597380.8054% (<110 g/l) 10% (<90 g/l) 107.3 ± 14.5Mean <110 g/l <90 g/l <70 g/l+5.50.74 0.63 0.53112.8 ± 15.1 40.0% 6.1% 0.8%107.3 ± 14.5 54.1% 9.7% 1.5%1121Data Data Data Data
Tanzania, 1997 (Bhargava et al. 2003)ABZ (400 mg) triple dose at 0, 12 weeks PQZSAC   15Hw = 100 Sh = 100423NR67% (<120 g/l) 112.1 ± 15.2Mean <115 g/l <100 g/l+8.80.34 0.23120.9 ± 11.4 19.3% 4.9%112.1 ± 15.2 57.6% 21.3%135Data Data Approximation Approximation Approximation
Uganda, 2003 (Koukounari et al. 2006)ABZ (400 mg) single dose PQZ6–14   12Hw = 52.1 Al = 2.4 Tt = 2.3 Sm = 43.93070.4650% (<115 or 120 g/l) 114.3 ± 13.5Mean <115 g/l <100 g/l <70 g/l+2.40.92 0.75 0.62116.7 ± 13.5 45.8% 10.8% 0.18%114.3 ± 13.5 50.0% 14.5% 0.29%2788Data Data Approximation Data
Burkina Faso, 2004 (Koukounari et al. 2007)ABZ (400 mg) single dose PQZ5–15   12Hw = 6.3 Sm = 6.2 Sh = 53.912.50.6866% (<115 or 120 g/l) 110 ± 14Mean <115 g/l <100 g/l+2.80.94 0.61112.5 ± 12 61.6% 14.9%109.7 ± 14 65.8% 24.4%1131Data Data Approximation
Niger, 2004 (Tohon et al. 2008)ABZ (400 mg) single dose PQZ7, 8, 1112Hw = 4.2 Al = 0.3 Tt = 0.09 Sm = 0.9 Sh = 75.4 Pf = 8NRNR62% (<115 g/l) 110Mean <115 g/l+40.81114 g/l 50.4%110 g/l 61.9%1642Data Data
Table 3.   Anthelmintic intervention studies investigating the impact of albendazole (ABZ) or mebendazole (MBZ) combined with iron supplementation on anaemia outcomes in non-pregnant populations
Site & yearIntervention*Age (years)Study duration (months)Parasite prevalenceHw mean intensity (epg)RR of Hw infection†Prevalence of anaemia & mean Hb ± SDOutcome measureHb impact‡Anaemia impact: RRAnaemia prevalence, mean Hb ± SD or change in Hb (SE)§NReported data or normal approx.**
InterventionControl
  1. Hw, hookworm; Al, Ascaris lumbricoides; Tt, Trichuris trichiura; SD, standard deviation; SE, standard error; NR, not reported; RR, relative risk.

  2. *PQZ administered by WHO praziquantel dose pole (40 mg/kg).

  3. †The reduction in the prevalence of hookworm infection at the time of follow-up (intervention group/control group).

  4. ‡The difference in mean Hb or mean change in Hb between intervention and control groups at follow-up.

  5. §Mean Hb in g/l.

  6. ¶Number in treatment group at follow-up.

  7. **Approximation of the prevalence of anaemia, assuming Hb concentrations to be normally distributed around the reported mean, with the reported SD.

  8. ††Gilgen et al. 2001 and Casey et al. 2009 only include women.

  9. ‡‡Change in Hb was estimated as the difference in reported pre-intervention and post-intervention Hb levels.

  10. §§Mean Hb is estimated from baseline Hb and change in Hb and assumed to have the same SD as at baseline.

  11. ¶¶Values estimated from graph.

  12. ***The adjusted odds ratio (age, baseline Hb, fever, Plasmodium falciparum) followed the same trend as crude RR.

  13. †††Standard error estimated from t-test.

  14. ‡‡‡Geometric mean.

