Parasites 3

Question 1

Schistosoma Intestinal/hepatic

Answer 1

S mansoni, S intercalatum, S japonicum (zoonotic), S mekongi

Question 2

Schistosoma Urogenital

Answer 2

S haematobium

Question 3

Schistosoma Public health relevance

Answer 3

78 endemic countries ~800 million at risk, ~250 million infected. 90% of cases are in sub-Saharan Africa. ~20 million cases of severe morbidity. ~300,000 deaths per year. >90% of cases are S mansoni or S haematobium. The most important Neglected Tropical Disease. The most important of all human helminth infections (second only to malaria among parasitic infections)

Question 4

Schistosoma Strongly associated with water sources

Answer 4

The River Nile, The Yangtze River, The Mekong - Schisto also follows man-made structures, dam buildings introduces Schisto into the environment. However, not just ‘tropical’ there is an outbreak in Europe in Corsica - 62% of cases were identified as having bathed in the River Cavu in early August 2013, but also other cases. Vector naturally present (Builnus snails, also naturally present in Portugal, Spain, southern France etc). Schistosoma haematobium/bovis hybrid species. Origin of outbreak believed to be S haematobium/bovis infected human from West African region (based on genetic analysis of worm eggs). More human cases in 2021 and infected snails are still found.

Question 5

Schistosoma Adult locations

Answer 5

S mansoni mesenteric vein of large intestine, S japonicum mesenteric veins of either small or large intestine. S haematobium small venules of the vesical plexus and pelvic plexus and sometimes also the rectal venules. The adult females produce eggs in these locations.

Question 6

Schistosoma Snail

Answer 6

Gastropod mollusc (‘stomach-footed’) miracidium infect snail through the foot, disappear into the mantle (area under the shell), mother sporocyst in mantle of snail, then development of daughter sporocyst, move to snail digestive gland (hepatopancreas) -> development of cercariae which then leave via the foot. S mansoni (Biomphalaria spp release >3000 cercs/day). S haematobium, S intercalatum (Bulinus ~2000 cercs/day. S japonicum (Oncomelania ~200 cercs/day) S mekongi (Tricula)

Question 7

Schistosoma Development

Answer 7

Eggs take 6d to develop after laying, remain viable for about 2-3 weeks. Miracidia ciliated, can swim around in water, 160um long as larval stages, within miracidium have larval glands that produce enzymes that are used for the penetration of the snail host. Migrate to snail mantle and develop mother sporocyst, cercariae develop in daughter sporocyst in snail digestive gland (hepatopancreas). Cercarial densities peak in the middle of the day for Sm and Sh (light is main stimulus to penetrate out of the snail foot). Sj peak densities at 11pm - this coincides with the target host mammals, as opposed to Sm and Sh which coincide with human peak water exposure. Cercariae live 48h in the water.

Question 8

Schistosoma Cercariae

Answer 8

Head (cercarial body) and Tail. Head contains various glands that produce enzymes for the penetration of the skin of the next host. Tail facilitates swim and bifurcated tail - propeller - they can swim backward and forward. Penetrate the skin and drop the tail off - only the head of the cercariae enters the skin and is now a schistosomula in the epidermis, enter blood circulation and end up in the lungs after 5d (doubled in size 300um), penetrate through alveoli and back out into circulation, follow circulation until end up in the hepatic vein (can take several rounds of circulation) where they develop into adult forms and then move to the final location

Question 9

Schistosoma Pathogenesis

Answer 9

To complete the life cycle, release eggs in faeces (or urine) -> water. Adult worm pair in mesenteric vein overlying the intestine, but around 50% of eggs are retained in the tissue - intestinal/hepatic species - in the wall of the intestine, but often can’t get through the endothelium of the blood vessel and the egg is carried by the blood and lodged in the liver. Urogenital species get stick in the wall of the bladder and ureters -> host response causes disease (the immune response)

Question 10

Schistosoma Dermatitis

Answer 10

Swimmers itch’ - commonly caused by animal or bird schistosome cercariae (non-human ones cannot develop any further and die), Infection with human species generally only give rise to mild dermatitis (if any)

Question 11

Schistosoma Acute Schistosomiasis ‘Katayama fever’

Answer 11

3-6 weeks post infection (onset of egg production). Up to 90% prevalence following first exposure, more unusual in endemic settings. Symptoms may include: malaise, low grade fever, head/neck ache, urticaria, eosinophilia, hepatomegaly, splenomegaly, diarrhoea, cough and wheeze. Aetiology uncertain but probably mediated by immune complexes of soluble worm or egg antigens and antibody (hypersensitivity reaction)

Question 12

Schistosoma Chronic Schistosomiasis

Answer 12

The main target for the parasite is to expel its ova to the external environment in order to maintain species survival. Pathology in the host is due to the immune response to the eggs accidentally stuck in tissues, as well as the damage caused by egg passage. Primary organ involvement: liver and intestine (Sm, Sj, Smekongi, Si) and urinary bladder/ureters (Sh). Secondary organ involvement ‘ectopic’ schisto’ (lungs, CNS, genital tract)

Question 13

Schistosoma Schistosoma egg granuloma

Answer 13

Infiltration of lymphocytes, eosinophils, macrophages, fibroblasts -> collagen deposition -> fibrosis. Egg granuloma changes over time - the egg dies and the granuloma slowly dissolves but fibrosis remains

