The cost of a school based mass treatment of schistosomiasis in Ugu District, KwaZulu Natal, South Africa in 2012.

INTRODUCTION: The Neglected Tropical Diseases Roadmap of the WHO set targets for potential elimination as a "public health problem" for the period 2012-2020 in multiple countries in Africa, with the aim of global elimination of schistosomiasis as a "public health problem" by 2025. AIM: The purpose of the study was to estimate the cost from a provider's perspective of the Department of Health's Schistosomiasis Mass Drug Administration (MDA) in Ugu District, KwaZulu-Natal in 2012, with a view to project the costs for the entire KwaZulu Natal Province. METHODS: A total of 491 public schools and 16 independent schools in Ugu District, a predominantly rural district in KwaZulu-Natal with a total of 218 242 learners, were included in the schistosomiasis control programme. They were randomly selected from schools situated below an altitude of 300 meters, where schistosomiasis is endemic. A retrospective costing study was conducted using the provider's perspective to cost. Cost data were collected by reviewing existing records including financial statements, invoices, receipts, transport log books, equipment inventories, and information from personnel payroll, existing budget, and the staff diaries. RESULTS: A total of 15571 children were treated in 2012, resulting in a total cost of the MDA programme of ZAR 2 137 143 and a unit cost of ZAR 137. The three main cost components were Medication Costs (37%), Human Resources Cost (36%) and Capital items (16%). The total cost for treating all eligible pupils in KwaZulu-Natal will be ZAR 149 031 888. However, should the capital cost be excluded, then the unit cost will be ZAR 112 per patient and this will translate to a total cost of ZAR 121 836 288. CONCLUSIONS: Low coverage exacerbates the cost of the programme and makes a decision to support such a programme difficult. However, a normative costing study based on the integration of the programme within the Department of Health should be conducted.

Seasonal variations in Schistosoma haematobium egg excretion in school-age girls in rural KwaZulu-Natal Province, South Africa.

BACKGROUND: A predominant feature of Schistosoma haematobium infection is urinary egg excretion, and microscopic egg detection remains the accepted standard field diagnostic tool. Praziquantel is the drug of choice for schistosomiasis, and the World Health Organization recommends that it should be administered to all children >4 years of age living in schistosomiasis-endemic areas. The frequency of mass drug administration depends on the prevalence rate in the community. Urinary schistosome egg output has a day-to-day and hour-to-hour intrasubject variation. Therefore, it is important to assess possible seasonal variations in egg excretion to improve the planning of drug treatment. OBJECTIVES: To assess the influence of seasonality on urinary schistosome egg excretion in South Africa (SA). METHODS: We performed a prospective cohort study, exploring seasonal variations of S. haematobium egg excretion in 184 girls aged 10 - 12 years from randomly selected schools in a rural area of KwaZulu-Natal Province, SA. The area has a subtropical climate characterised by a cool dry season and a hot humid season. For children, water contact is higher in the latter season. At baseline, 108 girls were examined in the hot season, and 76 in the cold season. In the next year's cold season the untreated patients were re-investigated before treatment. RESULTS: There was a decrease in infection in the group initially tested in the hot season compared with the group tested in the cold season at both time points when adjusted for age and water contact (adjusted odds ratio 3.61 (95% confidence interval 1.14 - 11.44); p=0.03). CONCLUSIONS: This unique study shows that schistosomiasis prevalence determined by microscopy exhibits seasonal variation, with a higher prevalence in the hot rainy season. Precise community prevalence estimations are key in decisions to treat communities. There was significantly lower egg output in the cold season, and sampling in that season may therefore underestimate the prevalence of urinary schistosomiasis. The study indicates that sampling in SA should be done in the hot season.

p24 antigen detection on dried blood spots is a feasible and reliable test for infant HIV infection in rural Tanzania.

The difficulty of diagnosing HIV in infants is a major obstacle to early antiretroviral therapy (ART) in resource-limited settings. As serological tests are unreliable during the first 18 months of life, and the cost and complexity of polymerase chain reaction (PCR)-based assays limit their access in resource-limited settings, p24 antigen detection has emerged as an alternative diagnostic tool. In this study, the performance of an ultrasensitive p24 antigen assay on dried blood spots was evaluated under field conditions in rural Tanzania. Specimens were stored and shipped at tropical room temperature, and analysed within six weeks. In total, 27 consecutive children aged <18 months and exposed to vertical HIV transmission were enrolled. Overall sensitivity and specificity was 100% (95% confidence interval [CI], 47.8-100) and 95.5% (95% CI, 77.2-99.9), respectively. Our findings suggest that detection of p24 antigen on dried blood spots can be a reliable and feasible diagnostic tool for infant HIV infection in rural resource-limited settings.

