Widespread use of pesticides and other agrochemicals can speed the transmission of the debilitating disease schistosomiasis

Widespread use of pesticides and other agrochemicals can speed the transmission of the debilitating disease schistosomiasis, while also upsetting the ecological balances in aquatic environments that prevent infections, finds a new study led by researchers at the University of California, Berkeley.

Schistosomiasis, also known as snail fever, is caused by parasitic worms that develop and multiply inside freshwater snails and is transmitted through contact with contaminated water.

The infection, which can trigger lifelong liver and kidney damage, affects hundreds of millions of people every year and is second only to malaria among parasitic diseases, in terms of its global impact on human health.

The study, published in the journal Lancet Planetary Health, found that agrochemicals can increase the transmission of the schistosome worm in myriad ways: by directly affecting the survival of the waterborne parasite itself, by decimating aquatic predators that feed on the snails that carry the parasite and by altering the composition of algae in the water, which provides a major food source for snails.

“We know that dam construction and irrigation expansion increase schistosomiasis transmission in low-income settings by disrupting freshwater ecosystems,” said UC Berkeley’s Christopher Hoover, a doctoral student in environmental health sciences and lead author of the study.

“We were shocked by the strength of evidence we found also linking agrochemical pollution to the amplification of schistosomiasis transmission.”

The findings come as the connections between environment and infectious disease have been laid bare by the COVID-19 pandemic, which is caused by an emerging pathogen thought to be linked to wildlife.

“Environmental pollutants can increase our exposure and susceptibility to infectious diseases,” said Justin Remais, chair of the Division of Environmental Health Sciences at the UC Berkeley School of Public Health and senior author of the study.

“From dioxins decreasing resistance to influenza virus, to air pollutants increasing COVID-19 mortality, to arsenic impacting lower respiratory tract and enteric infections – research has shown that reducing pollution is an important way to protect populations from infectious diseases.”

After combing through nearly 1,000 studies gathered in a systematic literature review, the research team identified 144 experiments that provided data connecting agrochemical concentrations to components of the schistosome life cycle.

They then incorporated these data into a mathematical model that captures the transmission dynamics of the parasite. The model simulates concentrations of common agrochemicals following their application to agricultural fields and estimates the resulting impacts on infections in the nearby human population.

The researchers found that even low concentrations of common pesticides – including atrazine, glyphosate and chlorpyrifos – can increase rates of transmission and interfere with efforts to control schistosomiasis.

Agrochemical amplification of parasite transmission was not inconsequential. In the study communities in the Senegal River Basin in West Africa, the excess burden of disease attributable to agrochemical pollution was on par with disease caused by lead exposure, high sodium diets and low physical activity.

“We need to develop policies that protect public health by limiting the amplification of schistosomiasis transmission by agrochemical pollution,” Hoover said. “More than 90% of schistosomiasis cases occur in areas of sub-Saharan Africa, where agrochemical use is expanding.

If we can devise ways to maintain the agricultural benefits of these chemicals, while limiting their overuse in schistosomiasis-endemic areas, we could prevent additional harm to public health within communities that already experience a high and unacceptable burden of disease.”

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Epidemiology
Schistosomiasis is a global cause of morbidity and mortality. Tropical endemic areas are the sources, in rivers, lakes, reservoirs, and irrigation channels, perpetuating the opportunities for infection. In fifty-two countries, S. mansoni causes debility with intestinal Schistosomiasis.

They include the Caribbean, Eastern Mediterranean, South American, and most countries in Africa.7,8 It is estimated that more than 207 million people in at least seventy-four countries still have an active schistosomal infection.

Approximately 60% are clinically affected, predominantly suffering from chronic anemia and malnutrition. More than 20 million are severely ill.

Factors propagating the infection are poverty with poor sanitation, contaminated freshwater irrigation, and manifest schistosomal infestation by human, animal, and snail populations.

Addressing all these factors, particularly improving water quality, medical treatment in endemic areas including China, Brazil, Egypt, and some areas of sub-Saharan Africa, has been successful.

