[e-drug] This week's NEJM on schistosomiasis

E-DRUG: This week's NEJM on schistosomiasis
-------------------------------------------

Dear colleagues,

Here are the links to 2 papers in this weeks NEJM.
I've copied the editorial and the abstract of the original paper
below.

Valeria

http://content.nejm.org/cgi/content/full/360/2/106?query=TOC

http://content.nejm.org/cgi/content/full/360/2/121?query=TOC

[Copied as fair use]

Volume 360:106-109 January 8, 2009 Number 2
Toward the Elimination of Schistosomiasis

Charles H. King, M.D.

Related Article by Wang, L.-D.
Schistosomiasis remains one of the world's most prevalent diseases.
Despite more than a century of control efforts and the introduction of
highly effective antischistosomal drug therapy in the 1980s, the disease
just will not go away. More than 207 million of the world's poorest
people are currently infected with schistosomiasis, which is often a
decades-long, chronic inflammatory disorder that is associated with
disabling anemia and undernutrition as well as poor performance in
school and at work.1

Schistosomiasis, also known as bilharziasis, results from long-lived
infection by multicellular intravascular parasites of one of five
trematode species Schistosoma japonicum, S. mansoni, S. haematobium,
S. intercalatum, or S. mekongi. Parasite transmission and the consequent
risk of human infection are strongly linked to specific geographic
locations, because the parasite goes through several developmental
stages that must occur in fresh water, including a period of growth
within particular species of intermediate host snails (diagram and
interactive graphic in article).

Life Cycle of the Schistosome.
Infection of humans with schistosoma species causes chronic hepatic and
intestinal fibrosis or fibrosis, stricturing, and calcification of the
urinary tract. Infection follows contact with fresh water harboring
larval parasites called cercariae, which penetrate humans' skin, become
schistosomula, and enter capillaries and lymphatic vessels. The worms
migrate to the portal venous system, where they mature and unite, and
then to the superior mesenteric veins, the inferior mesenteric and
superior hemorrhoidal veins, or the vesical plexus and veins draining
the ureters. Eggs are produced and pass into adjacent tissues; many are
shed in feces or urine. The eggs hatch, releasing miracidia that infect
freshwater snails, which ultimately release cercariae.

Even after infection ends, disease persists. In some patients,
especially those with intestinal schistosomiasis (see photo), the late
fibrotic complications of schistosomiasis-associated inflammation lead
to portal hypertension, which conveys a substantial risk of death due to
variceal gastrointestinal bleeding. In patients with urinary
schistosomiasis, late complications include irreversible urinary tract
obstruction with an associated risk of renal failure and
inflammation-induced bladder cancer. Arguably, the Asian form of
intestinal schistosomiasis caused by the species S. japonicum, reported
on by Wang et al. in this issue of the Journal (pages 121-128),
carries the highest risks of infection-related inflammation and other
complications.

From Dr. Xiao-Nong Zhou.

In the 1980s, after the introduction of the highly effective
antischistosomal drug praziquantel, it was believed that large-scale
drug delivery through school-based or community-based programs could
solve the problem of schistosomiasis transmission and, in so doing,
eliminate the risk of parasite-associated disease. Although such
mass-treatment campaigns substantially reduced the infectious burden and
the parasite-associated morbidity, they often failed to curb parasite
transmission in high-risk communities. Since these efforts failed to
prevent immediate reinfection itself, they also did not do a very good
job of reducing the substantial rates of illness associated with
reinfection.

Why didn't mass treatment stop transmission? As it turns out, the very
complexity of the parasite's life cycle helps to ensure that its
transmission continues within local ecosystems. Whereas public health
planners had assumed that a treatment-related reduction in the excretion
of parasite eggs by humans would stem the transmission of the parasite,
the process of infection is, in fact, more complicated, being abetted by
"superspreaders" (especially untreated children who do not attend
school) and by social and hydrologic linkages among focal "hot spots" of
transmission where the requisite human–snail interactions are most
likely to occur. The problem of persistent transmission is compounded in
the case of S. japonicum, because domesticated and wild animals can also
be infected by this species, providing a persistent zoonotic reservoir
that perpetuates local parasite transmission.

