Schistosomiasis and soil-transmitted helminthiasis preventive chemotherapy: Adverse events in children from 2 to 15 years in Bengo province, Angola.

Preventive chemotherapy campaigns with praziquantel and albendazole are being implemented in Angola, as a high priority public health intervention. However, there are no published data regarding adverse events associated with these medications. In this context, we analysed adverse events due to co-administration of praziquantel and albendazole in endemic areas of schistosomiasis and soil-transmitted helminths in Bengo, Angola. In the context of a targeted drug administration, between December 2012 and September 2013, we conducted two surveys after co-administrating single oral doses of praziquantel and albendazole tablets to children 2 to 15 years of age. About 24 hours after each treatment, participants answered a questionnaire about adverse events. At baseline, 605 children (55.0% male; mean age: 9.7 years) were treated; 460 were interviewed and 257 (55.9%) reported at least one adverse event, 62.3% (160/257) of children being infected with schistosoma haematobium. After six months of treatment, among 339 children surveyed, 184 (54.3%) reported adverse events, with 49.5% (91/184) of infected children. Adverse events were most common in preschool-aged children, with no significant difference between genders. The most frequent adverse events in the two surveys were abdominal pain (18.5%, 25.7%), headache (20.9%, 23.0%) and dizziness (15.7%, 19.8%). Children aged 12 to 15 years (adjusted OR = 0.40, p = 0.040) and those with mixed infection (adjusted OR = 0.04, p = 0.011) had lower odds of adverse events. After the second treatment, those with heavy infection (adjusted OR = 2.72, p = 0.018) and aged 9-11 years (adjusted OR = 2.01, p = 0.049) had significantly fewer adverse events. About 2.0% of children experienced severe adverse events. This study adds evidence that preventive chemotherapy for schistosomiasis and soil-transmitted helminths control is safe, but cases of adverse events are expected. Standardized methodologies to discriminate drug-related adverse events from the clinical manifestations of the infections are needed.

Introduction

Neglected tropical diseases (NTD), including schistosomiasis and soil-transmitted helminths (STHs), remain important public health issues in developing countries, where lack of adequate clean water and poor sanitation are common [1-3]. Schistosomiasis is one of the most socioeconomically devastating parasitic disease in the world, causing estimated 280 thousand deaths and 4.5 million Disability Adjusted Life Years (DALYs) [4]. On the other hand, STHs, namely infections by Ascaris lumbricoides, Trichuris trichiura and hookworms, affect more than one billion individuals worldwide, causing respectively, 60, 10 and 65 thousand deaths, respectively [5,6]. In Angola, the prevalence of those diseases are high and variable within the country [7]. Recently, in a community based survey conducted by Figueiredo et al [8] in the Dande municipality (northern Angola), prevalence of urogenital schistosomiasis in preschool-aged children (PSAC) and school-aged children (SAC) were reported to be 10% and 17%, respectively, with 10% of anaemia cases in the studied population. The same study determined the prevalence of infection by at least one STH of 22.6% in preschool-aged children and 31.6% in school-aged children in the Dande municipality [8]. Another study conducted in the same region found an association between A. lumbricoides infection and malnutrition in children [9].

Preventive chemotherapy (PC) refers to the periodic administration of anthelminthic drugs to populations at risk of morbidity, with the aim to reduce infection intensity and eliminate moderate and heavy infections [10]. Thus, mass drug administration (MDA) is the cornerstone of the current global strategy to control helminthiasis. In children aged 2 to 15 years, Schistosomiasis is recommended to be controlled by taking a single dose (40mg/Kg child weight) of praziquantel (PZQ) and STHs with a single dose (400mg) of albendazole (ALB) [11]. ALB has a remarkable safety record, considering that a very low frequency and incidence of adverse events (AEs), mainly gastrointestinal, are described in the literature [12,13]. On the other side, despite that minimal and transient adverse events are described to occur with PZQ (reported mainly in heavily infected people and normally associated to the response of the host immune system to the dying worms), serious adverse reactions can also take place and may reduce drug compliance [13-21]. In fact, AEs resulting from co-administrating both drugs are described to be similar in severity to those experienced with monotherapy, however, information regarding the safety of this combination in children under 4 years of age (or under 94 cm in height) is scarce, especially in Angola [22]. As a consequence, preschool-aged children (PSAC) were considered ineligible for MDA with PZQ and the control approach were the referral to health facilities for individual case management [11].

