Plasma levels of innate immune mediators are associated with liver fibrosis in low parasite burden Schistosoma mansoni-infected individuals.

In the murine model, it was demonstrated that pro-inflammatory cytokines and chemokines are essential to the formation and modulation of Schistosoma-induced granulomatous inflammation. However, the relationship of these immune mediators and disease severity is hard to be established in naturally infected individuals. The current study evaluates the association between plasma concentrations of MIF, sTNF-R1, CCL3, CCL7 and CCL24 and schistosomiasis morbidity in Schistosoma mansoni-infected patients with a low parasite burden. For this propose, 97 S. mansoni-infected individuals were subjected to abdominal ultrasound analysis and clinical examination. Among them, 88 had plasma concentration of immune mediators estimated by ELISA assay. Multivariate linear regression models were used to evaluate the relationship between the plasma concentration of immune mediators and the variables investigated. Although most individuals presented low parasite burden, over 30% of them showed signs of fibrosis defined by ultrasound measurements and 2 patients had a severe form of schistosomiasis. No association between parasite burden and the plasma levels of chemokine/cytokines or disease severity was observed. There was a positive association between plasma concentration of CCL4, sTNF-R1, CCL3 and MIF with gall bladder thickness and/or with portal vein thickness that are liver fibrosis markers. In contrast, no association was found between CCL7 plasma concentrations with any of the schistosomiasis morbidity parameters evaluated. The data showed that CCL24, sTNFR1, MIF and CCL3 can be detected in plasma of S. mansoni-infected individuals and their concentration would be used as prognostic makers of Schistosoma-induced liver fibrosis, even in individuals with low parasite burden.

Glomerulonephritis in Salmonella-Schistosoma mansoni association.

In 3 patients with Salmonella-Schistosoma mansoni association and clinical evidence of renal lesions, a percutaneous renal biopsy was performed. Renal function, assessed by endogenous creatinine clearance, was abnormal in 2 cases and serum levels of complement were decreased in all cases. Immune complex glomerulonephritis, evidenced by the presence of immunoglobulin and complement in the glomeruli was demonstrated in all cases. S. dublin and S. typhimurium antigens were found in the mesangium and in the capillary walls of 2 patients. After treatment with chloramphenicol, the S. mansoni infection persisted, but the clinical, laboratory, and immunopathological alterations were resolved. These findings suggest a direct role for Salmonella in the pathogenesis of glomerulonephritis described in patients with associated Salmonella and S. mansoni infections.

Immune responses during human schistosomiasis. XII. Differential responsiveness in patients with hepatosplenic disease.

Thirty-four hospitalized patients and 12 ambulatory patients, all with hepatosplenic schistosomiasis mansoni were evaluated in regard to their peripheral blood mononuclear (PBMN) cell responses to schistosomal antigenic preparations and compared with groups of 40 patients with the hepatointestinal form and 39 patients with the more common, chronic intestinal form of schistosomiasis mansoni. PBMN cell blastogenic responses were measured upon exposure to schistosomal egg antigens (SEA), adult worm antigens (SWAP) and a cercarial antigenic preparation (CERC). All groups had some individuals who did not respond to some or all of these preparations. In the hospitalized hepatosplenic group greater than 50% did not respond to SEA. Analysis of the responses in each group revealed that all responders could be subdivided into moderate and high responders. High responders to SEA had experimental minus control values of greater than 8,000 counts per minute (CPM). For SWAP and CERC, this arbitrary cut-off value was greater than 25,000 CPM and greater than 11,000 CPM, respectively. The percent of high SEA responders in the groups differed considerably. This was 23% in the chronic intestinal group, 40% in the chronic hepatointestinal group, 67% for ambulatory hepatosplenic patients and 20% for hospitalized hepatosplenic patients. Previous studies had demonstrated that 94% of patients with early (2-3 month) acute schistosomiasis mansoni were high responders to SEA and none were nonresponders. Furthermore, at the other end of the spectrum, 100% of former schistosomiasis mansoni patients (treated and cured 7-35 years previously) were high responders to SEA. None were nonresponders to any of the antigen preparations. It is proposed that during acute infection all patients express vigorous responses to SEA. Upon continued infection most patients (75%) modulate this florid response. However, continued high responders comprise 40% of the chronic hepatointestinal cases and almost 70% of the ambulatory hepatosplenic patients. These latter 2 groups may likely represent early forms of the severe clinical disease found in the hospitalized hepatosplenic patient population. Fifty percent of the hospitalized group appear anergic and no longer respond to SEA, while only 20% are high responders. Long after chemotherapy it appears that the anti-SEA regulatory mechanisms of former chronic patients have subsided, leaving strong anti-SEA responsiveness.