The effects of genital schistosoma haematobium on human papillomavirus and the development of cervical neoplasia after five years in a Zimbabwean population.

BACKGROUND: High-risk human papillomavirus (HPV) is responsible for cervical cancer and genital Schistosoma haematobium infection has been hypothesized to be an additional co-factor or even an independent risk factor for cervical neoplasia. The present study aimed to investigate the impact of schistosomiasis on HPV persistence and development of cell atypia in a group of rural Zimbabwean women with confirmed high-risk HPV. METHODS: A five-year follow-up was done among women previously included in a study on genital schistosomiasis. Women who had high-risk HPV at baseline were invited after 5 years for examination of cell atypia, genital schistosomiasis, and high-risk HPV. Both vaginal lavage samples (low-cost) and cervix brush samples (high-cost) were obtained for further analysis. RESULTS: Thirty-seven women were re-examined. Genital Schistosoma haematobium of a minimum of five years' duration was associated with the development high-grade squamous intraepithelial neoplasia, but not with persistent high-risk HPV. There was a high concordance between the brush and vaginal lavage (96.3% agreement, kappa 0.93); however, the number of beta-globin negative vaginal lavage samples was unacceptably high. CONCLUSIONS: Findings warrant an exploration in a larger longitudinal study where a vaginal swab should be explored.

Prevalence of urinary schistosomiasis and HIV in females living in a rural community of Zimbabwe: does age matter?

A cross-sectional study was conducted on 544 women living in Mupfure rural area of Zimbabwe to determine whether infection with urinary schistosomiasis is associated with HIV infection. Schistosoma haematobium infection was examined in urine samples and HIV infection was determined in sera. The prevalence of S. haematobium infection was highest (60%) in women below 20 years of age and declined to 29% in the oldest age group (test for trends, P<0.001). Overall, women infected with urinary schistosomiasis had an HIV prevalence of 33.3%, whilst women without urinary schistosomiasis had an HIV prevalence of 25.6% (chi(2), P=0.053). Women above the age of 35 years and infected with urinary schistosomiasis had a significantly higher HIV prevalence (37.5%) than those without urinary schistosomiasis (16.8%; chi(2), P<0.001).

Control of Biomphalaria pfeifferi population and schistosomiasis transmission in Ethiopia using the soap berry endod (Phytolacca dodecandra), with special emphasis on application methods.

The endod (Phytolacca dodecandra)-based schistosomiasis mansoni control project was implemented in Ethiopia between 1994 and 1999. The aim was to develop an effective, cheap and sustainable method of controlling schistosomiasis. First, different formulations of the Ethiopian endod strain 44 (E-44) were compared for potency in the laboratory. Secondly, spray and drip-feeding methods were compared for simplicity and effectiveness in the field. Lastly, the efficacy of endod powder soap was compared with the endod spray method. In Bati stream, endod powder soap was distributed to the residents every weekend at laundry sites. In Worke stream, endod was sprayed along a 1-km stretch of the stream at 3-month intervals. No endod was applied in Harbu stream. The immediate and long-term effects of endod application on the snail population and schistosomal infection were determined. Using the spray method, 100% snail mortality could be obtained, and it was simpler and more effective than the drip-feeding method. Snail mortality ranged from 20 to 100% using endod soap. There was a progressive decline in the snail population and infection in Bati stream compared with Worke stream, mainly due to sustained use of endod soap. The advantages and disadvantages of the different endod delivery systems are discussed.

The relationships between dehydroepiandrosterone sulphate (DHEAS), the intensity of Schistosoma mansoni infection and parasite-specific antibody responses. A cross-sectional study in residents of endemic communities in north-east Ethiopia.

