[Emerging Infectious Diseases * Volume 3 * Number 3 * July - September 1997]

Perspectives

Emerging and Reemerging Helminthiases and the Public Health of China

Peter J. Hotez,* Feng Zheng, Xu Long-qi, Chen Ming-gang, Xiao Shu-hua,
Liu Shu-xian, David Blair, Donald P. McManus, and George M. Davis
*Yale University School of Medicine, New Haven, Connecticut, USA; Chinese
Academy of Preventive Medicine, Shanghai, PR China; James Cook University
of North Queensland, Townsville, Australia; Queensland Institute of
Medical Research, Brisbane, Australia; and The Academy of Natural
Sciences, Philadelphia, Pennsylvania, USA
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      Despite great strides in their control throughout the People's
      Republic of China, helminth infections remain an important
      public health problem. The Institute of Parasitic Diseases of
      the Chinese Academy of Preventive Medicine, under the guidance
      of the Chinese Ministry of Health, completed a nationwide
      survey of more than 1 million people that showed the high
      prevalence and intensity of intestinal nematode infections;
      prevalence can sometimes exceed 50% in the Yangtze River valley
      provinces. Schistosoma japonicum is also a major cause of
      illness in this region. Attempts to control Chinese helminthic
      diseases with conventional anthelminthic drugs have been
      partially thwarted by high posttreatment rates of reinfection.
      Recently, several new human trematode pathogens have been
      identified. Novel approaches to chemoprophylaxis and
      vaccination may alleviate the public health problem caused by
      Chinese helminths. However, recombinant helminth vaccine
      development will depend on first cataloguing the extensive
      genetic diversity of Chinese helminths and candidate vaccine
      antigens. Evidence from biogeography, genetics, and systematics
      suggests that the genetic diversification of Chinese helminths
      and their vectors is an ongoing evolutionary process that began
      12 million years ago near the convergence of major Asian river
      systems. Construction of the Three Gorges Super Dam on the
      Yangtze River may promote the emergence and reemergence of new
      helminths and their snail vectors.

Since the early 1900s, hundreds of millions of Chinese living near the
Yangtze River have been at high risk for infection with helminths (1,2).
Aggressive campaigns to control schistosomiasis among the peasants in Hunan
Province and elsewhere in South China were a cornerstone of Chairman Mao's
"patriotic health campaigns" (3). During the 1950s and 1960s, entire
populations in schistosomiasis-endemic areas were mobilized against
Oncomelania snails and recruited to drain rivers and ditches; millions of
people were treated with anthelminthics (3). As a result, the number of
schistosome-infected persons was reduced from 10 million in 1955 to 1.52
million in 1989 (4); today fewer than 1 million people harbor schistosomes
of the Schistosoma japonicum complex. Similarly, lymphatic filariasis
caused by Wuchereria bancrofti and Brugia malayi has been reduced by
selective or reduced mass chemotherapy control programs, which have
included the use of salt medicated with diethylcarbamazine (4). By the year
1994, all 864 filariasis-endemic counties and cities in the country had
reached the criterion for effective control of filariasis (less than 1%
microfilaria rate in every village) through checkup. Although great strides
have been made over the last 40 years in controlling helminths in China,
many helminthiases remain public health problems, particularly in the
Yangtze River valley provinces (Anhui, Hubei, Hunan, Jiangxi, Jiangsu,
Sichuan, Yunnan). The application of modern biotechnology to their study
suggests that Chinese helminths are reemerging.

Intestinal Nematode Infections in the Yangtze River Basin

In a nationwide effort to assess the prevalence of parasitic diseases, the
Chinese Academy of Preventive Medicine and the Ministry of Health initiated
the largest human parasite survey ever undertaken. From 1988 to 1992,
1,477,742 persons were examined in 2,848 study sites in 726 sampled
counties (5-8). China's 30 provinces were divided into sectors; the
counties and townships in each sector were then grouped into high,
intermediate, and low on the basis of socioeconomic parameters (including
levels of sanitation, income, and literacy) (8). All long-term residents in
each randomly selected site (5,8,9) were asked to submit a fecal specimen
for examination (8); compliance was at least 90%. Fecal specimens were
collected at village offices or township health centers and examined by
personnel trained specifically to participate in the nationwide survey.

