FAKTOR RISIKO, GEJALA, PENYEBAB, DAN CARA PENCEGAHAN

TERHADAP PENYAKIT DIARE, KOLERA, KECACINGAN,

HEPATITIS A/E, DAN TYPHOID
Untuk Memenuhi Tugas Mata Kuliah Epidemiologi Penyakit Menular
Dosen Pengampu : Pebrianty, S.KM., M.Kes

Disusun Oleh:

Namira Milleniawati Wijatmiko (10318040)

PROGRAM STUDI S1 KESEHATAN MASYARAKAT

FAKULTAS ILMU KESEHATAN
INSTITUT ILMU KESEHATAN BHAKTI WIYATA KEDIRI
2019
A. Diare
Diare merupakan peningkatan frekuensi defekasi dengan konsistensi yang lebih berair,
lunak, dan encer selama tiga atau lebih per 24 jam, peningkatan frekuensi tinja atau likuiditas
yang dianggap abnormal.
1. Faktor Risiko
Praktek pembuangan sampah yang tidak benar, kurangnya fasilitas mencuci tangan, tinggal di
daerah pedesaan, keberadaan dua atau lebih saudara kandung dalam sebuah rumah tangga,
usia anak, pasokan air rumah tangga dari sumber yang tidak meningkat, pembuangan sampah
secara terbuka di sekitar rumah.
2. Gejala
Defekasi lebih dari 3 hari dalam sehari, terkadang dengan jarak antar defekasi dekat, badan
lemas, tidak nafsu makan, turgor kulit jelek, membran mukosa bibir kering, di dalam feses
bisa terdapat darah maupun lendir.
3. Penyebab
Diare bisa disebabkan karena virus, bakteri, maupun protozoa. Virus yang bisa menyebabkan
diare contohnya seperti Rotavirus, Norwalk virus, Enteric adenovirus, Calicivirus, dan
lain-lain. Bakteri yang bisa menyebabkan diare contohnya seperti Shigella, Salmonella,
Eschersia, Clostridium difficile, dan lain-lain. Sedangkan protozoa yang dapat menyebabkan
diare contohnya seperti Giardia lamblia, Entamoeba, Histolytica, dan Cryptosporidium.
4. Cara Pencegahan
Menggunakan air yang bersih dan melindungi air tersebut dari kontaminasi mulai dari
sumbernya sampai penyimpanan di rumah, air harus diambil dari sumber terbersih yang
tersedia, sumber air harus dilindungi dengan menjauhkannya dari hewan, membuat lokasi
kakus agar jaraknya lebih dari 10 meter dari sumber yang digunakan serta lebih rendah, dan
menggali parit aliran di atas sumber untuk menjauhkan air hujan dari sumber. Air harus
dikumpulkan dan disimpan dalam wadah bersih, dan gunakan gayung bersih bergagang
panjang untuk mengambil air, air untuk masak dan minum bagi anak harus dididihkan,
memasak atau merebus makanan dengan benar, menyimpan sisa makanan pada tempat yang
dingin dan memanaskan dengan benar. Mencuci tangan dengan sabun, terutama sesudah
buang air besar, sesudah membuang tinja, sebelum menyiapkan makanan, dan sebelum
makan. Setiap keluarga harus mempunyai jamban yang berfungsi baik dan dapat dipakai oleh
seluruh anggota keluarga, dan jamban harus dibersihkan secara teratur.
B. Kolera
Kolera adalah penyakit yang sudah langka di negara-negara perindustrian dalam seratus
tahun belakangan ini, tetapi penyakit ini masih sering terdapat di beberapa bagian dunia
termasuk sub-benua India dan bagian benua Afrika di sebelah selatan gurun Sahara
(sub-Sahara).
1. Faktor Risiko
Kurangnya penanganan pembuangan kotoran (sewage), pengolahan air minum yang kurang
memadai, makan ikan atau kerang-kerangan mentah atau setengah matang, makan jajanan di
pinggir jalan, buruknya sanitasi.
2. Gejala
Diare mendadak berupa air yang terlihat seperti air bekas cucian beras (rice water stool),
mual, muntah biasanya mengikuti diare, tidak ada demam, dehidrasi. Pada dehidrasi yang
berat pada penderita akan terlihat tanda-tanda seperti merasa haus, turgor kulit menurun,
selaput lendir dan kulit tampak kering, tangan keriput, mata cekung, denyut nadi kecil dan
cepat, urine berkurang.
3. Penyebab
Kolera adalah penyakit diare akut, yang disebabkan oleh infeksi usus akibat terkena bakteria
Vibrio cholera.
4. Cara Pencegahan
Vaksin, selain dengan vaksin kolera dapat dicegah dengan melakukan hal- hal seperti hanya
minum air matang; menggunakan air bersih untuk memasak, mencuci piring, sikat gigi,
mandi juga mencuci baju; berhati-hati jika minum minuman dengan es batu, pastikan es batu
terbuat dari air matang; jangan makan daging mentah atau makanan laut yang kurang matang
seperti kerang; mengupas buah atau sayuran saat akan memakannya; selalu mencuci tangan
sebelum dan sesudah makan; memiliki fasilitas MCK dengan pembuangan limbah yang baik
agar tidak mengontaminasi sumber air bersih atau air sumur.
C. Kecacingan
Kecacingan atau yang bisa disebut helminthiasis adalah infeksi yang disebabkan oleh
cacing yang mengontaminasi bagian tubuh manusia. Biasanya, cacing tidak hanya hidup di
saluran gastrointestinal tetapi mungkin juga berada di hati dan organ lainnya. Ketika orang
yang terinfeksi melakukan defekasi, pada tinja orang tersebut akan terdapat telur cacing, jika
sanitasi bruk maka tanah yang ada disekitar akan terkontaminasi.
 1. Faktor Risiko
Sanitasi lingkungan, sanitasi makanan dan minuman, perilaku kebersihan diri, iklim dan
cuaca.
2. Gejala
Lesu, lemah, tidak bergairah, kurang konsentrasi belajar, anemia, serta memiliki kondisi fisik
seperti anak yang menderita kekurangan gizi.
3. Penyebab
Cacing pita atau cestoda (Taenia saginata, Taenia solium, Hymenolepis nana,
Diphyllobothrium latum) dan cacing gelang atau nematoda (Ascaris lumbricoides, Enterobius
vermicularis, Trichuris trichiura, Strongyloides stercoralis, Necator americanus,
Ankylostoma duodenale) hidup di saluran pencernaan inang sedangkan trematoda
(Schistosoma haematobium, Schistosoma mansoni, Schistosoma japonicum), cacing gelang
jaringan (Trichinella spiralis, Dracunculus medinensis) dan cacing pita hidatid (Spesies
Echinococcus) hidup di jaringan inang.
4. Cara Pencegahan
Minum obat cacing sesuai dengan ketetapan, memperbaiki cara dan sarana pembuangan feses,
mencegah kontaminasi tangan dan juga makanan dengan tanah yaitu dengan cara cuci bersih
tangan sebelum makan dan sesudah makan, mencuci sayur-sayuran dan buah-buahan yang
ingin dimakan, menghindari pemakaian feses sebagai pupuk.
D. Hepatitis E
Hepatitis E adalah penyakit hati yang mengakibatkan lebih dari 20 juta kasus setiap
tahun. Hepatitis E sekarang dianggap oleh beberapa ilmuwan sebagai sesuatu masalah karena
HEV tidak hanya lazim di negara berkembang tetapi semakin berkembang di negara-negara
industri.
1. Faktor Risiko
Sumber air minum, kebiasaan minum air tidak dimasak, air untuk mencuci alat makan,
tempat buang air besar, air untuk mandi, pola konsumsi makanan, fasilitas sanitasi yang
kurang berkembang, dan standar kebersihan yang tidak memenuhi syarat.
2. Gejala
Tanda-tanda awal infeksi HEV, seperti demam, muntah, dan pingsan, biasanya diabaikan
atau disalahartikan sebagai tanda-tanda umum flu; gejala yang lebih khas, termasuk tetapi
tidak terbatas pada ikterus, gatal, tinja pucat, dan urin gelap, ditunjukkan pada tahap akhir
infeksi, dan juga berkorelasi dengan kerusakan hati kronis.
 3. Penyebab
Hepatitis E merupakan penyakit infeksi hati akut yang disebabkan oleh virus hepatitis E
(HEV).
4. Cara Pencegahan
Hepatitis E bisa dicegah dengan cara pemberian vaksin HEV, blood screening, konsumsi
daging yang dimasak dengan baik, meningkatkan higienitas dengan membangun lebih
banyak sistem drainase dan filtrasi di area populasi padat penduduk.
E. Typhoid
Demam tifoid terus menjadi masalah kesehatan di seluruh dunia, dengan perkiraan 16
juta kasus setiap tahun. Demam tifoid sangat endemis di negara-negara di mana tidak ada
pasokan air yang bersih atau sanitasi yang memadai.
1. Faktor Risiko
Tidak menggunakan sabun untuk mencuci tangan, tidak ada toilet di rumah tangga, banjir
mengkonsumsi minuman es, penggunaan es batu, dan berbagi makanan dari piring yang
sama.
2. Gejala
Menderita demam pada awal penyakit, perasaan tidak enak badan, lesu, nyeri kepala, pusing
dan tidak bersemangat. Demam berlangsung 3 minggu, konstipasi dapat merupakan
gangguan gastrointestinal awal dan kemudian pada minggu kedua timbul diare.
3. Penyebab
Demam Tifoid adalah penyakit food dan water borne yang disebabkan oleh Salmonella
typhi (S typhi).
4. Cara Pencegahan
Memperbaiki sanitasi, pengobatan karier, dan vaksinasi. Tindakan sanitasi harus dilakukan
untuk mencegah kontaminasi makanan dan air oleh hewan pengerat atau hewan lain yang
mengeluarkan Salmonella. Carrier tidak boleh diizinkan bekerja sebagai pemegang makanan
dan mereka harus melakukan tindakan pencegahan higienis yang ketat.
Vol.3, No.7, 446-453 (2013) Open Journal of Preventive Medicine
http://dx.doi.org/10.4236/ojpm.2013.37060

Prevalence of diarrhea and associated risk factors

among children under-five years of age in Eastern
Ethiopia: A cross-sectional study
Bezatu Mengistie1*, Yemane Berhane2, Alemayehu Worku2,3
1
College of Health Sciences, Haramaya University, Harar, Ethiopia; *Corresponding Author: bezex2000@yahoo.com
2
Addis Continental Institute of Public Health, Addis Ababa, Ethiopia; yemanebrehane@addiscontinental.edu.et
3
School of Public Health, Addis Ababa University, Addis Ababa, Ethiopia; alemayehuwy@yahoo.com

Received 25 July 2013; revised 1 September 2013; accepted 21 September 2013

Copyright © 2013 Bezatu Mengistie et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT should focus on improving household sanitation,

Diarrhea remains a major cause of mortality in
children under 5 years of age in Sub-Saharan
countries in Africa. Risk factors for diarrhea vary
by context and have important implications for
developing appropriate strategies to reduce the
burden of the disease. The objective of this
study was to assess the prevalence of diarrhea
and associated risk factors among children un-
der 5 years of age in Kersa district, located in
Eastern Ethiopia. A community-based cross-
sectional study was conducted among 1456
randomly selected households with at least one
child under 5 years of age. A questionnaire and
an observational check list were used for col-
lecting information on socio-economic charac-
teristics, environmental hygiene and behavioral
practices, and occurrence of diarrhea among
children under 5 years of age. Logistic regres-
sion was used to calculate the adjusted odds
ratio of 95% confidence interval. The two-week
prevalence of diarrhea among children under 5
years of age was 22.5% (95% CI: 20.3 - 24.6).
Improper refuse disposal practices (OR = 2.22,
95% CI: 1.20 - 4.03), lack of hand washing facili-
ties (OR = 1.92, 95%CI: 1.29 - 2.86), living in rural
area (OR = 1.81, 95% CI: 1.12 - 3.31), the pres-
ence of two or more siblings in a household (OR
= 1.74, 95% CI: 1.33 - 2.28), and age of the child
(OR= 2.25, 95% CI; 1.5-3.36) were the major risk
factors for diarrhea. This study demonstrated
that diarrhea morbidity was relatively high among
children under 5 years of age residing in Eastern
Ethiopia. Efforts to reduce childhood diarrhea
*
The authors declare that they have no competing interest.
personal hygiene, and child birth spacing.
Keywords: Diarrhea; Risk Factor; Children under 5
Years; Ethiopia; Cross-Sectional Study; Hygiene
1. INTRODUCTION
Diarrhea remains the leading cause of morbidity and
mortality in children under 5 years old worldwide. The
burden is disproportionately high among children in low-
and middle-income countries. Young children are espe-
cially vulnerable to diarrheal disease and a high propor-
tion of the deaths occur in the first 2 years of life.
Worldwide, the majority of deaths related to diarrhea
take place in Africa and South Asia. Nearly half of deaths
from diarrhea among young children occur in Africa where
diarrhea is the largest cause of death among children under
5 years old and a major cause of childhood illness [1-4].
Although some of the factors associated with diarrhea
in children in Ethiopia such as Acute Respiratory Infec-
tion (ARI), maternal history of recent diarrhea, maternal
education, well source of water, obtaining water from
storage container by dipping, availability of latrine facili-
ties, living in a house with fewer number of rooms, not
breast feeding, duration of breast feeding, and age of the
child, have been identified, diarrhea is still a major pub-
lic health problem among children under 5 years old [5-
8].
Epidemiologic studies show that factors determining
the occurrence of diarrhea in children are complex and
the relative contribution of each factor varies as a func-
tion of interaction between socio-economic, environ-
mental and behavioral variables [5,9-11]. Recent re-
search indicated that studies in differing environment and

