SCHISTOSOMIASIS (BILHARZIA) MODULE

Kurt Schibler, MD and Alexander Levit, BSCE

Colley, D. G. and W. E. Secor (2007). "A schistosomiasis research agenda." PLoS Negl Trop Dis 1(3): e32.

Importance

• Up to 600 million people affected in developing countries¹
• More than 90% of cases occur in Africa
• Schistosoma haematobium
• Africa and Middle East
• Schistosoma mansoni
• Africa, the Middle East (mostly Yemen) and the Americas (mostly Brazil)
• Schistosoma japonicum
• China, Philippines and Southeast Asia

CDC/ Dr. Shirley Maddison

Mating adult female (thinner) and male (thicker)

Historical Perspective

The disease is linked to the abandonment of Jericho² and to losses in Napoleon’s army during his military campaign in Egypt from 1798-1801³

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It was not until the mid-1800s that the disease was first described by a German physician, Theodor Bilharz, during an autopsy.

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Ruins of dwellings found at Tell es-Sultan, Jericho

Napoleon enters Alexandria in 1798

Historical Perspective

• After China became communist in 1949, the disease prevented the Chinese People’s Liberation Army from invading Taiwan⁴
• In 1958, China followed with massive low-tech efforts to eradicate the disease⁵
• While not eradicated, the laborious efforts of millions of peasants to kill snails did result in a nearly tenfold decrease of disease prevalence (12 million to 1.6 million cases by the mid-1980s)
• Efforts to control snails included marsh draining, burying of snails, snail removal and chemical spraying

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Richard Fisher, https://creativecommons.org/licenses/by/2.0/

Historical Perspective

• In the first half of the 20^th century, the disease infected many in the Nile Delta
• Efforts to control the disease in Egypt in Sudan were initially organized by the British

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The Nile Delta, a major region for schistosomiasis in the early 20^th century

Historical Perspective

• Efforts in the Nile Delta to curb schistosomiasis included:
• Multiple injections of toxic antimony compounds
• Use of molluscicides, such as niclosamide, which was later dismissed due to its destruction of other wildlife
• Use of the medications ambilhar and hycanthone, which were dismissed due to toxicity and unexplained deaths⁶
• Use of tartar emetic, which led to hepatitis C due to contaminated injection equipment⁷
• In the 1990s, the use of praziquantel (PZQ) in mass drug administrations (MDA); this is the current treatment method

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Tartar emetic, an antimony-based medication for schistosomiasis (Image: Mrgreen71, Wikimedia Commons, GDFL)

Praziquantel, the primary anthelmintic currently employed against schistosomiasis

Life Cycle and Transmission

BEGINNING

CDC/Alexander J. da Silva, PhD/Melanie Moser

Life Cycle and Transmission

• Life stages existing in human body are characterized by resistance to immune responses
• Eggs excreted into water through urine and feces may eventually lead to the development of cercariae following the snail-host portion of the life cycle⁴
• If humans are present in water containing cercariae, they may become infected through skin penetration
• Nearly 800 million people in developing countries live near irrigated agricultural fields or dam reservoirs, which are the major sources for infection¹

CDC/ Dr. Sulzer

Free swimming cercariae (S. mansoni); spines at end penetrate human skin

Clinical Manifestations

• Children and adolescents are at the highest risk for sequelae
• Eggs can cause mechanical damage
• Ruptured blood vessels
• Blood in urine and feces
• Granulomas that obstruct urine and blood flow
• Anemia results from hematuria and chronic blood loss

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Egg of S. mansoni with the prominent lateral spine, CDC

Clinical Manifestations

• Anemia, inflammation and organ damage lead to:^8,9
• Growth retardation
• Malnutrition
• Cognitive delays
• Abdominal Pain
• Exercise intolerance
• Poor school performance
• Reduced work capacity

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Clinical Manifestations

• S. haematobium
• Two thirds of cases in Africa
• Granulomas in bladder can obstruct urinary tract (hydronephrosis) and lead to renal failure
• Renal failure accounts for a significant portion of the 280000 deaths annually from schistosomiasis¹⁰

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Hydronephrosis (shown by arrow) on CT scan; (Image: James Heilman, MD, http://creativecommons.org/licenses/by-sa/3.0/legalcode)