The identification and quantitation of helminth eggs was determined by the
Kato-Katz thick-smear technique on all slides positive for hookworm and
Trichuris, but in only one slide of every 10 Ascaris-positive slides (8).
To examine eggs of Enterobius vermicularis, adhesive transparent tape was
applied to the perianal area on children under 12 years of age (5,8). To
ensure quality control for fecal examinations, random checks of selected
slides were made throughout the study. Specimens of previously unidentified
or questionable samples were referred to either a provincial institute of
parasitic diseases or to the Institute of Parasitic Diseases in Shanghai.
Data from the study were ultimately transferred to a VAX computer for
processing and analysis (8).

Survey results are summarized in Tables 1-3. An estimated 707 million
Chinese (62.6%) were found to harbor one or more parasites (5-8). The
overall infection rate for most parasites was higher in females than in
males (7). A high number of Chinese were infected with the "unholy trinity"
of intestinal nematodes, Ascaris lumbricoides, Trichuris trichiura, and
hookworms Ancylostoma duodenale and Necator americanus -- an estimated 531
million, 212 million, and 194 million cases, respectively (8; Table 1). Of
the 374,753 children under 12 years of age tested for E. vermicularis,
26.4% were infected (8). Intestinal nematode infections were particularly
abundant in the agriculturally intensive Yangtze River provinces (Table 2,
Figure 1). In addition, more than 60% of the South China Sea island
population of Hainan Province were infected with one or more intestinal
nematodes (10-12). A significant percentage of infected persons had
moderate and heavy intestinal nematode infections, although most had light
infections (Table 3). This pattern of aggregated distribution has been
encountered in other disease-endemic areas (8). High hookworm prevalence
with clinical disease was found throughout Hainan and the rural areas of
the Yangtze River provinces, where adequate moisture and warm temperatures
ensure survival of hookworm larvae in the soil. By comparison, Ascaris and
Trichuris eggs withstand greater extremes of moisture and temperature,
which may explain why ascariasis and trichuriasis are also endemic in urban
settings and other harsh environments usually unfavorable for hookworm
transmission (13,14).

The survey linked all three intestinal nematodes to foodborne infections,
which in China are caused by the common agricultural practice of using
uncomposted human manure for fertilizing crops such as corn, sweet
potatoes, mulberry trees, and bananas (15-18); foodborne nematode
infections are commonly transmitted by the ingestion of Ascaris eggs on
sugar cane or A. duodenale hookworm infective larvae on raw vegetables
(19). Vegetable garden farmers have the highest prevalence of hookworm
infection (31.0%) (5,8). Vegetable growers also have high rates of Ascaris
(36.7%) and Trichuris (47.9%) infections (8).
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Table 1. Prevalence of major intestinal helminths in China*
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 Helminth                               Number of Cases
                                            (millions)
 Ascaris lumbricoides             531 plus or minus 8
 Trichuris trichiura                  212 plus or minus10
 Hookworm                            194 plus or minus 7
 Clonorchis sinensis               4.1 plus or minus 0.4
 Fasciolopsis buski                1.9 plus or minus 0.3
 Taenia spp.                          1.3 plus or minus 0.2
 Hymenolepis spp.                  0.7 plus or minus 0.1
 Heterophyidae                       0.2 plus or minus 0.1

*Based on analysis of 1,477,742 fecal examinations and a Chinese population
of 1.13 billion people.

