CS3 - NTD Schistosomiasis 2 Flashcards
What are the later symptoms of schistosomiasis depending on parasite species and location in the host?
A:
Frequent, painful, or bloody urine (especially in urogenital schistosomiasis)
Abdominal pain and bloody diarrhea (intestinal schistosomiasis)
Anaemia due to chronic blood loss
Chills and muscle aches
Inflammation and scarring of the bladder (leading to urogenital issues)
Lymph node enlargement
Secondary blood disorders in cases of colon damage
Bladder cancer may develop in some cases (due to chronic infection)
Children with repeated infections can develop anaemia, malnutrition, and learning disabilities
Katayama fever (manifestation of acute schistosomiasis):
Fever
Urticarial rash (swimmer’s itch)
Enlarged liver and spleen
Bronchospasm
What are the stages of pathogenesis in schistosomiasis?
Acute
Established active
Late chronic
What happens during the acute phase (Katayama Fever) of schistosomiasis?
Cercarial Dermatitis: After cercarial skin penetration, some larvae die in the skin, while others enter the bloodstream.
What immune response occurs during the acute phase of schistosomiasis?
Type 1 hypersensitivity: Immune reactions to dying larvae cause a pruritic maculopapular rash (swimmer’s itch) due to mast cell degranulation and histamine release.
What happens during the acute phase (Katayama Fever) of schistosomiasis?
A:
Cercarial Penetration: Penetrating cercariae mature into schistosomula.
Timing: Symptoms appear 2 weeks to 3 months after exposure.
Immune Response: Symptoms are due to T helper type 1 (Th1) hypersensitivity and the formation of immune complexes in response to schistosomula antigens/secretions released during migration.
What are the immune and inflammatory responses in the acute phase of schistosomiasis (Katayama Fever)?
Cell-driven Inflammatory Response: Involves TNF, interleukins, and cytokines, leading to febrile illness.
Eosinophilia: Increased eosinophil count is commonly observed.
Pulmonary Infiltrates: Transient infiltrates occur, causing bronchospasm due to substances denser than air (e.g., oedema, blood, eosinophils) accumulating in the lung parenchyma.
What immune response is involved in the transition from acute to established schistosomiasis?
Th-1 Response: Initial response to egg antigens triggers proinflammatory cytokine production.
How does the immune response shift during the transition from acute to established schistosomiasis?
Th-1 to Th-2 Shift: Th-1 cells secrete interferon gamma, prompting a switch to a Th-2 response with anti-inflammatory cytokines, antibody production, and eosinophil recruitment.
What is the role of granulomas in established schistosomiasis?
Granulomas form in a Th-1 environment, leading to hepatocellular microvesicular changes, inflammation, and necrosis in the liver. Activated hepatic stellate cells (HSC) contribute to liver fibrosis.
What is the role of adult schistosome worms in established active infection?
A:
Adult worms in blood vessels usually do not stimulate local inflammation. They bind host antigens and regenerate their protective tegument, hiding worm antigens from the immune system.
What causes the symptoms and organ-related lesions in established schistosomiasis?
Symptoms are caused by inflammatory responses to eggs. Eggs actively secrete antigenic glycoproteins that facilitate their passage through blood vessels to the intestine or bladder and induce inflammation.
How do granulomas form around eggs in established schistosomiasis?
A:
Soluble egg antigens induce granuloma formation around eggs trapped in tissues. Hepatic granulomas during the Th-2 response limit egg secretion spread with minimal parenchymal inflammation.
How do organ-specific symptoms correlate with schistosomiasis infection intensity?
Organ-specific symptoms are mediated by egg-induced inflammation and granulomatous reactions, and often positively correlate with infection intensity.
Children in endemic areas are commonly affected.
Symptoms are reversible after treatment and removal of adult worms.
What happens during the late chronic infection phase of schistosomiasis?
Worm burden declines due to partial immunity and natural death of worms.
Egg excretion decreases, and new granulomas are smaller with less inflammation due to immunological downregulation.
Previous granulomas are replaced by fibrous tissue (scarring), reducing symptoms but potentially causing permanent pathology.
What are the consequences of the chronic inflammatory reaction to eggs in schistosomiasis?
Continuous inflammation leads to tissue destruction, fibrosis, and the formation of granulomata.
This results in fibrotic nodules known as sandy patches.
Chronic S. haematobium infection can lead to squamous cell carcinoma of the bladder.
