Characterization of the study population
1. Introduction
Schistosomiasis is a parasite chronic disease caused by the helminth of genus
One of the greatest public health problems in countries where the disease is highly endemic, including Brazil, is schistosomiasis control for the following reasons: (a) large intermediary hosts dissemination and their escape mechanisms from molluscicides and from biological control due to high costs and low efficacy; (b) high charges associated with implementation of sanitary conditions and water supply and the intense contact of rural population with polluted water, as well as engagement in agricultural and fishing activities; (c) the long time needed for sanitary education and for the community to adhere to controlling programs; (d) individual or massive treatment has been shown efficient for controlling the morbidity, but not for reducing prevalence due to reinfection; (e) individual protection is unlikely, except for specific groups of exposed people; (f) until the current days, there is no effective vaccine for preventing schistosomiasis [7, 8].
According to previous data published by our group [9, 10], the proliferation of rural tourism in endemic areas may be an important contributing factor to the outbreak of schistosomiasis cases. The preservation of natural environment on the site, in order to attract visitors from urban centers, unintentionally contributes to create an ideal habitat for the intermediate host. Additionally, most areas chosen for leisure activities accommodate rural communities without any type of sanitation and, thus, represent a permanent risk of contamination of the flowing water.
In this context, visitors from urban areas, who never had previous contact with the parasite, contract the infection, and develop acute schistosomiasis [11]. Acute schistosomiasis is associated with a primary exposure and is more commonly seen in non-immune individuals traveling through endemic regions [12]. The clinical symptoms most commonly observed in such patients include fever, general weakness, headache, nausea, vomiting, diarrhea, anorexia, colic, weight loss, dry cough and hepatosplenomegaly accompanied by marked eosinophilia and leucocytosis [13-16]. However, these clinical symptoms may be confused with a number of infections such as visceral leishmaniasis, typhoid fever, malaria, tuberculosis, viral hepatitis, mononucleosis and bacterial infections [17]. Hence, the diagnosis of acute schistosomiasis becomes a challenge for the assistant doctor due to the wide diversity of non-specific symptoms presented by the patients; in addition, the presence of eggs in stool may not to be easily detected by parasitological examination in this phase of the infection.
Abdominal ultrasound is a complementary tool often used to assist the diagnoses of the
From the immunological point of view, the acute phase of the infection is characterized by a series of humoral and cellular immunological events. Hiatt et al. [20] showed elevations of IgG, IgM, IgE, and high titers of total antibodies in serum of acute patients that indicated the illness is associated with intense immune activity, while the magnitude of the IgE responses was related to the intensity of the infection. De Jesus et al. [16] showed that there was no significant difference in total IgE level between patients with acute and chronic schistosomiasis. In addition, Caldas et al [21] showed that specific IgG, IgM and IgE titers against egg and worm antigens in acute patients do not differ from those presented by chronic patients. Regarding cellular immunological events, nitric oxide (NO) represents an important and versatile messenger in biological systems, and it has been identified as a cytotoxic factor in the immune system, presenting anti- or pro-inflammatory properties under different circumstances [22]. Oliveira et al. [23] demonstrated that human peripheral blood mononuclear cells (PBMC) are capable of
In this report, we evaluated the clinical/laboratorial parameters and ultrasonographic features of patients who suffered acute schistosomiasis resulting from a simultaneous exposure in a country house in the metropolitan area of Belo Horizonte, Minas Gerais State, Brazil.