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Table 2. Prevalence of soil-transmitted intestinal nematode infections in
the Yangtze River provinces*
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          No.
          Fecal                                                % Infection
Province  Exams           Ascaris                      Trichuris                         hookworm

Anhui     54,392    46.4 plus or minus 1.9  17.4 plus or minus 1.7   33.4 plus or minus 1.9
                           plus or minus 1.9

Hubei     53,382   39.5 plus or minus 2.2    18.3 plus or minus 1.4   8.8 plus or minus 1.1
                   
Hunan     63,794   67.7 plus or minus 1.3    20.2 plus or minus 1.3  22.9 plus or minus 1.4
                  
Jiangsu   63,699   39.5 plus or minus 1.7    27.3 plus or minus 1.8  21.8 plus or minus 1.5

Jianxi     52,079    71.1 plus or minus  1.4    17.1 plus or minus 1.7 17.6 plus or minus 1.3

Sichuan  97,222   68.4 plus or minus 1.2      30.4 plus or minus 1.3  40.9 plus or minus 1.9
                   
Yunnan    53,061   59.6 plus or minus 1.7     27.3 plus or minus 2.2  19.3 plus or minus 2.2
 
Zhejiang  55,284   60.0 plus or minus 1.7      40.3 plus or minus 2.3  28.2 plus or minus 1.8

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*Modified from a table in reference 8.

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Table 3. Intensities of soil-transmitted intestinal nematode infections
(based on eggs per gram [epg])(superscript a)
---------------------------------------------------------
                                                      Infection Level (%)

Helminth          No. Fecal         Light          Moderate       Heavy
                      Exams
Ascaris
lumbricoides     170,252            77.0            21.1             1.8
(superscript c) 

Trichuris
trichiura            247,020            94.6             5.2               0.2
(superscript c) 

Hookworm                                 75.4            21.9              2.7
(superscript d)
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(superscript a)Based on data provided in reference 8.
(superscript b)Light = <5,000 epg; Moderate = 5,000 to < 50,000 epg; 
Heavy = > 50,000 epg
(superscript c)Light = <1,000 epg; Moderate = 1,000 to < 10,000 epg; 
Heavy = > 10,000 epg
(superscript d)Light = <400 epg; Moderate = 400 to < 3,000 epg;
 Heavy = > 3,000 epg
---------------------------------------------------------

Intestinal nematodes affect maternal-child health. Schoolchildren have the
highest prevalence and intensity of ascariasis (48.5%) (5,8), and all three
major intestinal nematodes retard the intellectual and physical growth of
children. Approximately 66 million women 15 to 49 years of age, many with
underlying dietary iron-deficiency anemia, harbor hookworms (8). Cases of
infantile hookworm caused by A. duodenale were frequent; children with
infantile hookworm failed to thrive and had diarrhea, melena, and extreme
pallor resulting from hemoglobin concentrations below 6 g/dl (20,21).
Illness caused by heavy hookworm infection in infants was high (20,21).
Among the hypothetical sources of infantile hookworm infection is the use
of contaminated soil-filled diapers or the ingestion of contaminated breast
milk (21). 


Figures Not Available in Ascii
Figure 1. Distribution and prevalence of human hookworm infection in China.

Current efforts to control intestinal nematode infections with conventional
anthelminthic chemotherapeutic agents (e.g., albendazole) or combination
therapy with either pyrantel pamoate and oxantel or mebendazole and
levamisole have been only moderately successful. All regimens reduce the
number of worms (22,23). However, without altering ancient agricultural
practices and improving sanitation, reinfection to pretreatment levels may
occur within 6 months (24). Moreover, the benzimidazole anthelminthics have
shown low efficacy against N. americanus infections in China and have
stimulated the migration of adult Ascaris worms. The Institute of Parasitic
Diseases and Yale University have embarked on a basic research program to
evaluate genetically engineered polypeptides from hookworms as recombinant
subunit vaccines as an alternative control approach (25). The goal is to
develop a recombinant vaccine that reduces worm levels below the
disease-causing threshold. One recombinant molecule from the hookworm
Ancylostoma caninum has shown promise at reducing worm levels during
preclinical testing in mice (25,26).

Emerging Foodborne Helminthic Zoonoses

Some foodborne helminthic zoonoses are on the rise in China (17). Outbreaks
of trichinellosis have increased in Yunnan Province over the last 10 years,
in part because of the consumption of raw pork (called "oru" or "shengpi")
by some residents (27). The seroprevalence of antibodies to Trichinella
spiralis in this region averages 13.5%, and there is evidence that
trichinellosis has spread from the southwestern province of Yunnan to other
parts of China (5).