Copyright © 2013 SciRes. OPEN ACCESS

 B. Mengistie et al. / Open Journal of Preventive Medicine 3 (2013) 446-453
prioritizing interventions based on context would be
useful to prevent deaths from diarrhea [12]. In Ethiopia,
despite the high prevalence of the disease, reports from
population-based studies are sparse. The study would be
helpful in planning and implementation of prevention
strategies at the community level. Thus, the objective of
this study was to assess the prevalence of diarrhea and
associated factors among children of age under five.
2. METHODS
The study was conducted in Kersa Demographic Sur-
veillance and Health Research Center (KDS-HRC) field
site, located in Eastern Ethiopia in January 2011. The
study site is approximately 482 kilometers from Addis
Ababa, and it is divided into 2 urban and 10 rural kebeles
(the smallest administrative unit in Ethiopia), with total
population of 55,394 residents. Agriculture is the main
source of the district’s livelihood. Health services in the
district are provided by six health centers and28 health
posts. At the kebele level, health care is delivered by
extension workers who are assigned to render health ser-
vices at the local level [13].
The sample size was calculated using the formula for
estimation of single proportion [14], n = Z2*P(1 - P)/r2.
Where: Z value is 1.96: P is the prevalence of diarrhea
among children under-five years old that was assumed to
be 18% [15]; and r is the margin error of estimation that
was assumed to be 2% (0.02). This provided a sample
size of 1417 children. To account for predicted 5% non-
response rate, the final sample was 1488 children.
Households with at least one child under 5years of age
were eligible for the study. Study participants were se-
lected using a simple random sampling technique from a
sampling registry obtained from Kersa Demographic
Surveillance and Health Research Center (KDS-HRC)
registration book. For households with two or more chil-
dren under 5 year of age, the index child was selected by
a lottery method.
Data were collected using questionnaire tested previ-
ously and administered by an interviewer and the obser-
vational check list. The questionnaire was prepared
based on the Multiple Indicator Cluster Survey (MICS),
Demographic and Health Survey (DHS) and World
Health Organization (WHO) core questionnaires related
to diarrhea. The questionnaire was written in English,
translated into Affan Oromo (local language), and then
translated back into English to assure its accuracy. The
respondents were primarily mothers of eligible children
under 5 years of age, but in the absence of the mother,
the next primary caregiver was interviewed.
Thirteen individuals who were trained, and experi-
enced in the KDS-HRC questionnaire administration,
Copyright © 2013 SciRes.
447
and were fluent speakers of Affan Oromo collected the
data. The data collection was supervised by 3 supervisors
at the center. Their role was to daily check the consis-
tency and completeness of the collected questionnaires
and re-interview randomly selected 5% of the households
to check the data quality. Trained data clerks double en-
tered the data using EpiData 3.1 software.
The primary outcome variable was the occurrence of
diarrhea in the 2-week period preceding data collection.
The independent variables included socio-economic
(residence, family size, caregiver’s age, occupation,
educational status, parental age, occupation, educational
status, number of children under 5 years of age in the
household and wealth), environmental (the availability of
hand washing facility, latrine, type of and distance from
water source, refuse and stool disposal) and behavioral
and child-related (child feeding practice, measles vacci-
nation, age and gender of the child) factors.
In this study, diarrhea was defined as the passage of
three or more loose stools over 24 hours period or more
frequently than normal for a child [16]. Water from pro-
tected springs and/or wells, from pipe and from distribu-
tion post was considered as improved source [17]. Dis-
posal of child’s stool was considered proper if the stool
was put into the latrine or buried. The economic status of
the households was categorized into poor, middle and
better off using wealth index, which was calculated from
the households’ assets using principal component analy-
sis [18].
Descriptive statistics were used to summarize the study
variables. Logistic regression analysis was performed
separately for three variable blocks estimated the effect
socio-economic, environmental, and behavioral and child
related factors. The final model estimated the overall
effect of the three blocks of variables. All models used
simultaneous entry procedure to select the significant
determinants and adjusted for confounding factors. All
data were analyzed using SPSS v.16 statistical software
(IBM SPSS, Almaden, NY, US).
To reduce excessive number of variables and resulting
instability of the model, only variables with significance
P < 0.1 in the bivariate analysis were considered for in-
clusion in the multivariable analysis. Variables with P <
0.05 in the multivariable analysis were considered sig-
nificant. Multi-colinearity of variables was assessed by
calculating Variance Inflation Factor (VIF).
The study was approved by the Ethic Committee at the
College of Health and Medical Sciences of Haramaya
University. Mothers or caregivers of children were in-
formed about the study and its objectives before enroll-
ment. A written informed consent was obtained from the
mother or caregiver of each participating child. All col-
lected records were kept confidential.
OPEN ACCESS
448 B. Mengistie et al. / Open Journal of Preventive Medicine 3 (2013) 446-453

3. RESULT shown in Tables 1-3.

A total of 1456 households participated in the study
with a response rate of 97.8%. Almost all respondents
were biological mothers (98.4%), married (97.3%) and
housewives (96.7%), most had no formal education
(82.2%) and were from rural area (85.3%). Mean chil-
dren age was 26.6 ± 13.5 months. There was slightly
more male (51.9%) than female children (51.9% and
48.1%).
Out of 1456 children, 327 had diarrhea two weeks be-
fore the interview, provided a prevalence of 22.5% [95%
confidence interval (CI) 20.3% - 24.6%]. Children in the
age group 6 - 11 months had the highest prevalence of
diarrhea followed by the age groups 12 - 23 months. The
distribution of prevalence of diarrhea by socio-eco-
nomic, environmental and behavioral characteristics is
Factors Associated with Diarrhea
Multivariate analyses were carried out to identifythe
risk factors associated with diarrhea. In the first block
logistic regression model, diarrhea was significantly
higher among children living in the rural than urban area.
In the second model, childhood diarrhea was signifi-
cantly associated with lack of hand washing facility, do-
mestic water supply from unimproved sources and open
dumping of refuse around the house. In the third model,
diarrhea was significantly associated with age of the
child and number of under-five children in the house-
hold.
In the final logistic regression model, diarrhea was in-
dependently associated with open dumping of refuse,

Table 1. Socio-economic determinants of diarrhea among children under 5 years of age in Kersa District, Eastern Ethiopia, 2011.

Diarrhea (N = 1456) COR (95%) CI

Variables
Yes No

Residence

Urban 27 188 1

Rural 300 941 2.22 (1.45 - 3.39)

Age of mother/caregiver

15 - 24 70 194 0.75(0.55 - 1.02)

25 - 34 211 778 0.81(0.53 - 1.24)

>34 46 157 1

Education of mother/caregiver

No formal education 284 950 1.30(0.88 - 1.81)

Primary and above 42 179 1

Occupation of mother/caregiver

Housewife 317 1091 1.10(0.54 - 2.24)

Other 10 38 1

Education of father

No formal education 197 719 1.15(0.89 - 1.49)

Primary and above 130 410 1

Family size (persons per household)

≤4 94 398 1

>4 233 731 1.35(1.03 - 1.76)

Wealth index

Low 112 373 1.09(0.8 - 1.50)

Middle 106 379 1.03(0.93 - 1.41)

Better off 101 385 1

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 B. Mengistie et al. / Open Journal of Preventive Medicine 3 (2013) 446-453 449

Table 2. Environmental exposure variables associated with diarrhea among children under 5 years of age in Kersa district, Eastern
Ethiopia, 2011.

Diarrhea COR (95%) CI

Variables
Yes No

Availability of latrine

Yes 68 325 1

No 259 804 1.54(1.14 - 2.07)

Availability of hand washing facilities

Yes 40 254 1

No 287 875 2.08(1.45 - 2.98)

Main source of domestic water

Improved 194 761 1

Unimproved 133 368 1.41(1.10 - 1.82)

Separate room for cooking

Yes 163 589 1

No 164 540 1.09(0.85 - 1.40)

Refuse disposal

Waste Pit/burning 57 275 1

Open dumping 27 39 3.34(1.89 - 5.89)

Used for manure 241 813 1.43(1.03 - 1.96)

Child stool disposal

Proper 106 441 1

Improper 221 688 1.33(1.03 - 1.73)

Time to obtain drinking water (round trip)

< 15 minutes 118 472 1

15 - 30 minutes 117 392 1.19(0.89 - 1.59)

More than 30 minutes 92 265 1.38(1.01 - 1.89)

Number of sleeping rooms

One 299 965 1.81(1.19 - 2.76)

Two and more 28 164 1

lack of hand washing facility, rural residence, and num-
ber of siblings under 5 years in a household and age of
the child. More specifically, children in the households
who open dumped refuse around the house had 2.22
times higher odds of having diarrhea compared to chil-
dren in the households who used a waste disposal pit
(OR = 2.22, 95% CI 1.2 - 4.03). The odds of diarrhea was
1.74 times higher in children from the households with
two or more siblings compared to children in the house-
holds with only one sibling (OR = 1.74, 95% CI 1.33 -
2.28). Children in the households without hand washing
facilities had 1.92 times higher odds of having diarrhea
compared to children in the households with no hand
washing facility(OR = 1.92, 95% CI 1.29 - 2.86) (Table 4).
4. DISCUSSION
This study investigated the prevalence and socio-
economic, environmental and behavioral risk factors of
diarrhea morbidity in children <5 years old in Eastern
Ethiopia. The two-week prevalence of diarrhea among the
children was 22.5% (95% CI: 20.3 - 24.6). The occurrence

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450 B. Mengistie et al. / Open Journal of Preventive Medicine 3 (2013) 446-453

Table 3. Behavioral, child and care related risk factors for diarrhea among children under 5 years of age, Kersa District, Eastern
Ethiopia, 2011.

Diarrhea COR (95%) CI

Variables
Yes No

Bottle feeding (n = 737)

Yes 36 104 1.05(0.68 - 1.59)

No 159 438 1

Currently breast feeding (n = 737)

Yes 140 417 1

No 55 125 1.31(0.90 - 1.89)

Duration of breast feeding (n = 737)

<1 year 121 345 1.07(0.76 - 1.5)

≥1 year 74 197 1

Feeding children soon after food preparation

Yes 204 668 1.14(0.88 - 1.47)

No 123 461 1

Serving uncooked food to children

Yes 50 203 0.82(0.58 - 1.15)

No 277 926 1

Measles vaccination (n = 1302)

Yes 163 610 1

No 130 399 1.21(0.93 - 1.58)

Child sex

Male 166 590 1

Female 161 539 1.06(0.83 - 1.35)

Number of under 5 sibling per household

One 144 698 1

Two and more 183 431 2.05(1.60 - 2.64)

Child age (in months)

0-5 4 47 0.40(0.14 - 1.15)

6 - 11 61 114 2.54(1.73 - 3.73)

12 - 23 86 223 1.83(1.31 - 2.56)

24 - 35 84 308 1.29(0.93 - 1.80)
>35 92 437 1

*Measles vaccination is calculated for children 9 months and above; *bottle feeding and breast feeding is calculated for children < 2 years of age.

of diarrhea was positively associated with rural residence,
aged 6 to 23 months, open dumping of refuse around the
house, lack of hand washing facility and presence two or
more children under <5 years old in the household.
The two-week period of diarrhea occurrence used as a
criterion in our study is comparable with studies con-
ducted in Western Ethiopia [5], Egypt [19] and India
[20]. Such high rate of childhood diarrhea, despite con-
siderable improvements in water sources and sanitation
facilities, indicates the need for more attention.

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 B. Mengistie et al. / Open Journal of Preventive Medicine 3 (2013) 446-453 451

Table 4. Multivariable analysis of risk factors of diarrhea among children under 5 years of age in Kersa district, Eastern Ethiopia,
2011.
Model I Model II Model III Final model
Risk factors
AOR (95% CI) AOR (95% CI) AOR (95% CI) AOR (95% CI)
Area of residence
Urban 1 1
Rural 2.15(1.35 - 3.43)* 1.81(1.12 - 3.31)*
Education mother/caretaker
No formal education 1.14(0.76 - 1.69) 1.23(0.79 - 1.92)
Primary and above 1 1
Family size
≤4 1 1
>4 1.30(0.98 - 1.71) 1.13(0.84 - 1.51)
Availability of latrine facility
Yes 1 1
No 1.13(0.77 - 1.67) 1.14(0.75 - 1.73)
Availability of hand washing facility
Yes 1 1
*
No 1.80(1.22 - 2.66) 1.92(1.29 - 2.86)*
Main source of domestic water 1 1
Improved
Unimproved 1.35(1.02 - 1.80)* 1.16(0.86 - 1.55)
Time to fetch water (round trip)
< 15 minutes 1 1
15 - 30 minutes 1.03(0.75 - 1.40) 1.02(0.72 - 1.44)
More than 30 minutes 1.06(0.74 - 1.51) 1.04(0.71 - 1.51)
Refuse disposal
Waste pit/burning 1 1
Open dumping 2.68(1.51 - 4.79)* 2.22(1.20 - 4.03)*
Used for manure 1.22(0.87 - 1.72) 1.12(0.77 - 1.60)
Child stool disposal
Proper 1 1
Improper 1.23(0.88 - 1.70) 1.29(0.92 - 1.81)
Number of sleeping rooms
One 1.43(0.88 - 1.70) 1.40(0.91 - 2.20)
Two or more 1 1
Number of children under 5 in the household

One 1 1

Two or more 1.93(1.5 - 2.49)* 1.74(1.33-2.28)*

Child age (months)
0-5 0.39(0.13 - 1.11) 0.36(0.12 - 1.04)
*
6 - 11 2.31(1.56 - 3.41) 2.25(1.50 - 3.36)*
*
12 - 23 1.71(1.22 - 2.4) 1.83(1.29 - 2.60)*
24 - 35 1.30(0.99 - 1.81) 1.34(0.95 - 1.88)
>35 1 1
*= P < 0.05.

Copyright © 2013 SciRes. OPEN ACCESS

452 B. Mengistie et al. / Open Journal of Preventive Medicine 3 (2013) 446-453
The importance of refuse in transmitting diarrhea
pathogens has been documented [21]. In our study, open
disposal of refuse around the house was an independent
risk factor for diarrhea. This is in agreement with other
studies conducted elsewhere [22,23]. The simple expla-
nation might be that inappropriate disposal of refuse pro-
vides breeding site for insects, which may carry diarrhea
pathogens from the refuse to water and food.
Studies showed the importance of hand washing in
reducing the occurrence of childhood diarrhea [24,25].
However, monitoring correct hand washing behavior at
critical times is challenging. Hygiene behavior related
observational studies showed wide discrepancy between
what people said and did and suggested that reported
hand washing behavior over estimate observed behavior
[26-28] and supported the availability of water and soap
in places of hand washing as indicator of hand washing
behavior [29]. In this study, there was a significant posi-
tive association between the availability of hand washing
facility with childhood diarrhea.
The study showed that diarrhea was significantly as-
sociated with children in the age groups 6 - 11 months
and 12 - 23 months compared to children aged above 35
months. This finding is in agreement with other studies
[5,9]. The peak prevalence of diarrhea at the age of 6 - 11
months can be explained by the introduction of contami-
nated weaning foods [30]. In addition, crawling starts at
this age and the risk of ingesting contaminated materials
may cause diarrhea. The risk of diarrhea decreases sub-
sequently after 6 - 11 months; this is probably because
the children begin to develop immunity to pathogens
after repeated exposure [31].
The odds of diarrhea were higher among rural children
than urban ones and this was consistent with the findings
in Uganda [11] and Egypt [19]. This could be attributed
to the fact that the lack of access to water and sanitation
facilities in the rural areas was more than in the urban
areas [32].
In this study, diarrhea was significantly associated
with the presence of two or more under five children in
the family. This is in agreement with a study done in
Pakistan [33]. Other study also indicated that number of
children born was a predictor of diarrhea among under
five children [34]. This might be due to the incapability
of the caregiver to care for a large number of children
[19]. It is possible to suggest that child birth spacing might
have a positive influence on prevention of diarrhea.
In conclusion, childhood diarrhea remains an impor-
tant health concern in the study community. Occurrence
of diarrhea could be decreased by interventions aimed to
improve sanitation, hygiene and child birth spacing.
5. ACKNOWLEDGEMENTS
The authors would like to thank Haramaya University for its finan-
Copyright © 2013 SciRes.
cial support. We are also thankful for study participants, data collectors
and supervisors for their devotion and full participation.
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OPEN ACCESS
Open Journal of Epidemiology, 2014, 4, 243-247
Published Online November 2014 in SciRes. http://www.scirp.org/journal/ojepi
http://dx.doi.org/10.4236/ojepi.2014.44031

Outbreak Investigation of Cholera in a Slum

of Northern India
Manoj Kumar*, Vijay Lakshmi Sharma
Centre for Public Health, Panjab University, Chandigarh, India
*
Email: mkcph@pu.ac.in

Received 1 August 2014; revised 1 September 2014; accepted 1 October 2014

Copyright © 2014 by authors and Scientific Research Publishing Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY).
http://creativecommons.org/licenses/by/4.0/

Abstract
Cholera is one of the oldest and best understood endemic diseases. An actual bacterial enteric
disease, it is characterized in its severe form by sudden onset, profuse painless watery stools (rice-
water stool), nausea and profuse vomiting early in the course of illness. Endemic and pandemics
are strongly linked to the consumption of unsafe water, poor hygiene, poor sanitation and crowded
living conditions. A rapid survey was conducted for the outbreak investigation on August 4, 2008.
The objectives were to investigate the outbreak, risk factors for cholera and recommend control
measures immediately. Questionnaire based random convenient sample based investigative study.
60 families were contacted by the public health students. Approximate 300 individuals were screened
for cholera cases. Simultaneously six water samples were also collected from the contacted family.
Microbiological test for Vibrio cholera and E. coli was conducted. Randomly six water samples
were collected from the Rajive colony. Microbiological test for Vibrio cholera and E. coli was con-
ducted from the department of Microbiology, PU. Vibrio cholera and E. coli were found absent, in
all the samples. One sample was found positive for unidentified bacteria.