How, then, can we break the cycle of transmission? Clearly, in
implementing any new schistosomiasis-control campaign, the first
priority will always be to reduce the burden of illness and prevent
deaths, and these objectives are usually achieved through the currently
accepted mass-treatment strategies.2 However, the next, more
comprehensive and effective phase of disease control 'the elimination
of reinfection' will require efforts that are substantially more
intensive and expensive. Yet the incremental expense of these additional
control efforts would ultimately be offset by the greater health
benefits achieved with complete elimination of parasite transmission. As
Wang et al. show, in high-risk ecologic settings, drug treatment alone
may suppress transmission only partially. In such environments, any
program based solely on drug delivery will need to be continued for
decades (or perhaps indefinitely) to prevent a reemergence of infection
and disease. It is only through the incorporation of additional
strategies for interruption of parasite transmission that all forms of
schistosomiasis-associated disease can be prevented.

Because much schistosomiasis-associated illness remains subclinical in
resource-poor settings, it has effectively gone unmeasured and has often
been overlooked in assessments of global burdens of disease.1 The burden
of illness due to schistosomiasis is, in fact, quite substantial,
whether measured in terms of quality-adjusted life-years3 or
recalibrated disability-adjusted life-years4 or simply assessed through
careful consideration of the process of schistosome infection and its
known complications.1

Schistosomiasis is a disease of chronic inflammation that substantially
affects the daily performance of the millions of people who are or have
been infected. In particular, S. japonicum has important effects on
nutritional status, anemia, growth and development, and pregnancy
outcomes.1 The problem is due not only to fibrotic damage to specific
organs but also to the constant process of granulomatous inflammation
caused by the deposition of parasite eggs in host tissues. Chronically
elevated levels of interleukin-6 and tumor-necrosis factor cytokines
lead to the chronic elevation of acute-phase reactants, such as
hepcidin, that impair iron uptake and mobilization, resulting in anemia
of chronic inflammation. Even with low-intensity infection or
reinfection, the process of new inflammation (manifesting as
hepatosplenomegaly and anemia) in response to schistosomiasis can be
substantial. Lapses in parasite-control efforts can result in a
worsening of immunopathologic features when reinfection occurs.

It is becoming clear that the interruption of schistosome transmission
in high-risk areas will require more complicated, integrated control
strategies — that is, a combination of drug treatment, water
management, snail control (through habitat modification, irrigation
changes, and the use of molluscicidal sprays), and the control or
treatment of sewage. In the case of S. japonicum, it will also require a
reduction in the size of a nimal reservoirs. The community-based trial by
Wang et al. suggests that such a combination strategy can work to
significantly reduce or eliminate schistosome transmission in rural
China. Moreover, their strategy has external environmental benefits 'biofuel generation and improved water sanitation' that are likely to yield additional gains for the targeted community.

A good analogy for such integrated vector-control approaches to disease
elimination can be found in the malaria-eradication efforts of the early
20th century in the United States and Europe,5 during which public
health authorities came to realize that quinine would not eradicate
malaria, since human treatment alone cannot prevent the environmental
transmission of a parasitic disease. Nonetheless, long before the advent
of synthetic insecticides and modern antimalarial-drug prophylaxis,
malaria was effectively eradicated in many locales through combination
interventions that interrupted vectorborne transmission. In the southern
United States, these involved a combination of water management,
reduction of habitats favorable to mosquitoes, introduction of
mosquito-proof housing, and barrier screening.

Similarly, until now, preventive chemotherapy has been seen as the most
appropriate means of controlling schistosome-related disease in
resource-poor areas.2 Now we are coming to realize that drug delivery
may be only a stopgap measure. If the process of schistosoma infection
continues unchecked, its disabling effects in the context of rural
poverty will always limit the potential benefits of drug-treatment
programs while also necessitating that treatment continue indefinitely.
Obviously, the elimination of schistosomiasis will be a long-term
process requiring a long-term investment, but we must shoulder the
necessary extra effort, including long-term planning, intersectoral
government coordination, and decades-long commitment. Informed and
locally adaptive prevention strategies for long-term control will be
necessary. The integrated schistosomiasis-control strategies described
by Wang et al. are clearly an important step in this direction.