Question 14

Schistosoma Intestinal Schistosomiasis

Answer 14

Passage of eggs -> ulceration -> haemorrhage. Mucosal thickening and inflammatory polyps may cause obstruction (features of colitis, colon pseudopolyposis, and polyps)

Question 15

Schistosoma Hepatosplenic Schistosomiasis

Answer 15

Eggs trapped in the pre-sinusoidal vessels of the liver. The granulomatous response, fibrosis and calcification causes periportal fibrosis (severe in 5-10% of patients [influenced by immunogenetic regulation of susceptibility to infection and fibrosis]). Symmer’s pipe-stem fibrosis. Blockage of blood flow in liver -> portal hypertension -> haematemesis), hepatosplenomegaly, ascites, haematemesis (oesophageal and gastric varices). Treatment with praziquantel will kill the Schisto, but does not reverse the fibrosis. Collaterals can also form between portal vein and epigastric vein via relics of umbilical veins -> ‘Caput medusae’ pattern of dilated abdominal veins

Question 16

Schistosoma Intestinal/hepatic Summary

Answer 16

Cercarial penetration -> dermatitis. Maturing worm -> Katayama Fever (acute Schisto), Escaping eggs -> haemorrhages in bowel mucosa, inflammation, colitis. Trapped eggs -> granulomas -> periportal (Symmers’) fibrosis -> portal hypertension -> hepatosplenomegaly -> oesophageal varices -> haematemesis. Severe hepatosplenic morbidity only occurs in 10% with risk of death ~1%- 90% develop chronic anaemia, malnutrition leading to fatigue, growth retardation, loss of cognitive function/development. However, coinfection with Malaria, Filaria, Helminths and viral hepatitis contribute to accelerated pathology and more pronounced anaemia

Question 17

Schistosoma Urogenital

Answer 17

S haematobium -> haematuria, fibrosis and calcification of the bladder and ureters, obstructive uropathy, hydroureter, hydronephrosis, bladder cancer. The higher the burden of infection, the greater the risk of disease. Sites of inflammation include hydroureter, polyp, sandy patch, calcification of the bladder (squamous metaplasia increases risk of SCC bladder in combination with smoking). Hydroureter and hydronephrosis increase risk of ascending bacterial infections and pyelonephritis.

Question 18

Schistosoma Urinary Summary

Answer 18

Cercarial penetration -> dermatitis. Maturing worm -> Katayama Fever (acute Schisto), Escaping eggs -> haematuria, proteinuria, bladder polyps and sandy patches. Trapped eggs in bladder wall -> granulomas -> calcified bladder -> bladder cancer. Trapped eggs in ureters -> calcifications -> hydroureter, hydronephrosis, pyelonephritis

Question 19

Schistosoma Ectopic lung Schisto

Answer 19

Eggs embolise to pulmonary arterioles -> granulomas -> pulmonary hypertension -> right ventricular hypertrophy and failure (‘cor pulmonale;). Occurs in 15% of S m Symmers’ case. Also in Sh cases, but rare in Sj

Question 20

Schistosoma Ectopic CNS Schisto

Answer 20

Eggs +/- adults of Sm or Sh in spinal cord -> granulomas -> paraplegia. Eggs +/- adults of Sj in brain -> epilepsy etc

Question 21

Schistosoma Ectopic genital Schisto

Answer 21

Up to 75% of women with Sh have eggs in uterine cervix, vagina and vulva and less commonly in uterus, ovaries. Genital Schisto is associated with ‘sandy patches’, vascularisation and contact bleeding. Misdiagnosed as cervical cancer or STIs, linked to fertility. Women with genital schisto have up to 3-fold increased risk of acquiring HIV. Men: eggs commonly found in seminal vesicles, prostate, ~50% of egg positive men have eggs in semen. Eggs in scrotal lymphatics -> hydrocele, elephantiasis

Question 22

Schistosoma Clinical

Answer 22

Degree of symptoms will depend on intensity and duration of infection, and may take years to develop. Acute: fever, diarrhoea, abdominal pain, weight loss. Chronic intestinal/hepatic (chronic diarrhoea, abdominal pain, anaemia, hepatosplenomegaly. Urogenital (dysuria, frequency, terminal or total haematuria. Chronic disease -> obstructive uropathy, bacteriuria, bladder carcinoma, bladder calcification, genital lesions). Schisto is a protean (changing) multisystem disease with multiple abdominal symptoms (for both types)

Question 23

Schistosoma Diagnosis

Answer 23

Parasitology identify eggs in sedimented urine, filtrated urine or in semen (Sh). Direct smear, Kato katz or formol-ether faecal concentrates (Intestinal species). Morbidity markers: FOBT, macro/microhaematuria. Immunoassays: Eosinophilia (~45%), detection of specific Ab to soluble egg antigens by ELISA (but time to seroconversion often several months, and will remain positive for many years). Detection of antigen in urine (CCA circulating cathodic antigen) - the Ag is released by the adult worm (a proteoglycan regurgitated and in circulation and urine). Reported to be good for Sm as egg detection (but poor for S haematobium, also not useful for S japonicum)

Question 24

Schistosoma Treatment

Answer 24

Praziquantel is the only drug available to treat all species causing Schistosomiasis. Activates a transient receptor potential melastatin ion channel causing an influx of calcium and worm paralysis, which leads to a reduction in egg production, and worm death. 40-60mg/kg po single dose. Issues with PZQ: SE (abdominal cramps, nausea, diarrhoea, dizziness, vomiting - worse with higher intensity infections). it cannot be used for chemoprophylaxis due to its short half-life, and it is ineffective against migrating schistosomula and juvenile worms - need to treat six weeks after last exposure. Longstanding availability problems: in 2019 only 44% of people requiring treatment globally were reached, in 2021 only 30% were reached due to the pandemic (WHO)). New paediatric formulation (3m to 6y - smaller, water soluble, better taste)