Keywords
Cholera, Slum

1. Introduction
Cholera has been present in India since ancient times. During the 19th century, several pandemics of cholera ori-
ginated from India and spread to western countries. Currently the seventh pandemic which began in 1961 in In-
donesia is still continuing. It has involved more than 80 countries in Asia, Africa and Europe.
Cholera is both an epidemic and endemic disease. The epidemicity and endemictiy of a disease will depend
on Characteristics of the agent, and those of the system. Characteristics of the agent which influence its distribu-
*
Corresponding author.

How to cite this paper: Kumar, M. and Sharma, V.L. (2014) Outbreak Investigation of Cholera in a Slum of Northern India.
Open Journal of Epidemiology, 4, 243-247. http://dx.doi.org/10.4236/ojepi.2014.44031
M. Kumar, V. L. Sharma

tion include its ability to survive in a given environment, its virulence, the average number of organisms re-
quired to cause infection, etc. Characteristics of the system which affect the distribution of the agent include the
number of susceptible, and the opportunities it provides for transmission of the infection. Global experience has
shown that the introduction of cholera into any country cannot be prevented, but cholera can create a problem
only in areas where sanitation is defective.
Epidemics of cholera are characteristically abrupt and often create an acute public health problem. They have
a high potential to spread fast and cause death. Often-times, by the time control measures are instituted the epi-
demic has already reached its peak and is waning. Thus, cholera epidemic in a community is self-limiting. It
tends to decline after reaching its peak. This is attributed to the acquisition of temporary immunity, as well as
due to the occurrence of a large number of sub clinical cases.
The practical successes of anticontagionists were not limited to their victories over quarantines. Their opera-
tions against “filth” increased greatly their prestige. While it was difficult for the contagionists to prove that a
respective epidemic would have been even worse without quarantines; health improvements after removal of
“filth” seemed to be causally related to the latter action. Barcelona and Alicante did not experience further yel-
low fever epidemics after such campaigns in 1827, respectively 1804. The General Board of Health could point
in the cholera of 1848-1849 to the immunity of its cleaned “model houses” [1].
Peter Baldwin seeks to challenge the widely held, reductionist belief that “it was not the nature of the disease
which specified how it would be prevented and limited, but the kind of political regime under epidemic attack”.
The more interesting question, and one that Baldwin also poses but answers less satisfactorily, is whether these
dynamics determined the nature of the political systems themselves. He coins the appropriate term “neoquaran-
tinist” to describe the panoply of measures that served to control epidemiological outbreaks as opposed to pre-
venting their occurrence altogether. The emergence of these adaptive strategies is crucial to Baldwin’s interpre-
tation of the post-cholera period, and one cannot dispute the emphasis he places on them [2].
By the end of the 19th century, cholera epidemics no longer appeared in Europe and North America. The rea-
sons for this are uncertain, but standards of living had risen and many communities had made major changes in
sanitation practices and established permanent boards of health. As part of the transformation to the germ theory,
medical thought had changed in many ways as well. In 1831, most physicians believed cholera to be a nonspe-
cific, noncontagious miasmatic condition that favored the morally and physically predisposed. By the end of the
19th century, although the miasmatic interpretation still had influence, cholera was primarily understood to be a
specific contagious disease caused by a particular microscopic organism [3].
Ideas relating sickness to personal morality have long been important in European and American thought. In
the Judeo-Christian tradition, sickness has often been seen as divine punishment for sin. Cures for sexually
transmitted diseases, including syphilis, have been criticized in the belief that cures would encourage immoral
behavior. Moral and ethical issues associated with sex, food, drink, work, and emotions have also been con-
nected with the possibility of contracting or spreading disease [4].
Until Robert Koch identified the cholera bacillus in 1883; science continued to favor anticontagionism. Lead-
ing anticontagionists or contingent contagionists included Max von Pettenkofer and South wood Smith. Ac-
cording to the contingent contagionist perspective, cholera could be contagious, but only under particular cir-
cumstances [5]. The existence of the cholera bacillus did not necessarily prove cholera’s contagiousness either;
some argued that the bacillus was the product of the disease, not its cause. Another issue was how to explain the
existence of healthy carriers—people who had the cholera bacillus in their bodies but who were not sick. In
practice, public health measures often involved a blend of contagionist and anticontagionist views.
Cholera was the classic epidemic disease of the nineteenth century, as the plague had been for the fourteenth.
Its defeat was a reflection not only of progress in medical knowledge but of enduring changes in American so-
cial thought. Rosenberg has focused his study on New York City, the most highly developed center of this new
society. Carefully documented, full of descriptive detail, yet written with an urgent sense of the drama of the
epidemic years, this narrative is as absorbing for general audiences as it is for the medical historian. In a new
Afterword, Rosenberg discusses changes in historical method and concerns since the original publication of The
Cholera Years [6] [7].
Epidemic of cholera are frequent, striking adults as well as children. Epidemiological studies have shown that
cholera is responsible for about 5 - 10 per cent of all acute diarrhea cases in non epidemic situation. Global ex-
perience of the current pandemic has shown that cholera can get introduced into any country but can create

244
 M. Kumar, V. L. Sharma

problem only in areas where other acute enteric infections are endemic, i.e. where sanitation is defective.
Although cholera occurs from time to time in Chandigarh slums, and in Tricity, Large number of reports
started appearing in July, 2008 from areas in and around Chandigarh. To investigate the suspected epidemic, we
have conducted a rapid survey for this outbreak investigation on August, 4, 2008.

2. Methodology
In July 2008, outbreaks of Cholera illness were reported from Rajive colony, Panchkula. This provided a chal-
lenge for the centre for public health of Panjab University, Chandigarh to identify risk factors and network with
resources available in the Panchkula for outbreak response. The objectives were to investigate the outbreak, risk
factors for cholera and recommend control measures immediately.
The investigation team was from centre for public health of Panjab University, Chandigarh. The team identi-
fied part of total cases that occurred in this colony by house-to-house survey. Risk factors were assessed by us-
ing a questionnaire. Laboratory investigations for microbiological test of water samples were done from the de-
partment of microbiology, Panjab University, Chandigarh.
A cross-sectional study was conducted by using random sampling method in a sample size of 300 individuals.
Self structured questionnaire regarding sanitation and hygiene, quality of water used for drinking and domestic
purposes was collected. About 60 families were contacted by the public health team. Approximate 300 individu-
als were screened for cholera cases. Simultaneously six water samples were also collected from the contacted
family. Microbiological test for Vibrio cholera and E. coli was conducted.
It can be concluded that poor sanitary and unhygienic conditions may be responsible for the Cholera cases
occurred in rainy season in of July, 2008.

3. Results
Table 1, shows that almost equal numbers of cases were observed from both sex. More cases were reported
from the age group 20 - 60 years. More males were affected in <20 years of age groups as compared. And only
two female cases were reported from the >60 years age group.
According to Table 2, Out of 17 cases, 10 cases were from conformed and suspected category. Equal num-
bers of cases were reported for conformed and suspected diagnoses from males and females.
Randomly six water samples were collected from the Rajive colony. Microbiological test for Vibrio cholera
and E. coli was conducted from the department of Microbiology, Panjab University, Chandigarh. Vibrio cho-
lera and E. coli were found absent, in all the samples. One sample was found positive for unidentified bacte-
ria.

Table 1. Age group and sex distribution of cases.

Age Group Male Female Total

<20 years 3 1 4

20 - 60 years 6 5 11

>60 0 2 2

Total 9 8 17

Table 2. Distribution of cases according to diagnosis.

Diagnosis Male Female Total

Conformed 2 3 5
Suspected 2 3 5
Not conformed 4 3 7
Total 8 9 17

245
M. Kumar, V. L. Sharma

4. Discussion
The city of Hamburg was hit by one of the greatest urban disasters of the century: a cholera epidemic that within
six weeks left ten thousand people dead and many more suffering the appalling symptoms of this terrible disease.
Drawing on a mass of detailed source material, this book presents a graphic portrayal of a great European city in
the throes of a major social and political crisis [8]. Cholera is entirely multiform, as are typhoid fever, pneumo-
nia, cerebrospinal meningitis and all infectious diseases without exception [9].
Despite the continued discussion about the cause of cholera, over the course of the 19th century the actual
treatment of the disease did not change much. Patients with families were cared for at home. Physicians, when
called, would use such characteristic treatments as bleeding or opium. Homeopathic methods were popular
among the middle and upper classes, as were other eclectic treatments, and all manner of dietary and hygie-
nic regimens were promoted in newspapers and books. Those without families might find themselves in charity
hospitals, which could become grim places indeed during an epidemic. Preachers gave sermons on the meaning
of cholera for both individuals and society. Riots ensued due to popular revolt against mass burials [10].
As part of the transformation to the germ theory, medical thought had changed in many ways as well. In 1831,
most physicians believed cholera to be a nonspecific, noncontagious miasmatic condition that favored the mo-
rally and physically predisposed [11].
The main symptom of cholera is diarrhea. Cases range from symptom less to severe infections. The majority of
infections are mild or asymptomatic. Typical cases are characterized by the sudden onset of profuse, effortless,
watery diarrhea followed by vomiting, rapid dehydration, muscular craps and suppression of urine. Unless there
is rapid replacement of fluid and electrolytes, the case fatality may be as high as 30 to 40 per cent. The village
leaders helped the investigation team in instituting standard hygienic measures for controlling the outbreak im-
mediately
Vibrio transmission is readily possible in a community with poor environmental sanitation. The environmen-
tal factor of importance includes contaminated water and food. Flies may carry V. cholerae. Numerous social
factors have also been responsible for the endemicity of cholera in India. These comprise certain human habit
favoring water and soil pollution, low standards of personal hygiene, lack of education and poor quality of life.
Transmission occurs from man to man via faecally contaminated waste: Uncontrolled water sources such as
well, lakes ponds, streams and rivers pose a great threat, Contaminated food and drinks: Ingestion of contami-
nated food and drinks have been associated with outbreaks of cholera. Bottle-feeding could be significant risk
factor for infants. Fruits and vegetables washed with contaminated water can be a source of infection. After
preparation, cooked food maybe contaminated through contaminated hands and flies. There is growing opinion
that complex interaction of contaminated food, water and environment rather than through public drinking water
supplies and direct contact: In developing countries a considerable proportion of cases may result from second-
ary transmission i.e. person to person transmission through contaminated fingers while carelessly handling ex-
creta and vomit of patients. Incubation period is from few hours up to 5 days, but commonly 1 - 2 days.
Leakages in water pipes coupled with poor environmental sanitation were identified as reasons for contamina-
tion of drinking water. Health education, immediate repair of leaking pipes and chlorination of water supply led
to an early control of the outbreak.

5. Conclusion
It can be concluded that poor sanitary and unhygienic conditions may be responsible for the Cholera cases oc-
curred in rainy season in of July, 2008.

6. Recommendations
Taking measure given below can minimize the risk of an outbreak of cholera and its spread. There are no other
alternative for the control of outbreak of Cholera.
1) Provision of safe water;
2) Adopting safe practices in food handling;
3) Sanitary disposal of human waste;
4) Personal and domestic hygienic practices;
5) Particular attention should be given in the pre-monsoon periods before the expected seasonal increase of wa-

246
 M. Kumar, V. L. Sharma

ter-borne diseases: however these measures are expected to be in place round the year;
6) Arrange random checks for water quality for coliform organisms;
7) Ensure that the health personnel are adequately trained in oral rehyderation therapy and that recommended
guidelines are followed in hospitals.
The above steps are required both as long term measure to prevent Cholera, as well as measures to be taken in
focal area where an outbreak is anticipated. Community participation is essential to prevent an outbreak so that
safe practices are followed for storing water and for food handling.

Acknowledgements
We are thankful to the Centre for Public Health and Department of Microbiology, Panjab University for their
indispensable assistance.