However, the level of infection, while reduced, is still significant. Improvement of health in rural Chinese villages demonstrated substantial improvements in the human, snail, and wild mouse schistosomiasis infection rates.9

An earlier review stated that Schistosomiasis in China, dating back for over two millennia, had caused social and economic hardship, which compounded rates of mortality.10 Controlling morbidity from the infection by using one drug improved outcomes with a prevalence reduction from 11.6 million in the mid-1950s to an estimated 694,788 infections by 2000.

The World Health Organization5 stated that the global distribution of Schistosomiasis decreased with its eradication from Japan and the Lesser Antilles Islands. Transmission ceased in Tunisia and remains low in Morocco, Saudi Arabia, Venezuela, and Puerto Rico.

Schistosomiasis is more common in males than females from occupational and leisure activities. Age affects the prevalence and severity of schistosomal infections. Children and adolescents are most often more heavily infected.

Tourists to endemic areas need to take precautions and remain aware of the risks of contracting the disease during boat trips, rafting, and swimming.11 Even if asymptomatic, follow up within three months of exposure is advisable on returning home to exclude latent Schistosomiasis. Acute symptoms commonly affect non-immune travelers more due to a severe immune response.

A World Health Organization report5 noted that almost ninety million people had treatment for Schistosomiasis in 2016. This figure included 70.9 million school-aged children and approximately 18.3 million adults, mostly in Africa, where nine out of ten infected people live. Where treatment was required, thirty out of forty-one countries reported to the WHO.

Almost 75% of treatment coverage was achieved by twelve of the reporting countries, still leaving a shortfall of 25%. Japan and Tunisia are two countries that have successfully eradicated the disease in their populations.

The Caribbean Islands and Morocco have made good progress, too, while Brazil, China, and Egypt continue to eliminate Schistosomiasis actively. Neglected tropical diseases in sub-Saharan Africa were deemed to exert “great health, social and financial burden on economies of households and governments.”12

Poverty attributed to Schistosomiasis disrupted child development, morbidly affected pregnancy and reduced workforce production. Factors responsible for continued infection included “global warming, proximity to water, irrigation and dam construction as well as socio-economic factors.”

Pre-existing poverty in sub-Saharan Africa is still evident.12 Anecrotic-exudative granuloma surrounds the isolated central egg. Figures 1 and ​and22 illustrate the parasite’s histological versatility to penetrate human tissue, leading to the formation of granulomas.

More recent concerns appeared with Schistosomal infections arising in Corsica, acquired by French tourists bathing in the Cavu River between 2011 and 2013, necessitating the instigation of a screening program.15 The outbreak was the first reported Schistosomal infection in Europe since a report in Portugal in 1965.

Schistosomiasis infections of any type are uncommon in the United States unless imported. Although an estimated 400,000+ infected persons have emigrated in recent years, neither susceptible snail species nor chronically infected human reservoirs pose risks to contaminate freshwater in North America.

Pathogenic schistosomes have survived and replicated in human hosts for years. Migrants may present to Emergency Departments (EDs) with active cases of acute or chronic Schistosomiasis, with associated end-organ complications.

Characteristics Of Clinical Schistosomiasis
The parasitic trematode flatworm Schistosoma causes Schistosomiasis.16 Freshwater snails are intermediate hosts, contaminating water by releasing larval forms of parasitic worms, which penetrate the skin. Mature infective larvae reproduce in the blood vessels, liver, kidneys, and intestines.

Released egg antigens, trapped within organ tissues, stimulate granulomatous reactions involving T cells, macrophages, and eosinophils resulting in clinical disease. Symptoms and signs depend upon the load and location of trapped eggs.

While initial inflammatory reactions are reversible, later stages of the disease are more debilitating. Pathological collagen deposition increases organ fibrosis that may not be fully reversible.