Among the foodborne trematode zoonoses, several previously undescribed
human infections have been reported, including those caused by Echinostoma
angustitestis, Centrocestus formosanus, Echinochasmus fujianensis, and
Echinochasmus liliputanus (5,28,29). Clonorchiasis and paragonimiasis
remain highly endemic in China. Many of the Clonorchis sinensis infections
are in southern China, where nearly 3 million Cantonese (Guangdong
Province) are infected because of their raw fish consumption (30). High
prevalence rates are also found among Korean minority populations in the
northeastern provinces of Heilongjiang, Jilin, and Liaoning (30). Among the
reservoir hosts are mammals such as dogs, cats, pigs, and rats. Chronic C.
sinensis infection in childhood has been recently linked to delayed
physical growth and development, while chronic infection in adulthood is
associated with cholangiocarcinoma (30). Paragonimiasis is estimated to
occur in 1 million Chinese, and approximately 100 million Chinese are at
risk for infection. The study of Chinese Paragonimus infections is in its
infancy, having been eclipsed by a comparatively larger amount of
investigative work in schistosomiasis. However, preliminary studies suggest
that the taxonomy of these human parasites will be extensively revised.

The number and identity of species infecting humans in China is being
investigated through molecular phylogenetic studies at the Institute of
Parasitic Diseases, in collaboration with the Academy of Natural Sciences
and James Cook University. Approximately 25 species, of which some are
likely synonyms, have been recorded in China. Paragonimus westermani and
Paragonimus skrjabini are most commonly associated with human infection.
The former species produces the classical lung-fluke infection, while
juveniles of the latter rarely mature in humans but instead undergo
extrapulmonary migrations. Some Chinese investigators ascribe P. skrjabini
to a distinct genus Pagumogonimus. To complicate matters, both P.
westermani and P. skrjabini probably represent complexes of species that
differ in clinical importance and biologic properties. Several subspecies
of diploid sexually reproducing P. westermani have been proposed on the
basis of their clinical picture (31). In addition, a triploid
parthenogenetic variety is comm
on in northeastern China, where it is a
serious pathogen. Almost nothing is known about strains and species within
the P. skrjabini complex. However, novel findings may soon be made. For
instance, cercariae of P. skrjabini have been reported from no fewer than
23 snail families distributed among three tribes and two subfamilies of the
Pomatiopsidae throughout southern China (32). Barring misidentifications,
these records suggest that P. skrjabini must be unique among digeneans in
its lack of host specificity. A more likely explanation is that a complex
of different, as yet unrecognized, Paragonimus species occurs in these
regions (32,33). Also, studies of snail hosts of these parasites are being
initiated; most species transmitting P. skrjabini have not been described,
and many others are known only from shells and radulae. Snail hosts of P.
westermani in China have never been studied in terms of modern systematics.

Schistosomiasis: Novel Control Strategies

Asian schistosomiasis is caused by blood flukes of the S. japonicum complex
(S. japonicum, S. mekongi, and S. malayensis). Only S. japonicum has been
described in China, although identification of unique Chinese strains based
on molecular genetic data suggests emergence of new members of this complex
(34). Also found in China, S. sinensium, which may occupy its own taxonomic
complex, may ultimately be shown to infect humans. Although the national
control program through aggressive efforts over the last 30 years has
reduced the number of infected persons and cattle, schistosomiasis japonica
remains a major public health threat in China (35). The number of infected
persons and cattle is estimated at just under 1 million and 70,000,
respectively (35). The major endemic foci are in the marsh and lake regions
of southern China and the Yangtze River Basin (Hubei, Hunan, Jianxi, and
Anhui Provinces), which account for 86% of the cases. Sixty to 100 million
persons are at risk in these schistosomiasis-endemic areas. The Oncomelania
snail (the intermediate host)-infested areas have been reduced to 3.64
billion m2 in the lakes region and mountainous territories in Yunnan and
Sichuan Provinces. Aside from intestinal, liver, and central nervous system
damage from heavy infections with S. japonicum, ample evidence has also
documented the negative impact of moderate infections on childhood growth
and development.