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Helminthiasis and medicinal plants: a review

Mahesh Bandappa Manke*, Shashikant Chaburao Dhawale, Prasad Govindrao Jamkhande
Department of Pharmacology, School of Pharmacy, SRTM University, Nanded-431 606 (MS), Maharashtra, India

PEER REVIEW ABSTRACT

Peer reviewer
Prof. Ravi U. Mane, Assistant Professor,
K.S.S. College of Pharmacy, Shikrapur,
Dist. Pune, Maharashtra, India.
Tel: +918483925816
E-mail: maneravi13@gmail.com
Comments
T his is a good study in which the
authors have compiled the information
about helminthiasis and medicinal
plants with anthelmintic effect. All the
information will help researchers to
explore its scientific evidence in the
prospect studies.
Details on Page 178
Helminthiasis is the most common infection caused by worms that is contaminant to human body
parts. Normally, the worms live in the gastrointestinal tract, liver and other organs. The currently
available anthelmintic drugs, including albendazole, mebendazole, thiabendazole, niridazole,
dietylcarbamazine, ivermectin, praziquantel, are widely used to control helminthiasis. But
these drugs have serious drawbacks such as hepatotoxicity, loss of appetite, dizziness, nausea,
vomiting, abdominal pain, headache and diarrhea. Thus, it is necessary to look for more effective
anthelmintic drugs with the minimum side effects. Eighty percent of the world’s population relies
on traditional medicines and plant extracts and the active constituents are used to meet people’s
primary health care needs. This review focuses on helminthiasis and the role of traditional plants
in the treatment of helminthiasis.
KEYWORDS
Anthelmintics, Cysts, Helminthiasis, Medicinal plants, Nematodes

1. Introduction Trichuris trichiura, Strongyloides stercoralis, Necator

Helminth infections are the most common infections
in man, and exaggerated worldwide population. It may
cause anemia, eosinophilia, pneumonia and prevalence
of malnutrition [1]. H elminthiasis is the most common
infection caused by worms that is contaminant to human
body parts. N ormally, the worms not only live in the
gastrointestinal tract but may also reside into liver and
other organs. When infected people excrete faeces with
helminth eggs, the soil in the areas with poor sanitation
will be contaminated[2]. There are two clinically important
types of worm infections, one is the worms live in the
host’s alimentary canal and the other is worms live in
other tissues of the host’s body. Tapeworms or cestodes
( Taenia saginata, Taenia solium, Hymenolepis nana,
Diphyllobothrium latum) and intestinal roundworms or
nematodes (Ascaris lumbricoides, Enterobius vermicularis,
americanus, Ankylostoma duodenale ) are live in the
host’s alimentary canal while trematodes or flukes
( Schistosoma haematobium, Schistosoma mansoni,
Schistosoma japonicum), tissue roundworms (Trichinella
spiralis, Dracunculus medinensis) and hydatid tapeworm
( Echinococcus species ) are live in the host’s tissues [3].
Several nematodes that usually live in the gastrointestinal
tract of animals may communicate a disease to humans
and penetrate tissues. A skin infestation, termed
creeping eruption, is caused by the larvae of dog and cat
hookworms. Toxocariasis is caused by larvae of cat and
dog roundworms of the Toxocara genus[3].
2. Epidemiology
Helminthiasis is the most common infection mainly

*Corresponding author: Mahesh Bandappa Manke, Department of Pharmacology, Article history:

School of Pharmacy, SRTM University, Nanded-431 606, Maharashtra, India. Received 2 Jun 2014
Tel: +91 9923 092833 Received in revised form 13 Jun, 2nd revised form 24 Jun, 3rd revised from 2 Jul 2014
Fax: +91 2462 229242 Accepted 12 Jul 2014
E-mail: mahesh.bmanke@rediffmail.com Available online 11 Aug 2014
Foundation Progect: Supported by Swami Ramanand Teerth Marathwada University,
Nanded (431606), Maharashtra, India (Grant Ref. No. Acctts/Budget/2012-13/2169-2209).
176 Mahesh Bandappa Manke et al./Asian Pac J Trop Dis 2015; 5(3): 175-180

caused by the helminths. I t is observed in various

tropical and subtropical areas, and it is also classified Physical blockage Cysts

as neglected tropical diseases. They spread the majority

of common parasitic infection of human in developing Blockage of intestine due to large
Cysts of the tapeworm (Echinococcus
countries. Ascaris limbricoides, Trichuris tritura, Necator nematodes (Ascaris) or tapeworms
(Taenia, Diphyllobothrium). multilocularis).
americanus, Ancylostoma duodenale, schistosomes
and filarial worms cooperatively infect more than one
Formation of granulomas around Grows in the liver, brain, lungs or
billion people, rivaling AIDS and malaria[4]. As the recent schistosome eggs. other parts of body cavities.
evaluations, over a billion people have been infected due
to at least one helminth species in Asia, Africa, America Blockage of blood flow through the Leads to unusal enlargement, organ
and S u-saharan, which leads to severe morbidity, liver, which leads to pathological metastasis and causing necrosis due
changes. to pressure exerted by cysts.
accompanied by persistent shortage, decreased
Figure 1. Direct damage caused by large helminths.
efficiency, and poor socioeconomic development.
Helminthiasis has immunomodulatory effects on the host 4.2. Indirect damage caused by host responses
cells, with implications for many affecting pathogens. In
fact, in endemic areas, AIDS, malaria and tuberculosis are Indirect damage is seen in the pathology related with
recognized to be caused by helminthiasis. In most cases, schistosome infections, especially with Schistosoma
they can induce severe hypersensitivity reaction that mansoni ( F igure 2 ) . H ypersensitivity-based, formation
leads to chronic allergic reactions called anaphylaxis[4]. of granuloma produced blockage of liver sinusoids and
impeding blood flow, which leads to changes in liver
pathology. Hypersensitivity-based inflammatory changes
3. Etiology of helminthiasis probably also contribute to the lymphatic blockage
related with filarial infections[5].
Helminths have a complex life cycle that often links
Formation of adult schistosomes
several species. Helminth infections are mainly caused in blood vessels around the small
due to improper sanitation. T hey enter by mouth in intestine.
unpurified drinking water or in poorly cooked meat
from infected animals. It is also enter through the skin Eggs prepared by female are passed
by a skin cut, an insect bite or even after swimming in blood vessels and trapped in liver.
or walking on polluted soil. H umans are the primary
hosts for the helminth infections and most of the worms
Hypersensitivity-based, formation of
reproduce sexually in the human host, producing eggs or granuloma produced blockage of liver
larvae that pass out of the body and infect the secondary sinusoids and impeding blood flow.
host. I n some cases, the eggs or larvae may persevere
in the human host and become encysted, enclosed with
granulation tissue, giving rise to cysticercosis. This is Changes in liver pathology or fibrosis of liver.
characterized by encysted larvae in the muscles, viscera
and more critically in the eye or the brain[3,4]. Figure 2. Indirect damage caused by immunopathologic responses.

4. Pathogenesis of helminthiasis 5. Diagnosis of helminthiasis

4.1. Direct damage caused by worms
T he most evident forms of direct damage are those
resulting from the blockage of internal organs or from the
effects of pressure exerted by growing parasites (Figure 1).
Physically blockage of intestine due to large nematodes
( Ascaris ) or tapeworms ( Taenia, Diphyllobothrium )
that produced the formation of granulomas around
schistosome eggs and the blockage of blood flow through
the liver occured, which leads to pathological changes.
C ysts of the tapeworm ( Echinococcus multilocularis )
develop in the liver, brain, lungs or other parts of body
cavities can lead to unusal enlargement, organ metastasis
and cause necrosis due to pressure exerted by cysts[5].
Technical limitations of currently available diagnostic
methods are the most important problems in the control
of helminthiasis. L acking of standard clinical tests
encourages extensive invasion and poses a hindrance to
health managements. For basic diagnosis of helminths
infection, the specific helminths can be identified from
the faeces and their eggs microscopically examined
and established using fecal egg count method. T his
is commonly useful for most species, particularly in
veterinary investigations[6]. A range of diagnostic tools
currently available is (Figure 3): 1) Parasitological tests,
the parasites are identified microscopically; 2) Serological
assays, the parasite-specific antibodies are detected in
serum samples; 3) Antigen tests, a parasite biomarker is
 Mahesh Bandappa Manke et al./Asian Pac J Trop Dis 2015; 5(3): 175-180
177

detected; 4) Molecular diagnosis, the parasite nucleic acid patients. As a result, the young patients suffer from growth
is detected; and 5) Other specific tools for detection in the retardation, diminished physical fitness, and impairment in
intermediate hosts[6,7]. However, there are certain limitations memory and cognition[10].
such as the failure to identification of mixed infections and
the technique is extremely incorrect and unpredictable for
schistosomes and soil-transmitted helminths[8]. 7. Therapy for helminthiasis
Identification of parasite
Parasitological tests Anthelmintic are drugs that act either locally to expel
microscopically.
worms from the gastrointestinal tract or systemically to
eradicate adult helminthes or developmental forms that
Detection of parasite-
Serological assays specific antibodies in serum invade organs and tissues[11]. An anthelminthic drug can act
samples. by causing paralysis of the worm, or by damaging its cuticle,
which lead to partial digestion or rejection by immune
Detection of parasite biomarker. mechanisms. Anthelminthic drugs can also interfere with
Antigen tests
the metabolism of the worm, and since the metabolic
requirements of these parasites vary greatly from one species
Detection of parasite nucleic
Molecular diagnosis acid.
to another, drugs that highly effective against one type of
worm but be ineffective against others[3]. Anthelmintic drugs
with their proper mechanism of actions are given in Table
Detection in the intermediate 1[12].
Other specific tests hosts.

Figure 3. Currently available diagnostic tools for helminthiasis.

8. Plant remedies in the management of helminthiasis

6. Clinical features of helminthiasis Most of the existing anthelminthic drugs produce side effects
such as abdominal pain, loss of appetite, nausea, vomiting,
These features are depending on the helminth species, headache and diarrhea. Mebendazole is a well tolerated drug.
intensity of infection, and host age. Taenia solium can However, gastrointestinal side-effects, dizziness have been
cause not only neurocysticercosis but also mass lesions noted in few patients. Also prolonged use in hydrated or in
in brain. C hronic infection with Schistosoma causes cysticercosis, causes headache, fever, alopecia, jaundice
granulomas, fibrosis, and inflammation of the spleen and and neutropenia[13]. In order to eliminate the harmful side-
liver. Echinococcus granulosis ingested eggs can cause effects of these synthetic anthelmintic drugs, it is important
life-threatening anaphylaxis if antigens are released for us to promote the studies of traditionally used anthelmintic
from the cysts. Hookworm and schistosomiasis can infect plants which will lead to the development of new anthelmintic
pregnant women, cause neonatal prematurity and increase substances with ease of availability and lesser side-effects[14].
maternal morbidity and mortality[9]. Intestinal worms and As per World Health Organization, 80% world’s population
schistosomes infection are observed in children at school relies on traditional medicines to meet their primary health
age or younger as compared with any other age group care needs, most types of which use remedies from plants.
Table 1
Anthelmintic drugs with their mechanism of actions.
Drug Mechanism of action
Albendazole is thought to act against nematodes by inhibiting microtubule synthesis. It also has larvicidal effects in hydatid disease,
Albendazole
cysticercosis, ascariasis, and hookworm infection and ovicidal effects in ascariasis, ancylostomiasis, and trichuriasis.
Mebendazole probably acts by inhibiting microtubule synthesis; the parent drug appears to be the active form. Efficacy of the drug varies with gastrointestinal
Mebendazole
transit time, with intensity of infection, and perhaps with the strain of parasite. The drug kills hookworm, Ascaris, and Trichuris eggs.
Thiabendazole Thiabendazole is thought to act against nematodes by inhibiting microtubule synthesis.
Diethylcarbamazine Diethylcarbamazine citrate immobilizes microfilariae and alters their surface structure, displacing them from tissues and making them more
citrate susceptible to destruction by host defense mechanisms. The mode of action against adult worms is unknown.
Ivermectin appears to paralyze nematodes and arthropods by intensifying GABA-mediated transmission of signals in peripheral nerves. It is
Ivermectin
microfilaricidal. It does not effectively kill adult worms but blocks the release of microfilariae for some months after therapy.
The mode of action is thought to be related to cholinesterase inhibition. This inhibition temporarily paralyzes the adult worms, resulting in their
Metrifonate
shift from the bladder venous plexus to small arterioles of the lungs, where they are trapped, encased by the immune system, and die.
Niclosamide Adult worms are rapidly killed, presumably due to the inhibition of oxidative phosphorylation or stimulation of ATPase activity.
The mechanism of action is unknown. Contraction and paralysis of the worms results in detachment from terminal venules in the mesentery
Oxamniquine
and transit to the liver, where many die; surviving females return to the mesenteric vessels but cease to lay eggs.
It reversibly inhibits neuromuscular transmission in the worm, probably by acting like GABA, the inhibitory neurotransmitter on GABA-gated
Piperazine
Clˉ channels in nematode muscle.
Praziquantel Praziquantel appears to increase the permeability of trematode and cestode cell membranes to calcium, resulting in paralysis, dislodgement, and death.
The drug is a neuromuscular blocking agent that causes release of acetylcholine and inhibition of cholinesterase and results in paralysis, which
Pyrantel pamoate
is followed by expulsion of worms.
178 Mahesh Bandappa Manke et al./Asian Pac J Trop Dis 2015; 5(3): 175-180

Even the modern pharmacopoeia still contains at least 25% Conflict of interest statement
of drug derived from plants and many others which are
semi-synthetic, built on prototype compounds isolated We declare that we have no conflict of interest.
from plants[15]. The phytoconstituents showing anthelmintic
effect includes alkaloids, saponins, polyphenols, tannins,
etc. Alkaloids suppress the transfer of sucrose from stomach Acknowledgements
to small intestine, diminish the support of glucose to the
helminths, and act on CNS causing paralysis. Saponins possess Authors are thankful to Prof. S. G. Gattani, Director,
vacuolization and disintegration of teguments. Polyphenols and S chool of P harmacy, SRTM U niversity, N anded for his
tannins increase the supply of digestible proteins by animals valuable guidance. This work was supported by Swami
via forming protein complexes in rumen, interfere with energy Ramanand Teerth Marathwada University, Nanded (431606),
generation by uncoupling oxidative phosphorylation, cause Maharashtra, India (Grant Ref. No. Acctts/Budget/2012-
a decrease in gastrointestinal metabolism which leads to 13 / 2169 - 2209 . )
as a part of research project for partial
paralysis and death of helminths[16]. Medicinal plants list with fulfillment master degree in pharmacy.
proven anthelmintic effects are compiled in Table 2.
Table 2
Medicinal plants with anthelmintic potential. Comments
Plant name Family Part of the plant used Reference
Achyranthes aspera Amaranthaceae Stem [17] Background
Aerva lanata Amaranthaceae Aerial parts [18]
Helminth infections have severe consequences for the
Alstonia boonei Apocynaceae Bark [19]
Annona sqamosa Annonaceae Leaves [20]
health of millions of people worldwide. The synthetic drugs
Baliospermum montanum Euphorbiaceae Root [21] used in the treatment of helminthiasis can cause various
Bambusa vulgaris Bambusoideae Leaves [22] side effects, therefore, to overcome these traditional
Barleria buxifolia Acanthaceae Leaves [23] drug therapies have mainly preferred. The authors have
Cucurbitaceae Leaves [24]
compiled information about helminthiasis and medicinal
Benincasa hispida
Borassus flabellifer Palmae Leaves [25]
Capparis zeylanica Cappardiaceae Root [26] plants for its treatment.
Cassia auriculata Ceasalpinaceae Leaves [27]
Croton bonplandianium Euphorbiaceae Leaves [28] Research frontiers
Rutaceae Leaves [29]
The aim of this review article is to compile the entire
Citrus medica
Clerodendrum viscosum Verbenaceae Leaves [30]
Cocos nucifera Palmae Fruit [31] information of helminthiasis and the role of traditional
Coldenia Procumbens Boraginaceae Aerial parts [32] plants in the treatment of helminthiasis.
Coleus aromaticus Lamiaceae Root [33] Related reports
Cotyledon orbiculata Crassulaceae Shoots [34]
The authors have summarized the whole
Curcuma amada Zingiberaceae Rhizome [35]
Diplazium esculentum Athyriaceae Rhizome [36]
pathophysiological information about helminthiasis and
Drypetes sepiaria Euphorbiaceae Leaves [37] medicinal plants used in the treatment of helminthiasis.
Ficus bengalensis Moraceae Fruit [38]
Flacourtiaceae Leaves [39]
Flacourtia sepiaria Innovations & breakthroughs
Gymnema sylvestre Asclepiadaceae Leaves [40]
Hedychium spichatum Zingiberaceae Rhizome [41]
T his review article is very important to promote the
Helicteres isora Sterculiaceae Fruit [42] studies of traditionally used anthelmintic plants which will
Heliotropium indicum Boraginaceae Leaves [43] lead to the development of new anthelmintic substances
Hermannia depressa Malvaceae Shoots [34] with ease of availability and lesser side-effects.
Jasminum mesnyi Oleaceae Leaves [44]
Juglans regia Juglandaceae Stem bark [45]
Leea asiatica Vitaceae Leaves [46] Applications
Leonotis nepetiifolia Lamiaceae Leaves [47] T his review article has been found out to ba a new
Luffa cylindrica Cucurbitaceae Leaves [48] prospect in the treatment of helminthiasis with the help of
Bignoniceae Bark [49]
Millingtonia hortensis
Mimuosops elengi Sapotaceae Root and bark [37,50]
herbal drugs.
Murraya koenigii Rutacae Root [51]
Nicotiana glauca Solanaceae Shoots [34] Peer review
Oenothera rosea Onagraceae Stem and root [52] This is a good study in which the authors have compiled
Rubiaceae Leaves [53]
Paederia foetida
Pajanelia longifolia Bignoniaceae Bark [54]
the information about helminthiasis and medicinal
Portulaca oleracea Portulacaceae Leaves [55] plants with anthelmintic effect. All the information will
Saraca indica Leguminosae Leaves [56] help researchers to explore its scientific evidence in the
Spermacoce ocymoides rubiaceae Leaves [57] prospect studies.
Tamarindus indica Caesalpiniaceae Bark [58]
Tephrosia purpurea Fabaceae Leaves [59]
Terminalia arjuna Combretaceae Bark [60]
Uncaria gambier Rubiaceae Leaves [61] References
Vernonia amygdalina Asteraceae Leaves [19]
Zingiber zerumbet Zingiberaceae Rhizome [41] [1] B undy DA . I mmunoepidemiology of intestinal helminthic
Ziziphus mauritiana Rhamnaceae Leaves [62]
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 J. Biomedical Science and Engineering,
http://www.scirp.org/journal/jbise
2018, Vol. 11, (No. 10), pp: 275-288