Randomised-controlled trials (combined with iron; iron + AH placebo in control group)
Benin, (Dossa et al. 2001)ABZ (200 mg) at 0, 1 months. Iron (60 mg/day)3–510Hw = 13 Al = 38 Tt = 47755‡‡‡0.23 (3 months)76% (<100 g/l) 100.5 ± 11Mean Change <110 g/l <100 g/l+2 +20.89 1.17113 ± 13 +13 (2.6) 40.9% 15.9%111 ± 10 +11 (2.1) 46.0% 13.6% 34Data Data Approximation Approximation
Bangladesh, (Gilgen 2001)ABZ (400 mg) single dose at 0, 12 weeks. Ferrous fumarate (200 mg)  + folic acid (200 mg)14–66††5.5Hw = 74.4 Al = 47.6 Tt = 56.857.7‡‡‡NR86% (<120 g/l) 99.3Mean Change‡‡,§§+1.9 +2.3 106.9 +7.8 (1.3)105.0 +5.5 (1.3)130Data Data
Zanizibar, (Stoltzfus et al. 2004)***MBZ (500 mg) single dose every 3 months Ferrous sulfate (10 mg)0.5–512Hw = 31.3 Al = 31.3 Tt = 47.75.6‡‡‡0.7494% (<110 g/l) 91 ± 12Mean Change <110 g/l: <30 months ≥30 months <90 g/l: <30 months ≥30 months. <70 g/l:+1.0 +1.01.2 1.0 0.71 1.59 1.06100±16 +9 80.0% 81.3% 26.0% 17.2% 1.8%99±16 +8 65.9% 79.7% 36.4% 10.8% 1.7%220220 50  64  50  64 114Combined data Combined data Data Data Data Data Data
Viet Nam, 2004 (Le Huong et al. 2007)MBZ (500 mg) single dose at 0, 3 months Iron fortified noodles (10.7 mg/52 g noodle)6–8 6Hw = 8.5 Al = 67.9 Tt = 77.6Mostly ‘light’0.2887% (<115 g/l) 107.4 ± 7.6Mean¶¶ Change <115 g/l <100 g/l−0.5 −0.31.09 0.12124.8 ± 6.8 +17.5(0.85) 11.4% 0%125.3 ± 8.3 +17.8 (0.97) 10.5% 0.1% 79Data Data Data Approximation
Viet Nam, 2007 (Nga et al. 2009)ABZ (400 mg) single dose Micronutrients6–8 4Hw = 6.2 Al = 64.8 Tt = 22.8Mostly ‘light’1.226% (<115 g/l) 119.3 ± 7.5Mean Change‡‡ <115 g/l <100 g/l+1.0 +0.10.86 0.09122.2 ± 6.2 +2.5 12.8% 0%121.2 ± 7.3 +2.4 14.9% 0.2%118Data Data Data Approximation
Randomised-controlled trials (combined with praziquantel (PQZ) & iron; iron + AH placebo in control group)
South Africa, 1996 (Taylor 2001)***ABZ(400 mg) triple dose at 0, 6 months PQZ Ferrous fumarate 200 mg/wk × 106–1512Hw = 59.4 Pf = 5.1 Sm = 0LightNR34% (<120 g/l) 122.7Mean¶¶ Change+3.5 +5.9 124.7 +3.5 (1.5)121.2 −2.4 (1.2) 41Data Data
Kenya, 2003 (Friis 2003)ABZ(600 mg) single dose PQZ Micronutrients8–18 8Hw = 58.2 Al = 13.3 Tt = 42.7 Pf = 58.7 Sm = 69.645‡‡‡NR40% (age/sex specific) 123.6 ± 12.1Mean¶¶ Change <115 g/l <100 g/l+1.6 +1.20.99 1.34134.2 ± 12.6 +10.4 (1.1) 6.4% 0.3%132.6 ± 11.6 +9.2 (1.0) 6.5% 0.2%180Data Data Approximation Approximation
Côte d’Ivoire, 2007 (Rohner et al. 2010)ABZ (400 mg) single dose at 0, 3 months PQZ Fortified biscuits (20 mg Fe 4 times/week)6–14 6Hw = 53.4 Al = 1.4 Tt = 2.9 Pf = 56.1107.8‡‡‡0.2772% (<115 or 120 g/l) 111.2 ± 10.6Mean Change <115 g/l <100 g/+2.1 +2.00.88 0.89109.3 ± 10.7 −1.9 (0.7) 78.7% 19.2%107.2 ± 9.2 −3.9 (1.3) 89.0% 21.7% 64Data Data Data Approximation .
Observational study         BaselineFollow-up  
Viet Nam, 2005 (Casey et al. 2009)ABZ (400 mg) single dose every 4 months Ferrous sulphate/folic acid (60 mg/0.4 mg)15–45††12Hw = 76.2NR0.3838% (<120 g/l) 122.5†††Mean¶¶ <120 g/l <100 g/l+9.20.51 0.35132.0 19.3% 3.0%†††122.5 37.5% 8.5%†††382Data Data Data
Table 4.   Summary of 20 hookworm intervention studies investigating the impact of benzimidazole treatment (BMZ) on haemoglobin concentration (Hb), administered alone or in combination with praziquantel (PQZ) or iron
  Number of studiesMean (range)
  1. *The reduction in the prevalence of hookworm infection at the time of follow-up (intervention group/control group).

  2. †Limited to randomised controlled trials.

  3. ‡PQZ administered in the intervention arm only, iron in both intervention and control groups.