Short report: endomyocardial fibrosis and cardiomyopathy in an area endemic for schistosomiasis.

An association of schistosomiasis and endomyocardial fibrosis or cardiomyopathy has been suggested. Clinical, stool, abdominal ultrasound, electrocardiogram, and Doppler echocardiogram examinations were performed on 226 patients from an area endemic for schistosomiasis. The diagnosis of schistosomiasis was made in 152 patients (69%) but clinical, electrocardiographic, or Doppler echocardiographic evidence of a schistosome cardiomyopathy or endomyocardial fibrosis could not be detected in any patient.

Therapeutic efficacy of oral oxamniquine in the toxemic form of schistosomiasis mansoni: treatment of eleven individuals from two families, and experimental study.

Two families, comprising 11 individuals in the toxemic form of schistosomiasis mansoni, infected in Belo Horizonte, Brazil were treated. Parasitological cure was obtained in 5 (45%) of the patients after a single oral dose of oxamniquine (Mansil), 20 mg/kg body weight. No significant side effects were observed. To evaluate the possibility of resistance to the drug, cercariae collected from Biomphalaria glabrata infected with micracidia from eggs obtained from three of the individuals not cured were studied. Mice infected with these three strains were cured after a single dose of examniquine. It is suggested that research be continued with other therapeutic schedules and perhaps other, more potent, drugs.

Pathogenic aspects of pyogenic liver abscess associated with experimental schistosomiasis.

Schistosomiasis mansoni infection that occurs concurrently with Staphylococcus aureus bacteremia favors the formation of pyogenic liver abscess. The present experimental study in mice evaluated the following aspects of the relationship between infection with Schistosoma mansoni and liver abscess caused by S. aureus: a) the role of the eggs of S. mansoni in the genesis of the abscesses; b) the influence of different phases of schistosomiasis in the development of liver abscesses; and c) the effect of the treatment of schistosomiasis on the development of the abscesses. Macroscopic and histopathological study showed multiple liver abscesses around granulomas of S. mansoni in the acute and chronic phases of schistosomiasis. Treatment of acute schistosomiasis before experimentally-induced bacteremia did not prevent the formation of liver abscess. The study findings indicate that granulomas around S. mansoni eggs and worms lodged in the liver provide a focus and substrate for pyogenic abscesses caused by S. aureus.

The association of steroids and schistosomicides in the treatment of experimental schistosomiasis.

The best therapeutic approach to acute schistosomiasis (Katayama fever) is still unsettled. In this paper we report a synergistic effect between schistosomicides and steroids in the treatment of the early stages of Schistosoma mansoni infection in the mouse. CBA mice infected with 150 S. mansoni cercariae were treated with oxamniquine or praziquantel and dexamethasone or prednisolone. The rate of parasite egg excretion by treated mice and appropriate controls was monitored, and the mice were perfused 43 d after infection for estimation of worm burdens and tissue egg densities. Mice treated with schistosomicides alone or with schistosomicides plus steroids had worm burdens of similar size. Significant reductions in egg counts were, however, recorded in faeces, and in the intestines and livers (with consequent reduction in liver pathology), of mice treated with schistosomicide and steroid, when compared to mice treated with schistosomicide alone or steroid alone. The apparent inhibition of fecundity of S. mansoni by combining these drugs has clear implications for treatment of the Katayama syndrome.

Ultrasonography of periportal fibrosis in schistosomiasis mansoni in Brazil.

In patients with hepatosplenic schistosomiasis, characteristic thickening of the walls of the portal vein in the hilus and its central and peripheral branches is observed. In an area of high prevalence of the disease in Brazil, 424 individuals older than 5 years have been examined by abdominal ultrasonography and 146 presented fibrosis, classified as central in 31 (21%), peripheral in 56 (38%), and both central and peripheral in 59 (40%). The mean ages of the subjects in the 3 groups were 45.7, 24.1 and 31.9 years, respectively (P < 0.05). The presence of central fibrosis was associated with the presence of peripheral fibrosis (odds ratio 10.7, P < 0.000001). Splenomegaly was found in 16% and 15% of individuals with peripheral and both central and peripheral fibrosis, respectively. No subject with central but no peripheral fibrosis and splenomegaly was identified. We conclude that central fibrosis occurs among older subjects but should not be considered a criterion for advanced disease.