Question 25

Schistosoma Transmission

Answer 25

Freshwater (collecting drinking water, washing, occupational exposure). The risk of infection is also dependent on seasonal changes in snail populations, water levels, infection rates and cercarial output. Flooding events may also cause temporarily higher rates of infection in human communities. Water may also be transported and sold in villages miles away from lakes or rivers (and cercariae remains infective for up to 48h)

Question 26

Schistosoma Control

Answer 26

Health education, safe water supply, sanitation, snail control by habitat modification (concrete open pipes to remove vegetation so snails cannot feed) and/or molluscicides (but if kill all the snails the fish die), chemotherapy campaigns. China have done well managing Sj - a major focus was snail control - digging new irrigation canals and collecting the amphibious Oncomelania. But also replacing cattle with tractors, bovines fenced away from water, faeces management by building latrines -> gas for cooking. Nightstool collection for boatmen and mobile populations - elimination target by 2030. Eradication of Sj from Japan - replace night soils and farm oxen with chemical fertiliser and tractors, ricefields -> orchards, drainage and reclamation of marshlands, concreting irrigation ditches and canals, mollusciciding, declared eradicated in 196 but snails remain

Question 27

Schistosoma Mass drug administration

Answer 27

WHO “The strategy for schistosomiasis control aims to prevent morbidity in later life through regular treatment with praziquantel’ = morbidity control using praziquantel to prevent build-up of severe fibrosis in individuals living in endemic areas (primarily school age children). Reinfection after PZQ remains a major challenge to control efforts in Africa due tot he number of factors including: lack of effect of PZQ on juvenile worms means that treated individuals often are still infected and will continue shedding eggs for transmission. high levels of infection prevalence and intensity. Poor or non-compliance of PZQ treatment. Low coverage. Recontact with contaminated water as a result of daily activities and seasonal factors.

Question 28

Schistosoma WHO guidelines 2022

Answer 28

1 In endemic communities with prevalence of Schistosoma spp infection >10% WHO recommends a annual preventive chemotherapy with a single dose of praziquantel at >75% treatment coverage in all age groups from 2 years old, including adults, pregnant women after first trimester and lactating women, to control schistosomiasis morbidity and advance towards eliminating the disease as a public health problem. 2 WHO recommends WASH interventions, environmental interventions (water engineering and focal snail control with molluscicides) and behavioural change interventions as essential measures to help reduce transmission of Schistosoma spp in endemic areas)

Question 29

Schistosoma One drug - praziquantel

Answer 29

Under experimental conditions, schistosomes from mice receiving repeated subcurative doses of PZQ become highly resistant. Evidence from human infection less clear, but some reports of treatment failures. There remains a strong need for more sensitive diagnostics and new drugs including drugs targeting juvenile worms).

Question 30

Trematodes Metacercariae

Answer 30

Cyst stage of cercariae - encyst on various organisms and plants associated with water (fasciola on water plants, clonorchis on fish gills) - can survive in this form for many years

Question 31

Trematodes Fluke summary

Answer 31

Blood flukes = schistosoma, intestinal = fasciolopsis, lung = paragonimus, liver = opisthorchis, clonorchis and fasciola

Question 32

Trematodes Epidemiology

Answer 32

On the increase, particularly in Asia due to industrial scale aqua farming

Question 33

Paragonimus westermani Summary

Answer 33

Infection by eating infected undercooked crustaceans (crabs, crayfish), included pickled, salted, smoked etc or juice from raw crabs/crayfish. Approx 21 million cases, mainly in: China, Korea, Philippines, Laos, Thailand, Vietnam, Peru, Ecuador. Adults live in lung cysts, but may migrate to other sites (subcutaneous tissues, abdominal cavity, brain). Zoonotic: many reservoir hosts including dogs, cats, foxes, rats, pigs etc. Ectopic worms may be found in a number of tissues, including subcutaneous migrating nodules - most severe ectopic form is brain causing cerebral paragonimiasis (may be confused with brain tumour or other CNS pathogen). 1st intermediate host: Snail, 2nd intermediate host: Fresh water crabs (rice paddies) or crayfish, Chinese mitten crab found in rivers (very popular) - drunken crab - crab marinated in rice wine but not cooked. The ‘Chinese tiger’ economy has now made it affordable for more city people to eat ‘luxury’ foods such as crab - available at supermarket (sometimes ‘lightly’ cooked in steamers). Clinical: cough with brown sputum +/- fever, haemoptysis +/- bronchopneumonia, chest pains, night sweats. Ectopic CNS involvement: seizure, eosinophilic meningitis. Diagnosis: CXR may be mistaken for TB, Microscopy (Gold standard): eggs in sputum, stool. Serology. Treatment: Praziquantel repeated treatment. Control: health education, cooking customs, improved sanitation, sewage disposal