According to WHO guidelines [10,11], AEs occur 24–48 hours after drug administration but do not necessarily have a causal relationship with treatment. They may be mild when not affecting daily activities (e.g. playing) or moderate when affecting the performance of daily activities. However, severe AEs require complete rest and / or medication, while serious AEs are life-threatening and require admission to the hospital.

In 2010 WHO recognized that preschool-aged children were a high-risk group for schistosomiasis (when living in highly endemic settings), that should also be included in public health interventions, along with school-aged children and woman in childbearing age [15,23]. This was followed by several reports on the safety of PZQ in preschool-aged children (between 1 month and 7 years) and the recognition that administrating PZQ to those children was safe and efficacious [11,18,23-25]. Nevertheless, Angola is an endemic country for schistosomiasis and STHs and the therapeutic policy for those diseases is presently aligned with the 2006 WHO guidelines [11]. Currently, and at a national level, diagnosed cases of schistosomiasis in school-aged children are recommended to be medically treated at health care units and control activities for STHs are based in deworming campaigns [7,11].

Therefore, further evidence on adverse events (AEs) to the co-administration of PZQ and ALB, experienced in the context of TDA campaigns, are needed. Additionally, there is no published data in Angola regarding adverse events associated to the co-administration of PZQ and ALB, either in preschool-aged (particularly in under 4) or school-aged children. Thus, considering that the local health authorities of the NTD control program are implementing regular helminth control campaigns, these data are essential to inform these programs and to fill the treatment gap for children under 4 (currently excluded from TDA and often neglected).

Consequently, this pioneering study was carried out in the community of Cabungo and the Porto Quipiri School, located in the study area of the CISA project (Angola Health Research Centre, translated). We aimed to analyse the adverse events experienced following co-administration of PZQ and ALB for preventive chemotherapy against schistosomiasis and STHs.

Methods

Study site

We conducted this study between December 2012 and September 2013, in Cabungo community and Porto Quipiri School, located in the study area of CISA, in the Dande Municipality, Bengo Province—northern Angola. These hamlets were selected due to high prevalence of SCH, STHs and malaria observed in the area, whose structure, dynamics and geographical distribution of the population was previously described by Costa et al (2012) [26] and the epidemiology of schistosomiasis and STHs was detailed recently by Sousa-Figueiredo et al (2012) [8].

Study design and aim

This is a longitudinal study, conducted in the context of a plan intervention by local health authorities, aiming to investigate the adverse events experienced by PSAC and SAC following the mass drug co-administration of PZQ and ALB, for the control of schistosomiasis and STHs at baseline and 6 months after the first treatment.

Participants and therapeutic intervention

For this study, we enrolled 605 children, of whom 460 (76.0%) and 339 (56.0%) successfully participated in the first and second survey for AEs, respectively. All children, aged between 2 to 15 years old and living in those areas, were invited to participate and received a kit containing single doses of PZQ (40mg/kg), using the dose pole method to determinate the number of PZQ tablets to be administered to each child, and single doses of ALB (400mg) tablets. The tablets were crushed or broken when necessary and given with water or juice, as recommended by others [26], taken under direct observation of a health professional onsite. We also timely treated, with artemeter-lumefantrine (AL-20/120mg), children tested positive for malaria as recommended by the National Malaria Control Program [27]. In addition, refusals or failure in successful administration was documented. We excluded children if any severe adverse events were reported to be experienced in previous administration of PZQ and ALB.