How does schistosomiasis affect different stages of human growth and development?
Schistosomiasis has effects at various life stages, with associated health problems like growth impairment, developmental delays, and reduced cognitive function.
Systematic reviews (SR), meta-analyses (MA), randomized controlled trials (RCT), cohort studies (C), and cross-sectional studies (CS) provide varying levels of evidence for these associations.
What are the control measures in place for schistosomiasis at different life stages?
Red: Some interventions are in place, but neglected in endemic areas.
Yellow: More interventions, but no wide-scale Mass Drug Administration (MDA) in place.
Green: School-based MDA programmes target school-age children.
Grey: First 1000 days of life are not covered by current MDA programmes, which focus on children.
How does schistosomiasis impact children, and why is it considered a barrier to development?
Children are the primary targets of schistosomiasis infection.
The disease compromises physical and cognitive development, affecting their growth and ability to learn.
Schistosomiasis is not only a disease of poverty but also acts as a barrier to development in endemic countries.
How does praziquantel work in the treatment of schistosomiasis, and what are its limitations?
Praziquantel kills adult schistosomes, reducing morbidity in treated patients.
It is ineffective against juvenile worms and does not prevent reinfection.
The overall effect on disease transmission is transient, as prevalence quickly returns to baseline levels after treatment.
What are the challenges in developing a vaccine for schistosomiasis, and why is it a priority?
Funding issues and the complex immunology pathway make vaccine development difficult.
The human host oscillates between fighting off infection and managing tissue egg pathology from previous infections.
A schistosomiasis vaccine is considered one of the 10 most important vaccines that needs immediate and successful development due to its feasibility and high need.
How does the complex life cycle of Schistosoma affect vaccine development?
The complex life cycle of Schistosoma is a major barrier to vaccine development.
The parasite’s life cycle involves multiple stages, each requiring different immune responses, complicating the creation of a single effective vaccine.
How have schistosomes evolved to survive and enter the human host?
Schistosomes have developed sophisticated survival tactics over their evolution.
These tactics allow them to successfully navigate multiple, vastly different conditions in their life cycle, enabling effective entry into the human host.
What is the major reason for the spread of schistosomiasis?
The major reason for schistosomiasis spread is the inability of the immune system to effectively recognize and eliminate migrating larvae and adult worms.
What is the goal of developing a vaccine for schistosomiasis, and how would partial efficacy impact disease transmission?
The goal is not to achieve sterile immunity, as schistosomes do not replicate in their hosts.
A vaccine with even partial protective efficacy would significantly reduce disease burden and subsequent transmission.
How does schistosomiasis-induced immunomodulation affect the effectiveness of other vaccines, particularly for malaria?
Schistosomiasis-induced immunomodulation in the host may impair the host’s immune responses against other vaccines.
This is particularly problematic for diseases like malaria, as schistosomiasis and malaria often occur together endemically.
What is the role of chitosan nanoparticles (CSNPs) in schistosomiasis vaccine development?
Chitosan nanoparticles (CSNPs) loaded with cercarial antigen (CAP) have shown promising results in schistosomiasis vaccine development.
CSNPs enhance the host’s immune response and improve the protective effect of CAP compared to CAP alone.
This has been validated through parasitological, histopathological, and immunohistochemical studies.
How does praziquantel work in the treatment of schistosomiasis, and is there chemo-prophylaxis?
Praziquantel kills adult schistosomes, reducing morbidity in treated patients.
It is ineffective against juvenile worms and does not prevent reinfection, meaning the effect on disease transmission is transient. Prevalence quickly returns to baseline after treatment.
Currently, there is no effective chemo-prophylaxis for schistosomiasis.
How does praziquantel (PZQ) kill schistosomes?
Although the exact mechanism is not fully understood, PZQ exerts its effects through three main actions:
Calcium influx into the schistosome, which disrupts normal cellular function.
Spasmodic muscle contractions, impairing the parasite’s ability to move and feed.
Surface tegument modifications, causing damage to the schistosome’s outer protective layer and making it more vulnerable to immune attack.
What are the key effects of the (R)-enantiomer of praziquantel (PZQ) on schistosomes?
Tetanic muscle contraction (paralysis): Almost instant, causing a “corkscrewed” phenotype in schistosome musculature, measurable within 11 seconds.
Tegument damage: Surface blebbing and increased exposure of schistosome antigens at the parasite surface, observed within 15 minutes.