No potential conflict of interest relevant to this article was
reported.

Source Information

Dr. King is a professor of international health at the Center for
Global Health and Diseases, Case Western Reserve University, Cleveland.

References
King CH, Dangerfield-Cha M. The unacknowledged impact of chronic
schistosomiasis. Chronic Illn 2008;4:65-79. [Free Full Text]
Preventive chemotherapy in human helminthiasis: coordinated use of
anthelminthic drugs in control interventions: a manual for health
professionals and programme managers. Geneva: World Health Organization,
2006.
Jia T-W, Zhou X-N, Wang X-H, Utzinger J, Steinmann P, Wu X-H.
Assessment of the age-specific disability weight of chronic
schistosomiasis japonica. Bull World Health Organ 2007;85:458-465.
Finkelstein JL, Schleinitz MD, Carabin H, McGarvey ST. Decision-model
estimation of the age-specific disability weight for schistosomiasis
japonica: a systematic review of the literature. PLoS Negl Trop Dis
2008;2:e158-e158. [Free Full Text]
Humphreys M. Malaria: poverty, race, and public health in the United
States. Baltimore: Johns Hopkins University Press, 2001.

----------------------------------------------
Volume 360:121-128 January 8, 2009 Number 2
A Strategy to Control Transmission of Schistosoma japonicum in China

Long-De Wang, M.D., Hong-Gen Chen, Ph.D., Jia-Gang Guo, Ph.D., Xiao-Jun
Zeng, M.D., Xian-Lin Hong, Ji-Jie Xiong, Xiao-Hua Wu, M.Sc., Xian-Hong
Wang, Ph.D., Li-Ying Wang, Gang Xia, M.Sc., Yang Hao, M.Sc., Daniel P.
Chin, M.D., and Xiao-Nong Zhou, Ph.D.

ABSTRACT

Background. Schistosoma japonicum causes an infection involving humans,
livestock, and snails and is a significant cause of morbidity in China.

Methods. We evaluated a comprehensive control strategy in two
intervention villages and two control villages along Poyang Lake in the
southeastern province of Jiangxi, where annual synchronous chemotherapy
is routinely used. New interventions, implemented from 2005 through
2007, included removing cattle from snail-infested grasslands, providing
farmers with mechanized farm equipment, improving sanitation by
supplying tap water and building lavatories and latrines, providing
boats with fecal-matter containers, and implementing an intensive
health-education program. During the intervention period, we observed
changes in S. japonicum infection in humans, measured the rate of
infection in snails, and tested the infectivity of lake water in mice.

Results. After three transmission seasons, the rate of infection in
humans decreased to less than 1.0% in the intervention villages, from
11.3% to 0.7% in one village and from 4.0% to 0.9% in the other (P<0.001
for both comparisons). The rate of infection in humans in control
villages fluctuated but remained at baseline levels. In intervention
villages, the percentage of sampling sites with infected snails
decreased from 2.2% to 0.1% in one grassland area and from 0.3% to no
infection in the other (P<0.001 for both comparisons). The rate of
infection in mice after exposure to lake water decreased from 79% to no
infection (P<0.001).

Conclusions. A comprehensive control strategy based on interventions to
reduce the rate of transmission of S. japonicum infection from cattle
and humans to snails was highly effective. These interventions have been
adopted as the national strategy to control schistosomiasis in China.

------------------------------------------
Dr Valeria Frighi
University Dept. of Psychiatry
Neurosciences Building
Warneford Hospital
Oxford
OX3 7JX
UK
Tel. -44 -1865 -223779
Fax -44 -1865 251076
Mobile phone 07974920013
Valeria.Frighi@psych.ox.ac.uk