Laboratory analysis

Pre-treatment stool samples were collected for the diagnosis of intestinal parasites (Schistosoma mansoni, hookworms, Ascaris lumbricoides, Trichuris trichuria and Hymenolepis nana), performed by Kato-Katz method [28,29], and the presence and intensity of S. haematobium was determined by the examination of the pellet resulting from 10ml centrifuged pre-treatment urine [28]. The intensity of S. haematobium infection was recorded as light, moderate and heavy if 1–49, 50–499 and equal or more than 500 eggs per 10 ml of urine were observed, respectively, according to WHO recommendations [30]. We collected capillary blood samples for the diagnosis of uncomplicated malaria, performed by rapid diagnostic tests (RDTs) according to the manufacturer (SD BIOLINE Malaria Ag P.f/P.v, Standard Diagnostics, Inc). For the measurement of haemoglobin levels, we used the Hemocue System (HemoCue® 201+, Angelholm, Sweden).

Adverse events data collection

We used a structured questionnaire to collect information on the adverse events (AEs) experienced by the children, performed to caretakers between 24 and 72 hours after treatment. When the caretaker was, absent and children had discernment to respond, the interview was performed with the children. Mild-to-moderate AEs were defined as undesirable experiences following drug administration, similarly to others, and severe AEs were defined as symptoms and signs due to administration drugs, which forced parents or caretaker to take their children to the health facility to be observed or hospitalized [31].

Statistical analysis

The collected data was first entered into the CISA database and then statistical analysis was conducted with SPSS version 23.0 computer software (IBM Corporation, New York, USA). Pearson's chi-square tests were used to compare the occurrence of AEs between the two surveys and for categorical variables. Alternatively, Fisher's exact test was used when any 2x2 contingency table cell expected a count below five.

We performed binary logistic model to identify possible independent predictors of AEs in the two surveys, using adjusted odds ratios (OR) and their 95% confidence interval (CI). The threshold for significant level was 0.05.

Ethics

All procedures performed in this study were in accordance with the standards of the 1964 Declaration of Helsinki and its later amendments. The Ethics Committee of the Angolan Ministry of Health approved the study protocol and all use of secondary data. Written informed consent was obtained and signed by a guardian, parent or a caretaker for each of the participants. A copy of the signed consent form, as well as contact information, was subsequently delivered to each participant. The Provincial health office, local leaders and parents were previously informed about the study in the area.

Results

A total of 605 children aged between 2 to 15 years (55.0% of males, 333/605) mean age 9.7 years ± 3.5, were subject to preventive chemotherapy with PZQ and ALB. Children with RDT positive for malaria were also treated with AL. At the baseline, of the 605 participating children, 548 took PZQ + ALB tablets while 57 took PZQ + ALB + AL. From those, 460 interviews were performed (76.0%, 460/605), responded mainly by the children themselves (75.0%) and guardians (25.0%). AEs were reported by 257 (55.9%, 257/460) children, 22 PSAC and 235 SAC. In this group of participants, 62.3% (160/257) were infected with either S. haematobium (100.0%, 160/160), STHs (20.6%, 33/160) and/or Plasmodium falciparum (19.4%, 31/160). On the other hand, 64.0% (130/203) of children, that had not experienced AEs, were also infected with those parasites (Fig 1). At the sixth month follow-up, 339 children included at the baseline, were surveyed for AEs after second round of medications (with PZQ+ALB or with PZQ+ALB+AL), from which 184 (54.3%, 184/339) reported to have experienced at least one adverse event, 19.6% (36/184) PSAC and 80.4% (148/184) SAC, as shown in Fig 1.

Fig 1

Study participants and dropouts.

PSAC, preschool-aged children; SAC, school-aged children; SCH, schistosomiasis; SHTs, soil-transmitted helminths; AEs, adverse events; PZQ, praziquantel; ALB, albendazole; AL, Artemeter-Lumefantrine.