Question 34

Clonorchis sinensis & Opisthorchis viverrini Summary

Answer 34

C sinensis: 25 million cases (Chinese or Oriental liver fluke), O viverrini: 10 million cases (SE Asia liver fluke), O felineus 1 million cases (Cat liver fluke). Important parasite in East Asia (mainly in Thailand, Cambodia, Lao, China, Korea, Japan and Vietnam) but also Central Asia and Russia. Ingested from undercooked/raw/pickled freshwater fish. Parasites of fish-eating mammals: Zoonotic: Animal reservoirs: Cats, dogs, pigs, rats. Adult worms live in gallbladder, bile and pancreatic ducts. 1st intermediate host (fresh water snail), 2nd intermediate host (fresh water fish). Adult worm in bile duct causes marked hyperplasia and oedema in bile duct epithelium and may eventually lead to adenocarcinoma. Clinical: light infections often asymptomatic. Heavy infections: 2-3 weeks after exposure (diarrhoea, fever, abdominal pain, hepatomegaly, eosinophilia), later (gallstones, bacterial infections in biliary tree, liver abscess, cholangitis, acute pancreatitis), chronic infection (inflammation and fibrosis of bile duct walls, biliary obstruction, destruction of adjacent liver parenchyma, jaundice, anorexia). Cholangiocarcinoma (average age of onset 54y which is 20-30y earlier than in non-endemic areas. In endemic areas of Thailand 40x higher risk than non-endemic). International agency for research on cancer/WHO: Classified as a group 1 biological carcinogen. Not everyone infected gets cholangiocarcinoma, nor is there an absolute correlation between prevalence and incidence, likely additional factors needed to promote malignancy. Animal experiments show that concurrent exposure to nitrosamine (fermented food sources) increases cholangiocarcinoma incidence during Clonorchis infection. Some dishes in region are fermented raw fish = high levels of nitrosamines. Association with Vietnam War Veterans - increased incidence of cholangiocarcinoma. Diagnosis: eggs in stool, ultrasound and other imaging. Serology. Transmission: fertilisation of fishpond with ‘night soil’, latrine built over fishpond. Fish from rice paddy. Treatment: Praziquantel (single 40mg/kg dose). Control: cooking fish to 63C inside, or freezing at -20C for 7 days. Improved sanitation (latrines, not using nightsoil for fishponds). Zoonosis: control animal access to fish/ponds. WHO recommend annual MDA with PZQ where prevalence is >20% or every 24 months in areas <20%

Question 35

Fasciola hepatica Summary

Answer 35

Worldwide, estimated 17 million human cases. Zoonosis of sheep, goat, cattle and buffalo (important pathogen in livestock farming). Human infection by ingestion of contaminated waterplants (commonly watercress, water-mint, water spinach) or drinking contaminated water. Fasciola season ‘autumn’ after foraging water cress in the summer. Acute phase: juvenile fluke migration through liver (feeding on liver tissue -> liver tissue destruction) - fever, abdominal pain (sometimes severe), weight loss, urticaria, hepatomegaly (lasting 6-12w). Chronic phase: bile duct fibrosis, jaundice, cholecystitis, pancreatitis, gallstones, bacterial infections (but not cholangiocarcinoma). Diagnosis: increased eosinophils, increased WCC, upper abdominal pain. History of eating water plats. Stool microscopy for eggs, serology. False egg positives may occur after eating liver from infected animals (ie beef liver). In the middle east: Pharyngeal fascioliasis (‘halzoun’ (‘suffocation’)) eating infected raw sheep or goat liver: adult fluke attaches to pharyngeal mucosa (dysphagia, dyspnoea, bleeding and airway obstruction). Treatment: Triclabendazole (Praziquantel is NOT effective). Control: cultivation of vegetables in water which is free of faecal pollution (animals or human), thorough cooking of water vegetables, exclusion of livestock from aquatic vegetable crops, some countries now employing MDA with triclabendazole in communities with high prevalence (eg Peru, Bolivia, Egypt). Comparison in histology - Fasciola has multiple gut branches with rough tegument. Whereas clonorchis/opisthorchis has only 2 gut branches and smooth tegument

Question 36

Fasciolopsis buski Summary

Answer 36

Giant intestinal fluke. Estimated up to 15 million cases in China, SE Asia, India, Bangladesh. Infection through ingestion of water plants Water caltrop (Buffalo nut) is an important source of metacercariae - people tend to peel them with teeth which is how they ingest the metacercariae, also water chestnut, lotus. Often associated with raising pigs (Zoonotic) in close association with edible water plants. Adult flukes reside in small intestine and sometimes colon. Clinical: symptoms according to burden low (<20) asymptomatic, high (>100) intestinal inflammation, diarrhoea, malabsorption, intestinal obstruction. Diagnosis: eggs in stool. Treatment: Praziquantel. Control: Sanitation, exclusion of pigs from aquatic vegetable crops, peel and wash vegetables.

Question 37

Trematodes Other intestinal flukes

Answer 37

Heterophyes spp, Metagonimus yokogawai, Haplorchis spp, Gastrodiscoides hominis. Small (a few mm) intestinal flukes common across SE Asia, eastern Russia, Middle East. Transmission: undercooked/raw fish. Symptoms: diarrhoea and colicky abdominal pain. Migration of the eggs to extraintestinal sites (heart, brain) can occur with resulting symptoms. Diagnosis: Eggs in stool. Treatment: Praziquantel.

