1 Schistosoma clinical aspects and treatment ESCMID Postgraduate Technical Workshop for Basic and Clinical Parasitology. June 2013 Ana Cláudia Carvalho Infectious Diseases Department Centro Hospitalar São João, Porto Department of Clinical Epidemiology, Predictive Medicine and Public Health University of Porto Medical School Institute of Public Health - University of Porto
5 1 Adult schistosomes are macroscopically visible worms, with a white-grayish, cylindrical body approximately 1 to 1.5 cm in length.
6 1 The worms live in the bloodstream of the human host, where they can survive for up to 30 years with an average of 3 to 5 years. Bee ( queen) Lion
7 1 Schistosomes have separate genders, with the male holding the female in a continuous, monogamous embrace. Wolves Swans Love birds schistosomes
8 2 Transmission cycle
9 2 BMJ 2011;342
10 3 Acute Pathology
11 3 Cercarial dermatitis : swimmers itch Minutes after the cercarial infection, local urticaria may appear. Usually last for a few hours but sometimes persist for days.
12 3 Bird schistosomes as causative agents of swimmer s itch in Europe.Although schistosomes of the genus Trichobilharzia may infect humans, they are not able to complete their life cycle within these accidental hosts, and most die soon after penetration. Trends in Parasitology February 2013, Vol. 29, No. 2
13 3 Systemic hypersensitivity reaction: Katayama fever Occurs one to eight weeks after infection by the migrating and maturing schistosomula. Symptoms are mediated by the immune complex. Symptoms last for a few weeks to 2-3 months and gradually abate without therapeutic intervention. Katayama fever A flulike syndrome with protracted fever, fatigue, myalgia, headache and dry cough. Differential diagnosis: gastroenteritis, pneumonia, viral hepatitis HIV, salmonellosis Lambertucci., Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 105(4), July 2010
14 3 Systemic hypersensitivity reaction : Katayama fever The liver or spleen may be swollen and tender, and thorax radiography may reveal patchy infiltrates. Lambertucci., Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 105(4), July 2010
15 3 Systemic hypersensitivity reaction : Katayama fever Diagnosis: Leukocytosis with 10-75% eosinophils is common (>80% of patients) and aids diagnosis. Immunoglobulins are elevated in the serum, especially IgE, IgG and IgM. Serum alkaline phosphatase may be increased. Positive serologic tests. A history of tropical water contact: lakes Malawi, Victoria, Volta; the Zambesi and Niger deltas Remember! Stool or urine examinations are still negative.
16 3 Acute Pathology affects mainly tourists/travellers! Cercarial dermatitis and acute schistosomiasis are rarely seen in local people, probably because they have been desensitized at an early age but probably also because of underdiagnosis. High-risk groups for acute schistosomiasis: soldiers during military manoeuvres, religious organisations that baptise their followers in stream waters, fishermen, canoers and rural tourists.
17 4 Chronic Pathology
18 4 Morbidity is caused by years of chronic infection in wich the eggs and not the worms are the main culprit. The female produce hundreds (300) to thousands ( 3000) of eggs per day. Eggs migrate from blood vessels trough the tissues into the lumen of the bladder or intestine but: Some are carried away with the bloodstream Most are trapped in tissues Excreted with urine /faeces (1/3)
19 Granuloma The eggs forms the foci of a classical type 2 granulomatous inflammation, characterized by an eosinophil-rich, CD4C T helper (Th) 2 cell dominated infiltrate with additional infiltration of alternatively activated macrophages (M2). Sequela : marked fibroblast infiltration and development of fibrosis. The Schistosoma granuloma: friend or foe FrontiersinImmunology Inflammation April 2013 Volume4 Large necrotic-exudative granuloma in the liver of a patient with acute schistosomiasis mansoni. Note the isolated central egg surrounded by extensive necrosis. Lambertucci., Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 105(4), July 2010
20 4 S.haematobium Vesical/ureteral walls Hematúria Dysuria Hidronephrosis Renal failure Bladder cancer (?) Eggs trapped in tissues Inflammatory and granulomatous reactions Ulcerations/micropolyps/macropolyps Fibrosis/calcification S. mansoni/japonicum Large bowel/rectum walls Abdominal pain; Diarrhoea Stricture/ Stenosis
22 4 Schistosomiasis and urinary bladder cancer in North Western Tanzania: a retrospective review of 185 patients. Rambau et al. Infectious Agents and Cancer 2013,
23 Invasive bladder cancer : Courtesy of Carlos Bras-Silva, MD. Mozambique
24 Vesical polyps associated with schistosomiasis : Courtesy of Carlos Bras-Silva, MD. Mozambique
26 4 Hepatic schistosomiasis Early hepatic schistosomiasis : an early inflammatory reaction to eggs trapped in presinusoidal periportal spaces of the liver. Hepatomegaly is typical. Chronic hepatic schistosomiasis: irreversible fibrosis which develops in longstanding intense infections and presumably, some form of immunogenetic predisposition. Portal HT; splenomegaly; portocaval shunting, gastrointestinal varices. In S.mansoni the fibrotic process takes 5-15y ( the infection might no longer be present). In S.japonicum the progression is often rapid. Important: S. haematobium only rarely reaches the portal circulation! It is not a cause of hepatic disease!