Clinical Manifestations

• S. haematobium (cont.)
• Unusual form of bladder cancer
• Squamous cell carcinoma of the bladder
• Affects female reproductive tract in up to 75% of women
• Fibrotic lesions in the vulva, vagina, cervix and uterus
• Causes genital bleeding, painful intercourse, infertility, clinical depression and increased susceptibility to HIV/AIDs transmission

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“Squamous cell carcinoma of the urinary bladder”

Clinical Manifestations

• S. mansoni
• One third of cases in Africa and 1 million cases in Brazil
• Bloody diarrhea
• Abdominal pain
• Liver involvement (often from granulomas)⁸
• Hepatomegaly
• Fibrosis
• Inflammation

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Clinical Manifestations

• S. mansoni (cont.)
• One third of cases in Africa and 1 million cases in Brazil
• Intestinal bleeding, diarrhea and loss of appetite caused by eggs in the intestinal wall
• Chronic schistosomiasis can cause
• Liver fibrosis
• Splenic enlargement
• Bleeding from the esophagus

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Diagnosis and Management

• Unlike China, snail control has not been successful in Africa
• Preventative measures include cooperation with treatment programs and education promoting the use of latrines¹¹
• Can be diagnosed by detected eggs in urine or stool
• Diagnosis is not often necessary due to the fact that treatment is administered in MDAs where the disease is endemic

Diagnosis and Management

• A height pole is used to determine dosage, this is designed for patients to receive approximately 40mg/kg body weight in praziquantel

Swar, M. O. and M. Amin (2011). "The use of height versus weight in determining praziquantel dose for treatment of Schistosomiasis in children." Sudan Journal of Medical Sciences 6(2): 2.

WHO dose pole for praziquantel (Africa)

Diagnosis and Management

• PZQ is delivered and distributed at health centers, schools and community-based drug distributors⁶
• Treatment with PZQ results in improvement of growth and physical fitness and reduction of anemia
• Multiple treatments can reduce urinary and liver pathology

Interaction with Healthcare Partners

• PZQ was expensive until manufacturing improvements in the 1990s^12,13
• Mass treatment programs were thus launched in several middle income countries including Brazil, China, Egypt, Morocco, the Philippines, Saudi Arabia, Tunisia and Puerto Rico^6,8,12,13
• The disease is near elimination in Morocco and Puerto Rico

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Interaction with Healthcare Partners

• The 54^th World Health Assembly (WHA) in 2001 adopted a resolution to treat at least 75% of school-age children at risk for schistosomiasis and soil-transmitted helminthes (STHs) by 2010
• Polyparasitism with schistosomiasis and STHs is common in sub-Saharan Africa^14,15

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Assembly Hall in Palace of Nations, meeting place of the WHA; Geneva, Switzerland; Photo: Tom Page, http://creativecommons.org/licenses/by-sa/2.0/legalcode

Interaction with Healthcare Partners

• In response to the poor coverage by 2010 (only slightly above 10% infected were treated), the Bill and Melinda Gates Foundation partnered with the World Bank, WHO and other NGOs in a London Declaration in 2012 to reaffirm support for NTDs through MDA¹⁶
• Merck KGaA (d.b.a. EMD Millipore in USA/Canada) committed to dramatically increase PZQ donations

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Front Building, Bill and Melinda Gates Foundation; Seattle, Washington, USA; Photo: Adbar (wikimedia), http://creativecommons.org/licenses/by-sa/3.0/legalcode

Interaction with Healthcare Partners

• Children 5 years old and younger form a “treatment gap” of schistosomiasis patients that are infected but not being given MDA¹⁷
• Young children were neglected due to the fact that they were thought to be rarely infected until recently
• MDA is often administered at schools, school typically starts around age 5
• Young children are often bathed in water drawn from the environment
• Merck KGaA is developing a pediatric formulation of PZQ¹⁸
• It has been shown that young children may received standard PZQ in a dissolved or partial pill form

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Interaction with Healthcare Partners

• The Schistosomiasis Control Initiative (SCI), is a key partner assisting African health ministries in implementing PZQ administration
• The SCI is a private-public partnership established by Alan Fenwick at Imperial College London (www3.imperial.ac.uk/schisto)
• With the WHO, the SCI facilitates once-yearly PZQ administration in several sub-Saharan African countries as well as Yemen
• Donated medication from Merck KGaA and generic medication from MedPharm and other sources