No significant difference in the characteristics between participants and dropout children were observed at baseline. However, after the second round of treatment, a significantly lower proportion of PSAC (98.1% to 1.9%, p<0.001) and SAC (75.9% to 24.1%, p<0.001) were observed in the dropout group (Table 1).

Table 1

Characteristics of participants and dropouts in AEs survey.

	Baseline (n = 605)			6 months follow-up (n = 431)
Characteristics	Participants n = 460 (76.0%)	Excluded n = 145 (24.0%)	P value*	Participants n = 339 (78.7%)	Excluded n = 92 (21.3%)	P value*
Age group
PSACa	70 (77.8)	20 (22.2)	0.674	53 (98.1)	1 (1.9)	<0.001
SACb	390 (75.7)	125 (24.3)		286 (75.9)	91 (24.1)
Gender
Male	258 (77.5)	75 (22.5)	0.357	193 (80.1)	48 (19.9)	0.415
Female	202 (74.3)	70 (25.7)		146 (76.8)	44 (23.2)
S. haematobium eggs
Positive	290 (76.1)	91 (23.9)	0.951	159 (81.5)	36 (18.5)	0.184
Negative	170 (75.9)	54 (24.1)		180 (76.3)	56 (23.7)
Soil-transmitted helminths eggs
Positive	156 (80.4)	38 (19.6)	0.058	58 (90.6)	6 (9.4)	0.603
Negative	205 (71.7)	81 (28.3)		163 (87.2)	24 (12.8)
Missed examination	99 (79.2)	26 (20.8)		118 (65.6)	62 (34.4)

* chi-square test

a Preschool-aged children

b School-aged children.

In the first survey, headache (20.9%, 96/460), abdominal pain (18.5%, 85/460) and dizziness (15.7%, 72/460) were the three most frequently reported AEs. PSAC experienced mainly headache (18.6%), vomiting (14.3%) and abdominal pain (7.1%), whereas SAC, after headache (21.3%) and abdominal pain (20.5%) reported dizziness (18.2%). PSAC experienced significantly more vomiting than SAC (14.3% vs 6.7%, p = 0.029). SAC in turn experienced more abdominal pain (20.5% vs 7.1%, p = 0.008) and dizziness (18.2% vs 1.4%, p<0.001). Blood in stool and light sensitivity was only reported for SAC. After the second treatment, reports of abdominal pain, headache, dizziness and fatigue were also more frequent.

In this survey, PSAC reported significantly more fatigue (30.2% vs 15.4%, p = 0.009), blood in urine (20.8% vs 5.6%, p<0.001) and blood in stool (7.5% vs 1.0%, p = 0.002). Light sensitivity was not experienced by PSAC in both treatments, neither breathing difficulty after the second treatment (see Table 2).

Table 2

Frequency of reported AEs of children treated with PZQ and ALB in two medication rounds.