Question 38

Trematodes Summary

Answer 38

Complex lifecycles involving aquatic snails as intermediate hosts, and other animals/plants as hosts/carriers of metacercariae. Humans and other animals are definitive hosts (zoonotic). Infection through ingestion of (uncooked) infected fish/crustaceans/plants. Paragonimus (crayfish/crab), Clonorchis/Opisthorchis (fish), Fasciola (water plants eg water cress), Fasciolopsis (water vegetables, eg water caltrop). Disease depends on worm burden and site of infection. Treatment generally praziquantel (or triclabendazole for Fasciola). Control: Proper cooking of food products, sanitation, removing animals from water sources. On the increase in many countries (increase in aquaculture and consumption)

Question 39

Lymphatic filariasis Epidemiology

Answer 39

Statistics: W bancrofti 51M infected 2018 (down from 120M in 2000) accounts for 90% of burden (reduced due to global program for the elimination of LF). B malayi 15M. W bancrofti: Coastal Brazil, Haiti, West Africa, coastal East Africa, India and SE Asia. B malayi: SE Asia

Question 40

Lymphatic filariasis Vector

Answer 40

W bancrofti -Anopheles, Culex, Aedes, Mansonia (definitive host = humans). B malayi (periodic) - Mansonia (definitive host = humans). B malayi (subperiodic has zoonotic reservoirs) - Mansonia, Aedes, Anopheles, Culex (definitive host = humans, monkeys, domestic cats, forest carnivores - remain a reservoir for ongoing infection). O volvulus - Simulium (definitive host = humans)

Question 41

Lymphatic filariasis Periodicity

Answer 41

Nocturnal periodicity (sequestered in vasculature of lung and liver during daytime, peripheral blood highest numbers coincides with the peak biting effects of the vectors Culex and Anopheles). Subperiodic periodicity (reduction in parasites during daylight but not completely). In Pacific Islands Wb is transmitted by Aedes polynesiensis (day biter - complete reverse in the pattern of periodicity) - we don’t know why, but assume there must be some disadvantage to being in the blood all the time. Important when using direct parasitological detection.

Question 42

Lymphatic filariasis Sequestration mechanisms in subperiodic B malayi

Answer 42

B malayi adhere to endothelium in vitro. Binding occurs at high but not low flow rates. Binding reduced in lower oxygen conditions. Anaesthesia (mouse model) increases peripheral microfilaraemias. Binding is dependent on host complement (C3) opsonisation of mf sheath. Conclusions - circadian oscillations in oxygen tension and blood pressure influence extent of complement-dependent sequestration to endothelium.

Question 43

Lymphatic filariasis Blood films

Answer 43

Found in blood, sheathed. Wb nuclei do not extend to tip of tail. Bm two small terminal posterior nuclei

Question 44

Lymphatic filariasis Mansonella

Answer 44

Mozzardi and M perstans are non-pathogenic(ish) and need to be distinguished from Wb/Bm. M streptocerca is in skin and needs to be distinguished from Onchocerca

Question 45

Lymphatic filariasis Ag detection

Answer 45

Wb CFA Ag, Bruga spp rapid dipstick.

Question 46

Lymphatic filariasis US

Answer 46

US detection of adult worm nests - bancroftian filariceles - a type of hydrocele. Can be used as indicator of treatment. Macrofilaricidal activity determined by loss of filarial dance sign at follow up by ultrasound. Also infrared thermal imaging: Temperature increases with severity of LE stage and patients with a history of ADLA have higher temperature regardless of stage - novel tool has great potential to be used to detect subclinical cases, predict progression of disease and ADLA status, monitor pathological tissue changes and stage severity following enhanced care package or other interventions in people affected by lymphoedema

Question 47

Lymphatic filariasis Pathogenesis

Answer 47

Early developing larvae will enlarge the lymphatic vessels to ensure they are big enough to live in, even after 14d the vessels are enlarged, and it is retained for chronic infections. Adults will stay in lymphatics for entire lifespan of ~10y. The tortuous collaterals causes diverted and backflow of lymph. The parasites also stimulate growth of new lymphatic vessels. Early stage is inflammatory relating to the parasite death, damage the structure of the lymphatics. Longterm chronic progression. Recurrent bouts of ADLA lead to chronic progressive elephantiasis. Male hydrocoele is also progressive and associated with increasing dilation of lymphatics (Wb only). LF lymphoedema and hydrocele patients have an altered circulating pro-angiogenic profile (VEGF)

Question 48

Lymphatic filariasis Clinical progression

Answer 48

Acute lymphangitis stage (fever, rash, red streaks, painful lymph nodes, orchitis, epididymoorchitis), Dermatolymphangioadenitis stage( episodic inflammation, secondary bacterial infection, severe pain, disability). Chronic stage (oedema, skin changes, hydroceles)

Question 49

Lymphatic filariasis Grading

Answer 49

Grades: 2 unreversible swelling 3 shallow skin folds 4 alternation of skin texture, formation of knobs 5 deep skin folds 6 mossy lesions 7 inability to perform work.