2. Population, materials and methods
2.1. Study population
The patients evaluated in this study acquired the acute phase of
To participate in the study, patients in the acute phase of schistosomiasis have fulfilled the following criteria for inclusion: age between 10 and 65 years; did not report having received any treatment with anti-helminthic drugs in the last 24 months; diagnosis of acute schistosomiasis mansoni based on epidemiological data (recent contact with
After blood collection, all patients who had positive stool examination for
A group of healthy volunteers formed by nine individuals, one woman and eight men aged 25 to 42 years, blood donors of the blood bank of Hospital Felicio Rocho, Belo Horizonte, Minas Gerais, Brazil constituted a control group (CT). It is important to mention that these individuals were screened and selected after serological tests for negativity for Chagas disease, leishmaniasis, human immunodeficiency virus (HIV), hepatitis, and did not report previous infection with
The study was carried out according to the National Health Council resolution 196/96, which regulates the research involving human beings, and was approved by the Ethics Committees of the Faculty of Medicine, Federal University of Minas Gerais, Oswaldo Cruz Foundation, and the Brazilian National Committee on Ethics in Research.
2.2. Parasitological examination
Parasitological examination was performed using the Kato-Katz method [26]. The presence and the number of
2.3. Evaluation of clinical parameters
All the individuals who came into contact with water contaminated by cercariae were subjected to a detailed history, performed by a physician of our team. The survey used during this study contained data referring to number of the protocol, name, gender, age, education and place of birth and questions about the clinical symptoms/signs such as fever, diarrhea, nausea, vomiting, abdominal pain, cough, weight loss, headache, asthenia, facial edema and cercarial dermatitis.
2.4. Evaluation of hematological parameters
Peripheral blood was collected in 5 mL vacuum tubes containing ethylenediamine tetraacetic acid (EDTA) as anticoagulant (Vacutainer, Beckton Dickinson, CA, USA), approximately 40 days after contact with contaminated water by cercariae and only once prior to treatment with praziquantel. The hemograms were performed in automated hematological electronic counter (Coulter MD18, E.U.A). The parameters measured were hemoglobin, number of erythrocytes and hematocrit values as well as total and differential counts of leukocytes including absolute counts of eosinophils, neutrophils, lymphocytes and monocytes.
2.5. Total IgE measurement
The plasma levels of total IgE antibodies were quantified using
2.6. Nitric oxide plasma levels
The plasma levels of nitric oxide were quantified using
2.7. Evaluation of hepatic enzymes
For the analysis of hepatic functions for the study group, plasma concentration of the enzymes ALT (alaline amino transferase), AST (aspartate amino transferase) and γ-GT (gamma-glutamyl transferase) were quantified by kinetic method using
2.8. Ultrasonographic analysis
Ultrasonographic evaluation was performed using a Nemio SSA/550ª machine (Toshiba, Town, Japan) with a 3-MHz sector probe for patients ≥ 10 years old and a 5-MHz probe for patients under 10 years old. The group of healthy individuals non-infected with
2.9. Statistical analysis
The statistical analysis of the data was made through GraphPad PRISM® 5.00 software release for Windows (La Jolla, CA, USA). Student's t test was used for parametric data comparison between two groups, while for non-parametric data we used the Mann-Whitney test. In all cases, the data were considered significant at P < 0.05.
3. Results
3.1. Demographic data and intensity of S. mansoni infection
Out of forty-two people who were present in the country house, thirty-eight (90.5%) participated in this study and reported contact with water contaminated with cercariae. Out of these, thirty-four (89.5%) had eggs of
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42 (100%) | 38 (90.5%) | 10 (23.8%) |
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Range | 01 - 65 | 01 - 65 | 14 - 31 |
Mean ± SD | 22.4 ± 15.2 | 22.5 ± 15.5 | 21.4 ± 6.2 |
Median | 21.5 | 20.5 | 22.5 |
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Female | 25 (59.5%) | 22 (57.9%) | 05 (50.0%) |
Male | 17 (40.5%) | 16 (42.1%) | 05 (50.0%) |
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Negative |
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04 (10.5%) | 0 |
Positive |
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34 (89.5%) | 10 (100%) |
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Range |
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0 - 768 | 8 - 768 |
Mean ± SD |
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50.8 ± 132.2 | 152.0 ± 224.7 |
Median |
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10.0 | 86.0 |
3.2. Clinical manifestations
The magnitude of clinical manifestations of schistosomiasis varies from light to severe intensity. Two patients showed serious clinical symptoms and required hospitalization due to the severity of the disease. The patients reported the onset of symptoms 20-30 days after water exposure. Headache and fever (60.0% and 50.0%, respectively) were the most common symptoms among patients, followed by diarrhea and weight loss (both 40.0%). Other clinical symptoms/signals were also recorded such as nausea/vomiting, abdominal pain, cough, asthenia, facial edema (each one with frequency of 30.0%) as well as urticaria and cercarial dermatitis (both 10.0%).