Evaluation of proteinuria in an area of Brazil endemic for schistosomiasis using a single urine sample.

A two-step protocol was designed to evaluate the frequency of proteinuria related to Schistosoma mansoni infection in an endemic area, as measured by the protein/creatinine ratio (P/C R). A pre-test on 32 in-patients with renal disease and 20 healthy individuals showed a high correlation (r = 0.948) between the classical measurement of protein excretion per square metre of body surface during 24 h and the P/C R. The P/C R was then used to evaluate the frequency of proteinuria in 189 individuals in an endemic area in the northeast of Minas Gerais state, Brazil, with a schistosomiasis prevalence of 49.3% and 3.4% with the hepatosplenic form. The low prevalence of proteinuria (1.06%) in the studied population can be attributed to the accuracy of the method used and to the low prevalence of the hepato-splenic form of schistosomiasis. The P/C R is a reliable and appropriate method for the measurement of proteinuria in field studies.

Pulmonary schistosomiasis mansoni: post-treatment pulmonary clinical-radiological alterations in patients in the chronic phase: a double-blind study.

A double blind trial was set up to study the pulmonary effects of specific treatment with oxamniquine of 40 patients with chronic schistosomiasis mansoni. Radiological alterations characterized by bronchopneumonitis were seen in 17.5% of the patients after treatment, but in none of the placebo group; non-migratory condensation occurred between 25 and 72 h after treatment, with a mean duration of 7 d. 86% of the patients showed spontaneous healing with no radiological sequelae after 30 d of follow-up. Slight pulmonary clinical manifestations without any functional repercussions were also seen. The alterations were probably related to the host-parasite interaction, and the lesions may have been caused by deposition of immune complexes in the lungs with local activation of complement.

Pulmonary hypertension in schistosomiasis mansoni.

To evaluate cardiopulmonary involvement in schistosomiasis mansoni, 246 patients from an endemic area of Brazil were examined; 152 had been previously treated for schistosomiasis. Based on stool examination and/or abdominal ultrasonography, the patients were divided into those with schistosomiasis (69%) and those in whom the disease was not present (31%). M mode measurements were similar in the 2 groups. Pulmonary pressure was measured by Doppler echocardiography; 25% of the subjects had pulmonary hypertension. Those with pulmonary hypertension had a higher prevalence of schistosomiasis (80%) than those without (64%; P = 0.03). No case of cor pulmonale was diagnosed by electrocardiography or Doppler echocardiography. The prevalence of pulmonary hypertension correlated neither with periportal fibrosis nor with prior treatment for schistosomiasis.

A double blind trial with oxamniquine in chronic schistosomiasis mansoni.

Ninety-one children with chronic schistosomiasis mansoni were selected for this double blind trial. 48 (Group 1) were treated with a single oral dose of oxamniquine (20mg/kg body-weight) and 43 (Group 2) received the placebo. Clinical, laboratory and radiological examinations were performed before and after treatment. Dark urine and vomiting were observed only in the oxamniquine group. Pulmonary condensations with or without air bronchogram were observed in the chest X-ray of 15% of Group 1 patients, between days 3 and 5 after treatment. In the urinalysis made on the first day after treatment, a false positive reaction was reported for urobilinogen and bilirubin in up to 50% of the patients treated with oxamniquine. In Group 1, 69.6% of the patients were cured. No patient was cured in Group 2. There was a 4.4% incidence of infection in the control group. There was a 77.9% egg excretion reduction in the 14 Group 1 patients not cured by oxamniquine. The authors conclude that oral oxamniquine in the prescribed dosage, has low toxicity and good therapeutic efficacy in children with chronic schistosomiasis mansoni.

Pyogenic liver abscesses and acute schistosomiasis mansoni: report on 3 cases and experimental study.