Question 50

Lymphatic filariasis Morbidity management and disability prevention

Answer 50

MMDP package alongside MDA. Hydrocoelectomy (surgical inversion of tunica vaginalis - significant quality of life improvement post-hydrocele surgery). Standard self care activities slows progression to more severe status (leg washing and drying, attending to entry lesions, applying medicated cream, trimming nails, standing & seated exercises, day and nighttime elevation, managing acute attacks, accessing support services. Enhanced self-care (deep breathing, lying down exercises, mobilising the skin and tissue, lymphatic massage, walking, drinking clean water, eating fresh fruit and vegetables)

Question 51

Lymphatic filariasis Antihelminthic drugs for LF

Answer 51

Annual treatment cycle, mass treatment of at risk population with the bigger aim of interrupting transmission. Africa: Albendazole, Ivermectin. Asia/Americas: Albendazole, Diethylcarbamazine citrate (DEC). Alternative strategies DEC or DEC and Ivermectin for 4-6y, DEC-fortified salt

Question 52

Lymphatic filariasis Wolbachia

Answer 52

Components of worm genome are missing, but are present in Wolbachia - and is important in providing purine/pyrimidine synthesis, haem biosynthesis, riboflavin/FAD biosynthesis. Wolbachia provides metabolic pathways to support growth and development of filarial nematodes at time of greatest demand (larval development, embryogenesis). Wolbachia drives inflammatory innate and adaptive immunity. The endosymbiotic bacteria are essential for Development (larval development, embryogenesis -> prophylaxis transmission blocking), Disease pathogenesis (Inflammatory reactions, clinical disease -> clinical case management), Adult worm survival (adults depleted of Wolbachia die 1-2y later -> macrofilaricidal).

Question 53

Lymphatic filariasis Doxycycline

Answer 53

Effect on adult female: 4 weeks 92%, 5 weeks 95%, 6 weeks 97%. Benefits of doxycycline: curative - slow kill avoids side effects. Safe in Loa loa coinfection. Not microfilaricidal - no risk of ocular side effects. Permanently sterilises adult worms - no recrudescence. Blocks transmission - parasites without Wolbachia unable to develop in mosquito (unable to lose sheath). Improves clinical disease: skin, hydrocele, lymphoedema. There is no recrudescence as the uterine contents degenerate in the absence of Wolbachia. Doxycycline reverses lymphoedema. Effect is independent of the anti-Wolbachia activity, even patients without adult worms had improvement in symptoms. Probably clearing skin bacterial infections and possibly having a host-directed anti-inflammatory activity. Reduction in lymphangiogenic mediators VEGF in circulation precede antimorbidity effects following doxycycline therapy. SOME REVERSIBLE CHANGES IN THOSE WITH ELEPHANTIASIS ARE SEEN WITH DOXYCYCLINE AND SELF-CARE.

Question 54

LF control NTD

Answer 54

Entirely dependent on donation from pharma industry - lots of pressure about whether open ended provision of drugs should continue. ALB, IVM, MEB for STH, Azith Trachoma, Praziquantel Schisto, DEC LF

Question 55

LF control WHO Road map

Answer 55

1 Moving away from process-driven targets to measures of the impact on public health 2 Replacing vertical and siloed disease specific programmes with holistic cross-cutting approaches integrated into national health system with a people and community centred focus 3 To transfer programme ownership away from partner support and reliance on donor funding to country ownership with NTDs integrated into national health plans and budgets. The overarching goals for 2021-2030 are 1 reduce by 90% the number of people requiring treatment for NTDs 2 eliminate at least one NTD in 100 countries 3 eradicate two diseases (dracunculiasis and yaws) 4 reduce by 75% the disability-adjusted life years (DALYs) related to NTDs

Question 56

LF control MDA for filarial nematodes

Answer 56

LF: D+A(+I) - out of Africa. A+I (or Ax2) - Africa. From 2018 I+D+A in countries with no Oncho or Loa. For Oncho -> Ivermectin

Question 57

LF control MDA to stop spread of infection

Answer 57

1 To stop spread of infection (MDA): Map area with sufficient prevalence -> six annual treatments -> six years (need to cover reproductive lifespan of the adult female) - these drugs do not kill adult worms, only kill the Mf -aim is to block the transmission of the parasite to the mosquito vector. Post-MDA surveillance requires Transmission assessment survey (TAS) - randomly pick foci (Ab in children born during the MDA period, if they have no Ab they haven’t been exposed, can xenomonitor if you can catch mosquitoes). Can then apply to WHO for verification. In parallel need to have 2 To alleviate the suffering (MMDP) full package of care for those already affected. The aim is to get below R0 (if do not reach R0, will experience recrudescence). MMDP = morbidity management and disability prevention.

Question 58

LF control Centre for NTD

Answer 58

Supporting 12 countries in West, Central and East Africa, Nepal, Sri Lanka to help set up interruption of transmission, make basic care available to those with clinical disease, capacity strengthening to improve endemic country labs to do the test surveys, conducted monitoring and evaluation to improve approaches. 1 To stop the spread of infection (interrupt transmission - MDA) 2 To alleviate the suffering of affected populations (morbidity management and disability prevention). MMDP is essential

Question 59

LF control Challenges beyond the programme

Answer 59

WHO uses mathematically modelling which does not take into account challenges (or reality). They are known for positive propaganda. Challenges encountered: Earthquakes in Nepal, Terrorist attacks in Bangladesh, Civil unrest in DRC and Burkina Faso, Flooding in Mozambique, Ebola in Liberia and Guinea, Central African Republic has no MoH or functioning health system. Political pressures on USAID/UKAID funding - none of these were taken into account in the WHO targets or mathematical model predictions for elimination endpoints

Question 60

LF control Global burden

Answer 60

Significant reduction 57% in first 20 years, but the easier areas were undertaken initially, funding cuts, and more difficult areas are ahead

Question 61

LF control Strategy

Answer 61

Triple therapy IDA (Ivermectin, DEC, Albendazole) will have more activity than any two together. IDA is a superior microfilaricide for LF. Modelling suggests it can reduce number of rounds of (high coverage) by 2 years compared with DEC+ABZ to achieve elimination. Recommended by WHO in 2018 as the standard treatment for LF outside of Africa. But the whole problem is that they don’t kill the adult worms, only the microfilaria - so the long period of MDA is needed to cover the lifespan of the female worm.