28 4 Ectopic schistosomiasis Potencial complication of acute or chronic schistosomiasis.
29 4 Ectopic schistosomiasis Pulmonary In advanced hepatic disease ( S.mansoni/S.japonicum) complicated by portocaval shunting, eggs may leak into the perialveolar capillary beds. In S.haematobium infection embolization to lungs also occurs. Granulomas»» fibrosis»» pulmonary HT»» cor pulmonale
30 4 Ectopic schistosomiasis Genital Ulcerative lesions of the vulva, vagina, cervix, ovaries, fallopian tubes Epididymis, testicles, spermatic cord,prostate Infertility Increased risk of sexual transmitted infections?
31 4 Schistosomiasis and HIV Both empiric data and mathematical models support the hypothesis that schistosome infections lead to increased susceptibility to infection with HIV-1, a more rapid progression to disease through more vigorous viral replication and immunosuppression, and a higher likelihood of transmitting the infection to others through both vertical and horizontal routes. Different species of schistosome infection vary in the magnitude of their effects on these mechanisms with Schistosoma haematobium playing a greater role for increased susceptibility and transmission because of its association with urogenital disease. Current Opinion in HIV & AIDS: May Volume 7 - Issue 3 - p
32 4 Ectopic schistosomiasis Central Nervous System Neuroschistosomiasis is arguably the most severe clinical outcome associated with schistosome infection. Myelopathy (acute transverse myelitis and subacute myeloradiculopathy) of the lumbosacral region is the most commonly reported neurological manifestation of both S mansoni and S haematobium infection, whereas acute encephalitis of the cortex, subcortical white matter, basal ganglia, or internal capsule is reportedly typical of S japonicum.
33 Lancet Neurol 2011; 10:
34 4 Cerebellar pseudotumoral schistosomiasis mansoni Sagittal (A) and coronal (B) T2-weighted MRI of the brain revealing confluent high signal in the cerebellum, especially in the right hemisphere. (C) Coronal gadolinium-enhanced T1- weighted sequence shows areas of nodular enhancement in the cerebellum, especially in the right hemisphere. Lancet Neurol 2011; 10:
35 Fig. 19: magnetic resonance of the spinal cord shows thickening of the connus medullaris (arrows: a sagittal section on the left and an axial on the right) with enhancement after contrast injection in a patient with acute schistosomiasis mansoni. Lambertucci., Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 105(4), July 2010
37 4 Schistosomiasis and other infections Pyogenic liver abscesses - Lambertucci et al. (1990) described the cases of two children with skin pustules and acute schistosomiasis who also developed multiple pyogenic liver abscesses caused by Staphylococcus aureus. Mechanisms have been proposed as probable explanations for the association of schistosomiasis with pyogenic abscesses: (i) liver necrosis caused by S. mansoni eggs or dead worms colonised by bacteria (ii) transient impairment of cell-mediated immunity in the acute phase of schistosomiasis
38 4 Schistosomiasis and other infections Animal studies: Prior infection with Schistosoma decreased the severity of the subsequent infection as with Helicobacter pylori, Fasciola hepatica, Echinostoma or Plasmodium More often, however, a prior infection with Schistosoma increased the severity of the second infection as with Leishmania, Toxoplasma gondii, Entamoeba histolytica, Staphylococcus aureus or Salmonella. Additional research is needed, particularly on Schistosoma coinfections which currently have a small body of research and are current problems in human populations. Adv Parasitol. 2011;77:1-85
39 5 Diagnosis
40 5 Diagnosis Microscopic detection of eggs in stools or urine Urine collection (10ml): Antibody-based serologic assays Detection of circulating antigen PCR Between 10h-14h After exercise Terminal urine Schistosomiasis in areas of low endemicity: a new era in diagnosis. Cavalcanti et al. Trends in Parasitology February 2013, Vol. 29, No. 2
43 Fifty-two trials enrolling 10,269 participants were included. The evidence was of moderate or low quality due to the trial methods and small numbers of included participants.