The present policy to control Chinese schistosomiasis relies primarily on
two approaches: large-scale chemotherapy with praziquantel (produced in
China since 1978) and snail control with molluscicides and environmental
modification. Although praziquantel can reduce the incidence of severe
forms of the disease, it does not prevent reinfection and may not reverse
many of the hepatosplenic complications of heavy S. japonicum infections.
Three novel schistosomiasis control programs (using qinghaosu,
bromoacetamide, and vaccine) are under investigation at the Institute of
Parasitic Diseases.

On the basis of studies suggesting that derivatives of the antimalarial
drug qinghaosu (artemisinin) are also effective in animal schistosome
infections (36), human clinical investigations have been initiated with
oral artemether (37). In field studies conducted in a disease-endemic area
in the southern Dongting Lake region of Hunan Province, residents who
frequently contacted infested water were pretreated with praziquantel and
then, in a randomized pattern, received either artemether or a placebo
control (37). Approximately 1 month after the final dose, patients who
received artemether had significantly reduced rates of newly acquired
schistosomiasis. Further studies are under way to evaluate artemether for
schistosomiasis chemoprophylaxis.

Bromoacetamide, a new type of molluscicide, was synthesized and developed
in China during the early 1980s and is now being produced (35). The lethal
dose of bromoacetamide is 1 ppm for Oncomelania snails -- approximately one
tenth that required when pentachlorophenate, a traditional molluscicide, is
used (35). At 1 ppm, bromoacetamide has been shown to be nontoxic to fish.

A third control strategy -- schistosome vaccination -- is also being
developed at the Institute of Parasitic Diseases, in collaboration with the
Queensland Institute of Medical Research. Injection of mice and pigs with a
recombinant S. japonicum 26 kDa glutathione-S-transferase (Sjc26GST)
vaccine induced a pronounced antifecundity effect after experimental
infection with a Chinese strain of S. japonicum (38,39). This finding is
important because the eggs released from female schistosomes cause both the
pathogenic sequence leading to clinical schistosomiasis and transmission of
the infection. Encouraged by these results, the Institute of Parasitic
Diseases and the Queensland Institute of Medical Research vaccinated water
buffaloes, a principal animal reservoir host for S. japonicum in southern
China. Results suggest that immunization of animal reservoir hosts might
reduce schistosomiasis transmission to humans. Field studies to test this
hypothesis are in progress.

One concern about the development of recombinant antigen-based vaccines is
the marked antigenic diversity of different geographic isolates of Chinese
schistosomes (40). The genetic diversity of Chinese schistosomes probably
parallels an often underappreciated diversity of Oncomelania snail vectors.
By both classical and molecular phylogenetic techniques, the Academy of
Natural Sciences has provided evidence for the coevolution of S. japonicum
with their snail vectors (41). The coevolution of Schistosoma and snail
hosts involves reciprocal selective pressures affecting the genetic
diversification of both parasites and snails (41). These data may explain
the high degree of snail host specificity compared with very loose
mammalian host specificity for S. japonicum. Thus, through the careful
genetic analysis of host snails, the emergence of S. mekongi within the S.
japonicum complex was predicted years before it could be confirmed by using
parasites from clinical specimens (42). A similar analysis led to the
discovery in China of a separate triculine snail-transmitted S. sinensium
complex (43), which may yet reveal new species of human schistosomes. The
discovery of a new triculine-transmitted schistosome species may be easily
overlooked since Oncomelania (transmitting S. japonicum) is frequently
sympatric with triculine snails and a schistosome infection could
erroneously be identified as schistosomiasis japonica. Indeed, members of
the S. japonicum species complex have worm and egg morphologic
characteristics that are virtually identical qualitatively. If snail
evolution is a predominant driving force behind the evolution of the
trematode parasite, then the marked genetic variation observed among
populations of the genus Oncomelania, as it evolved down emerging river
systems from Xizang (Tibet) and Yunnan Provinces, China, will drive the
evolution of new and emerging schistosomes.