Adverse events	1st survey				2nd survey
	PSACa 70 (15%)	SACb 390 (85%)	Total 460 (100%)	p value*	PSACa 53 (16%)	SACb 286 (84%)	Total 339 (100%)	P value*
Overall	22 (31.4)	235 (60.3)	257 (55.9)	<0.001	36 (67.9)	148 (51.7)	184 (54.3)	0.043
Abdominal pain	5 (7.1)	80 (20.5)	85 (18.5)	0.008	19 (35.8)	68 (23.8)	87 (25.7)	0.065
Headache	13 (18.6)	83 (21.3)	96 (20.9)	0.607	13 (24.5)	65 (22.7)	78 (23.0)	0.775
Dizziness	1 (1.4)	71(18.2)	72 (15.7)	<0.001	9 (17.0)	58 (20.3)	67 (19.8)	0.580
Fatigue	1 (1.4)	29 (7.4)	30 (6.5)	0.061	16 (30.2)	44 (15.4)	60 (17.7)	0.009
Vomiting	10 (14.3)	26 (6.7)	36 (7.8)	0.029	2 (3.8)	33 (11.5)	35 (10.3)	0.088
Blood in urine	1 (1.4)	29 (7.4)	30 (6.5)	0.061	11 (20.8)	16 (5.6)	27 (8.0)	<0.001
Fever	1 (1.4)	27 (6.9)	28 (6.1)	0.077	2 (3.8)	21 (7.3)	23 (6.8)	0.343
Itching	2 (2.9)	30 (7.7)	32 (7.0)	0.143	4 (7.5)	13 (4.5)	17 (5.0)	0.358
Diarrhoea	2 (2.9)	18 (4.6)	20 (4.3)	0.507	3 (5.7)	11 (3.8)	14 (4.1)	0.542
Light sensitivity	0 (0.0)	25 (6.4)	25 (5.4)	0.029	0 (0.0)	7 (2.4)	7 (2.1)	0.250
Joint pain	2 (2.9)	15 (3.8)	17 (3.7)	0.686	1 (1.9)	6 (2.1)	7 (2.1)	0.921
Blood in stool	0 (0.0)	4 (1.0)	4 (0.9)	0.395	4 (7.5)	3 (1.0)	7 (2.1)	0.002
Red skin	1 (1.4)	8 (2.1)	9 (2.0)	0.729	1 (1.9)	3 (1.0)	4 (1.2)	0.604
Breathing difficulty	2 (2.9)	11 (2.8)	13 2.8)	0.061	0 (0.0)	3 (1.0)	3 (0.9)	0.454

* chi-square test

a Preschool-aged children

b School-aged children.

Although, 2.3% (6/257) of children reporting AEs after the first treatment, and 1.6% (3/184) after the second treatment searched for medical attention in a nearby health facility but no admission notification was reported. Data on hospital care was not collected and therefore classification of the seriousness of AEs was not possible to perform.

Most children reported two simultaneous AEs followed by those reporting only one event (32.1% vs 31.5% in the first survey and 30.7% vs 29.2% in the second survey). There were also children who reported three or more simultaneous events. The most common single AEs were abdominal pain (37.9%, 22/58), headache (29.3%, 17/58) and fatigue (17.2%, 10/58) while double AEs were “abdominal pain + headache” (15.3%, 9/59), “fatigue + dizziness” (11.9%, 7/59) and “abdominal pain + fatigue” (6.8%, 4/59). Triple AEs were “abdominal pain + headache + dizziness” (12.1%, 4/33) and “abdominal pain + fatigue + dizziness” (6.1%, 2/33).

In the first survey, we observed that children with mixed infections had lower odds ratio to develop AEs than those with simple infections (adjusted OR = 0.14, p = 0.016 vs adjusted OR = 0.04, p = 0.011). Only the age group from 12 to 15 years old presented a significant OR of developing AEs (adjusted OR = 0.40, p = 0.040). All of these associations observed in the first survey lost their statistical significance after the second treatment. However, children with severe S. haematobium infection (adjusted OR = 2.72, p = 0.018) and children aged 9 to 11 years (adjusted OR = 2.01, p = 0.049) were significantly more probability to have AEs. (Table 3).

Table 3

Association between AEs and characteristics of participants in two AEs survey moments.