Question 62

LF control A-WOL

Answer 62

Goal: to find a new anti-Wolbachia drug with shorter regimen (7d or less), utility in children and women of childbearing age, alternative drug against drug-resistant parasites, safe alternative drug for Loa loa coendemic areas. Proof of concept that it is possible, but will need to do further work (1066S has been able to be used for dogs, but cannot be progressed for humans - Phase 1 - low dose, build up to what you think will be therapeutic dose - reached a level with 1066S which caused toxicity so promising drug eliminated from use)

Question 63

LF control Safe macrofilaricides

Answer 63

Filarial nematode worms contain the mutualistic endosymbiotic bacterial Wolbachia. Wolbachia are essential for larval development, embryogenesis and adult worm survival. Adult worm longevity is 10-14y for Onchocerciasis and 5-8y for LF - current drugs needed annually for the life span of parasite. Wolbachia depletion provides macrofilaricidal activity with benign adult worm death occurring in 1-2 years. Wolbachia depletion blocks transmission of residual mf and through arresting embryogenesis halts new mf production. Safe macrofilaricidal activity without the toxicity caused by directly acting antihelminthics. Proof of concept with 4-6w doxycycline in multiple phase II clinical/implementation trials. Potential to deliver disease elimination - AWOL strategy adopted by elimination programmes. Current A-WOL treatment options limited by dosage regimen and contraindications. Aim to deliver an oral anti-Wolbachia drug effective in <=7 days

Question 64

LF control New approaches

Answer 64

Brugia malayi RNA virus closely related to alphaviruses. Onchocerca volvulus RNA virus (OVRV) is closely related to Lyssa viruses - 100% of patients with these symptoms had Ab to the virus. Relationship not yet understood. Nodding syndrome - epilepsy with resultant injuries inc burns. Nakalanga - developmental problems deformities with growth restriction, scoliosis etc. These are only found in high endemic areas. Doxycycline for the treatment of nodding syndrome - decrease acute seizure-related hospitalisation, decrease deaths related to nodding syndrome, substantially reduce antibodies to the Onchocerca parasite. Diverse RNA viruses of parasitic nematodes are a hidden diverse group of viruses infecting 70% of parasitic nematodes. Potential impacts on parasite biology and disease. Possible that Rhabdovirus linked to onchocerciasis-associated epilepsy.

Question 65

Loa loa Introduction

Answer 65

African eye worm’ Loa loa was regarded as not constituting an important health challenge. A benign colonisation by a worm. It is so neglected it is not an NTD - there is no funding for research.

Question 66

Loa loa Onchocerciasis control and renewed interest in Loa loa

Answer 66

African programme for Onchocerciasis Control: relied mostly in ivermectin MDA. Since mid-1990s reports of death in the MDA-programmes (DRC, Cameroon), encephalitis as important cause of death identified. Hypermicrofilaraemic loiasis as major risk factor. Consequence: renewed interest in loiasis. Mapping of loiasis endemic regions. No ivermectin-based MDA for onchocerciasis control in regions with >20% Loa loa microfilaraemia or hypoendemic regions for onchocerciasis

Question 67

Loa loa Vector

Answer 67

Chrysops, associated with water.

Question 68

Loa loa Epidemiology

Answer 68

20million infected in Central Africa and parts of West Africa (Gabon, Congo, Cameroon, Central African Republic, DRC). 100-200 million at risk. Where: rural regions, forest and savannah regions, poorest regions of these LIC. Features: gradual increase in prevalence - highest in adults, lifelong infection. Cases seen in returning travellers are generally VFR in endemic regions (high exposure to rainforest)

Question 69

Loa loa Clinical

Answer 69

Typical migratory signs (eye worm migration usually 12h-4d associated inflammation. Dermal migration (virtually no inflammation). Calabar swelling (transient erythematous non-pitting oedema)). Common but unspecific (pruritus, urticaria, arthralgia, myalgia, severe headache, asthenia and fatigue (transient nerve palsies), transient tooth pain).Rare but important complications (encephalitis, endomyocardial fibrosis, nephropathy, pulmonary inflammation, pleural effusions, vision loss, septic arthritis, septic granulomatic lesions)

Question 70

Loa loa Encephalitis

Answer 70

Spontaneous (may occur with high mf), Treatment-associated (associated with high mf load, DEC, Ivermectin [Albendazole it is unclear whether this causes it or not]) signs: palpebral haemorrhages, CRP, fever, headache, confusion, agitation, coma. Pathophysiology: dying microfilariae blocking small vessels? Inflammatory response to trigger?

Question 71

Loa loa Burden of disease

Answer 71

Morbidity driven by eye worm and arthralgia. DALY: Regional 413, country-side 82, Schisto ~100/100,000. Excess mortality: 14.5% attributable mortality in high transmission region in Cameroon. Mf main risk factor associated with death.

Question 72

Loa loa Differences in Clinical presentation

Answer 72

Endemic regions: Asymptomatic disease (often microfilaraemic individuals), Symptomatic disease (often when typical signs are present). Complicated disease (long term consequences). Returning travellers: more often symptomatic, higher inflammatory response, higher psychological distress (in patients and doctors)

Question 73

Loa loa Diagnosis

Answer 73

Direct detection: microfilariae in blood - diurnal periodicity 10am-4pm, stained blood, concentration technique, LoaScope, PCR, LAMP, antigen-test. Adult worm: extraction (limitation in diagnostics). Indirect: filarial serology (IgG4?), Eosinophilia, IgE - specificity in endemic versus non-endemic regions. LoaScope is designed for when not to treat for oncho - smartphone based microscopy.