Ectopic eggs can settle in the skin, brain, muscle, adrenal glands, eyes, and genitourinary system, leading to new clinical syndromes. Granulomas may develop in the uterus, fallopian tube, and ovaries. The central nervous system (CNS) is prone to egg embolization from the portal-mesenteric system traveling to the brain and spinal cord tissue via the paravertebral venous plexus.17

S. haematobium egg retention and granuloma formation in the urinary tract can cause hematuria, dysuria, bladder polyps, ulcers, and obstructive uropathies. Central nervous system involvement rarely causes transverse myelitis.

Infectivity Risks
Poor hygiene, playing in riverbank mud and contaminated water, exposes children to a higher risk of infection. Some forty million women of childbearing age were affected in 2010.18 Almost ten million women in Africa sustained Schistosomiasis during pregnancy.19

The intensity and prevalence of infection rise with age and peaks between 15 to 20 years of age. In older adults, no significant change occurs in the incidence of disease, as the parasite burden, and intensity decrease.17

Women washing clothes in contaminated water, or living near open water, lakes or rivers, were also at higher risk of infection.20 Uganda has a unique feature with virtually no occurrence of infection at altitudes higher than 1400m or where land is drier and the annual rainfall is less than 900 mm.21

Most human Schistosomiasis commonly arises from three species, Schistosoma haematobium, Schistosoma japonicum, and Schistosoma mansoni. Less common species, such as Schistosoma mekongi and Schistosoma intercalatum, may also cause systemic human disease.22

Snail Hosts
Schistosomiasis is endemic in seventy-four developing countries, 80% of those infected living in sub-Saharan Africa with humans acting as the parasite’s reservoir. A seven-year study (2005–2012) in Nanchang City, China, indicated the use of health education for susceptible populations.23 Morbidity fell from 46% in 2005 to 0% by 2012.

The different species of Schistosoma infecting specific types of snails as intermediate hosts are listed in Table 1. Biomphalaria glabrata, an example of a snail host (Figure 3), is illustrated.24

Table 1

Snail Carriers And Their Respective Infective Schistosoma Species And Snail Carriers

Snails	Infective Species
Biomphalaria	Schistosoma mansoni
Oncomelania	Schistosoma japonicum
Tricula (Neotricula aperta)	Schistosoma mekongi
Bulinus	Schistosoma intercalatum

Acute And Chronic Schistosomiasis
Acute Schistosomiasis, (Katayama fever), is a “serum sickness-like illness that develops after several weeks elapse from infection by new schistosomal infections.”21 The first cycle of egg deposition promotes marked peripheral eosinophilia and circulating immune complexes. While symptoms usually resolve over several weeks, infections can overwhelm the immune response.

Paradoxically, early treatment with bactericidal drugs may exacerbate this syndrome. Steroid therapy usually settles the syndrome’s inflammatory reaction. Water contact, i.e., bathing and swimming, is the most common finding in a history of infection. Mild, maculopapular skin lesions can develop in an acute infection within hours after exposure to cercariae.

Tourists visiting endemic areas are at high risk of infection and may present diagnostic problems to home physicians unfamiliar with the schistosome lifecycle.

Chronic Schistosomiasis may occur when adult worms absorb host proteins and can live for years in the bloodstream coated with host antigens if unaffected by the immune system. Bowel granulomas with egg retention can cause bloody diarrhea, bowel cramps, and inflammation associated with colonic polyposis.

The bowel wall becomes less resistant to infections such as Salmonella, allowing a higher opportunity for bacteremia. Chronic Schistosomiasis can complicate acute appendicitis.25 Eggs penetrate the bowel adjacent to mesenteric vessels where adult worms reside. Unshed eggs lodged in the portal circulation, induce granulomatous reactions in the portal tracts.