	1st survey			2nd survey
Characteristics	Total 257/339 (75.8%)	Adjusted 0R (95% CI)	P value	Total 184/339 (54.3%)	Adjusted OR (95% CI)	P value
Gender
Female	113/146 (77.4)	1	-	75/146 (51.4)	1	-
Male	144/193 (74.6)	0.96 (0.54–1.70)	0.904	109/193 (56.5)	1.18 (0.75–1.84)	0.463
Age group
2–5 y	45/55 (81.8)	1		25/55 (45.5)	1	-
6–8 y	51/65 (78.5)	0.80 (0.30–2.09)	0.652	38/65 (58.5)	1.95 (0.91–4.18)	0.085
9–11 y	84/111 (75.7)	0.66 (0.28–1.59)	0.366	64/111 (57.7)	2.01 (1.00–4.05)	0.049
12–15 y	77/108 (71.3)	0.40 (0.16–0.95)	0.040	57/108 (52.8)	1.69 (0.84–3.39)	0.139
S. haematobium eggs
Negative	97/130 (74.6)	1	-	102/195 (52.3)	1	-
Light (1-49eggs)	17/25 (68.0)	0.63 (0.23–1.71)	0.370	28/46 (60.9)	1.43 (0.73–2.80)	0.291
Moderate (50-499eggs)	75/100 (75.0)	1.13 (0.59–2.19)	0.700	29/62 (46.8)	0.73 (0.40–1.35)	0.324
Heavy (≥500eggs)	68/84 (81.0)	2.11 (0.76–3.26)	0.213	25/36 (69.4)	2.72 (1.18–6.24)	0.018
STHs Eggs
Negative	205/251 (81.7)	1	-	159/298 (53.4)	1	-
Positive	52/88 (59.1)	2.11 (0.42–10.57)	0.361	25/41 (61.0)	0.43 (0.08–2.15)	0.310
Hymenolepis nana eggs
Negative	241/313 (77.0)	1	-	177/328 (54.0)	1	-
Positive	16/26 (61.5)	1.77 (0.36–8.51)	0.475	7/11 (63.6)	1.95 (0.41–9.11)	0.395
Plasmodium parasites
Negative	235/307 (76.5)	1	-	179/327 (54.7)	1	-
Positive	22/32 (68.8)	0.82 (0.34–1.94)	0.653	5/12 (41.7)	0.59 (0.17–2.00)	0.402
Number of infections
Null	191/228 (83.8)	1	-	159/298 (53.4)	1	-
One	59/94 (62.8)	0.14 (0.30–0.69)	0.016	21/33 (63.6)	3.02 (0.58–15.69)	0.188
Two	7/17 (41.2)	0.04 (0.01–0.49)	0.011	4/8 (50.0)	1.67 (0.50–5.63)	0.402
Anaemia
No	65/82 (79.3)	1	-	89/159 (56.0)	1	-
Yes	192/257 (74.7)	0.69 (0.36–1.34)	0.282	95/180 (52.8)	0.78 (0.50–1.24)	0.309

CI: confidence interval, OR: odds ratio, SHT: soil-transmitted helminths.

Discussion

In this study, 55.9% of the children who completed both surveys reported having experienced AEs after the first treatment with ALB, PZQ and/or AL and 54.3% after the second treatment. In general, the main AEs reported were abdominal pain, headache and dizziness, both after the first and after the second treatment, and only a low proportion of children searched for medical attention after both treatments (2.3% and 1.6%, respectively). The present study reported different proportions of AEs comparable to those found in other studies involving praziquantel and / or albendazole. However, there are variations that may occur due to the heterogeneous antecedents of the participating individuals, such as age, nutritional and immunological status, socioeconomic conditions, environmental exposure, prevalence and intensity of infection, stage of parasite development, etc[13,18,20,21,31-37]. Zwang et al reviewed the efficacy and safety of PZQ (40mg/kg), and report that the main AEs experienced and their incidences are mainly abdominal pain (31.8%), muscle pain (29.2%), joint pain (20.2%), headache (13.6%), diarrhoea (12.9%), fatigue (9.6%), nausea (10.6%), dizziness (11.9%), vomiting (7.9%) and itching (9.8%) [18]. Additionally for ALB, there are reports of the occurrence of epigastric pain, dry mouth, fever and itching [18,21,32,38-40]. However, the occurrence of AEs are reported to be associated with the proportion of dying S. haematobium worms, i.e., with the pharmacologic effect of the drug on the parasite (for example; abdominal pain is reported to be associated with the deposition of dead worms in the mesenteric veins), they can also occur due to the natural course of disease [19,32,37,41,42].