Does Hepatitis E Virus Need to Be Considered as a

Re-Emerging Problem in Both Industrialized and
Developing Countries?
Ziyue Zhang1, Tong Wu2, Miranda Zhong3, Jiawen Xiao4, Ziyu Dong5
1
Beijing No. 101 Middle School, Beijing, China; 2Suzhou Singapore International School, Suzhou, China; 3BASIS
International School, Shenzhen, China; 4Arrowhead Christian Academy, Redlands, CA, United States; 5Wuhan
Institute of Biological Engineering, Wuhan, China
Correspondence to: Ziyue Zhang,
Keywords: Hepatitis E Virus, Virology, Transmission, Prevention, Treatment
Received: September 11, 2018 Accepted: October 23, 2018 Published: October 26, 2018
Copyright © 2018 by authors and Scientific Research Publishing Inc.
This work is licensed under the Creative Commons Attribution-NonCommercial International License (CC BY-NC
4.0).
http://creativecommons.org/licenses/by-nc/4.0/
Open Access

ABSTRACT
Hepatitis E caused by the Hepatitis E Virus (HEV) is a liver disease resulting in over 20
million cases every year. Hepatitis E is now considered by some scientists as an emerging
issue as HEV is not only prevalent in developing countries but is increasingly detected in
industrialized nations. In this paper, we try to provide evidence for this notion and what
actions may need to be implemented to prevent further spreading of HEV. The prevalence
of HEV, including its distinct genotype distribution in different geographic regions (in-
cluding both developing countries and industrialized countries) will be discussed; further
discussions of HEV treatments will include the availability and the mechanism of HEV vac-
cines and antiviral treatments used to treat and contain the disease. Additionally, the pre-
vention and spreading of Hepatitis E disease will be discussed in the later section of the pa-
per. With the presentation of HEV transmission route, infection regions, and treatment, we
aim to raise the awareness of the general public toward this liver disease and discuss
whether the high prevalence disease is an emerging disease worldwide. According to the
data we collected, the rate of HEV infection is high and shows a trend of increasing, which
leads to our conclusion and proves our hypothesis that Hepatitis E is a re-emerging disease.

1. INTRODUCTION
In 1978, in the Kashmir Valley of India, an unprecedented outbreak of a water-borne disease swept
around the area and resulted in over 52,000 infected cases, including 1700 deaths, raising the attention of

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the local authorities [1, 2]. This unknown phenomenon drew up a high public health concern and subse-
quently led to intensive studies focusing on identifying the cause of these symptoms. The clinical symp-
toms of patients were similar to those of Hepatitis A, but symptomatic individuals did not have antibodies
for both Hepatitis A Virus (HAV) and Hepatitis B Virus (HBV). These observations suggested that pa-
tients were suffering from a new “enteric non-A non-B Hepatitis (ENANBH) form”. However, little was
known about this disease until 1983, when the etiologic agent was successfully isolated by Russian scientist
Mikhail Balayan. He conducted a self-experiment ingesting a stool sample from infected soldiers, allowing
him to transfer the disease back to his laboratory [3]. Similarly, larger outbreaks emerged in India, China,
and Germany and killed thousands of people. Through autopsies, scientists discovered that all the patients
infected with this virus had severe liver damages; hence, the virus was later classified as the Hepatitis E
Virus (HEV).

1.1. Hepatitis E Disease Description & Symptoms

Ample epidemiological surveys testing for the presence of anti-HEV antibodies have been performed,
all of which demonstrate that large numbers of people have been exposed to HEV at some point in their
lives; however, HEV does not always provoke clinical apparent symptoms [4]. Early signs of HEV infec-
tions, such as fever, vomiting, and faintness, are usually ignored or misinterpreted as signs of the common
flu; more characteristic symptoms, including but not limited to jaundice, itching, pale stools, and darkened
urine, are shown in the terminal stage of infection, and also correlate with chronic liver damage [5].
Two stages of Hepatitis E are detected, including acute and chronic phase. Generally, patients who are
affected by acute infection do not proceed to the chronic phase. People who have immunodeficiencies or
received immune suppressants e.g. due to organ-transplantation are prone to develop chronic Hepatitis E.
Pregnant women also exhibit particularity severe symptoms; their unique immune features make them
incapable to receive most of the clinical drugs; consequently, a high mortality rate around 30% is disclosed
among the infected pregnant women [4].

1.2. HEV Transmission

The main HEV transmission route is through food consumption—consumers who ingest infected
food and then get infected. HEV can also be transmitted through the fecal-oral route, meaning that pa-
thogens in fecal particles would pass from one person to the mouth of another person [5]. Due to the mul-
tiple transmission route of HEV, it is crucial to minimize the intake of uncooked foods (it has been proven
that HEV in raw animal products can be eliminated by cooking above 70 degrees Celsius for 20 mins).
WHO has stated that there is a drastic increase of the Hepatitis E positive population in Germany in the
last decade—the annual rate of endemic cases increased from 30% to approximately 78% [4].
Blood-transfusion and organ-transplantation are the other two transmission pathway. In one of the
reported cases, the patient who received full blood plasma transfusion, got infected by HEV, thus, devel-
oped into chronic HEV due to the immune suppressants he took, which led to a further damage to his
health condition. The blood transfusion-associated HEV appears globally in recent years among European
countries such as Germany and France, Asian regions such as Japan, and North American countries such
as the United States [4].
The underdeveloped sanitary facility and the unqualified hygiene standard establish the fundamental
condition that triggers the outbreak of HEV. Subsequently, rate of HEV infection is extremely high in de-
veloping countries. In short, the primary task is to improve the environmental conditions in those under-
developed areas [4].

1.3. HEV Molecular Virology & Heterogeneity

There are currently 8 known HEV genotypes (parts of the genetic makeup of a cell that determines
the phenotype of a specific organism). It has previously been shown that genotypes 5, 6, and 8 are only
infectious to animal species whereas genotype 1 and 2 are specifically infectious to human. Studies have

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suggested that genotype 3 and 4 could be spread to both humans and animals through different routes. [6]
Current research has shown evidence of infection of genotype 7 on camels and only one case of infection
on humans; hence, more research needs to be constructed for the indication of susceptible species of this
genotype [7].
HEV is a non-enveloped, single-stranded, positive-sense RNA virus which presents three Open
Reading Frames (ORFs) in its genome: ORF1, ORF2, and ORF3. ORF1 occupies two thirds of the HEV
genome and encodes for non-structural proteins of domains of methyltransferase, papain-like cysteine
protease, RNA helicase, and RNA-dependent RNA polymerase activity of the virus; ORF2 encodes for the
viral capsid protein, and it overlaps with ORF3; ORF3, shown in recent research, serves as viroporin and
encodes for the ion channel that facilitates ion influx and outflow of the virus [8, 9].
Although scientists are now able to propagate HEV in laboratories, the life cycle of the virus remains
incompletely understood (Figure 1). However, it is believed that HEV enters the host cells by binding to

Figure 1. Proposed Life Cycle of HEV. Step a: HEV attaches to cell surface via HSPGs or HSC70 and
then enters the cell through unknown receptor. Step b: HEV penetrates the cell membrane and en-
ters the cell. HSPGs and HSC70 may be involved in the process. Step c: the positive-sense genomic
viral RNA serves as the template of translation of ORF1 proteins. Step d: The viral RdRp synthesizes
an intermediate, replicative negative-sense RNA. Step e: transcription of viral RNA. Step f: ORF2
and ORF 3 are translated. Step g: assembly of HEV virus. Step h: the nascent virus is transported to
the cell membrane. Step i: the virus is released from the infected cell (Dianjun Cao, et al. 2012) [10].

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cellular receptors with its capsid proteins allowing the virus to enter the host cell, then the viral genome is
released into the host cell, the ribosome is recruited to translate viral RNA into viral proteins. The process
of resembling and release of Hepatitis E virus is partially comprehended; hence, advanced researches in the
life cycle of Hepatitis E virus are necessary. As by the further comprehension of the life cycle of the virus,
scientists may eventually find a way of treating or preventing HEV infection by interfering the process of
replication of the HEV [10].
HEV is now spreading globally and becoming an immediate emerging problem due to its specific
transmission route and various genotypes. Through intermediates such as uncooked meat or contami-
nated water, healthy individuals would then be infected by HEV, resulting in a consequential effect in a
larger cycle. In different geographic regions, different HEV genotypes are prevalent: The outbreaks of ge-
notype 1 and 2 mostly occurred in developing countries, whereas outbreaks of genotype 3 and 4 are more
commonly discovered in developed countries (e.g. Gt 1, 2 in China and Gt 3 in Germany); hence, the virus
is diverse among its hosts, which increase the difficulty in controlling the spread of the virus [11]. Howev-
er, due to its limited treatments, alternatives are desperately needed to replace RBV and IFN. It will be ne-
cessary to contain HEV more efficiently viral transmission, possible ways including screening blood sup-
plies, assuring food safety and more wide-spread use of the HEV vaccine. In this paper, questions related
to the current situation of hepatitis E will be further discussed, including prevention, treatments, and the
problems researchers encounter within current studies of HEV.

2. HEPATITIS E INFECTIONS IN BOTH INDUSTRIALIZED AND DEVELOPING COUNTRIES

HEV is prevalent in many countries. The main routes of HEV transmission vary, however, signifi-
cantly in different geographical regions. Our further analysis is based on the different situation facing by
countries such as China, Germany, and India, illustrating the variety of HEV infection in developed coun-
tries and developing countries.

2.1. Infection in Germany

Hepatitis E has been an under-reported infectious disease in Germany until recently. 17% of the
Germany population was once infected with HEV and this infection rate has been increased for at least 40
folds in the past decades, subsequently, gaining publicity and health concerns within the country. A pri-
mary factor that contributes to the spread of HEV is eating uncooked pork products, which is fairly popu-
lar among the Germans. It has been identified that four wild boar populations in east and west Germany
are also reservoirs of HEV genotype 3 and present high rate of HEV infections [12, 13].
HEV within pork products cannot be eradicated if uncooked. In a research conducted in 2001, 200
porcine liver samples in 81 butcher shops and groceries collected from all across Germany were tested, and
4 of the 200 samples were contaminated with HEV. Further research showed that 14 out of 70 (20%) of the
tested raw sausages and 11 out of 50 (22%) of the liver sausages were HEV RNA positive [14].
The consumption of these pork products will lead to a wide range of HEV infection in humans, in
fact, it has already contributed to 300,000 cases per year nationwide [12].
People who live in close contact with pigs daily, usually pig farmers and swine hunters, are especially
susceptible to HEV infection. Statistical records comparing the seroprevalence of subjects in contact with
pigs (13.2% - 32.8%) to that of non-exposed individuals (7.7% - 21.7%) shows a significant difference [15].
Hence, the focus of controlling HEV infection rate in industrialized countries such as Germany should be
on the screening of pig herds for swine HEV infection and vaccination of susceptible people. The latter
would require, however, the approval of the Chinese HEV vaccine to the European market.
In addition to the transmission of HEV from infected swine to humans, human to human transmis-
sion is another route of spreading viral infection. Human to human transmission of HEV in Germany is
occasionally caused by blood transfusion—people who receive blood donation from HEV positive patients
generally get infected by the virus and develop Hepatitis E. In Germany, the first recorded case of transfu-
sion-associated HEV infection was in 2013. The patient was tested HEV RNA positive and suffered from

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chronic HEV infection after receiving aphaeresis platelets from a blood donor on July 4th, 2013. The donor
was tracked down and tested, and the result showed that he was infected with HEV during the blood do-
nation but did not show any initial symptoms [16]. This specific incidence raised public awareness to-
wards the safety of blood transfusion. 69 in 1019 blood donors (6.8%) tested are anti-HEV IgG positive,
meaning they were once infected with HEV. Later, a sample of 16,125l blood donors was screened during
donation, about 0.08% of which is tested HEV RNA positive, indicating that around 20,000 blood donors
will transmit HEV to patients receiving blood transfusion [17, 18]. Although no vaccine is available in
Germany to prevent transfusion-associated HEV infection among patients, the method of screening blood
pools with viral RNA is now under research.

2.2. Infection in India

India has long been an endemic zone of enterically transmitted viral hepatitis. Recent research shows
the HEV prevalence in different regions of India: 53% in Kashmir, 9.4% - 58.9% in Uttaranchal, 44.6% in
Punjab, 53.3% in Delhi, 17.9% in Uttar Pradesh, 42% in Bihar, 41.05% in West Bengal, 49.7% in Rajasthan,
35.76% in Mumbai, and 17.3% in Chonnal [19] (Figure 2).
However, unlike Germany, the main transmission routes of HEV in India are not porcine or transfu-
sion-associated. HEV is transmitted through sewage-contaminated water in India due to their low sanita-
tion standard. About 80% of the sewage generated flows into the main water resource: natural rivers, lakes,
ponds, and the underground water [20]. A recent study showed that in Northern India, 79 out of the 192
(41%) sewage samples were HEV RNA positive, and in Southern India, 80 out of 144 (55.6%) were tested
positive [21]. As mentioned in the previous sections, HEV can be transmitted through the fecal-oral route,
Hence, it is reasonable to conclude that most cases of HEV infections in India are caused by consumption
of contaminated water. Therefore, the main focus has to be on ensuring clean water supplies across the
continent to limit the spread of HEV. Additionally, mass vaccination could further aid in spreading HEV.
However, as stated numerous times, the HEV vaccine is currently only available in China.

Figure 2. Rate of infection of HEV in different regions of India (Jain P., et al. 2013) [19].