Question 74

Loa loa Occult loiasis

Answer 74

Occult: 2/3 of patients have no microfilaria in blood, create a diagnostic challenge. Microfilaraemia is associated with death, complicates treatment, often asymptomatic - therefore less treatment/diagnosis seeking. Clinical: migratory versus non-migratory (eye worm migration, Calabar swellings) - subjective burden highest in migratory loiasis. If occult, then often misdiagnosed as negative

Question 75

Loa loa Establishing the diagnosis

Answer 75

Endemic: exposure, eye worm migration, calabar swelling. Microfilaraemia (only ~30% harbour microfilariae, often misclassified as ‘negative’ for loaiasis despite subjective burden). Indirect signs (often not helpful due to low specificity, Serology, eosinophilia, IgE). Returning traveller: Relevant exposure, eye worm migration, calabar swelling. indirect signs (serology eosinophilia, IgE often positive and helpful). Microfilariaemia commonly occult loiasis (cannot detect)

Question 76

Loa loa Treatment

Answer 76

1 DEC (very rapid and potent activity on mf, string activity on adult worms. Mazzotti reaction, encephalitis in patients with high mf, contraindication in onchocerciasis, indicated in patients with mf<2000/ml, 3 weeks treatment (60-70% cure rate) 2 Ivermectin (very rapid and potent activity on mf, no activity on adult worms. Mazzotti reaction, encephalitis in patients with high mf. indicated in patients with mf<8000/ml, single dose not curative) 3 Albendazole (very slow activity against mf (probably sterilising effect), low activity against adult worms, Indicated if DEC and ivermectin cannot be used. 3-5 weeks regimens, cure rates. Mechanical extraction of adult worm during eye passage or dermal migration. Doxycycline has no effect as there is no Wolbachia. Antihistamines often prescribed for symptomatic management. Corticosteroids reduce frequency of mild adverse drug reactions. No benefit for severe, life-threatening adverse drug reactions.

Question 77

Loa loa How to reduce microfilarial load

Answer 77

High microfilarial count constitutes risk factor for treatment associated encephalitis. Potential sources: albendazole (unclear, reports of encephalitis). Apheresis (several cycles to mechanically remove microfilariae, lowering mf below 2000, consecutive definitive treatment with DEC.

Question 78

Loa loa Treatment challenges

Answer 78

Treatment generally not available - no DEC, no apheresis. Risk-benefit analysis - risk of treatment (encephalitis), risk of reinfection

Question 79

Loa loa Prevention

Answer 79

Avoidance of deer fly bites (clothing, mosquito net cloths, repellents, citridiol > DEET > Placebo. Chemoprophylaxis: 300mg DEC weekly, 100% protective efficacy. Indications: selected cases of highest risk, Peace corps, missionaries, military, forest worker

Question 80

Loa loa Control

Answer 80

Deforestation and human land change (longterm reduction of transmission regions). Currently available control-tools are insufficient (MDA-drugs: safety risks and/or not efficacious and/or inappropriate regimens. Vector: no tools available for efficient vector control). No control programs implemented in endemic regions. Priority for future (develop new tools for vector control, MDA programs, distribute knowledge about disease - mode of transmission)

Question 81

Loa loa Summary

Answer 81

Pathogen: Filarial nematode: Loa loa (sheath with nuclei extending into the tail). Diurnal periodicity of mf. Vector: Deer fly Chrysops silacea, C dimidiata. Wood fire, day biting. Epidemiology: Forest and adjacent savannah regions of Central Africa (parts of West Africa) ~20 million patients, often life-long infection. Rural populations. Clinical signs and symptoms: typical (eye worm migration, Calabar swelling, derma migration of adult worm) Common (unspecific: dermal rash, arthralgia, myalgia, severe headache, asthenia). Rare (encephalitis, EMF, renal, pulmonary). Migratory - non-migratory loiasis. Diagnostics: Adult worm: clinical observation, Mf microscopy, PCR, LAMP (LoaScope). Serology useful in returning travellers from non-endemic regions. Occult-microfilaraemic loiasis. Treatment: DEC, (Ivermectin), Albendazole. Treatment algorithm based on microfilaria count; apheresis in hypermicrofilaraemia. Risk-benefit analysis? In versus outpatient?. Prevention and prophylaxis: Avoidance of fly bites (mosquito nets, clothes, repellent). Very high-risk travellers: weekly DEC prophylaxis. No control programmes in endemic countries. Advocacy: not yet on the list of NTDs, new drugs, diagnostics, tools for the control of loiasis are urgently needed.

Question 82

African Trypanosomiasis Treatment

Answer 82

Stage 1 and 2 Fexinidazole if >6yo >20kg

Question 83

African Trypanosomiasis Summary

Answer 83

West African early stage 1 (blood or lymphatic) is often subacute or mild. Late stage 2 (encephalitis) gradual onset dysregulation of sleep-wake cycle various motor disorders and neuropsychiatric disorders. Somnolence often mistaken for depression. If CSF WCC>100/ul Rx Eflornithine and Nifurtimox. East African Early stage 1 (blood, lymphatic) is very acute, often fulminant (including cardiac involvement) febrile illness that may be accompanied by a rash. Late stage 2 (encephalitis)