RegionSites  
Asia, SouthBangladesh 1 
India 1 
Asia, SoutheastViet Nam 3 
sub-Saharan Africa, EastKenya 4 
Tanzania 5 
Uganda 1 
sub-Saharan Africa, SouthernSouth Africa 1 
sub-Saharan Africa, WestBenin 1 
Burkina Faso 1 
Côte d’Ivoire 1 
Niger 1 
Study design:Observational studies 6 
Randomised controlled trials14 
Benzimidazole typeAlbendazole17 
Mebendazole 3 
AssessedBMZ alone11 
BMZ + PQZ 9 
BMZ + iron 5 
BMZ + PQZ + iron 3 
Age category (years)0–4 3 
5–1815 
18–70 2 
Study duration (months) 209.4 (1.6–24)
Mean baseline hookworm prevalence (%) 2050.7 (3.6–100)
Mean baseline hookworm intensity (epg) 141387(5.6–6229)
Mean relative risk of infection* 140.58 (0–1.2)
BMZ Alone
 Comparison arm mean change in Hb† 102.5 (−6 to 15.4)
 Intervention arm mean change in Hb† 104.0 (−4 to 14.6)
 Increase in mean change in Hb 11+2.3 (−0.8 to 9.3)
 Mean relative risk of Hb<115 g/l 110.91 (0.56–1.5)
 Mean relative risk of Hb<100 g/l 100.77 (0.21–1.34)
BMZ + PQZ‡
 Comparison arm mean change in Hb†  4−1.9 (−5.8 to 5.5)
 Intervention arm mean change in Hb†  40.6 (−3.8 to 8.6)
 Increase in mean change in Hb  8+3.7 (2–8.8)
 Mean relative risk of Hb<115 g/l  80.72 (0.31–0.9)
 Mean relative risk of Hb<100 g/l  70.58 (0.23–0.8)
BMZ + iron‡
 Comparison arm mean change in Hb†  49.2 (2.4–17.8)
 Intervention arm mean change in Hb†  410.2 (2.5–17.5)
 Increase in mean change in Hb  5+2.7 (−0.3–9.2)
 Mean relative risk of Hb<115 g/l  50.93 (0.51–1.2)
 Mean relative risk of Hb<100 g/l  50.67 (0.1–1.6)
BMZ + PQZ + iron‡
 Comparison arm mean change in Hb†  31.0 (−3.9 to 9.2)
 Intervention arm mean change in Hb†  34.0 (−1.9 to 10.4)
 Increase in mean change in Hb  2+3.0 (1.2–5.9)
 Mean relative risk of Hb<115 g/l  20.94 (0.9–1.0)
 Mean relative risk of Hb<100 g/l  21.11 (0.9–1.3)

Across all 20 RCTs and observational studies, the mean change in Hb was higher in the treatment arm for all intervention packages than in the control arm: 2.3 g/l higher in the BMZ group; 3.7 g/l higher in the BMZ and PQZ group; 2.7 g/l higher in the BMZ and iron group; and 3.0 g/l higher in the BMZ, PQZ and iron group (Table 4). The effect of BMZ alone on mild and moderate anaemia was small (mean RR of 0.91 and 0.77), whereas the mean RR of BMZ plus PQZ was 0.72 for mild anaemia and 0.58 for moderate anaemia.

Eleven RCTs reported the effect of intervention on mean Hb with corresponding standard deviations (SD) or allowed their estimation (three studies did not report SDs: Awasthi et al. 2000; Stoltzfus et al. 2004; Nga et al. 2009). There was no overall effect of BMZ (SMD 0.05, 95%CI: −0.02 to 0.12), but looking at the drug effects separately, treatment with ABZ corresponded to a 1.89 g/l increase in mean Hb (SMD 0.15, 95% CI 0.01 to 0.29) whereas MBZ had no apparent impact (Figure 3a). Furthermore, combining ABZ and PQZ resulted in a 2.37 g/l increase in mean Hb (SMD 0.23, 95% CI 0.13 to 0.34) (Figures 3b). There was no evidence to support a beneficial impact of BMZ treatment when iron supplementation was co-administered in both arms of the trial (SMD 0.09, 95% CI −0.09 to 0.27) compared to neither arm (SMD 0.04, 95% CI −0.04 to 0.12).

image

Figure 3.  Forest plot of the difference in the mean change in haemoglobin concentration (Hb) among individuals treated with an anthelmintic and individuals given a placebo in interventions studies (= 10). Standardised mean difference greater than zero indicates a greater increase in Hb levels in the treated group (or a smaller decrease) compared to the control group. The area of the shaded box represents the contribution (or weight) assigned to the treatment effect estimated from each study (centre point). Diamonds represent pooled estimates among studies stratified by (a) benzimidazole type in those studies not administering praziquantel and (b) co-administration of praziquantel in the intervention arm. The lowest diamond represents the overall pooled estimates of the effect of any treatment on the mean change in Hb.