Neumayr et al mentions that symptomatic acute schistosomiasis or treatment‐induced reactions can manifest themselves with identical symptoms [32]. This group and others further discuss that the exposure to a high level of parasite antigens, caused by larval migration and maturation (of helminth larvae) or early oviposition in symptomatic acute schistosomiasis, can lead to an immune overreaction, resulting in symptoms that are similar to those reported as AEs to PZQ, but totally independent from treatment [19,32,43-45]. Although increasing the number of infections significantly reduced the chances of AE occurrence, we found that heavy S. haematobium infection was significantly associated with AEs occurrence, with odds ratio twice as high in individuals with this parasitic load in the second survey.Also, H. nana infections alone can cause headache, dizziness, abdominal pain and diarrhoea, A. lumbricoides can cause nausea, vomiting, diarrhoea and abdominal pain, T. trichiura can cause abdominal pain and diarrhoea, and S. stercoralis can cause erythema, itching, fever, abdominal pain and diarrhoea [35,38,46]. Thus, we postulate that children with mixed infections between schistosomiasis, STH and hymenolepiasis can be manifesting additive drug-unrelated AEs, overestimating the frequency of AEs reported here.

Despite that other authors have found no progression of AEs between treatment rounds, we found that after the second treatment the reports of abdominal pain, headache, dizziness and fatigue generally increased and the reports of joint pain and breathing difficulty generally decreased [20]. Additionally to that, experiencing 2 simultaneous AEs was slightly more frequent than experiencing only one event, and experiencing 3, 4 or 5 simultaneous events was also reported, despite of less frequent. Considering that the literature reports an association between AEs and the intensity of infection and anemia status, we found a statistically significant association between heavy infection and AEs [18,20,36]. Nevertheless, it should be considered that the administration of PZQ following a high-lipid or high-carbohydrate diets can increase its bioavailability (by a factor of 2.7 and 3.9) and in turn may alter the pharmacokinetic profile of the drug, possibly influencing the effect of the drug on the parasite and probably the frequency and type of AEs [18,19,33,41]. In this study children aged 9 to 15 years old, were at lower risk of experiencing AEs than younger children, however, it should be considered that this association lost their statistical significance after the second treatment and that the number of individuals within the PSAC group is small. Thus, these results should be interpreted carefully. Nevertheless, similar frequencies of AEs were observed by others between preschool and school children [21].

Regarding the 45% of “uninfected” children experiencing AEs in our study, in addition to the fact that these children may have AEs due to drug use only; we also considered the stages of infection undetected by the diagnostic technique used here [43,47]. The limited effect of PZQ on young forms of parasites and the progression of disease would still manifest signs and symptoms [40,43,47].

Conclusions

This study adds evidence that chemotherapy for the control of schistosomiasis and soil-transmitted helminthiasis with PZQ and ALB is safe, although mild to moderate cases of AEs are expected. In these two surveys of AEs, we recorded 3.1% of children reporting medical attention due AEs after the medication. To assess the safety of co-administration of PZQ and ALB with artemeter-lumefantrine for positive cases of uncomplicated malaria in children, more standardized methodologies are needed to discriminate drug-related AEs from the clinical manifestations of the infections studied.

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12 Dec 2019

PONE-D-19-22164

Schistosomiasis and soil-transmitted helminthiasis preventive chemotherapy: adverse events in children from 2 to 15 years in Bengo province, Angola

PLOS ONE

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We look forward to receiving your revised manuscript.

Kind regards,

Mary Hamer Hodges

Academic Editor

PLOS ONE

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Additional Editor Comments (if provided):

The topic is of importance but as described by 2 reviewers the content needs review and the all three agree the overall presentation need improvement.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This paper describes and quantifying the adverse affects of Praziquantel treatment in a cohort of people. The findings are important in raising awareness of adverse affects and also to show the level of severity or not. There are very few corrections needed and I have no specific comments. The English could be improved in places so I suggest the authors have a careful read to try and improve the English as needed.