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2.3. Infection in China
The infection rate of HEV in China varies by the disparity between rural and urban areas. Low quality
of hygiene and consumption of contaminated food is the main cause of HEV transmission in the rural
areas. Tibet, for example, a typical representative of rural regions in China, develops a high infection rate
of HEV genotype 3 and 4 due to the nomadic lifestyle adopted by the locals who rely on the domestication
of livestock as a financial resource. A recent study has shown that 236 of the 600 individuals, i.e. approx-
imately 40 percent, in a study cohort from that region present positive results for anti-HEV IgG [22]. In
contrast, some of the more developed areas in China such as Anhui, Beijing, and Henan, the infection rate
ranges from 10% - 20%; in Jiangsu, Chongqing, and Shanxi 20% - 30% of the whole population has been
exposed at some point in their lives to HEV [23]. The detailed infection rate in percentage categorized by
districts of China is listed below in the pie chart.
Another factor contributing to the overall fairly high HEV prevalence in China is the large consump-
tion of pork. Over 400,000 tons of pork is imported to China every year. Furthermore, research has shown
that HEV prevalence among pig herds in different regions of China is relatively high, ranging from 1.6% to
37.5% [23]. However, the safety of pork products, irrespective of whether they are domestic or imported,
cannot be guaranteed: there is an underlying risk of being contaminated with HEV (primarily HEV geno-
type 3 and 4), which likely contributes to spreading the disease to humans nationwide. One possibility to
break the transmission cycle would be to vaccinate more people or even consider veterinary vaccinations.
However, the latter is impractical when considering the significant costs of vaccinating entire pig herds of
millions of animals.

3. HEPATITIS E DISEASE CONTROL & PREVENTION

3.1. HEV Vaccine
HEV vaccine is made up of a type of HEV capsid-derived protein antigen in conjunction with an ad-
juvant [25]. Its mechanism is hinging on the function of ORF2, encoding for capsid protein involved in
virion assembly and virus’ immunogenicity, and infectious particles composed of three glycosylation sites
could be formed when the corresponding protein is transcribed [26].
Multiple studies were then directed to assess the immunogenicity and efficacy of the HEV vaccine. In
a clinical trial conducted in 2007, 2000 out of the 5323 investigated subjects, who were at risk of contract-
ing HEV, were involved in the experiment to determine the efficacy of the HEV vaccine. Within the test-
ing group excluded from the dropout, 1000 randomly selected subjects were immunized and another 1000
received a placebo. Then, each sample is measured for anti-HEV immunoglobulin that affiliates the reci-
procal antigen. The result showed that the immunoglobulin found inside the vaccinated group increased
to 100% till the third dose; by the time that the trial ended, their immunoglobulin count has decreased to
56.3%. Meanwhile, in the placebo group, the HEV antibody presented increased to10.6%, which indicates
infections of HEV (Figure 3) [27].
The chart (Figure 4) illustrates the HEV antibody percentage in respond to days during clinical trial,
a measurement of antibody was conducted after each dose. A significant increase of antibody in vaccine
group could be seen after the third dose. The slightly increase of antibody in placebo group may indicates
the infection of HEV [27].
The final conclusion was drawn from the measurement of anti-HEV immunoglobulin that affiliates
the reciprocal antigen. Hence, this vaccine was proven to be effective. Fortuitously, this outcome shows
that other regions would yield the same effects since all HEVs are generated from one single serotype.
Another long-term efficiency test of the HEV vaccine shows that in order to prevent people from HEV
infection in a long run, at least three doses of such vaccine need to be injected, and after these three doses
of vaccine injected, full immunity towards HEV will be conducted [28].
While the clinical trial reflects that this vaccine is effective, the HEV vaccine is only available in Chi-
na. However, HEV vaccination in China is not compulsory. Although there are conclusive data on how
many people in China have been vaccinated, a survey conducted by a group of Chinese researchers attests

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 Figure 3. Seroprevalence of Anti-HEV in 11 provinces, China (Dong, et al. 2012) [24].

Figure 4. HEV antibody percentage after vaccination.

that 82.49% of the investigated population are willing to pay for such vaccines [29]. This indicates a great
prospect of this vaccine in high risk areas.
Practicality of Implementing the HEV Vaccine in Industrialized Countries
On the bright side, the prevalence of such vaccine is shown to be practical, especially in highly in-

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fected developed countries in Germany. Assuming each county is in equilibrium, one could therefore use
GDP per Capita PPP, GDP per capita calculated based on purchasing power parity, as an indicator as av-
erage annual income in a given country, providing an impartial reflection of punching ability in the dis-
cussed countries. Of the three previously discussed countries, Germany has the highest purchasing power
in 2017 (44,432 USD), followed by China (14,401 USD) and India (6096 USD) [30, 31]. This statistic shows
that the dissemination in Germany and China should be relatively easier, since the family has more ex-
crescent income used for family health care. For countries that have the condition to implicate vaccination
to pigs and other susceptible animals should create standardized examinations before the meat has been
imported inside the market.
Practicality of Implementing the HEV Vaccine in Developing Countries
As for India, other preventions that interrupts with HEV’s transmission cycle could be implemented,
such as proclaiming the consumption of well-cooked meat cuisine, or improving their hygiene by con-
structing more drainage and filtration system in the condensed population areas. Especially the latter ap-
proaches may be particularly important since sewage is the main route of HEV transmission [32]. What is
more, the local government should take the risk of potential HEV outbreaks more seriously. The adminis-
trator from the government needs to provide subsidies to vaccine researchers and producers to abate its
market price if needed.
Last but not least, the last threshold must be implemented in order to fully eliminate HEV transmis-
sion, which means vaccination for recipients prior to transplantation and subsequent immunosuppression.
For instance, recommendation of vaccination shall be made to those patients who are about to receive or-
gan transplantation. If one is informed that he or she will need an organ transplant at some point, it’s bet-
ter for them to get vaccinated before the surgery. Statistics from the organ donation administration centers
of each countries shows that, in Germany, there are 797 cases of recorded successful organ transplanted in
2017, whereas there are 5148 cases recorded in China [33, 34]. This implies that the demand of such vac-
cines from organ transplant patients in China is much higher than those in Germany.

3.2. Blood Screening

The transmission diversity in HEV with an increasing infection rate indicates the importance of HEV
prevalence being assessed in blood screenings. In industrialized countries (China and Germany included),
blood samples are usually selected for anti-HEV IgM or IgG testing before donation [17, 35, 36]. Con-
versely, no definite blood screening policy is set in HEV screening in India [37] and common assays like
PCR in blood HEV RNA is also rarely practiced due to their lax blood screening policies; a study of HEV
blood testing assays are conducted in different geographical regions for research purposes. In a Chinese
study, a high viremia prevalence ranging from 0.1% to 29.2% among the blood samples tested for an-
ti-HEV IgM and IgG, and the viral antigen HEV RNA is presented [38]. An increase of HEV prevalence
was observed in Germany in 2014 to 2015 from 670 to 1267 [12]; therefore, the establishment of blood
screenings are necessary in both developed and developing countries, since cirrhosis and severe liver
damages may be developed after the acute infection; in some epidemiological areas like Punjab in India,
routine examinations should be conducted in blood centers to prevent further spreading of the disease.
Possible prevention could be conducted by using serological screening for anti-HEV IgM in blood
donors, reducing transfusion-transmitted risks especially for immunocompromised individuals and preg-
nant women [4, 39]. Moreover, a routine HEV antibody testing could be performed among blood donors
to control the prevalence of HEV. In recent years, HEV-antigen testing paper was invented (WANTAI
BioPharm, China), which uses the “enzyme-linked immunosorbent” assay, primarily focusing on the IgM
within the patient’s body and providing instant results [40]. Moreover, the price for the testing paper is
approximately $25 per 1000 testing papers [41], which is a reasonable cost that the blood donation organ-
izations are able to afford; hence, it is possible to generalize the HEV-antigen testing paper usages in blood
centers and clinics and add it to blood testing to effectively monitor HEV, to those people who tested posi-
tive could be further tested and receive treatments in time if needed.

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 Routine blood screenings are necessary for the control of HEV transmission and prevalence, and it
should be used in more countries to address the global health concern; however, there might be some un-
derlying difficulties that blood centers could face, including the size of sample pool and limited financial
support in addition to the unlikeness of testing blood the samples used in an emergent time like transfu-
sions (the time needed for PCR and the sample size).
Ranging from 4.10% to 27.9%, the seroprevalence of HEV showed in German study has indicated is
higher in humans living in area with a lot of pig farming in Germany [15]. The group of individuals who
are exposed to easily-infected and infected species have a higher risk of getting infected by HEV. Consi-
dering the limited treatments, blood screenings should be used advocated specifically corresponding to the
individuals who have high-risk in epidemic areas as well as transplant or blood donation recipients; Nev-
ertheless, to achieve the full control of this zoonosis (HEV), it is necessary to address the safeties of the
domestic pigs and other animals entering the human food chain.

3.3. Treatments
Studies have shown that pregnant women and those who are immunocompromised, usually those
who received organ-transplantation, are the most vulnerable to HEV infection. Unfortunately, they are
also the ones who are not able to receive existing treatments, such as ribavirin (RBV) or interferons (IFN),
since RBV is teratogenic and IFNs can lead to graft rejection [42]. Thus, alternatives to these drugs need to
be developed.
The most common way of treating HEV infection is by using the antiviral therapy, which includes the
usage of RBV or IFNs [4]. IFNs are cytokines induced by the immune system usually in response to infec-
tion [43]. There are generally three classes of IFNs, type I, II and III. In this case, type I IFN, specifically a
subtype called IFNα is used against HEV. IFNα was shown effective in treating Hepatitis E (research
showed that 95% of HEV was eliminated in the observed patient) [44]. To increase the half-life of ex-
ogenously administered IFN, a pegylated form (pegIFNα) has been developed which is highly effective in
abrogating HEV (100% in the sixth month) [45]. More specifically, before the patients have intake the
RBV, they should first wait for a few months no matter whether their immunological risk is high or low
and then see if their bodies could immunologically fight the pathogen themselves. If their infections do not
get any better after these months, an antiviral therapy using ribavirin will be needed. Then, if further test-
ing shows that the HEV RNA still test as positive, then the ribavirin therapy should be continuously pro-
ceeded. Otherwise, the patient could continue the treatment after the HEV relapses (Figure 5).
However, treatment with IFNs has substantial side effects and can increase the risk of graft rejection
and thus their practical utility is limited. The side effects of RBV include hemolytic anemia, pulmonary
disorders, hypersensitivity and even bone marrow suppression [42]. Furthermore, cardiac patients, preg-
nant women, and their male partners should not be taking RBV, as a reverse effect in treating HEV may be
established, which further lead to side effects like hypertension, birth defects and even stillbirth [5, 47].

4. CONCLUSION
Based on our research, we can draw on the conclusion that Hepatitis E can be now identified as a
re-emerging disease and is causing millions of cases worldwide every year. HEV is highly prevalent in both
many developing and industrialized nations and significantly contributes to human morbidity and mortal-
ity world-wide. Thus, raising public awareness to the prevalence of Hepatitis E is necessary. Further, gen-
eration of novel treatments that suit all groups of people (including pregnant women) and methods of
prevention that can be applied in all countries must be a priority. As mentioned in previous sections, the
current treatment for Hepatitis E includes the use of ribavirin and interferons which have proven efficacy.
However, both treatments can cause severe side effects and cannot be employed when treating pregnant
women infected by HEV and chronic Hepatitis E in immunocompromised transplant recipients; thus,
there is an urgent need for developing novel, more tolerable treatments. Furthermore, actions in prevent-
ing HEV from spreading should be taken. Since there are great differences in the cause of HEV infections

https://doi.org/10.4236/jbise.2018.1110023 283 J. Biomedical Science and Engineering

Figure 5. Simplified procedure of treating acute HEV infection Kamar, N., Lhomme, S., Peron, O.
M., Alric, L., & Izopet, J. (2016, August 15) [46].

between industrialized countries and developing countries, preventive strategies need to be considered
based on separate situations. In industrialized countries such as Germany, where HEV infections are gen-
erally caused by consumption of HEV contaminated pork and transfusion of HEV positive blood, routine
screenings for blood resource and pork can be put into application. In contrast, for those developing
countries such as India where HEV are transmitted to humans primarily through sewage contaminated
water, assurance in clean water supply should be their primary task. Global vaccination against HEV is
also a possible solution in preventing the spread of viral infections. Although effective vaccines have been
invented it is only approved for use in China but no other parts of the world. Efforts should be undertaken
to make HEV vaccines widely accessible to all parts of the world, both industrialized and developing
countries, under affordable costs. This would be a major tool for containing the spread of HEV and pre-
venting the severe and sometimes fatal disease.

ACKNOWLEDGEMENTS
Special thanks to Professor Alexander Ploss from Princeton University for the academic support of
this article and to the CIS program for offering this opportunity of studying and doing research upon this
subject.

https://doi.org/10.4236/jbise.2018.1110023 284 J. Biomedical Science and Engineering

CONFLICTS OF INTEREST
The authors declare no conflicts of interest regarding the publication of this paper.