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Among RCTs, treatment with BMZ alone had little impact on the risk of mild (RR 0.98, 95%CI: 0.89–1.06) and moderate (RR 0.87, 95%CI, 0.59–1.15) anaemia as determined by linear regression. When BMZ treatment was co-administered with PQZ, the mean relative risks of mild and moderate anaemia were 0.67 (95% CI −0.11 to 1.45) and 0.61 (95% CI 0.58–0.64). Among studies administering BMZ alone, a higher Hb at baseline was associated with a larger impact on moderate anaemia (= 0.02), but there was no evidence of a differential impact when iron supplementation was co-administered in both arms of the trial (= 0.69 and = 0.63). No determinants of impact were identified for studies co-administering BMZ and PQZ.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

The aetiology of tropical anaemia is complex, but the present systematic review confirms that hookworm infections of moderate or heavy intensity are associated with lower Hb levels in both school-aged children and adults (Layrisse & Roche 1964; Stoltzfus et al. 1997). The mechanisms by which hookworms reduce Hb are well established: adult worms attached to intestinal villi and pass a stream of blood through their intestines to obtain oxygen and nutrients. Fortunately, however, the current results show that anthelmintic treatment is an effective means of improving Hb levels, but that the effects of treatment appear to differ according the benzimidazole drug used (Figure 3). Among the included RCTs, treatment using albendazole was associated with an 1.89 g/l increase in Hb, whereas mebendazole treatment afforded no apparent benefit. However, the impact of benzimidazole treatment on Hb is enhanced by the co-implementation of praziquantel treatment and iron supplementation: for example, the addition of praziquantel resulted in a 2.37 g/l increase.

WHO currently recommends that school-aged children living in areas of high prevalence of soil-transmitted helminths (hookworms, Ascaris lumbricoides and Trichuris trichiura) receive mass treatment with either albendazole or mebendazole (WHO, 2002). Whilst these drugs are both highly efficacious against A. lumbricoides, with demonstrable gains for growth and school performance (Taylor-Robinson et al. 2007; Bundy et al. 2009), single-dose mebendazole treatment is less effective against T. trichiura and hookworm (Keiser & Utzinger 2008). Thus, the differential impact of albendazole and mebendazole on Hb levels can be explained in part by their varying efficacies against hookworm, although it should be noted that observed cure and egg reduction rates of mebendazole against hookworm vary among populations (Keiser & Utzinger 2008). However, this review identified only three published RCTs that investigated the impact of mebendazole on Hb, making it difficult to draw difficult definite conclusions about the effect of mebendazole in different hookworm-endemic regions of the world.

In areas co-endemic with schistosomiasis, benzimidazole is typically co-implemented with praziquantel. Previous attempts to quantify the haematological benefits of praziquantel have been hindered by the lack of RCTs evaluating the effects of PQZ alone (Friedman et al. 2005). Praziquantel has a direct effect against schistosomes, which may cause anaemia through a variety of proposed mechanisms, including extra-corporeal blood loss, sequestration of red blood cells, haemolysis and inflammation (Friedman et al. 2005). A previous systematic review of schistosomiasis-related morbidity (King et al. 2005) identified five studies evaluating the impact of praziquantel on Hb levels in hookworm-endemic areas; but two of these trials co-administered benzimidazole or metrifonate treatment. Metrifonate is partially effective against hookworm infection (Kurz et al. 1986), and therefore, inclusion of studies using metrifonate would potentially overestimate the impact of praziquantel treatment. A large multi-centre RCT of praziquantel and albendazole included by King et al. (2005) found that only treatment with praziquantel had an impact on Hb, but the estimate of impact for albendazole was not reported (Olds et al. 1999).

One of the difficulties of attributing effects of hookworm and anthelmintic treatment on anaemia, particularly among populations exposed to malaria and with inadequate dietary intake, is the exclusion of other causes. The multiple aetiologies of anaemia can confound cross-sectional estimates of association and influence the observed impact of anthelmintic treatment. Malaria (both symptomatic and asymptomatic) is an important aetiological factor for anaemia operating through several mechanisms including increased destruction of red blood cells (RBCs) through rupturing, phagocytosis and hypersplenism and reduced RBC production through inflammation and dyserythropiesis (Kurtzhals et al. 1999; Menendez et al. 2000; Tolentino et al. 2007). Extensive geographic overlap of hookworm and malaria yields a high prevalence of co-infection, which may increase in an additive manner the risk of anaemia (Brooker et al. 2007b). A further aetiological factor for anaemia is schistosomiasis, and co-infection with schistosomes and hookworm has been associated with enhanced anaemia risk (Ezeamama et al. 2008; Stephenson et al. 1985; Brito et al. 2006). In the present review, cross-sectional studies did not report adjusted intensity-stratified estimates of Hb and only 5 RCTs stratified results by nutritional status. Studies reported conflicting results: some found a differential impact based on anaemic status (Beasley et al. 1999) and intensity of hookworm infection (Stoltzfus et al. 1998; Adams et al. 1994), while others found no difference in impact between these groups (Taylor et al. 2001; Friis et al. 2003). Among children with S. mansoni infections, Friis et al. 2003 reported a greater impact on Hb associated with malaria co-infection, suggesting that malaria may influence the impact of schistosomiasis treatment.