44 6 Praziquantel PZQ was synthesized by Bayer and Merck in Germany in 1972 and introduced for clinical use in the People s Republic of China since PZQ exhibits stage-specific functions in killing adult worms ( of all Schisto sp). Safe ( children and pregnant women also) Well tolerated A single oral dose of mg/kg PZQ or 40/60 mg/kg divided in two doses during RCTs resulted in protection rates of 73% (95% CI: 67%- 78%). S.Mansoni Higher doses, up to 60 mg/kg, do not appear to show any advantage (four trials, 783 participants, moderate quality evidence).
45 6 Oxamniquine (its effect is restricted to S. mansoni!) Compared to placebo, oxamniquine 40 mg/kg probably reduces parasitological treatment failure at three months (RR 8.74, 95% CI 3.74 to 20.43, two trials, 82 participants, moderate quality evidence). These trials are now over 20 years old Praziquantel versus oxamniquine Only one small study directly compared praziquantel 40 mg/kg with oxamniquine 40 mg/kg and we are uncertain which treatment is more effective in reducing parasitological failure (one trial, 33 participants, very low quality evidence). A further 10 trials compared oxamniquine at 20, 30 and 60 mg/kg with praziquantel 40 mg/kg and did not show any marked differences in failure rate or percent egg reduction. Combination treatments Two trials also compared combinations of praziquantel and oxamniquine in different doses, but did not find statistically significant differences in failure (two trials, 87 participants).
46 6 Artemisinin derivatives They are active against S. japonicum, S. mansoni and S. haematobium, mainly targeting the immature, pre-adult stage, the schistosomulum. Have been used for prevention (alone) or treatment (combined with praziquantel). PZQ and AM or AS in combination for treatment resulted in higher protection rates (84% [95% CI: 64%-91%]) than PZQ alone (73% [95% CI: 67%-78%]), respectively. Liu et al. Parasites & Vectors 2011, 4:201
47 6 Combination treatment (artemisinins and praziquantel) Attention to Artemisin and Plasmodium! Using ARTs for schistosomiasis control is not advisable in areas where schistosomiasis and malaria are co-endemic!
48 6 Treatment Individual case management ( eg tourist) vs Community morbidity control ( endemic areas)
49 6 Treatment - Acute schistosomiasis Association of steroids and schistosomicides - Clinical and experimental evidence indicate that steroids act synergistically with schistosomicides in the treatment of acute schistosomiasis. Prednisone first (1 mg/kg, body weight, for 7 days, 0.5 mg/kg for 7 days and 0.25 mg/kg for 7 days) + Praziquantel (60 mg/kg, body weight, single oral dose) The association of steroids and schistosomicides in the treatment of symptomatic patients augments the cure rate, speeds the recovery time, prevents the recurrence of symptoms and improves the quality of medical care.! Before starting steroids, however, it is good medical practice to treat patients for strongyloidiasis with ivermectin or albendazole to prevent the development of fatal strongyloides sepsis triggered by prednisone.
50 6 Treatment Individual case management/ individual who have left endemic area: Praziquantel: 60mg/kg ( may split doses); repeat 2-3days (?) Consider repeat treatment 6-12 weeks later to cure prepatent infections. Practical note: Eggs can be excreted for several weeks after treatment: the preferred time for follow up is 4-6 weeks after treatment!
51 6 Treatment Community morbidity control (endemic areas) WHO For morbidity control, mass treatment is targeted at high risk groups. The high risk group targeted and the frequency of treatment depends on the prevalence of infection. In 2012 more than 35 million people, 83% of them in sub-saharan Africa, were treated for schistosomiasis. Experience from China and Egypt shows that preventive chemotherapy, mass treatment without individual diagnosis, with high coverage can result on significant impacts on indices of infection and also reduced requirements for praziquantel. Treatment several times during childhood is likely to prevent disease in adulthood. Praziquantel is now available free of charge to high-disease burden countries in sub-saharan Africa, through a donation from Merck Serono to the World Health Organization.