Table 2 highlights the main features observed in different human studies evaluating acute phase of schistosomiasis mansoni performed in distinct brazilian states such as Pernambuco, Sergipe and Minas Gerais. Although in these studies the frequency of exposed/infected individuals was similar ranging 90-100% and the incubation period has also occurred in comparable times such 20-30 days, we have observed strongly heterogeneous symptoms between them. Nonetheless, our study demonstrated some similar clinical symptoms in comparison to those found by Barbosa et al. 2001b [30] like the frequency of fever (50.0% and 54.0%, respectively), cough (30.0% and 33.0%, respectively) and urticaria (10.0% and 8.0%, respectively). However, other parameters presented distinct results like the frequency of headache (60.0% and 33.0%, respectively) and diarrhea (40.0% and 25.0%, respectively).
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Site/State | Ilha de Itamaracá Pernambuco |
Escada Pernambuco |
Aracaju Sergipe |
Igarapé Minas Gerais |
Exposed/infected | 92% | 100% | 92% | 90% |
Incubation period (days) | 15-30 | 20 | 20-30 | 20-30 |
Headache | 36% | 33% | 87% | 60% |
Fever | 100% | 54% | 90% | 50% |
Diarrhea | 64% | 25% | 81% | 40% |
Cough | 91% | 33% | 91% | 30% |
Abdominal pain | 64% | N.E. | 93% | 30% |
Urticaria | 18% | 08% | N.E. | 10% |
Cercarial dermatitis | 100% | N.E. | N.E. | 10% |
Hepatomegaly | 75% | N.E. | 35% | 86% |
Transaminases (increase) | 36% | N.E. | 38% | N.L. |
3.3. Plasma levels of total IgE and nitric oxide
The plasma levels of total IgE and nitric oxide from the ACT group are illustrated in Figure 1. The analysis of the results showed that the ACT group presented a significant (
3.4. Hematological profile
The main findings related to the hematological profile from the ACT group are illustrated in Figures 2 and 3. The analysis showed a significant reduction in the concentration of hemoglobin in the ACT group as well as an increase in the total leukocytes count as compared with the CT group. Increased total leukocytes were reflected in the absolute values of lymphocytes and eosinophils also increased in the ACT group as compared with the CT group. No significant difference was found between these two groups regarding other analyzed parameters such as number of erythrocytes, percentage of hematocrit, and absolute values of neutrophils and monocytes.
3.5. Profile of hepatic enzymes
Acute patients presented levels of ALT, AST and γ-GT enzymes similar to reference values and there were no significant differences between these levels and those presented by CT group. (Table 3).
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ALT (alaline amino transferase) (3-50 U/mL)* |
12.5 ± 11.2 | 8.6 ± 5.5 |
AST (aspartate amino transferase) (12-46 U/mL)* |
18.7 ± 5.9 | 23.0 ± 6.7 |
γ-GT (gamma-glutamyl transferase) (9-61 U/L)* |
23.4 ± 9.9 | 33.9 ± 16.6 |
3.6. Ultrasonographic analysis
The results demonstrated that the ACT group presented some significant differences as compared with the CT group: medium increase in the measurement (in mm) of longitudinal left/right lobe of liver (117.4 ± 19.7 and 99.0 ± 12.3 or 150.1 ± 18.2 and 102.2 ± 16.0, respectively), size of longitudinal spleen (110.6 ± 16.3 and 91.2 ± 12.7, respectively) as well as dimension of Hilar portal vein wall (3.4 ± 1.0 and 1.5 ± 0.3, respectively) (Table 4). Periportal lymph node enlargement was observed in six of seven patients (85.7%). The periportal lymph nodes were larger, round or ovoid in shape and sharply defined with thin halos surrounding hypoechoic areas (Figure 4). An additional ultrasonographic feature observed was an incipient periportal echogenic thickening named as grade I fibrosis (Figure 5).