Impact of the Three Gorges Super Dam on Human Transmission

Superimposed on the preexisting coevolutionary forces driving schistosomes
and snails is a human-made intervention of enormous scale. Begun in 1994
and scheduled to be completed by the year 2009, the Three Gorges Super Dam,
which rises to a height of 180 m on the Yangtze, will affect Hubei and
Sichuan Provinces by creating a reservoir area of 50,700 km2 and submerging
more than 220 counties extending from Yichang County, Hubei Province, in
the east to Jiangjin and Hechuan Counties, Sichuan Province, in the west
(Figure 2). The reservoir will displace an estimated 1.4 million people.
Several of the environmental changes created by the dam and the resultant
reservoir will affect both Oncomelania populations and schistosomiasis
transmission. 1) After the dam is completed, the perennial high water level
in the reservoir region will elevate the groundwater level and contribute
to the breeding and propagation of Oncomelania spp. One site of special
concern is the Jianghan Plain, Hubei Province. 2) Alluvial land and beaches
will appear near many of the Yangtze River tributaries and provide beds
suitable for the development of snails; immigrants to the area exploiting
these new environments for aquaculture and agriculture will be exposed to
schistosomes. 3) The sand deposits and beach areas of Dongting and Boyang
lakes will be altered in a way that may either increase or decrease snail
breeding. 4) For the first time in history, lateral canals may permit easy
distribution of Oncomelania snails around the gorges from Sichuan to Hubei
and downstream. 


Figures Not Available in Ascii
Figure 2. Projected size and location of Three Gorges Reservoir in Sichuan
and Hubei Provinces resulting from the Three Gorges Super Dam construction.


Investigations by the Chinese Academy of Sciences and the Water Conservancy

Committee of the Yangtze River have resulted in programs to evaluate the
distribution of Oncomelania snails; the infection rates among children ages
7 to 14 years; changes in census and immigration; and alterations in soil
composition, vegetation, rainfall, and topographic features, to identify
high risk areas for schistosomiasis transmission. Observation sites will be
established in selected schistosomiasis-endemic administrative villages (of
approximately 10,000 residents) located midstream and downstream from the
Yangtze River - two village sites will be in Jiangsu Province and four in
Hunan, Hubei, Jiangxi, and Anhui Provinces. Data will be collected on
census, socioeconomic status, daily activities, duration and frequency of
water contact, and schistosomiasis infection rates among the residents and
domestic animals. In addition, two or three beaches will be selected at
each observation site to measure the change in monthly water level, the
duration of beach submersion, change in beach vegetation, soil type and
water content, snail density and range, and infected-snail density and
range.

Conclusions

Chinese helminthiases are intimately connected to the nation's social and
ecologic fabric. Traditional agricultural and foodhandling practices
account for the high prevalence of ascariasis, hookworm infection,
paragonimiasis, and schistosomiasis near the Yangtze River. Increasing
evidence also suggests that the major helminthiases are intricately woven
into the relationships between families and between mothers and their
children (44-47). China is undergoing major social changes due to economic
reforms which, in some rural areas, have not improved the access to
healthcare (48). Major ecologic changes are anticipated as a consequence of
the Three Gorges Super Dam project. The Institute of Parasitic Diseases of
the Chinese Academy of Preventive Medicine is now poised to examine the
impact of these huge changes on the genetic diversity of helminths and
their snail vectors. This information will be used to design novel helminth
control measures for specific geographic regions of China.

About the Author

Dr. Hotez is associate professor of epidemiology and public health and
pediatric infectious diseases, Yale University School of Medicine. He heads
a laboratory group that develops chemically defined vaccines for helminth
infections, including hookworm infection. Dr. Hotez is also assistant
program director for the Tropical Medicine Research Center on Emerging
Helminthiases in the People's Republic of China, sponsored by the National
Institutes of Health.

Address for correspondence: Feng Zheng, Institute of Parasitic Diseases,
Chinese Academy of Preventive Medicine, 207 Rui Jin Er Lu, Shanghai 200025,
P.R. China; fax: 86-21-6-4332670; e-mail: zfeng@fudan.ihep.ac.cn or
tmrc@fudan.ihep.ac.cn.

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Emerging Infectious Diseases
National Center for Infectious Diseases
Centers for Disease Control and Prevention
Atlanta, GA

URL: ftp://ftp.cdc.gov/pub/EID/vol3no3/ascii/hotez.txt