A further potentially confounding factor is anthelmintic treatment efficacy. Reported estimates of the impact of benzimidazole treatment may underestimate the true magnitude of association because of incomplete treatment cure and the potential reinfection that occurs during follow-up (Bradley et al. 1993; Stoltzfus et al. 2000). Reinfection dynamics of helminths are well described and depend on a number of factors that vary between populations, including transmission intensity, efficacy of treatment and treatment coverage (Anderson & Schad 1985). Studies of hookworm reinfection support the view that prevalence and intensity of hookworm infection can return to pre-treatment levels within 1–2 years, with reinfection fastest in areas of high transmission and where treatment efficacy and coverage is lowest (Quinnell et al. 1993; Schad & Anderson 1985; Reynoldson et al. 1997 & De Clerq et al. 1997). A related issue is variation in follow-up time of included studies because a longer follow-up will allow more opportunities for reinfection and may therefore underestimate the impact of treatment on haemoglobin.

Diagnostic uncertainty may introduce additional bias. The dominant hookworm species present as well as the haemoglobin and diagnostic methods may influence observed impact. Few of the included studies distinguished between the two hookworm species N. americanus and A. duodenale because of the practical difficulties of differential diagnosis. However, it is suggested that A. duodenale causes greater blood loss than N. americanus (Pawlowski et al. 1991), with data from Zanzibari schoolchildren indicating that A. duodenale is associated with an increased risk of anaemia (Albonico et al. 1998). Finally, although Hb is routinely assessed as a measure of iron stores, it is insensitive to significant (20–30%) decreases in iron stores from higher Hb levels and is not specific to iron-deficiency anaemia (Zimmermann 2008). Other indicators of iron stores might provide a more sensitive measure of baseline nutritional status and influence the observed impact.

In conclusion, this systematic review confirms the benefits of anthelmintic treatment for improving Hb levels of infected populations but highlights important differences according to the type of benzimidazole drug used and the package of interventions treatment is combined with. This finding highlights the need for continual evaluation of the beneficial effects of deworming on Hb, with randomised evaluations providing the most robust evidence. However, there is also a need for rigorous, long-term evaluation of large-scale control programmes to ensure that they are having maximal benefits for the targeted populations. This would avoid denying individuals the benefits of treatment through randomised evaluations. The results additionally emphasise the public health benefits of combing health interventions and are of particular relevance to efforts implementing an integrated school health package, which may include deworming, iron supplementation, school feeding and malaria control (Bundy et al. 2006).