There are speculations that the puberty-related hormone dehydroepiandrosterone sulphate (DHEAS) might influence the intensity of infection and immune responses during Schistosoma infections. We studied the relationships between DHEAS, intensity of Schistosoma mansoni infection and humoral immune responses in 135 residents of Ethiopia. Serum levels of eight antibody isotypes against worm and egg antigens were determined by ELISA. DHEAS was measured with an immunoluminometric assay. There was a significant negative correlation between serum levels of DHEAS and intensity of S. mansoni infection. A significant increase in serum levels of DHEAS in the age group 15-19 years was accompanied by a progressive decline in the intensity of infection. Peak level of DHEAS coincided with the lowest intensity of infection in the age group 20-29 years. Multiple regression analysis showed that DHEAS alone had a significant (p<0.0001) negative effect when the effect of age was removed. Age also had a significant (p<0.0001) negative effect on the intensity of infection, after removing the effect of DHEAS. The two predictive variables accounted for 34.4% of the decline in the intensity of infection. Age accounted for 24.9%, whereas DHEAS accounted for 15.2% when the effect of each of the variables was removed. DHEAS had significant negative effects on AWA-specific IgG (p=0.02) and IgG1 (p=0.018) and SEA-specific IgG1 (p=0.009), after adjusting for the effect of age.

Assessment of eosinophil cationic protein as a possible diagnostic marker for female genital schistosomiasis in women living in a Schistosoma haematobium endemic area.

Eosinophil cationic protein (ECP) levels were measured in vaginal lavage extracts from 518 Zimbabwean reproductive women, age range 15-49 years, to assess the potential use of ECP as a diagnostic marker for female genital schistosomiasis (FGS). One hundred and fifty women had confirmed FGS status. These included 77 (cases) women who had ova in genital tissue and 73 (controls) women who had no ova in genital tissue. Participants were examined at baseline, 3 and 15 months post-treatment with praziquantel. ECP levels were determined using the enzyme linked immunosorbent assay (ECP-ELISA). ECP levels from 18 Norwegian women were used to calculate the diagnostic values of the test. FGS was diagnosed from the study population using genital biopsy and smears. Women were also diagnosed for urinary schistosomiasis using the urine filtration technique. The prevalence of urinary schistosomiasis was 39 % at baseline and this declined to 8% and 6% at 3 and 15 month post-treatment surveys, respectively. There was a higher mean ECP level in women with FGS, 889.3 ng/mL (95% CI: 457.0-1327.5) compared to the endemic control group, 359.1 ng/mL (95%, CI: 227.3-490.9), P = 0.027. Mean ECP levels declined at 3 months following treatment of infected individuals. There was no correlation between ECP levels and tissue ova density, and urine egg intensity. The sensitivity, specificity, positive and negative predictive values for the ECP-ELISA test were 35%, 80%, 65% and 53%, respectively. Our results indicate that FGS causes an inflammatory immune response that increases ECP levels in genital fluid. Treatment of schistosomiasis results in a regression of pathology and a decline in ECP levels. However, other factors such as allergy and microbial infection could also be responsible for increased ECP levels in genital mucosa. These conditions will affect the validity of the test in diagnosis of FGS.

Differences in prevalence, intensity of infection and parasite-specific antibody levels do not predict different age-infection profiles.

Acquired immunity is believed to influence the age-infection profile of Schistosoma infections. We compared antibody responses against Schistosoma mansoni adult worm antigen (AWA) and soluble egg antigen (SEA) in 164 residents of two communities with different levels of infection. IgG, IgA, IgM, IgE, and IgG subclass 1 to 4 antibodies were determined by ELISA. Seventy-five of the subjects were from Harbu, an area with a prevalence of 39% and an intensity of infection of 116 eggs per gram of stool (EPG), whereas 89 subjects were from Bati, with a prevalence of 66% and intensity of infection of 256 EPG. In both communities the prevalence and the intensity of infection were highest in the age group 10-14 years, although both were significantly higher in Bati than in Harbu. Mean levels of AWA-specific IgA, IgM, IgG, IgG1 and IgG2, and of SEA-specific IgG, IgM, IgG2 and IgG3 were significantly higher in Bati than in Harbu. However, mean levels of IgE against worm and egg antigens were significantly higher in Harbu than in Bati. Significant differences were detected in the levels of IgA, IgE, IgG, IgM, IgG1 and IgG2 against AWA, and in IgE, IgM, IgG2 and IgG3 against SEA according to the place of residence. The levels of anti-AWA IgG, IgG1 and IgG2 and anti-SEA IgG, IgG1 and IgG4 were significantly associated with the intensity of infection. Anti-AWA IgM levels were associated with age, whereas sex and age had interacting effects on the levels of AWA-specific IgG1 and SEA-specific IgG and IgM. Antibody responses exhibited different age-related patterns in the two communities. This may indicate that differences in history of exposure influence the evolution of immune responses. However, the study did not support the view that differences in antibody levels between communities subject to different levels of infection result in a systematic deviation in age-infection profile (the "peak shift").