Both effects require the presence of Ca2+ ions.
Note: The (S)-PZQ enantiomer is largely ineffective, highlighting the stereoselectivity of PZQ action.
What proteins are responsible for sensing temperature and touch stimuli in schistosomes?
Transient Receptor Potential (TRP) and PIEZO ion channels.
Specifically, TRP Melastatin channels (non-voltage activated) are involved in sensing these stimuli.
What are the host targets for (R)-PZQ and (S)-PZQ?
R)-PZQ targets a G-protein-coupled receptor 5-HT2BR.
(S)-PZQ targets a transient receptor potential (TRP) channel, specifically TRPM8.
Sm.TRPMPZQ, a TRPM channel in S. mansoni, is activated by (R)-PZQ at nanomolar concentrations.
How does PZQ induce paralysis and what are the side effects?
PZQ-induced paralysis prevents mating and egg production, enabling the host’s immune system to clear the worms.
Side effects occur due to the release of parasite contents upon lysis, triggering a host immune response.
Heavier parasite burden leads to more frequent and intense side effects.
Sex-specific susceptibility: Male parasites are more susceptible to PZQ than female parasites, though the reason remains unclear.
What are the adverse effects of praziquantel (PZQ)?
Common adverse events:
Abdominal pain
Allergic reactions (generalized hypersensitivity)
Polyserositis (inflammation of serous membranes with effusion)
Anorexia
Arrhythmia (bradycardia, ectopic rhythms, ventricular fibrillation, AV blocks)
Asthenia (fatigue)
Bloody diarrhoea
Convulsions
Eosinophilia
Myalgia (muscle pain)
Pruritis (itching)
Somnolence (drowsiness)
Vertigo (dizziness)
Vomiting
Heavier worm burden increases the frequency and intensity of these side effects.
Some effects may be due to endogenous reactions as the parasites die, rather than the drug itself.
What are the contraindications and precautions for using praziquantel (PZQ)?
Contraindications:
Hypersensitivity to PZQ or any of its excipients.
Concomitant use with strong Cytochrome P450 (P450) inducers (e.g., rifampin), as it may reduce the therapeutic effectiveness of PZQ by preventing effective blood levels.
Patients receiving rifampin should consider alternative schistosomiasis treatments.
Precautions:
Grapefruit juice may increase PZQ activity, but its impact on efficacy and safety has not been fully evaluated.
Cardiac conduction issues: Patients with heart conditions should be monitored due to potential cardiac adverse effects.
Why is Mass Drug Administration (MDA) considered unsustainable in the control of schistosomiasis, and what is the best approach for its management?
Challenges with MDA:
MDA faces sustainability issues, including breakdowns in the process, such as logistical challenges and reinfection rates after treatment.
Best approach:
Combination of strategies: A safe and effective vaccine, alongside drug treatment, health education, snail control, and Water, Sanitation, and Hygiene (WASH) interventions, is seen as the most effective way to control and eliminate schistosomiasis.
What are some challenges with the administration of Praziquantel (PZQ) for schistosomiasis treatment?
Tablet size and taste: PZQ tablets (500/600mg) are unsuitable for preschool children, and the very bitter taste reduces patient compliance.
Adverse Drug Reactions (ADRs): Common ADRs include fever, nausea, abdominal pain, diarrhoea, and fatigue associated with dying worms, especially after the first treatment. ADRs are particularly common in patients over 6 years old, leading to reluctance for follow-up treatments.
What is the composition of Praziquantel (PZQ), and how do the enantiomers differ in terms of activity and side effects?
PZQ is a 1:1 racemic mixture of two enantiomers:
R-PZQ: Effective as a vermicide with low toxicity.
S-PZQ: Has little anthelmintic activity, unpleasant smell, bitter taste, and more severe side effects.
Pure R-PZQ is used for preschool children due to smaller tablet size, reduced unpleasant taste/odour, and fewer side effects, but its manufacture is costly due to the difficulty of separating S-PZQ.
What are the pros and cons of Mass Drug Administration (MDA) in the control of schistosomiasis?
Pros:
Reduces prevalence and morbidity of the disease, improving health, quality of life, and economic conditions at the community level.
Decreases disease transmission, preventing Disability-Adjusted Life Years (DALYs) in various populations.
Provides economic benefits by alleviating healthcare system strain and offering returns to impoverished populations.