Footnotes

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

This work was supported by the Albert B. Sabin Vaccine Institute’s Human Hookworm Vaccine Initiative (HHVI) funded by the Bill and Melinda Gates Foundation, which also supports JLS. SB is supported by the Wellcome Trust through a Career Development Fellowship (081 673) and acknowledges the support of the Kenyan Medical Research Institute. We are grateful to Naufil Alam for helping conduct the initial literature review and to John Horton and Peter Hotez for constructive comments on an earlier draft.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information
  • Adams EJ, Stephenson LS, Latham MC & Kinoti SN (1994) Physical activity and growth of Kenyan school children with hookworm, Trichuris trichiura and Ascaris lumbricoides infections are improved after treatment with albendazole. Journal of Nutrition 124, 11991206.
  • Albonico M, Stoltzfus RJ, Savioli L et al. (1998) Epidemiological evidence for a differential effect of hookworm species, Ancylostoma duodenale or Necator americanus, on iron status of children. International Journal of Epidemiology 27, 530537.
  • Anderson RM & May RM (1985) Helminth infections of humans: mathematical models, population dynamics, and control. Advances in Parasitology 24, 1101.
  • Anderson RM & Schad GA (1985) Hookworm burdens and faecal egg counts: an analysis of the biological basis of variation. Transactions of the Royal Society of Tropical Medicine and Hygiene 79, 812825.
  • Awasthi S & Bundy DAP (2007) Intestinal nematode infection and anaemia in developing countries. British Medical Journal 334, 10651066.
  • Awasthi S, Pande VK & Fletcher RH (2000) Effectiveness and cost-effectiveness of albendazole in improving nutritional status of pre-school children in urban slums. Indian Pediatrics 37, 1929.
  • Beasley M, Tomkins AM, Hall A et al. (1999) The impact of population level deworming on the haemoglobin levels of schoolchildren in Tanga, Tanzania. Tropical Medicine and International Health 4, 744750.
  • Beaver PC (1951) Hemoglobin determination in hookworm disease case-finding. American Journal of Tropical Medicine 21, 9097.
  • Bennett A & Guyatt H (2000) Reducing intestinal nematode infection: efficacy of albendazole and mebendazole. Parasitology Today 16, 7174.
  • Bhargava A, Jukes M, Lambo J et al. (2003) Anthelmintic treatment improves the hemoglobin and serum ferritin concentrations of Tanzanian schoolchildren. Food and Nutrition Bulletin 24, 332342.
  • Bradley M, Chandiwana SK & Bundy DAP (1993) The epidemiology and control of hookworm infection in the Burma Valley area of Zimbabwe. Transactions of the Royal Society of Tropical Medicine & Hygiene 87, 145147.
  • Brito LL, Barreto ML, Silva Rde C, et al. (2006) Moderate- and low-intensity co-infections by intestinal helminths and Schistosoma mansoni, dietary iron intake, and anemia in Brazilian children. American Journal of Tropical Medicine & Hygiene 75, 939944.
  • Brooker S, Bethony J, Hotez PJ et al. (2004) Human hookworm infection in the 21st century. Advances in Parasitology 58, 197288.
  • Brooker S, Peshu N, Warn PA, et al. (1999) The epidemiology of hookworm infection and its contribution to anaemia among pre-school children on the Kenyan coast. Transactions of the Royal Society of Tropical Medicine and Hygiene 93, 240246.
  • Brooker S, Jardim-Botelho A, Quinnell RJ et al. (2007a) Age-related changes in hookworm infection, anaemia and iron deficiency in an area of high Necator americanus hookworm transmission in south-eastern Brazil. Transactions of the Royal Society of Tropical Medicine and Hygiene 101, 146154.
  • Brooker S, Akhwale W, Pullan R et al. (2007b) Epidemiology of plasmodium-helminth co-infection in Africa: populations at risk, potential impact on anemia, and prospects for combining control. American Journal of Tropical Medicine & Hygiene 77, 8898.
  • Brooker S, Hotez PJ & Bundy DAP (2008) Hookworm-related anaemia among pregnant women: a systematic review. PLoS Neglected Tropical Diseases 2, e291.
  • Bundy DAP, Shaeffer S, Jukes M et al. (2006) School based health and nutrition programs. In: Disease Control Priorities for Developing Countries (eds JGBreman, ARMeasham, GAlleyne & et al. ) Oxford University Press, Oxford, pp. 10911108.
  • Bundy DAP, Kremer M, Bleakley H, Jukes MCH & Miguel E (2009) Deworming and Development: Asking the Right Questions, Asking the Questions Right. PLoS Neglected Tropical Diseases 3, e362.
  • Carr HP (1926) Observations upon hookworm disease in Mexico. American Journal of Hygiene 6, 4261.
  • Casey GJ, Phuc TQ, Macgregor L et al. (2009) A free weekly iron-folic acid supplementation and regular deworming program is associated with improved hemoglobin and iron status indicators in Vietnamese women. BMC Journal Public Health 24, 261.
  • Chernin E (1954) Problems in tropical public health among workers at a jute mill near Calcutta. IV. Hemoglobin values and their relation to the intensity of hookworm infections in the labor force. American Journal of Tropical Medicine & Hygiene 3, 338347.
  • Crompton DWT & Stephenson LS (1990) Hookworm infection, nutritional status and productivity. In: Hookworm Disease, Current Status and New Directions (eds GASchad & KSWarren) Taylor and Francis, London, pp. 231265.
  • Crompton DWT & Whitehead RR (1993) Hookworm infections and human iron metabolism. Parasitology 107, S137S145.
  • De Clercq D, Sacko M, Behnke J, Gilbert F, Dorny P & Vercruysse J (1997) Failure of mebendazole in treatment of human hookworm infections in the southern region of Mali. American Journal of Tropical Medicine and Hygiene 57, 2530.