Epidemiological studies on intestinal schistosomiasis in Wondo Genet, southern Ethiopia.

A cross-sectional epidemiological survey was made on intestinal schistosomiasis due to Schistosoma mansoni in Wondo Genet, southern Ethiopia, in 1999 to generate preintervention parasitological and malacological baseline data to be used as a reference in evaluation of community-based pilot control trial to be launched using wild-growing Endod. A total of 3000 stool specimens were collected from schoolchildren enrolled in 14 schools and microscopically examined using Kato method. The overall prevalence and intensity of schistosomiasis mansoni was 34.6% and 184 eggs per gram of stool (EPG), respectively. Children excreting Schistosoma mansoni eggs were found in all of the 14 schools surveyed with a prevalence of infection ranging from 1.9% in Abaye School to 80.6% in Shesha Kekele School. The overall prevalence of S. mansoni infection among males and females was 38.4% and 27.3%, respectively (P = 0.0001, 95% C.I = 7.5%-14.7%) where as the intensity of infection was 186 EPG and 181 EPG, respectively (P = 0.8045, 95% C.I = 1.17%-1.23%). Malacological surveys of 27 water contact sites revealed the occurrence of Biomphalaria pfeifferi in 8 sites out of which 3 harbored infected snails shedding schistosome cercariae. The necessity for initiating community-based sustainable control programme is discussed.

Control of Schistosoma mansoni by the soapberry Endod (Phytolacca dodecandra) in Wollo, northeastern Ethiopia: post-intervention prevalence.

OBJECTIVES: To record the effect of Endod soap and spraying of soaked Endod suspension on the prevalence of human schistosomiasis. DESIGN: A cross-sectional epidemiological study in which pre- and post-intervention parasitological results were compared. SETTING: Kemise, Bati and Harbu towns in northeastern Ethiopia. SUBJECTS: The study subjects included all members of the five per cent households systematically selected from the three towns. RESULTS: In Kemise town, where suspension of ground Endod was sprayed on the stream containing infected snails, the prevalence of the disease was reduced from 59% to 53% and the mean intensity of infection was reduced from 239 eggs per gram (EPG) of faeces to 99 EPG (p < 0.05). In Bati town where Endod soap approach was used, the respective reduction in the prevalence and intensity of infection was from 51% to 43% and from 195 EPG to 162 EPG (p < 0.05). There was also a significant reduction of the disease in the control town probably due to the effects of praziquantel treatment and other factors. CONCLUSION: The reduction achieved in the prevalence and intensity of schistosomiasis after an intervention period of four years was limited. This observation corroborates the fact that molluscicides must always be considered as supplementary to chemotherapy in the control of schistosomiasis. Although both approaches can be used, the spraying approach appears to be simpler and more feasible because two or three times yearly application of Endod suspension would suppress snail population and reduce transmission. Nevertheless, the choice as to what approach to use must be made on the basis of community preference, and for some soap-effect of Endod would be attractive

Implication of Papio anubis in the transmission of intestinal schistosomiasis in three new foci in Kime area, Ethiopia.