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Interaction with Healthcare Partners

• The SCI operates based on algorithms generated from local school surveys for schistosomiasis prevalence
• Several countries have shown great progress in schistosomiasis reduction^19,20
• In 2012 the WHA adopted a resolution affirming the feasibility of elimination²¹
• “Elimination” denotes interrupted transmission, public health measures may still be needed; “Eradication” denotes that the disease essentially no longer exists in the respective region

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Smallpox, the only human disease eradicated to date

Guinea worm in treatment; hopefully the second disease to be eradicated with 148 cases globally in 2013 (provisional, Carter Center)

Interaction with Healthcare Partners

• It remains unclear whether population-based PZQ approaches to morbidity reduction will reduce transmission or prevent reinfection²²
• Low reinfection levels can lead to persistent health problems such as anemia, growth impairment and diminished productive capacity
• Anthelmintic drug resistance is also a concern with repeated use of PZQ
• Measures to reduce the threat of resistance and reinfection include the development of recombinant vaccines currently in early clinical trials^23-26

Interaction with Healthcare Partners

• The current approach of MDA includes the use of PZQ alone or in combination of albendazole or mebendazole in schistosomiasis/STH co-infected areas
• These MDA treatments might also be linked with MDA efforts controlling other NTDs such as lymphatic filariasis, onchocerciasis and trachoma

Albendazole, a major anthelmintic used to treat many parasitic worm infections

June 2015 Updates

• A study in the Angolan town of Caxito found that S. haematobium prevalence decreased after 1 month but returned to baseline 6 months after one round of MDA with praziquantal²⁷
• The town is located in a river basin with additional manmade waterways
• This finding emphasizes the importance of environmental and behavioral preventative measures in addition to MDA

June 2015 Updates

• Vaccine targets for S. haematobium have been identified in patients receiving PZQ²⁸
• PZQ kills the schistosome and exposes surface antigens
• A spatial analysis for S. mansoni and S. haematobium prevalence was conducted; estimated findings for national prevalence are²⁹:
• S. haematobium: Kenya, 10.2%; Uganda: 4.3%; Rwanda: 0.1%
• Much of Kenya’s prevalence is concentrated in the eastern and coastal regions of the country
• S. mansoni: Kenya, 5.9%; Uganda: 10.3%; Rwanda: 3.8%

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Update 2022

• WHO Preferred Product Characteristics (PPC) for a schistosomiasis vaccine, is that an effective prophylactic vaccine should reduce adult worm burden by 75% in immunized individuals and that the reduction in egg excretion rates by infected individual should be close to 75% as well.
• Evidence from human field studies have shown that people living in endemic areas can develop partial immunity to infection. In fact, a small cohort of people living in Brazil, referred to as putative resistant, are naturally resistant to schistosomiasis, showing no clinical signs of the disease despite years of exposure

Gazzinelli A, Bethony J, Fraga LA, LoVerde PT, Correa-Oliveira R, Kloos H. Exposure to Schistosoma mansoni infection in a rural area of Brazil. I: water contact. Tropical Med Int Health. 2001;6(2):126–35.

Molehin AJ, Rojo JU, Siddiqui SZ, Gray SA, Carter D, Siddiqui AA. Development of a schistosomiasis vaccine. Expert Rev Vaccines. 2016;15(5):619–27.

Update 2022

• Data from experimental animal models of schistosomiasis also provide a strong case for schistosomiasis vaccine development. Studies utilizing non-permissive hosts such as rats and rhesus macaques, have shown that resistance to schistosome infections and subsequent worm elimination is entirely host immune dependent

Wilson RA, Langermans JA, van Dam GJ, Vervenne RA, Hall SL, Borges WC, et al. Elimination of Schistosoma mansoni adult Worms by rhesus macaques: basis for a therapeutic vaccine? PLoS Negl Trop Dis. 2008;2(9):e290

References

Take Home Messages

• Schistosomiasis is an extremely debilitating disease that stunts growth, causes abdominal pain and impairs cognitive capability.
• If left untreated, the disease can cause liver damage, kidney failure, reproductive damage and bladder cancer.
• Access to Praziquantel will dramatically increase Schistosomiasis control efforts.
• Make tremendous efforts to cease any submerging, bathing or contact with surface water in a Schistosomiasis-endemic region.

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