  • Dossa RA, Ategbo EA, De Koning FL, Van Raaij JM & Hautvast JG (2001) Impact of iron supplementation and deworming on growth performance in preschool Beninese children. European Journal of Clinical Nutrition 55, 223228.
  • Ezeamama AE, McGarvey ST, Acosta LP et al. (2008) The synergistic effect of concomitant schistosomiasis, hookworm, and trichuris infections on children’s anemia burden. PLoS Neglected Tropical Diseases 2, e245.
  • Fleming AF (2000) Iron deficiency. In: Hunter’s Tropical Medicine, 8th edn (ed GTStrickland) W.B. Saunders, Philadelphia, pp. 3260.
  • Friedman JF, Kanzaria HK & McGarvey ST (2005) Human schistosomiasis and anemia: the relationship and potential mechanisms. Trends in Parasitology 21, 386392.
  • Friis H, Mwaniki D, Omondi B et al. (2003) Effects on haemoglobin of multi-micronutrient supplementation and multi-helminth chemotherapy: a randomized, controlled trial in Kenyan school children. European Journal of Clinical Nutrition 57, 573579.
  • Gilgen DD, Mascie-Taylor CG & Rosetta LL (2001) Intestinal helminth infections, anaemia and labour productivity of female tea pluckers in Bangladesh. Tropical Medicine and International Health 6, 449457.
  • Gilles HM & Williams EJW (1964) Hookworm infection and anaemia. an epidemiological, clinical, and laboratory study. Quarterly Journal of Medicine 33, 482486.
  • Gulani A, Nagpal J, Osmond C & Sachdev HPS (2007) Effect of administration of intestinal anthelmintic drugs on haemoglobin: systematic review of randomised controlled trials. British Medical Journal 334, 10951097.
  • Guyatt HL, Brooker S, Kihamia CM, Hall A & Bundy DAP (2001) Evaluation of efficacy of school-based anthelmintic treatments against anaemia in children in the United Republic of Tanzania. Bulletin of the World Health Organization 79, 695703.
  • Hall A (2007) Micronutrient supplements for children after deworming. Lancet Infectious Diseases 7, 297302.
  • Higgins JPT & Green S (eds) (2009) Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 [updated September 2009]. The Cochrane Collaboration. Available from http://www.cochrane-handbook.org.
  • Horton J (2003) Global anthelmintic chemotherapy programs: learning from history. Trends in Parasitology 19, 405409.
  • Hotez PJ, Brooker S, Bethony JM, Bottazzi ME, Loukas A & Xiao S (2004) Hookworm infection. New England Journal of Medicine 351, 799807.
  • Keiser J & Utzinger J (2008) Efficacy of current drugs against soil-transmitted helminth infections: systematic review and meta-analysis. Journal of the American Medical Association 299, 19371948.
  • King CH, Dickman K & Tisch DJ (2005) Reassessment of the cost of chronic helmintic infection: a meta-analysis of disability-related outcomes in endemic schistosomiasis. Lancet 365, 15611569.
  • Koukounari A, Fenwick A, Whawell S et al. (2006) Morbidity indicators of Schistosoma mansoni: relationship between infection and anemia in Ugandan schoolchildren before and after praziquantel and albendazole chemotherapy. American Journal of Tropical Medicine & Hygiene 75, 278286.
  • Koukounari A, Gabrielli AF, Toure S et al. (2007) Schistosoma haematobium infection and morbidity before and after large-scale administration of praziquantel in Burkina Faso. Journal of Infectious Diseases 196, 659669.
  • Kurtzhals JA, Addae MM, Akanmori BD et al. (1999) Anaemia caused by asymptomatic Plasmodium falciparum infection in semi-immune African schoolchildren. Transactions of the Royal Society of Tropical Medicine and Hygiene 93, 623627.
  • Kurz KM, Stephenson LS, Latham MC & Kinoti SN (1986) The effectiveness of metrifonate in reducing hookworm infection in Kenyan school children. American Journal of Tropical Medicine and Hygiene 35, 571574.
  • Latham MC, Stephenson LS, Hall A, Wolgemuth JC, Elliott TC & Crompton DW (1982) A comparative study of the nutritional status, parasitic infections and health of male roadworkers in four areas of Kenya. Transactions of the Royal Society of Tropical Medicine and Hygiene 76, 734740.
  • Layrisse M & Roche M (1964) The relationship between anemia and hookworm infection. Results of surveys of rural Venezuelan population. American Journal of Hygiene 79, 279301.
  • Le Huong T, Brouwer ID, Nguyen KC, Burema J & Kok FJ (2007) The effect of iron fortification and de-worming on anaemia and iron status of Vietnamese schoolchildren. British Journal of Nutrition 97, 955962.
  • Lwambo NJS, Bundy DAP & Medley GFH (1992) A new approach to morbidity risk assessment in hookworm endemic communities. Epidemiology and Infection 108, 469481.
  • Martinez-Torres C, Ojeda A, Roche M & Layrisse M (1967) Hookworm infection and intestinal blood loss. Transactions of the Royal Society of Tropical Medicine and Hygiene 61, 373383.
  • Menendez C, Fleming AF & Alonso PL (2000) Malaria-related anaemia. Parasitology Today 16, 469476.
  • Miller TA (1979) Hookworm infection in man. Advances in Parasitology 17, 315384.
  • Murray CJ, Lopez AD, Black R et al. (2007) Global Burden of Disease 2005: call for collaborators. Lancet 370, 109110.
  • Nga TT, Winichagoon P, Dijkhuizen MA et al. (2009) Multi-micronutrient-fortified biscuits decreased prevalence of anemia and improved micronutrient status and effectiveness of deworming in rural Vietnamese school children. Journal of Nutrition 139, 10131021.
  • Olds GR, King C, Hewlett J et al. (1999) Double-blind placebo-controlled study of concurrent administration of albendazole and praziquantel in schoolchildren with schistosomiasis and geohelminths. Journal of Infectious Diseases 179, 9961003.