Epidemiological studies were conducted in the Lake Langano area in the Rift Valley of Ethiopia to determine the occurrence of schistosomiasis and assess factors involved in its transmission. Microscopic examination of faecal specimens from free ranging Papio anubis (anubis baboon) troops from Bishan Gari and Burka Dita forest reserves revealed Schistosoma mansoni eggs with a prevalence of 12.1% (11/91) and 26.2%(34/130), respectively. The eggs were viable as confirmed by miracidial hatching and infectivity tests. Out of the total 12 communities (three schools, five villages and one herdsmen community) surveyed for schistosomiasis around Lake Langano, individuals excreting S. mansoni eggs were found in nine communities with prevalence of infection ranging from 1.4 to 43%. The intensity of infection ranged from 24 EPG (eggs per gram of faeces) to 243 EPG. Excretion of viable eggs by the baboons indicate that they play a role in maintenance of S. mansoni infection in the locality. The detection of S. mansoni eggs in young children, collection of cercarial-infected Biomphalaria pfeifferi in water bodies, and establishment of S. mansoni infection in lab-bred mice have confirmed establishment of transmission foci in Kime area, south-east of Lake Langano. However, the lake itself does not seem to support transmission of schistosomiasis since no snails were found along the shore of the Lake. Further investigations are indicated to fully elucidate the role baboons play in the epidemiology of schistosomiasis in the Rift Valley of Ethiopia. The risk of introduction of water-based development projects in these new endemic foci in relation to S. mansoni infection in the baboons is discussed.

Age- and sex-related differences in antibody responses against Schistosoma mansoni soluble egg antigen in a cohort of school children in Ethiopia.

Acquired immunity is believed to be the main factor in the age-related differences in prevalence and intensity of Schistosoma infections. We studied antibody responses against S. mansoni soluble egg antigen (SEA) by ELISA in children before treatment, 5 weeks and one year after treatment. After screening for S. mansoni infection, positive children were treated with praziquantel (40 mg per kg body weight). Infection rate was significantly higher in boys younger than 12 years than in girls in the same age group. Levels of all antibody isotypes, except IgG1 (before treatment) or IgA (one year after treatment), were higher in children older or equal to 12 years than in those younger. The difference between age groups was significant for IgE, IgM, IgG3 and IgG4 (before treatment) and IgE (one year after treatment). Similarly, all antibody isotypes, except IgE, before treatment were higher in boys than in girls. At 5 weeks after treatment, IgG, IgE and IgG1 showed an increasing tendency, whereas IgM and IgG3 tended to decrease. One year after treatment, significant decreases were observed in IgG, IgG1 and IgG4 and a significant increase in IgG2 levels. The study presents further evidence for the difference in acquired immunity between younger and older children, and between boys and girls. The study also suggests that praziquantel differentially affects antibody responses against S. mansoni SEA.

Praziquantel side effects and efficacy related to Schistosoma mansoni egg loads and morbidity in primary school children in north-east Ethiopia.

A total of 611 Schistosoma mansoni infected primary school children from three schools in north-east Ethiopia were treated with praziquantel at 40 mg/kg body weight in a single dose. Pre-treatment, 40.4% had no presenting symptoms and 30-40% had nausea, abdominal cramps and/or bloody-mucoid diarrhoea. None of the pre-treatment symptoms was related to nutritional status, intensity of S. mansoni egg excretion, or to the presence of other concomitant intestinal parasitic infections. During the first 4-6 h post-treatment observation period, 90 (14.7%) children self-presented with severe gastro-intestinal symptoms. Children who self-presented with severe symptoms had a higher mean age and mean S. mansoni egg excretion compared with children who did not self-present. The following day a total of 529 (86.6%) children, including all who self-presented during the first 4-6 h post-treatment, reported for clinical check-up and were subjected to a structured questionnaire interview on symptoms they had experienced over the time lapse following treatment. Among these, 91.5% reported one or more treatment related symptoms which were at times severe. Abdominal cramps (86.9%), diarrhoea with blood and/or mucus (49.5%), dizziness (31.2%) and vomiting (24.9%) were the most common treatment related symptoms. Skin rash with oedema were observed in four cases. Among treatment related symptoms, the combination of abdominal cramps with vomiting, bloody diarrhoea, vomiting alone and general weakness were significantly higher among the malnourished. A proportion of these symptoms increased with increasing categories of S. mansoni egg excretion before and after adjusting for nutritional status and concurrent intestinal parasitic infections. Overall, the cure rate of praziquantel, among 541 children who had stool examination 5 weeks after treatment was 83.2% and this rate decreased with increasing pre-treatment egg counts. In conclusion, most of the treatment related symptoms were mild. However, some of the objective symptoms were at times severe and may reduce drug compliance in primary health care based population chemotherapy.

Delayed reinfection of Schistosoma mansoni in the Blue Nile Valley of western Ethiopia 10 years after mass chemotherapy.