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 ORIGINAL CONTRIBUTION
Risk Factors for Typhoid and
Paratyphoid Fever in Jakarta, Indonesia
Albert M. Vollaard, MD
Soegianto Ali, MD, MSc
Henri A. G. H. van Asten, MD, MPH
Suwandhi Widjaja, MD, PhD
Leo G. Visser, MD, PhD
Charles Surjadi, MD, PhD
Jaap T. van Dissel, MD, PhD
T
YPHOID FEVER, A FOOD- AND WA-
terborne disease caused by Sal-
monella enterica serotype typhi
(S typhi), is a serious public
health problem in developing coun-
tries that claims 600000 lives every year.1
Paratyphoid fever, caused by Salmo-
nella paratyphi A, B, or C, has a disease
presentation similar to that of typhoid
fever, but its incidence is reportedly
about one tenth that of typhoid (ratio,
1:10-20).2,3 In developing countries the
identification of risk factors and rel-
evant route of transmission for a dis-
ease such as typhoid fever is essential for
the development of rational control strat-
egies. Resources could consequently be
allocated to where they count most, eg,
to the construction or expansion of
water distribution networks or sewage
systems, chlorination of drinking wa-
ter, ensurance of food safety, hygiene
education, mass vaccination cam-
paigns, and/or the identification of car-
riers within or outside the households
of patients.
Risk factors for typhoid fever have
been identified in several epidemio-
logic studies suggesting either water-
borne 4 - 8 or foodborne transmis-
sion.7,9-11 Whether these factors coincide
with those for paratyphoid fever has not
been determined. The assumption is
that in paratyphoid fever, a higher dose
©2004 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 10/20/2019
Context The proportion of paratyphoid fever cases to typhoid fever cases may change
due to urbanization and increased dependency on food purchased from street ven-
dors. For containment of paratyphoid a different strategy may be needed than for ty-
phoid, because risk factors for disease may not coincide and current typhoid vaccines
do not protect against paratyphoid fever.
Objective To determine risk factors for typhoid and paratyphoid fever in an en-
demic area.
Design, Setting, and Participants Community-based case-control study con-
ducted from June 2001 to February 2003 in hospitals and outpatient health centers in
Jatinegara district, Jakarta, Indonesia. Enrolled participants were 1019 consecutive pa-
tients with fever lasting 3 or more days, from which 69 blood culture–confirmed ty-
phoid cases, 24 confirmed paratyphoid cases, and 289 control patients with fever but
without Salmonella bacteremia were interviewed, plus 378 randomly selected com-
munity controls.
Main Outcome Measures Blood culture–confirmed typhoid or paratyphoid fe-
ver; risk factors for both diseases.
Results In 1019 fever patients we identified 88 (9%) Salmonella typhi and 26 (3%)
Salmonella paratyphi A infections. Paratyphoid fever among cases was indepen-
dently associated with consumption of food from street vendors (comparison with com-
munity controls: odds ratio [OR], 3.34; 95% confidence interval [CI], 1.41-7.91; with
fever controls: OR, 5.17; 95% CI, 2.12-12.60) and flooding (comparison with com-
munity controls: OR, 4.52; 95% CI, 1.90-10.73; with fever controls: OR, 3.25; 95%
CI, 1.31-8.02). By contrast, independent risk factors for typhoid fever using the com-
munity control group were mostly related to the household, ie, to recent typhoid fe-
ver in the household (OR, 2.38; 95% CI, 1.03-5.48); no use of soap for handwashing
(OR, 1.91; 95% CI, 1.06-3.46); sharing food from the same plate (OR, 1.93; 95% CI,
1.10-3.37), and no toilet in the household (OR, 2.20; 95% CI, 1.06-4.55). Also, ty-
phoid fever was associated with young age in years (OR, 0.96; 95% CI, 0.94-0.98).
In comparison with fever controls, risk factors for typhoid fever were use of ice cubes
(OR, 2.27; 95% CI, 1.31-3.93) and female sex (OR, 1.79; 95% CI, 1.04-3.06). Fecal
contamination of drinking water was not associated with typhoid or paratyphoid fe-
ver. We did not detect fecal carriers among food handlers in the households.
Conclusions In Jakarta, typhoid and paratyphoid fever are associated with distinct
routes of transmission, with the risk factors for disease either mainly within the house-
hold (typhoid) or outside the household (paratyphoid).
JAMA. 2004;291:2607-2615 www.jama.com
of bacteria is required for infection than Author Affiliations: Department of Infectious Dis-
eases, Leiden University Medical Center, Leiden, the
in typhoid fever; consequently, food is Netherlands (Drs Vollaard, Visser, and van Dissel); De-
implicated as the major vehicle for partment of Biology, Medical Faculty (Dr Ali), Depart-
ment of Internal Medicine (Dr Widjaja), and Center
transmission of paratyphoid fever, since for Health Research (Dr Surjadi), Atma Jaya Catholic
Salmonella bacteria can multiply in University, Jakarta, Indonesia; and Institute for Inter-
national Health, University Medical Center Nijme-
food.12 Comparison of the transmis- gen, Nijmegen, the Netherlands (Dr van Asten).
sion of both diseases is becoming in- Corresponding Author: Jaap T. van Dissel, MD, PhD,
Department of Infectious Diseases, C5-P, Leiden Uni-
creasingly relevant, because recent re- versity Medical Center, PO Box 9600, 2300 RC Leiden,
ports have demonstrated an increasing the Netherlands (j.t.van_dissel@lumc.nl).
(Reprinted) JAMA, June 2, 2004—Vol 291, No. 21 2607
 RISK FACTORS FOR TYPHOID AND PARATYPHOID FEVER IN INDONESIA
occurrence of paratyphoid fever.3,13 It
is not clear whether this is due to in-
completeness of epidemiologic data in
endemic countries or to a downward
trend in the incidence of typhoid fe-
ver1,14 and a consequent relative or
absolute increase in the incidence of
paratyphoid fever. In consequence,
however, public health measures may
well be refocused. In particular, re-
cent interest in mass immunization as
a control strategy in regions of ende-
micity needs to be reconsidered if the
incidence of typhoid fever is decreas-
ing and paratyphoid fever is on the rise,
because current typhoid fever vac-
cines (ie, parenteral Vi and oral Ty21a
vaccine) do not protect against paraty-
phoid fever.2
In this community-based case-
control study in an endemic area in East
Figure 1. Study Area ( Jatinegara, Jakarta, Indonesia), Showing Households of Cases
With Typhoid and Paratyphoid Fever and Fever Controls
INDIA CHINA
MYANMAR
LAO PDR
THAILAND
VIETNAM
CAMBODIA
BRUNEI
MALAYSIA
INDONESIA
Jakarta
N Jatinegara Area
Cili w u n g
0 1
km
2608 JAMA, June 2, 2004—Vol 291, No. 21 (Reprinted)
Downloaded From: https://jamanetwork.com/ on 10/20/2019
Jakarta, Indonesia, we compared case
patients having paratyphoid and ty-
phoid fever with random community
controls to identify hygienic prac-
tices, eating habits, and environmen-
tal and household characteristics that
could elucidate prevailing transmis-
sion routes. For this purpose we also
examined the microbiological quality
of drinking water and cultured stools
of intrahousehold food handlers to de-
tect transient or chronic carriers. A sec-
ond control group composed of pa-
tients with nonenteric fever was used
for comparison and confirmation of
the results. Patients with typhoid fe-
ver, paratyphoid fever, and nonen-
teric fever were identified in a prospec-
tive passive-surveillance study involving
hospitals and outpatient health cen-
ters in the study area.
N June 11, 2001, to February 4, 2003.
Teluk
TAIWAN
PACIFIC
Jakarta
OCEAN
PHILIPPINES
JAKARTA
Jakarta
PAPUA
NEW GUINEA
0 10
km
er
u nt
li S
Ka
Household
Typhoid Fever Case
Cipinang
Paratyphoid Fever Case
Fever Control
METHODS
Study Area and Population
The Jatinegara district in East Jakarta, a
10.6-km2 area with 262699 registered
inhabitants (as of March 2002), was se-
lected as the study area (FIGURE 1) be-
cause of its varied socioeconomic con-
ditions and good access to puskesmas
(ie, public community health centers
providing medical care for low-income
residents of Indonesia). The local cli-
mate has 2 distinctive seasons: a rainy
season (December-April) and a dry sea-
son (May-November). Three rivers cross
the area, making the adjacent subdis-
tricts prone to flooding. There is no sew-
age system in the area. Vaccination cam-
paigns have not been initiated in the area.
Study Design and Selection Criteria
The study was approved by the Indone-
sian National Institute of Health Re-
search and Development (Litbangkes)
and provincial authorities. A passive sur-
veillance system was established from
Health care facilities in the study area
were approached for the surveillance
study. Those participating included all
4 hospitals in the immediate vicinity, 8
of the 13 additional small private out-
patient clinics in the area, and all 12
Area of Detail puskesmas. A fee of US $0.35 covers 3
days of antibiotic treatment, but cul-
tures or Widal tests are not part of the
usual diagnostic practice in puskesmas.
Eligible patients were individuals living
in the study area who consulted one of
the participating health care facilities be-
cause of self-reported fever for 3 or more
consecutive days. A single blood speci-
men for culture was collected from each
eligible patient. Depending on the age of
the patient, 5 to 10 mL of blood was col-
lected into blood culture vials (aerobic)
containing antibiotic-absorbing resins
(Bactec; Becton Dickinson, Franklin
Lakes, NJ) that were provided to the cen-
ters by the study group free of charge.
Cases were eligible patients with
blood culture–confirmed S typhi or
S paratyphi infection. All cases were
subject to a household visit within a
month after the febrile episode that
prompted the blood culture.
©2004 American Medical Association. All rights reserved.

Blood cultures of patients with non-
enteric fever showed either no growth
or bacteria other than S typhi or S para-
typhi as cause of fever. Malaria could
be excluded in the differential diagno-
sis of prolonged fever, because trans-
mission does not occur in Jakarta. Ev-
ery second consecutive patient with
nonenteric fever was selected as a fe-
ver control and visited. Also, during the
surveillance, community controls were
randomly selected within a random
household in every third rukun tet-
angga (ie, the smallest administrative
unit of 40-60 area households) of a total
of 1140 rukun tetanggas. When a com-
munity control reported fever in the 30
days preceding the interview or re-
fused participation, the house on alter-
nating sides of the initially selected
household was approached. The selec-
tion of both groups of controls was
nonmatched for age, sex, or neighbor-
hood (ie, residence in 1 of the 8 sub-
districts of Jatinegara) to limit selec-
tion bias and prevent overmatching.
Four controls from both groups for
every case of enteric fever were se-
lected to increase statistical power.
Household Visits
and Sample Collection
Cases and controls were interviewed by
trained medical school graduates, us-
ing a standardized questionnaire that
included the known risk factors from
previous studies and questions from a
questionnaire that was used in a simi-
lar risk factor study, which had been lo-
cally tested and validated.6 Written in-
formed consent was provided by all
participants at the household visit. To
prevent the overrepresentation of mul-
tiple-case households, only 1 patient
(ie, the first reported case or fever con-
trol) per household was interviewed. If
cases or controls were younger than 13
years, the mother or guardian was in-
terviewed. No time frame for hygiene
behavior and food habits was men-
tioned, because it aimed at the descrip-
tion of usual practice. A household was
defined as a dwelling whose inhabit-
ants ate from the same pot. Flooding was
defined as inundation of the house of
©2004 American Medical Association. All rights reserved.
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RISK FACTORS FOR TYPHOID AND PARATYPHOID FEVER IN INDONESIA
a participant in the 12 months preced-
ing the interview. Intrahousehold food
handlers were defined as individuals
preparing meals for cases or controls
3 or more times a week. A single stool
sample of 2 g was collected from all
cases, controls, and their intrahouse-
hold food handlers in a vial with Cary-
Blair transport medium and samples
were processed within 24 hours after
collection. Water samples of 150 mL di-
rectly from the source of running drink-
ing water were collected in the house-
holds of 62 typhoid and 20 paratyphoid
cases, 341 community controls, and 233
fever controls using World Health Or-
ganization guidelines.15
Laboratory Methods
Blood culture vials from outpatient fa-
cilities were transported on the day of
collection to Mitra Internasional, one of
the participating private hospitals with
a microbiology laboratory certified by the
International Organization for Standard-
ization. Blood cultures were incubated
for up to 7 days. Samples demonstrat-
ing growth were plated on blood agar
medium. Salmonella typhi or S para-
typhi A were identified by use of agglu-
tination antisera (Polyvalent, D, Vi, H,
and Paratyphi A; Murex Biotech Ltd,
Dartford, England) and biochemical tests
(Microbact; Medvet Diagnostics, Ad-
elaide, Australia). Susceptibility against
chloramphenicol, ampicillin, cotrimoxa-
zole, and ciprofloxacine was tested by
disk diffusion on Mueller-Hinton agar.
Stool samples were cultured for Salmo-
nella bacteria using selenite enrich-
ment broth (Oxoid Ltd, Hampshire,
England). Suspected colonies as iden-
tified by visual inspection were plated
on xylose-lysine-desoxycholate agar and
Salmonella-Shigella agar, and on triple
sugar iron agar, SIM (sulphide and in-
dole production and motility) me-
dium, and Simmons citrate (Oxoid).
Bacterial identification was identical to
that for bacteria from blood cultures.
Samples from the sources of drink-
ing water were transported on ice and
processed within 6 hours after collec-
tion at the Nusantara Water Centre.15
In samples from piped water the bac-
(Reprinted) JAMA, June 2, 2004—Vol 291, No. 21 2609
tericidal effect of chlorine during trans-
port was neutralized by 0.1 mL of 10%
sodium thiosulphate. Water samples
were examined for total and fecal co-
liforms by use of most probable num-
ber method.15 Fecal contamination was
defined as a most probable number in-
dex for fecal coliforms of 1⁄100 mL or
greater.
Statistical Methods
Data from the questionnaires were en-
tered twice using EpiInfo 6.04b soft-
ware (US Centers for Disease Control
and Prevention, Atlanta, Ga), vali-
dated, and imported into SPSS version
11.5 (SPSS Inc, Chicago, Ill) for statis-
tical analysis. After the first 3 months of
surveillance, an interim analysis was per-
formed and the needed sample size was
calculated; a minimum sample size of 80
enteric fever cases (assuming 4 times as
many fever controls) was required to de-
tect significant associations (P⬍.05) be-
tween key exposure variables and out-
come, with a power of 0.80. Normally
and nonnormally distributed numeri-
cal variables were analyzed using t tests
and Mann-Whitney U tests, respec-
tively. Measures for association were ex-
pressed as odds ratios (ORs) for dis-
ease with their 95% confidence intervals
(CIs) for categorical variables. To con-
trol for confounding, a multivariate
analysis was performed using logistic re-
gression with a forward likelihood ra-
tio test with the significantly associ-
ated variables from the bivariate analysis
and potential confounders (eg, age,
sex, income, and neighborhood resi-
dence).16 Sex and income were also in-
cluded in the bivariate analysis; age and
neighborhood residence were not. Effect
modification by interaction of age, sex,
or income was tested, but these terms
were not significantly associated and did
not change the ORs of associated vari-
ables. The attributable risk of each in-
dependently associated variable from the
multivariate analysis was calculated.17
RESULTS
Surveillance Study
During the study period 1019 consecu-
tive patients with fever lasting 3 or more
 RISK FACTORS FOR TYPHOID AND PARATYPHOID FEVER IN INDONESIA

days were included. We identified 88 cotrimoxazole; all S paratyphi A Household Visits