52 6 Treatment
53 September 2011 Volume 5 Issue 9 e1321
54 7 Prevention
55 7 Prevention Individual: multiple doses of Artemether or Artesunate at 6 mg/kg given in 1- or 2-week intervals for prevention against schistosome infection during exposure to infected water. ( experience with S. japonicum by short term exposure during fighting against floods)
56 7 SCHISTOSOME VACCINE DEVELOPMENT Despite the discovery and testing of many vaccine candidates, and advances in understanding protective immunity, none is currently available. Novel immunomic technologies for schistosome vaccine Development. MCWILLIAM et al. Parasite Immunology, 2012, 34,
57 7 Prevention Water supply and sanitation Mozambique, 2010.
58 7 Prevention Education Mozambique, 2010.
59 7 Prevention Mass treatment Mozambique, 2010.
60 7 Prevention Fight poverty Mozambique, 2010.
61 7 Take Home Messages Schistosomiasis is a tropical parasitic disease, caused by macroscopic worms of Schistosoma. Schistosoma mansoni and S japonicum live in the mesenteric venules, S haematobium in the perivesical venules. Swimmers itch can occur shortly after cercarial infection. Search for history of exposure! Acute schistosomiasis is an allergic reaction occurring in the weeks after primary infection and present as a flulike syndrome. High index of suspicion! Steroids are the mainstay of therapy. Eggs that are trapped in the tissues provoke immunogenic inflammatory, granulomatous and fibrotic reactions that cause intestinal, hepatosplenic or urinary disease which develops over many years. Most infected people show no, limited or non-specific symptoms. Severe disease develops in people with heavy, long-standing infections and probably unbalanced immune responses.
62 7 Take Home Messages Schistosomiasis can be complicated by ectopic lesions especially in the central nervous system, the pulmonary system or in the genital area. The diagnosis of schistosomiasis relies on microscopic examination of stools or urine, serologic tests, PCR and imaging. Praziquantel is the drug of choice, active against all species. In some cases adjunct therapies may be useful. Current control strategies consist mainly of preventive therapy in communities or groups at risk. There is as yet no vaccine against schistosomiasis. On the long-term, only sanitation, water supply, education and socioeconomic development can reduce and eliminate the transmission of schistosomiasis. Gryseels B. Schistosomiasis. Infect Dis Clin North Am Jun;26(2):
63 References Gryseels B. Schistosomiasis. Infect Dis Clin North Am Jun;26(2): Gray DJ et al. Diagnosis and management of schistosomiasis. BMJ May 17;342:d2651. Lambertucci JR. Acute schistosomiasis mansoni: revisited and reconsidered. Mem Inst Oswaldo Cruz Jul;105(4): Soldánová M et al. Swimmer's itch: etiology, impact, and risk factors in Europe. Trends Parasitol Feb;29(2): Pavlin BI et al. Acute pulmonary schistosomiasis in travelers: case report and review of the literature. Travel Med Infect Dis Sep;10(5-6): Secor WE. The effects of schistosomiasis on HIV/AIDS infection, progression and transmission. Curr Opin HIV AIDS May;7(3): Danso-Appiah A et al. Drugs for treating Schistosoma mansoni infection (Review). The Cochrane Library.2013, Issue 2 Cavalcanti MG et al. Schistosomiasis in areas of low endemicity: a new era in diagnosis. Trends Parasitol Feb;29(2): Wilson RA. Virulence factors of schistosomes. Microbes Infect Dec;14(15): Liu et al. Efficacy of praziquantel and artemisinin derivatives for the treatment and prevention of human schistosomiasis: a systematic review and meta-analysis. Parasites & Vectors 2011, 4:201 Ferrari TC, Moreira PR. Neuroschistosomiasis: clinical symptoms and pathogenesis. Lancet Neurol Sep;10(9): King CH et al. Utility of repeated praziquantel dosing in the treatment of schistosomiasis in high-risk communities in Africa: a systematic review. PLoS Negl Trop Dis Sep;5(9):e1321 McWilliam HE et al. Novel immunomic technologies for schistosome vaccine development. Parasite Immunol May;34(5): Siddiqui AA et al. Schistosomiasis vaccines. Hum Vaccin Nov;7(11):
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Reproductive DHT Analyte Information - 1 - DHT Introduction Dihydrotestosterone (DHT) together with other important steroid hormones such as testosterone, androstenedione (ASD) and dehydroepiandrosterone
BBS Fall Conference, 16 September 211 Use of modeling & simulation to support the design and analysis of a new dose and regimen finding study Didier Renard Background (1) Small molecule delivered by lung