In the Blue Nile Valley of western Ethiopia a successful control programme against Schistosomiasis mansoni starting from 1985 was in 1989 interrupted by local guerrilla warfare. The control was based on human mass chemotherapy campaigns during the rainy season of 1985 and 1986 and a limited annual, focal molluscicidal activity where re-infection was demonstrated. In 1995 the area was revisited and selected schools in previously hyperinfected villages were examined for reinfection. The results were compared to re-calculated figures for the 5-19 year age group from previous pre-, per- and post-control surveys in the same localities. In 1995 prevalence rates in the 5-19 year age group had risen to 68% (Salba-Korka) and 63% (Sirba), which are very close to the 1985-1986 pre-control prevalences. Infection intensities, however, had not risen to the same degree. In Salba-Korka the 1986 pre-control geometric mean S. mansoni eggs per gram of faeces in the 5-19 year age group was 73, after mass treatment until 1989 it was close to 0, whereas in 1995 it was still only 27. In Sirba the result was similar. This might indicate a slower transmission rate after the control period than previously. The reported seasonality of transmission and the local use of the molluscicidal bark of the 'Bitza' tree might possibly have had some delaying effect.

Epidemiology of schistosomiasis mansoni in three endemic communities in north-east Ethiopia: baseline characteristics before endod based intervention.

As part of a pre-intervention baseline data collection the epidemiological characteristics of schistosomiasis mansoni were studied in 3 endemic communities (Kemise, Harbu and Bati towns) in northeast Ethiopia in April and May 1994. The objective was to generate data based on which post-intervention differences (in changes), if any, in transmission level could partly be explained for the 3 towns. After calculating the sample size required for each town 132, 75, 158 households were selected by systematic random sampling from Kemise, Harbu and Bati, respectively and all members of the selected households stool was examined by the Kato's thick smear method. Eighty eight and 85% of the houses harboured one or more cases of Schistosoma mansoni in Kemise and in Bati, respectively, all members of the households being positive in 27% in Kemise and in 28% in Bati. The overall prevalences were 59%, 33% and 51% in Kemise, Harbu and Bati, respectively, with the corresponding geometric mean egg counts (epg) of 240, 123 and 195 for positives and 26.5 and 15 for the whole populations. All ages combined, there were no significant differences due to sex both in prevalence and intensity of infection. By age, children in the 10-14 years age group were most affected (p = 0.007), their prevalences reaching 86%, 52% and 66% in Kemise, Harbu and Bati, respectively and their corresponding geometric mean epg being 377, 157 and 401, respectively. Heavy infection (> 100 epg) reached 42%, 32% and 16% in Kemise, Bati and Harbu, respectively, reaching an average of 55% among the 10-14 years of age. The implications of the epidemiological findings and the possible use of the household approach for rapid assessment of schistosomiasis magnitude in an area are discussed.

[Dengue fever. Another infectious disease out of control?]. / Denguefeber. Enda en smittsom sykdom ute av kontroll?

In the 1950s dengue fever left its home in South-East Asia. The result, as we see it 40 years later, is terrifying. From being an almost unknown infection, dengue fever is today's most common arboviral disease with up to 100 million cases annually. In addition, the clinical picture has changed from a benign influenza-like disorder (classic dengue fever) to a serious disease with bleeding and hypovolemic shock (dengue hemorrhagic fever). In this article the authors give an overview of the present epidemiology, prognosis and possible preventive measures against dengue fever.

[Dengue fever imported to Norway. Serologically confirmed cases 1991-96]. / Denguefeber importert til Norge. Serologisk verifiserte tilfeller 1991-96.

With up to 100 million cases annually, dengue fever is today's most important arboviral disease. Dengue fever is endemic in many parts of South-East Asia, the Indian subcontinent, Oceania and the Americas. The disease mainly affects the local population, but occasionally also visitors from non-endemic areas. In this article we present epidemiological and clinical data on all 26 cases with serological confirmed dengue fever diagnosed in Norway in 1991-1996. 21 patients (81%) were infected in Asia. Typical exanthema, leucopenia, and thrombocytopenia were seen in 71%, 79% and 84% of the cases, respectively. A 37-year-old Indian-born woman developed dengue haemorrhagic fever grade 1 after a visit to New Delhi, while the remaining 25 patients had classical dengue fever. Postinfectious complications were common, and four weeks after the acute illness, hair loss, mental depression and asthenia were reported by 45%, 50% and 100% of the cases, respectively.