Three children with acute schistosomiasis mansoni developed pyogenic liver abscesses. The abscesses were diagnosed by ultrasonography and confirmed during laparotomy. Staphylococcus aureus were the sole bacteria isolated from the abscesses. An experimental study was carried out in mice to establish whether schistosomiasis is a predisposing cause for pyogenic liver abscesses. Seventeen mice (group 1) were infected with 40 Schistosoma mansoni cercariae (LE strain) and 60 d later inoculated intravenously with a strain of Staph. aureus, isolated from a patient with bacteraemia; 17 mice infected with Sch. mansoni (group 2), 19 infected with bacteria alone (group 3), and 18 uninfected mice (group 4), served as controls. Thirteen group 1 mice (77%) developed multiple liver abscesses while none was observed in the controls. These results indicate that acute schistosomiasis mansoni concurrent with Staph. aureus bacteraemia favours the colonization of the liver by bacteria and the development of pyogenic hepatic abscesses.

Analysis of anti-keyhole limpet haemocyanin antibody in Brazilians supports its use for the diagnosis of acute schistosomiasis mansoni.

Antibody (immunoglobulin (Ig) G) to the haemocyanin of the keyhole limpet (KLH) (Megathura crenulata), which shares a well defined carbohydrate epitope with the surface of schistosomula of Schistosoma mansoni, was determined by enzyme-linked immunosorbent assay (ELISA) in the sera of Brazilians with acute schistosomiasis. Of 53 such individuals tested, 51 had a level of KLH reactivity in excess of the mean +2 standard deviations of that exhibited by chronically infected individuals. This difference in reactivity allowed the acute cases to be readily identified by visual inspection of ELISA plates. The levels of IgG in patients with hepatointestinal and hepatosplenic schistosomiasis, as well as in non-infected, seropositive residents of endemic areas and infected children from endemic areas, were not statistically different from those of intestinal patients. Significant levels of anti-KLH IgG were not detected in patients with leishmaniasis, Chagas disease, ancylostomiasis or ascariasis. The results support the use of KLH as a means of rapidly and easily identifying individuals with acute schistosomiasis.

Schistosoma mansoni: assessment of morbidity before and after control.

The literature on the assessment of morbidity due to Schistosoma mansoni infection is updated. Imaging techniques such as ultrasonography, echodoppler cardiography, computerized tomography (CT scan) and magnetic resonance imaging (MRI) introduced a new perspective, and expanded our knowledge on morbidity. Three well-defined syndromes caused by schistosomiasis mansoni have been described: the stage of invasion, acute schistosomiasis (Katayama fever), and chronic schistosomiasis. Complications of the acute and chronic syndromes have also been reported: pulmonary hypertension, neuroschistosomiasis, association with Salmonella, association with Staphylococci, viral hepatitis B, glomerulonephritis. In most individuals with hepatosplenic schistosomiasis the spleen is increased in size. Hepatosplenic schistosomiasis can, however, occur without splenomegaly. The definition of hepatosplenic schistosomiasis in endemic areas as the finding of S. mansoni eggs in the stools in an individual with hepatosplenomegaly is not satisfactory anymore. Many aspects of morbidity are expected to change after schistosomiasis control. Some are expected to change quickly (worm burden, Salmonella bacteremia, hepatosplenic schistosomiasis in children) whereas others shall remain for years (pulmonary hypertension, glomerulonephritis, neuroschistosomiasis). Intestinal schistosomiasis in individuals with low worm burdens is very difficult to diagnose and therefore laborious to control.

Abdominal ultrasound in acute schistosomiasis mansoni.

Reports on abdominal ultrasound studies in patients with acute schistosomiasis are still scarce and limited data are available on structural changes of the liver parenchyma in this stage of the disease. 26 patients with acute schistosomiasis mansoni were submitted to clinical and ultrasound examination. For ultrasound comparison, each acute patient was paired by age, gender, weight and height to a non-infected individual. Ultrasound showed a non-specific homogeneous size increase of the liver, and spleen in all acute patients, and easily identified intraabdominal lymph nodes in the periportal region in most cases. Three out of the five patients with periportal thickening underwent percutaneous liver biopsy. Periportal thickening disappeared 6 months after treatment for schistosomiasis. 24 months after successful treatment there was involution of the liver and spleen; lymph nodes, although reduced in size, were still easily recognized. Liver biopsy showed dense inflammatory infiltration of neutrophils, macrophages and eosinophils in the portal tracts associated with discrete fibrous tissue formation.

Cytokines as determinants of resistance and pathology in human Schistosoma mansoni infection.