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Longitudinal left lobe of liver | 99.0 ± 12.3 | 117.4 ± 19.7* |
Anteroposterior left lobe of liver | 46.7 ± 10.0 | 53.3 ± 10.9 |
Longitudinal right lobe of liver | 102.2 ± 16.0 | 150.1 ± 18.2* |
Anteroposterior right lobe of liver | 68.6 ± 11.9 | 63.4 ± 9.6 |
Longitudinal spleen | 91.2 ± 12.7 | 110.6 ± 16.3* |
Anteroposterior spleen | 35.1 ± 6.3 | 43.5 ± 11.1 |
Portal vein | 10.0 ± 1.2 | 9.9 ± 1.9 |
Hilar portal vein wall | 1.5 ± 0.3 | 3.4 ± 1.0* |
Splenic vein | 6.4 ± 1.3 | 7.1 ± 1.4 |
Superior mesenteric vein | 6.7 ± 1.1 | 7.1 ± 1.3 |
Periportal lymph node | N.V. | 1.8 ± 1.0* |
4. Discussion
The transmission of
During the last decades, the traditional epidemiological pattern showed a tendency to change. Accelerating migration from the countryside to cities threatened to overwhelm existing water and sanitation systems, and to increase urban schistosomiasis [9, 32, 33]. In Brazil, especially in urban areas, acute schistosomiasis outbreaks were observed and documented with a certain frequency [9, 14, 15, 17, 34-36]. The increase of acute schistosomiasis cases also indicates that a non-immune fraction of the population became exposed to the disease [9, 10, 36].
The incidence of the acute form of schistosomiasis mansoni is certainly underestimated. This illness has been mainly described as a disease of travelers. Many scientific publications concerning this acute disease refer to groups of tourists, fishermen or sailors originally from a non-endemic country who have visited a tropical zone [17, 37, 38]. However, as schistosomiasis is a focally distributed infection [17, 39, 40], the acute form is also diagnosed in inhabitants from endemic countries who do not live in endemic areas. Nevertheless, acute disease is seldom recognized in infected patients from endemic areas. According to Lambertucci [41], acute schistosomiasis is most evident in primary infection in non-immune individuals. Among people living in endemic areas, the acute phase may pass undiagnosed. Because in endemic areas exposure to infection occurs early in life, symptoms would be inconspicuous and diagnosis not even suspected.
The clinical features of the acute phase of schistosomiasis mansoni present a wide spectrum [42, 43] and the relative contribution of host and parasite factors in the pathogenesis of the disease is not completely elucidated [20, 43-45]. According to Neves [46], the clinical forms of the disease will depend on the interaction of at least three sequential events: (a) the evolution phase of the worms, whether before or after oviposition and the deposition of eggs in the tissues; (b) the organ predominantly involved by young or mature worms and by their eggs; and (c) the type and the qualitative/quantitative deviation of the total and local host response to antigenic products derived from the disintegration of schistosomula, adult worms and their eggs.
The main clinical findings presented in our study such as headache, fever, diarrhea and weight loss were consistent with those found by other authors [9, 15-17]. Different intensities of clinical manifestation are observed in patients with acute schistosomiasis, some of them evolved with a relatively severe picture while others with mild symptoms. In our study, we have also observed a similar profile.