Can reduce the burden of co-endemic infectious diseases (e.g., other NTDs, parasites).
Cons:
MDA can result in severe rebound disease, especially in high-transmission regions.
Limited benefits to chronic disease patients and the uninfected majority.
Side effects, from mild to serious, are poorly managed and can economically burden individuals.
Poor sensitization, lack of trust, and social pressure in communities can restrict autonomy and informed consent, especially with opt-out policies in schools.
What is the efficacy of oxamniquine and metrifonate in the treatment of schistosomiasis?
Oxamniquine is effective only against Schistosoma mansoni.
Metrifonate is effective only against Schistosoma haematobium.
Praziquantel is superior to both drugs, with proven efficacy against multiple species of schistosomiasis.
How does oxamniquine (OXA) work and what are its limitations?
Mechanism of action: OXA is a prodrug activated by parasite sulfotransferase to an electrophilic agent that alkylates DNA, halting nucleic acid metabolism.
Effect on worms: Disorganization of suckers, leading to detachment of worms from blood vessels and their destruction in the lungs and liver. Female worms may return to the mesenteric veins but cannot produce eggs.
Adverse effects: Substantial CNS effects limit its use to second-line treatment when praziquantel (PZQ) fails.
Efficacy: Active against Schistosoma mansoni but not S. haematobium or S. japonicum, limiting its use outside South America.
How does metrifonate work and what are its limitations?
Mechanism of action: Metrifonate is metabolized to dichlorvos, which inhibits schistosome acetylcholinesterase, causing paralysis.
Effect on worms: Paralyzed schistosomes lose their grip on blood vessel walls and are carried away in the bloodstream.
Limitations: Metrifonate is no longer commercially available.
Why aren’t adverse drug reactions (ADRs) of oxamniquine and metrifonate a major concern?
These drugs are either rarely used, no longer used, or no longer available, so ADRs are not a significant concern.
Why is praziquantel (PZQ) considered the main treatment for schistosomiasis, and what is being done to improve treatments?
PZQ is the primary treatment for schistosomiasis, but further optimization of this class of anti-schistosomal drugs is ongoing. This could lead to the development of an urgently needed alternative to praziquantel to aid in schistosomiasis elimination strategies.
Why is the development of an alternative to praziquantel (PZQ) unlikely to happen soon?
Despite considerable preclinical evaluation of many compounds, the translation of these compounds into clinical evaluation is unlikely in the near future due to a dry drug development pipeline and a lack of advanced preclinical compounds. This suggests that the expectation for a safe, more effective, and cheaper alternative to praziquantel remains unlikely for now.
What is promising about the new compounds LSHTM-1507 and LSHTM-1945 in the treatment of schistosomiasis?
These compounds are unrelated to praziquantel (PZQ) and have shown potency in killing both adult and juvenile parasitic worms in vitro and in mice after a low single oral dose. Predictions suggest that a single oral dose of these compounds, approximately 10-fold smaller than praziquantel, could cure the infection in people. However, the mechanism of action remains unknown.
How is artemether used in the context of schistosomiasis?
Artemether is effectively used in chemoprophylaxis for high-risk groups, such as fishermen and flood relief workers, in schistosomiasis-endemic areas. It may also be useful for individuals traveling to such areas to prevent infection.
What is the mechanism of action of artemisinin derivatives in schistosomiasis?
The schistosomicidal mechanism of action of artemisinin derivatives is not fully known. It is believed to involve an interaction with haemin, which leads to a toxic effect on the parasite.
Why is caution needed when using artemether in areas endemic with malaria?
The use of artemisinin compounds, such as artemether, is not recommended in areas endemic with malaria due to concerns about resistance to these “gold standard” drugs used in malaria treatment. This could undermine their efficacy in treating both malaria and schistosomiasis.
What is the role of betamethasone, doxazosin, and praziquantel in schistosomiasis treatment?
Betamethasone (BET): A synthetic corticosteroid that binds to the glucocorticoid receptor, inhibiting pro-inflammatory and promoting anti-inflammatory signals.
Doxazosin (DOX): An alpha-1 adrenergic receptor antagonist.
Praziquantel (PZQ): A drug that reduces parasite load by 90% in vivo, while BET and DOX achieve around 50% reduction.
The EC50 values: PZQ ~1 μM, BET and DOX ~35–50 μM.
Adverse Effects: Both BET and DOX may have issues with their adverse effect profiles compared to PZQ.