Systems Most Severely Affected From Schistosoma Infection
Cardiopulmonary (associated with hepatic disease)

Gastrointestinal tract

Genitourinary tract

Central nervous system

Cardiopulmonary Arterial Hypertension Linked To Hepatic Disease
Hepatic disease is more prevalent with heavy infestations, promoting collateral veins, and enabling eggs to reach the pulmonary circulation. Subsequent pulmonary granulomatosis and fibrosis can lead to irreversible pulmonary hypertension and frank cor pulmonale with a high mortality rate.26

This critical complication develops in about 7.7% of patients with a hepatosplenic disease from S. mansoni, S. japonicum, and possibly S. mekongi infections. The prevalence of the disease’s pulmonary artery complication worldwide was estimated to exceed 270,000 individuals in 2009.26

Gastrointestinal
Gallbladder cancer has an association with schistosomal infections. S. haematobium infection can increase the rate of bladder cancer, usually squamous cell, rather than the transitional cell type.27 Local tissue invasion by eggs stimulates toxin and enzyme release, provoking a Th2–mediated immune response.28

When glomerulonephritis occurs, the renal changes are often irreversible, and pathological symptoms can persist for years. Periportal fibrosis, also termed Symmers pipestem fibrosis, is the most common complication of gastrointestinal Schistosomiasis (GS).

The fibrosis leads to portal hypertension and gastrointestinal bleeding. Liver failure is uncommon, except in the presence of chronic hepatitis B or cirrhosis.26 S. mansoni tends to be the species associated with the rapid progression of liver disease. GS patients with low worm loads are difficult to diagnose accurately and more challenging to control.29,30

Genitourinary Tract
Long after the initial infection, a parasitic infection may cause renal failure from obstructive uropathy, pyelonephritis, or bladder carcinoma. The five main schistosome parasitic species have a widespread distribution Table 2. illustrates. Schistosomiasis infections during pregnancy can cause debility with severe anemia. Low birth weights are common.5 Infant and maternal mortality increases. Placental infection, with an infant confirmed with the disease, establishes congenital infection.4

Vulval genital Schistosomiasis, spread by S. haematobium causes significant social and medical problems. It increases the risk factors of spreading certain sexually transmitted diseases, such as HIV and human papillomavirus (HPV) by up to 30%.31 S. haematobium increases male genital organ pathology in the epididymis, spermatic cord, testes, and prostate gland, which can lead to sterility.

Table 2

Parasitic Species And Geographical Distribution Of Schistosomiasis

Species	Geographical Distribution
Schistosoma mansoni	Africa, Middle East, Caribbean
Schistosoma hematobium	Africa, Middle East, India, Turkey
Schistosoma japonicum	Asia only: China, Indonesia, Philippines, Thailand
Schistosoma mekongi	Cambodia, Lao People’s Democratic Republic – 200km area of Mekong River basin, extending towards northern provinces
Schistosoma intercalatum	Central and West Africa

CNS Schistosomiasis
S. japonicum is mainly responsible for 60% of all Schistosoma brain infections because of its small egg size.32

CNS involvement occurs in 2 – 4% of all S. japonicum infections. S. mansoni has a larger egg size and can affect spinal tissue. S. haematobium can also affect the brain. S. mekongi, limited to the Mekong River basin in Laos and Cambodia, affects an estimated 140,000 people at high risk of being infected. Temporal brain masses, causing paresthesia of the arm and leg with dysphasia, are associated with this species. Neurologic symptoms such as cauda equina syndrome, anterior spinal artery syndrome, and quadriparesis can develop months after the initial infection.34

Lifecycle
Schistosomes in endemic areas infect specific freshwater snails, with intrinsic parasitic species. The infected snails release cercariae four to six weeks after infection. The fork-tailed cercariae are free-swimming larvae approximately 1mm in length, capable of freshwater survival for up to 72 hrs.

To live, they must attach to human skin or another suitable animal host. Once connected using oral and ventral suckers, the larvae progressively burrow through intact skin, entering dermal veins.

Following access, the larvae migrate to the pulmonary vasculature. During this phase, the cercariae metamorphose and develop an outer coating, which resists a sustained host immune attack. As schistosomulae worms, they reach pulmonary capillaries through the systemic circulation, maturing in the portal veins of the liver.