The role of different cytokines in the peripheral blood mononuclear cell (PBMC) proliferative response and in in vitro granuloma formation was evaluated in a cross-sectional study with patients with the different clinical forms and phases of Schistosoma mansoni infection, as well as a group of individuals "naturally" resistant to infection named normal endemic (NE). The blockage of IL-4 and IL-5 using anti-IL-4 and anti-IL-5 antibodies significantly reduced the PBMC proliferative response to soluble egg (SEA) and adult worm (SWAP) antigens in acute (ACT), chronic intestinal (INT) and hepatosplenic (HS) patients. Similar results were obtained in the in vitro granuloma formation. Blockage of IL-10 had no significant effect on either assay using PBMC from ACT or HS. In contrast, the addition of anti-IL-10 antibodies to PBMC cultures from INT patients significantly increased the proliferative response to SEA and SWAP as well as the in vitro granuloma formation. Interestingly, association of anti-IL-4 and anti-IL-10 antibodies did not increase the PBMC proliferative response of these patients, suggesting that IL-10 may act by modulating IL-4 and IL-5 secretion. Addition of recombinant IL-10 decreased the proliferative response to undetectable levels when PBMC from patients with the different clinical forms were used. Analysis of IFN-gamma in the supernatants showed that PBMC from INT patients secreted low levels of IFN-gamma upon antigenic stimulation. In contrast, PBMC from NE secreted high levels of IFN-gamma. These data suggest that IL-10 is an important cytokine in regulating the immune response and possibly controlling morbidity in human schistosomiasis mansoni, and that the production of IFN-gamma may be associated with resistance to infection.

HTLV-I associated infective dermatitis may be an indolent HTLV-I associated lymphoma.

When present for a first time blood donation, a 28-year-old Brazilian white female reported a pruritic eczema of the scalp and retroauricular areas since childhood that had been frequently infected. Her mother had been diagnosed as having HTLV-I-associated myelopathy (HAM), and the patient was found to be a human T-lymphotropic virus type-I (HTLV-I) carrier. The patient had been breast-fed for 6 months. The patient had a complete examination, and a biopsy was taken from eczema in the retroauricular area. The biopsy indicated chronic lymphohistiocytic dermatitis with no abnormal lymphocytes. Eleven months later, the patient had an infiltration in the skin of the retroauricular area and a new biopsy revealed atypical lymphocytes. Nested polymerase chain reaction (PCR) was positive for HTLV-I and immunohistochemistry of the tissue at this time confirmed adult T-cell leukemia/lymphoma (ATLL). Retrospective immunohistochemistry showed that the first fragment submitted from the biopsy 11 months before was also compatible with the diagnosis of ATLL. This case fulfilled all major criteria for diagnosis of HTLV-I-associated infective dermatitis (HTLV-I-ID). We postulate that the patient had indolent ATLL associated with HTLV-I infective dermatitis since childhood. We recommend that tissue immunohistochemistry analysis be done in any patient with HTLV-associated infective dermatitis.

Acute schistosomiasis: clinical, diagnostic and therapeutic features.

Three distinct syndromes caused by schistosomiasis have been described: cercarial dermatitis or swimmer's itch, acute schistosomiasis or Katayama fever, and chronic schistosomiasis. Complications of acute schistosomiasis have also been reported. The absence of a serological marker for the acute stage has hindered early diagnosis and treatment. Recently, an ELISA test using KLH (keyhole limpet haemocyanin) as antigen, has proved useful in differentiating acute from chronic schistosomiasis mansoni. Clinical and experimental evidence indicate that steroids act synergistically with schistosomicides in the treatment of Katayama syndrome. In this paper, clinical, diagnostic and therapeutic features of acute schistosomiasis are updated.

Salmonella-S. mansoni association in patients with acquired immunodeficiency syndrome.

Two young men with Salmonella bacteraemia, active schistosomiasis and the acquired immunodeficiency syndrome are reported. The clinical presentation comprised nonspecific signs and symptoms, such as fatigue, malaise, weight loss, diarrhoea, prolonged fever, and hepatosplenomegaly. In one patient, liver biopsy showed poorly formed granulomata around Schistosoma mansoni eggs and hepatitis. Treatment of schistosomiasis alone induced consistent clinical improvement with eventual cure of both Salmonella and S. mansoni infections. Recognition of the Salmonella-S. mansoni association in patients with AIDS is important because treatment of schistosomiasis makes a difference, improving the prognosis of this otherwise, recurrent, potentially fatal bacteraemia.