The development of non-apparent clinical form characterized by blood eosinophilia and a positive immediate cutaneous reaction in the initial phase of the
According to this report, acute patients presented increased plasma levels of IgE and nitric oxide as compared with the CT group. Our result is similar to the data published by De Souza et al. [59], which evaluated the humoral immune response through quantifying of the total IgE levels from patients with acute clinical form of schistosomiasis. Thus, we suggest that total IgE may be related to disease morbidity, as established by Pereira et al. [60]. Nitric oxide (NO) has been identified as an important cytotoxic factor and versatile messenger in the immune system being responsible to induce both anti- and/or proinflammatory effects [61]. There are broad direct and indirect evidences that NO can act as an anti-schistosomal and antiparasitic molecule [62-64]. Moreover, NO produced by human leukocytes has been shown to kill larval schistosome parasites [64, 65]. Studies in experimental models of acute schistosomiasis showed that the inhibition of iNOS resulted in cachexia and exacerbated hepatic pathology, suggesting that in schistosomiasis, NO limits hepatocyte damage [66-68].
From two to eight weeks after a first contact with natural water infested by
Normal abdominal lymph nodes are usually not visualized by sonography. Neoplastic lymph nodes are generally rounded and hypoechoic, sometimes with an irregular shape and borders [19, 71, 72]. Lymphomas can also affect periportal and peripancreatic lymph nodes, but there is generally an extensive involvement of other abdominal lymph nodes, mainly retroperitoneal, that is almost anechoic and usually rounded. In this circumstance, the liver and spleen are enlarged and can show focal lesions [19, 72]. Patients with acquired immunodeficiency syndrome (AIDS) can also show hepatoesplenomegaly and abdominal lymphadenopathy, but the echogenicity of the liver is usually increased. Tumors related to AIDS, such as Kaposi’s sarcoma, have also been reported as a cause of lymphadenopathy [73]. Mesenteric and periportal lymphadenomegaly is a common finding in blastomycosis and these are almost anechoic [19].
In the current study, we have also evaluated the liver function of acute schistosomiasis patients by the ALT, AST and γ-GT assessment. Comparing with other studies in literature [15, 16], we did not observe changes in any of the enzymes evaluated, suggesting that the hepatocellular function is preserved or minimally compromised in the study population. In patients presenting intestinal or hepatointestinal clinical form of schistosomiasis,it has been observed that the liver function is maintained. In those patients showing the hepatosplenic form, liver function related to protein metabolism was in general changed, but rarely this function is compromised in a broad spectrum. Only after repeated blood spoliation, in the terminal stage of illness, there is strong involvement of the liver parenchymal. According to some authors, when liver cell damage occurs there is an increase of ALT and AST levels, but in the
γ-GT levels is the chronic stimulation of the microsomal fraction of hepatocytes and the presence of cholestasis [76]. According to Martins & Borges [77], the chronic stimulation of the microsomal occurs only in patients with hepatosplenic form of schistosomiasis. Kardorff et al. [74] observed that the increase of γ-GT occurs only in patients with severe periportal fibrosis, irregular texture liver and collateral vessels.
5. Conclusion
In conclusion, the data presented here suggest that alterations identified by analyses of clinical/laboratorial parameters and ultrasonographic features, although not specific, are compatible with the acute phase of Schistosomiasis mansoni and provide a reliable complementary tool for the diagnosis of the infection.
Acknowledgments
This work was supported by grants from Oswaldo Cruz Foundation (FIOCRUZ), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa de Minas Gerais (FAPEMIG), and UNDP World Bank/WHO Special Program for Research and Training in Tropical Diseases. The authors are grateful to the technical staff at the Laboratory of Cellular and Molecular Immunology and the Laboratory of Biomarkers of Diagnosis and Monitoring, Oswaldo Cruz Foundation, Brazil for their invaluable assistance during this study. The authors also thank the Program for Technological Development in Tools for Health - PDTIS - FIOCRUZ for the use of its facilities. OAMF, PMZC, RCO, GG, and ATC are grateful for the CNPq fellowships.References
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