The highly antigenic eggs migrate through the bowel or bladder wall by fecal or urinary shedding. Over approximately ten days, the organisms begin to mature into miracidia. Unshed eggs may remain in the tissues or flow back to the portal circulation from the mesenteric vessels, or the pulmonary circulation from the vesicular vessels via the inferior vena cava.

The free-swimming miracidia shed into fresh water survive one to three weeks. They must complete their life cycle by infecting a snail. Two generations of sporocysts multiply, mature into free-swimming cercariae, and exit the snail to seek a human host and begin a new cycle. S. japonicum, most likely the species with the highest risk of complications, infect cattle and other domesticated animals.

Its life-cycle pattern provides a source of the disease that often thwarts control efforts based on treating human infection and reducing snail populations. Comparative Schistosoma species are illustrated for egg size in Figure 4 and the life cycle of the schistosoma parasite in Figure 5.

Prognosis
Early treatment of disease produces better outcomes, even those affected by a hepatic, urinary, or neuro-cerebral disease. Hepatosplenic Schistosomiasis has a relatively good prognosis with preserved hepatic function until the end of the disease, in the absence of variceal bleeding. Late-stage treatment provides less benefit with multiple system involvement, especially with a past heavy worm load in tissues.

Morbidity And Mortality
Acute Schistosomiasis, or Katayama fever,36 can increase the mortality rate by up to 25%. Even with asymptomatic disease, morbidity affects health. Hepatic, cardiac, pulmonary, renal, neurological diseases, along with malignancy, are the main problems. In women, genital infections can complicate pregnancy. Repeated courses of therapy are often required as reinfection is a constant risk in endemic areas. Schistosomiasis often develops over a while, leading to the delay of diagnosis (Table 3 & 4).

Table 3

Schistosomiasis Signs and Symptoms (WHO, 2016)

System	Signs And Symptoms
Gastrointestinal	Fatigue, abdominal pain, diarrhea, dysentery
Cardiopulmonary	Pneumonitis, cough, wheezing, palpitations, dyspnea on exertion, hemoptysis
Urinary	Frequency, terminal hematuria, dysuria
Central Nervous System	Seizures – focal and generalized, headache, lower limb and back pain, cona medullaris, cauda equina
Female genital	Post coital bleeding, genital ulceration, nodular lesions on cervix, vulva, or vagina, disrupted menstruation, pelvic pain
Male genital	Pain and inflammation of genitals – epididymis, spermatic cord, testes, and prostate gland

Note: Data from WHO.⁵

Table 4

System Complications

System	Complications
Cardiac	Cor pulmonale, pulmonary hypertension
Circulatory	Severe anemia, portal hypertension
Female genital	Vulvar granulomas, ulcerated lesions on cervix, vulva, or vagina; cervicitis, vesicovaginal fistulas, menstrual disorders, infertility
Male genital	Infertility
Gastrointestinal	Hematemesis, malabsorption leading to malnutrition, diarrhea (± hematochezia), hepatosplenomegaly, bowel obstruction, colonic polyposis
Neoplasms	Bladder cancer (squamous cell), hepatic, gallbladder
Neurological	Transverse myelitis (with flaccid paraplegia), cerebral microinfarcts, cerebral granulomatosis
Obstetrical	Low birth weight, pregnancy issues
Renal	Pyelonephritis, nephropathy, hematuria, obstructive uropathy, glomerulonephritis, renal failure
Skin	Vulvar granulomas
Systemic	Increased risk of sepsis, low grade fever, opportunistic infections, e.g. salmonella, end-organ disease, eosinophilia, anemia
General	Varies with the state of illness, worm load, location, and organ involved

Some signs and symptoms are common to a large number of disorders.

The result can lead to serious systemic complications and multidimensional organ involvement (Table 4).

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More information: Christopher M Hoover et al, Effects of agrochemical pollution on schistosomiasis transmission: a systematic review and modelling analysis, The Lancet Planetary Health (2020). DOI: 10.1016/S2542-5196(20)30105-4