Reviewer #2: Schistosomiasis and STH PC: Adverse events in children in Bengo province, Angola.

This ms is fine and adds to the information on adverse events during MDA and control programs in preschool age children and school age children. It looks at PZQ and ALB and concludes that treatment programs should continue despite small amounts of adverse events.

Title: fine

Abstract: fine – minor corrections –

L30 maybe put gender in here.

L32 correct spelling - Schistosoma from schistosome

L32 ‘follow-up’ – treatment or questionnaire – clarify

Introduction:

General points – if using acronyms spell out in first use then use the acronym

A clear definition of adverse events is needed; define the difference between mild/severe.

L56 -- ‘60, 10 and 65 thousand’ what? Unsure what is meant DALYs? Deaths?

L58 reference number needed for Figueiredo et al

L62 using geohelminth here – define.

L65 can used PC common acronym for preventative chemotherapy

L67 may be use mass drug administration (MDA) instead of targeted unless you are performing test and treat control strategy?

L70 use a ] instead of ) to enclose citation.

L74 consider word change to ‘normally’ from ‘possibly’

Methods:

Map?

L112 odd phrasing – ‘selected by convenience’?

L121 odd phrasing – ‘two deworming moments’ ?

L162 reference for the software

Ethical approval – is there an associated number for this study from the ethical committee?

It might be good to have the number of children enrolled in the study in your methods?

Results:

All tables – change ‘yes’ ‘no’ to egg positive negative or something. These need to be made clearer – particularly table 2 – it contains a lot of information but perhaps consider a graph or different way to display which highlights important results.

L185 change ‘themself’ to themselves and ‘caretakers’ to guardians

L188 Plasmodium in full not just P.

Discussion:

L259 – 262 Reword and break up – strange wording here.

L269 italicize S. haematobium

L273 ref in list please

L280 please clarify – not sure what it means

References:

Check formatting with the journal

Reviewer #3: This is an interesting report on adverse events during systematic preventive administration of praziquantel and albendazole in children. The prevalence in this area in Angola is impressive and thus the study area is adapted to have excellent data on the subject.

The paper is well written although the methodology and result section lack on clarity and can not be clear enough without the reading of the complementary documents : this should be improved.

There are some sentences that are unclear because of english or missing items : line 53 to 56 ; line 63 ; 70; 233 ; line 243-246.

In the discussion again it is not clear why the 45 % of uninfected children who have AES should be underdiagnosed ? why it is not possible to have AES with the drug alone ? (line 308)

These different points should be improved.

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6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: BISSER SYLVIE

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

10 Jan 2020

We wish to thank this opportunity, careful revision and adequate comments that improve the final manuscript, as you may see on the enclosed documents. Further detailed answers to the reviewers are stated in the attached document.

Regarding the journal requirements, a full revision was made and we hope that everything is correct. In relation to data availability, we confirm that there is no ethical or legal restriction on sharing a de-identified data set that we will share upon acceptation of this manuscript.

Submitted filename: AE_NTDs - Response to Reviewers Jan20.docx

Click here for additional data file.

4 Feb 2020

Schistosomiasis and soil-transmitted helminthiasis preventive chemotherapy: adverse events in children from 2 to 15 years in Bengo province, Angola

PONE-D-19-22164R1

Dear Dr. Joao M Pedro,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

With kind regards,

Mary Hamer Hodges

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

This article will be welcomed by programmers in highly endemic communities and enable the planning of medications to address the usually mild AEs experienced. It will also be useful to help inform parents, teachers and communities about AEs that are likely to occur and how best to prepare for them and manage them at large scale.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #3: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #3: No

13 Feb 2020

PONE-D-19-22164R1

Schistosomiasis and soil-transmitted helminthiasis preventive chemotherapy: adverse events in children from 2 to 15 years in Bengo province, Angola

Dear Dr. Pedro:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Mary Hamer Hodges

Academic Editor

PLOS ONE