  • Olsen A, Magnussen P, Ouma JH, Andreassen J & Friis H (1998) The contribution of hookworm and other parasitic infections to haemoglobin and iron status among children and adults in western Kenya. Transactions of the Royal Society of Tropical Medicine and Hygiene 92, 643649.
  • Pawlowski ZS, Scahd GA & Stott GJ (1991) Hookworm Infection and Anaemia. Approaches to Prevention and Control. World Health Organization, Geneva.
  • Perroncito E (1880) Helminthological observations upon the endemic disease developed among the labourers in the Tunnel of Mount St Gothard. Queckett Journal of Microscopy Club 6, 141148.
  • Quinnell RJ, Slater AFG, Tighe P et al. (1993) Reinfection with hookworm after chemotherapy in Papua New Guinea. Parasitology 106, 379385.
  • Reynoldson JA, Behnke JM, Pallant LJ et al. (1997) Failure of pyrantel in treatment of human hookworm infection (Ancylostoma duodenale). in the Kimberely region of North West Australia. Acta Tropica 68, 301312.
  • Rohner F, Zimmermann MB, Amon RJ et al. (2010) In a randomized controlled trial of iron fortification, anthelmintic treatment, and intermittent preventive treatment of malaria for anemia control in Ivorian children, only anthelmintic treatment shows modest benefit. Journal of Nutrition 140, 634641.
  • Schad GA & Banwell JG (1984) Hookworms. In: Tropical and Geographical Medicine (eds KSWarren & AAFMahmoud) McGraw-Hill Book Company, New York, pp. 359372.
  • Schad GA & Anderson RM (1985) Predisposition to hookworm infection in humans. Science 228, 15371540.
  • Sharman A (2000) Anemia Testing in Population-Based Surveys: General Information and Guidelines for Country Monitors and Program Managers. ORC Macro, Calverton, Maryland USA.
  • Stephenson LS, Latham MC & Kurz KM (1985) Relationships of Schistosoma haematobium, hookworm and malarial infections and metrifonate treatment to hemoglobin level in Kenyan school children. American Journal of Tropical Medicine and Hygiene 34, 519528.
  • Stephenson LS, Latham MC, Kinoti SN, Kurz KM & Brigham H (1990) Improvements in physical fitness of Kenyan schoolboys infected with hookworm, Trichuris trichiura and Ascaris lumbricoides following a single dose of albendazole. Transactions of the Royal Society of Tropical Medicine and Hygiene 84, 277282.
  • Stephenson LS, Latham MC, Adams EJ, Kinoti SN & Pertet A (1993) Physical fitness, growth and appetite of Kenyan school boys with hookworm, Trichuris trichiura and Ascaris lumbricoides infections are improved four months after a single dose of albendazole. Journal of Nutrition 123, 10361046.
  • Stoltzfus RJ, Albonico M, Chwaya HM et al. (1996) Hemoquant determination of hookworm-related blood loss and its role in iron deficiency in African children. American Journal of Tropical Medicine and Hygiene 55, 399404.
  • Stoltzfus RJ, Dreyfuss ML, Chwaya HM & Albonico M (1997) Hookworm control as a strategy to prevent iron deficiency. Nutrition Reviews 55, 223232.
  • Stoltzfus RJ, Albonico M, Chwaya HM, Tielsch JM, Schulze KJ & Savioli L (1998) Effects of the Zanzibar school-based deworming program on iron status of children. American Journal of Clinical Nutrition 68, 179186.
  • Stoltzfus RJ, Chwaya HM, Montresor A, Albonico M, Savioli L & Tielsch JM (2000) Malaria, hookworms and recent fever are related to anemia and iron status indicators in 0- to 5-y old Zanzibari children and these relationships change with age. Journal of Nutrition 130, 17241733.
  • Stoltzfus RJ, Chway HM, Montresor A et al. (2004) Low dose daily iron supplementation improves iron status and appetite but not anemia, whereas quarterly anthelminthic treatment improves growth, appetite and anemia in Zanzibari preschool children. Journal of Nutrition 134, 348356.
  • Taylor M, Jinabhai CC, Couper I, Kleinschmidt I & Jogessar VB (2001) The effect of different anthelmintic treatment regimens combined with iron supplementation on the nutritional status of schoolchildren in KwaZulu-Natal, South Africa: a randomized controlled trial. Transactions of the Royal Society of Tropical Medicine and Hygiene 95, 211216.
  • Taylor-Robinson D, Jones AP & Garner P (2007) Deworming drugs for treating soil-transmitted intestinal worms in children: effects on growth and school performance. Cochrane Database of Systematic Reviews. Issue 4. Art. No. CD000371. DOI: 10.1002/14651858.CD000371.pub3.
  • Tohon ZB, Mainassara HB, Garba A et al. (2008) Controlling schistosomiasis: significant decrease of anaemia prevalence one year after a single dose of praziquantel in nigerian schoolchildren. PLoS Neglected Tropical Diseases 2, e241.
  • WHO (2002) Prevention and Control of Schistosomiasis and Soil-Transmitted Helminthiasis: Report of a WHO Expert Committee. World Health Organization, Geneva.
  • WHO (2008) Worldwide Prevalence of Anaemia 1993–2005: WHO Global Database on Anaemia. World Health Organization, Geneva.
  • Zimmermann MB (2008) Methods to assess iron and iodine status. British Journal of Nutrition 99, S2S9.

Supporting Information

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  9. Supporting Information

Table S1. Baseline characteristics of cross-sectional surveys included in the analysis of the impact of hookworm infection on haemoglobin concentration in non-pregnant populations.

Table S2. Quality assessment of randomised controlled trials investigating the impact of benzimidazole treatment on haemoglobin.

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TMI_2542_sm_Supplementarytables.doc102KSupporting info item

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.