S typhi and 26 S paratyphi A infec- strains were susceptible to these anti- In total, 69 typhoid fever cases, 24
tions. In 905 patients with nonenteric biotics. paratyphoid fever cases, 289 fever con-
fever, 11 had bacteremia of another Patients with typhoid and paraty- trols, and 378 community controls
cause (Staphylococcus aureus [n = 7], phoid fever reported a median of 4 days were available for analysis (Figure 2).
Klebsiella pneumoniae [n=2], and Strep- (interquartile range [IQR], 3-7) of fe- Not all of the cases and fever controls
tococcus spp [n = 2]), whereas the re- ver before blood cultures were taken. could be interviewed. Two fever con-
maining 894 patients were culture- This period was similar to that in pa- trols died. Three cases (3%) and 8
negative (F IGURE 2). Most of the tients with nonenteric fever (median, 4 fever controls (2%) were secondary
patients were treated in the puskes- days; IQR, 3-54). The age of all pa- patients from households in which
mas (n = 717 [70%]), and fewer pa- tients enrolled in the surveillance study only the first patient was interviewed
tients in hospitals (n = 113 [11%]) and ranged from 1 to 76 years (3-59 years to prevent overrepresentation of these
outpatient clinics (n=189 [19%]). The for patients with enteric fever and 1-76 households. Five cases (4%) and 47
relative number of patients with ty- years for those with nonenteric fever). fever controls (10%) were not living in
phoid or paratyphoid fever among fe- The number of enteric fever cases en- the study area. Some addresses could
brile patients was similar for all health rolled in the dry season was higher than not be found or patients had migrated
care centers (P=.81). that in the rainy season (ratio, 7:3) and out of the area (13 [11%] and 79
Typhoid and paratyphoid fever this ratio was similar (P⬎.05) in pa- [18%] for cases and fever controls,
accounted for 114 (11%) of the febrile tients with nonenteric fever (ratio, 6:4). respectively). Due to manpower con-
episodes identified. Twenty-three per- Referring physicians reported prior use straints, 10 fever controls (2%) could
cent (26/114) of enteric fevers were of antibiotics in 26 patients (23%) with not be visited; 11 fever controls (2%)
paratyphoid fever. Three (3%) of typhoid or paratyphoid fever and in 200 but none of the remaining cases
the 88 S typhi strains were resistant patients (22%) with nonenteric fever refused cooperation. Two fever con-
to chloramphenicol, ampicillin, and (P=.86). trols had positive stool culture results
(for S typhi [n = 1] and S paratyphi A
Figure 2. Study Inclusion of Typhoid and Paratyphoid Fever Cases, Fever Controls, and
[n = 1]) at the household visit and
Community Controls in Jatinegara, Jakarta, Indonesia, June 2001-February 2003 were therefore excluded from the
analysis.
1019 Consecutive Patients With Fever ≥3 d 380 Community Controls Enteric fever cases and fever con-
trols were visited a median of 24 (IQR,
21-29) days after the blood culture. Fe-
114 With Enteric Fever 905 With Nonenteric Fever
ver controls reported to be diagnosed
88 Salmonella typhi 11 Had Positive Blood and treated for the following diag-
26 Salmonella paratyphi Culture
7 Staphylococcus aureus
noses: suspected typhoid fever (n=126
2 Klebsiella pneumoniae [44%]), dengue fever (n=11 [4%]), res-
2 Streptococcus spp
894 Had Negative Blood piratory tract infections (n=10 [3%]),
Culture tuberculosis (n = 3 [1%]), influenza
(n=3 [1%]), gastroenteritis (n=2), uri-
450 Fever Controls Selected for nary tract infection (n = 1), and en-
Household Visit
cephalitis (n = 1); 132 patients (46%)
were not informed of the working
21 Excluded 161 Excluded 2 Excluded (Same Household as diagnosis.
3 Not First Case Reported in 2 Died Fever Control)
Household 8 Not First Reported Case During the study period, 380 ran-
5 Not Living in Study Area in Household dom households in the study area
13 Not Located or Moved Out 47 Not Living in Study Area
of Study Area 79 Not Located or Moved community were visited; 289 (76%)
Out of Study Area of the community controls agreed to
10 Could Not Be Visited
11 Refused to Participate participate at the first approach and
2 Had Positive Stool Culture the remaining 91 (24%) were the
1 S typhi
1 S paratyphi
neighbors from the initially selected
2 Same Household as households. From 2 households of
Community Control
community controls a patient with
nonenteric fever was included later
93 Cases Included 289 Fever Controls Included 378 Community Controls Included in the course of the study period.
69 Typhoid Fever
24 Paratyphoid Fever These 2 households were excluded
from the analysis.
2610 JAMA, June 2, 2004—Vol 291, No. 21 (Reprinted) ©2004 American Medical Association. All rights reserved.

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 RISK FACTORS FOR TYPHOID AND PARATYPHOID FEVER IN INDONESIA

Demographic Data From phoid fever. Among the 2 control ver: crowding (⬎6 household mem-
the Visited Cases and Controls groups, fever controls were more of- bers) and recent typhoid fever of house-
The median age of the typhoid cases was ten male, from a lower income group, hold contacts (TABLE 2). The association
16 (range, 3-57) years; of paratyphoid observed poorer handwashing hy- of recent typhoid fever of household
cases, 22 (range, 4-59) years; of com- giene, had fewer toilets and connec- contacts and typhoid fever also re-
munity controls, 27 (range, 1-80) years; tions to the water mains in their houses, mained significant in a subgroup of
and of fever controls, 20 (range, 1-75) shared food more frequently, were more households with more than 6 house-
years (TABLE 1). Typhoid and paraty- likely to consume iced drinks, and were hold members: from the 34 typhoid
phoid fever cases and fever controls more likely to report flooding than were cases, 8 (24%) reported recent typhoid
were significantly younger than the community controls (Table 1). fever in a household contact, whereas
community controls (P⬍.01). The age In addition, for all interviewed par- from 137 community controls, 9 (7%)
of patients with typhoid fever did not ticipants, low income was signifi- did (OR, 4.38; 95% CI, 1.54-12.40). In
differ significantly from that of those cantly associated with purchasing food the comparison with community con-
with paratyphoid fever (P = .12). Fever from street vendors (OR, 1.58; 95% CI, trols, other significantly associated risk
controls were significantly more often 1.03-2.41). When ice cubes were used, factors for typhoid fever were no use of
of male sex than were community con- these were purchased from ice ven- soap for handwashing, no toilet in the
trols (P=.003 by ␹2 test) and typhoid dors by equal proportions in the groups: household, and flooding. With respect
cases (P = .03). No significant differ- 41 (69%) patients with typhoid or para- to eating habits, typhoid was not signifi-
ences in the sex ratio were found when typhoid fever, 107 (61%) community cantly associated with eating food from
typhoid or paratyphoid cases were com- controls, and 93 (71%) fever controls street vendors, but a significant associa-
pared with community controls. Com- (P = .12). tion was found with consuming iced
pared with the number of community drinks, use of ice cubes, and sharing food
controls per subdistrict, who had been Bivariate Analysis from the same plate. Sharing of food oc-
included proportionally to the size of Risk Factors for Typhoid Fever. Bi- curred mostly with household con-
the population, in 1 subdistrict pro- variate analysis of risk factors compar- tacts: 84% (26/31) of typhoid and para-
portionally more typhoid cases than ing typhoid cases with community con- typhoid cases and 84% (85/101) of
community controls were enrolled trols showed the following significantly community controls and in lower fre-
(P = .07), whereas in another subdis- associated risk factors for typhoid fe- quencies in all groups at work or school.
trict more patients with paratyphoid fe-
ver were enrolled (P = .05). Within the Table 1. Risk Factors for Typhoid and Paratyphoid Fever in Jakarta
group of patients with enteric fever it- Cases, No. (%) Controls, No. (%)
self, no significant overrepresentation
of any subdistrict was found in the com- Typhoid Fever Paratyphoid Fever Community Fever
Risk Factor (n = 69) (n = 24) (n = 378) (n = 289)
parison of patients with typhoid and Age, median (range), y 16 (3-57) 22 (4-59) 27 (1-80) 20 (1-75)
paratyphoid fever (P = .37) Female sex 40 (58) 9 (38) 211 (56) 126 (44)
Low family income* 40 (58) 9 (38) 182 (48) 174 (60)
Risk Factors for Typhoid
Household size, median (range)† 6 (3-200) 5 (2-8) 6 (1-50) 6 (1-20)
and Paratyphoid Fever
Crowding‡ 34 (49) 8 (33) 137 (36) 101 (35)
Risk factors for typhoid and para- Recent typhoid fever 11 (16) 3 (13) 23 (6) 27 (9)
typhoid fever in comparison with com- in the household
munity and fever controls are shown in No use of soap for handwashing 49 (71) 15 (63) 214 (57) 183 (63)
Table 1. Compared with paratyphoid No toilet in household 15 (22) 5 (21) 33 (9) 38 (13)
cases the typhoid cases were more of- Eating food from street vendors 22 (32) 13 (54) 85 (23) 59 (20)
ten female, lived in more crowded con- Consumption of iced drinks 17 (25) 5 (21) 51 (14) 62 (22)
ditions, were more frequently from a Use of ice cubes 45 (65) 14 (58) 176 (47) 131 (45)
lower income category, more fre- Sharing food from same plate 31 (45) 7 (29) 102 (27) 101 (35)
quently reported recent typhoid fever Eating with hands 33 (48) 11 (46) 164 (43) 121 (42)
among household contacts in the pre- Drinking water: piped water 7 (10) 2 (8) 77 (20) 42 (15)
ceding 12 months, used ice cubes more Fecal contamination of 30 (48) 11 (55) 192 (56) 125 (54)
drinking water source§
often, shared food more often, and ob-
Flooding 26 (38) 14 (58) 79 (21) 99 (34)
served poor handwashing hygiene. *Defined as below the median monthly income of the community controls (900 000 Rupiah [US $105]).
Flooding and eating food purchased †Includes 2 outliers: an orphanage with 200 individuals and a dormitory with 50 individuals in the typhoid cases and
community controls, respectively.
from street vendors were more fre- ‡Defined as more than the median number of household members of community controls (median, 6).
quently reported by patients with para- §Water samples obtained from 62 typhoid cases, 20 paratyphoid cases, 341 random community controls, and 233
fever controls.
typhoid fever than by those with ty-
©2004 American Medical Association. All rights reserved. (Reprinted) JAMA, June 2, 2004—Vol 291, No. 21 2611

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 RISK FACTORS FOR TYPHOID AND PARATYPHOID FEVER IN INDONESIA

Table 2. Bivariate Analysis of Risk Factors for Typhoid and Paratyphoid Fever in Comparison With Community Controls and Fever Controls
Odds Ratio (95% Confidence Interval)

Typhoid Fever Paratyphoid Fever

Risk Factor Community Controls Fever Controls Community Controls Fever Controls
Female sex 1.09 (0.65-1.84) 1.78 (1.05-3.04) 0.48 (0.20-1.11) 0.78 (0.33-1.83)
Low family income 1.49 (0.88-2.50) 0.91 (0.54-1.55) 0.65 (0.28-1.51) 0.40 (0.17-0.94)
Crowding 1.71 (1.02-2.86) 1.81 (1.06-3.07) 0.88 (0.37-2.11) 0.93 (0.39-2.25)
Recent typhoid in the household 2.93 (1.36-6.32) 1.84 (0.86-3.92) 2.21 (0.61-7.94) 1.39 (0.39-4.95)
No use of soap for handwashing 1.88 (1.07-3.28) 1.42 (0.80-2.52) 1.28 (0.55-2.99) 0.97 (0.41-2.28)
No toilet in household 2.90 (1.48-5.70) 1.84 (0.94-3.57) 2.75 (0.97-7.85) 1.74 (0.61-4.93)
Eating food from street vendors 1.61 (0.92-2.83) 1.83 (1.02-3.26) 4.07 (1.76-9.42) 4.61 (1.96-10.81)
Consumption of iced drinks 2.10 (1.13-3.90) 1.20 (0.65-2.22) 1.69 (0.60-4.72) 0.96 (0.35-2.68)
Use of ice cubes 2.15 (1.26-3.68) 2.26 (1.31-3.91) 1.61 (0.67-3.71) 1.69 (0.73-3.93)
Sharing food from same plate 2.21 (1.31-3.74) 1.52 (0.89-2.59) 1.11 (0.45-2.77) 0.77 (0.31-1.91)
Drinking water: piped water 0.44 (0.19-1.01) 0.66 (0.29-1.55) 0.36 (0.08-1.54) 0.54 (0.12-2.36)
Fecal contamination of drinking water source 0.73 (0.42-1.25) 0.81 (0.46-1.42) 0.95 (0.38-2.35) 1.06 (0.42-2.64)
Flooding 2.29 (1.33-3.95) 1.16 (0.67-2.00) 5.30 (2.27-12.38) 2.69 (1.15-6.27)

Female sex was associated when ty-
phoid cases were compared with fever
controls, which was likely due to the
overrepresentation of males in the fe-
ver control group (Table 2). In the fe-
ver-control comparison crowding was
associated with typhoid fever, as was
eating foods from street vendors and use
of ice cubes. None of the hygiene-
related risk factors (ie, no use of soap
for handwashing, no toilet in the house-
hold) was significantly associated with
typhoid in comparison with fever
controls.
Risk Factors for Paratyphoid Fever.
In comparison with community con-
trols and fever controls, paratyphoid fe-
ver among cases was significantly as-
sociated with eating foods from street
vendors and flooding. Fever controls
had a lower family income than did pa-
tients with paratyphoid fever.
Water Examination
During the study period, 656 samples
from the sources of running drinking
water of cases and controls were col-
lected; 358 (55%) contained fecal co-
liforms (median, 30; IQR, 6-250 per 100
mL). Fecal contamination of drinking
water was not significantly associated
with either typhoid or paratyphoid fe-
ver in comparison with both control
groups (Table 2). Also, bacterial num-
bers in water samples were not signifi-
2612 JAMA, June 2, 2004—Vol 291, No. 21 (Reprinted)
cantly different for typhoid or paraty-
phoid fever cases vs those for fever
controls (P = .54 and P = .90, respec-
tively, by Mann-Whitney U test) or
community controls (P=.43 and P=.95,
respectively). All respondents re-
ported that they boiled drinking water
before consumption and that they kept
water boiling for several minutes.
Food Handlers
A food handler was not present in all
households of cases or controls be-
cause some cases and controls always
ate outside of the household or cooked
their own food. No S typhi or S para-
typhi A were isolated in the single stool
samples that could be obtained from
96% of the 78 food handlers of (para)
typhoid cases, 246 of the fever con-
trols, and 298 of the community con-
trols, respectively.
Multivariate Analysis
Residence of participants in 1 of the 8
subdistricts was not evaluated in the
bivariate analysis, but was included in
the multivariate analysis as a potential
confounder. In this analysis, neigh-
borhood residence was not indepen-
dently associated with either typhoid
fever or paratyphoid fever. The sig-
nificant risk factors for typhoid
and paratyphoid fever from the bivari-
ate analysis that were evaluated in
©2004 American Medical Association. All rights reserved.
the multivariate analysis are shown
in TABLE 3.
Risk Factors for Typhoid Fever. Us-
ing the community control group, ty-
phoid fever continued to be indepen-
dently associated with hygienic
practices (no use of soap for handwash-
ing, sharing of food, and no toilet in the
household) and recent intrahouse-
hold typhoid fever in the preceding 12
months. These are presented in order
of decreasing magnitude of attribut-
able risk (Table 3). Typhoid cases were
significantly younger than commu-
nity controls, suggesting that either ex-
posure to S typhi or susceptibility to
symptomatic infection when exposed
is greater among young people.
Using the fever controls for compari-
son, we identified ice cubes and fe-
male sex (related to the high percent-
age of male participants in the fever
control group) as independent risk
factors for typhoid fever. Hygiene-
related factors were not indepen-
dently associated.
Risk Factors for Paratyphoid Fe-
ver. In the multivariate analysis, para-
typhoid fever continued to be indepen-
dently associated with eating foods from
street vendors when paratyphoid cases
were compared with both control groups
(Table 3). Flooding also remained a sig-
nificant risk factor for paratyphoid fe-
ver. The individual contribution of eat-

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 RISK FACTORS FOR TYPHOID AND PARATYPHOID FEVER IN INDONESIA

ing habits and flooding as calculated by

Table 3. Multivariate Analysis of Independent Risk Factors for Typhoid and Paratyphoid
the attributable risk alternated in impor- Fever in Comparison With Community Controls and Fever Controls
tance for both control groups. Low in- Typhoid Fever Paratyphoid Fever
come was inversely associated with para-
typhoid fever in the comparison with OR (95% CI) Attributable OR (95% CI) Attributable
Risk Factor (n = 69) Risk, % (n = 24) Risk, %
fever controls. Comparison With Community Controls (n = 378)
No use of soap for handwashing 1.91 (1.06-3.46) 34 NA*
COMMENT
Sharing food from same plate 1.93 (1.10-3.37) 22 NA*
The main finding of this study is that in No toilet in household 2.20 (1.06-4.55) 12 NA*
Jatinegara, Jakarta, typhoid and paraty- Recent typhoid in household 2.38 (1.03-5.48) 9 NA*
phoid fever largely follow distinct routes Young age 0.96 (0.94-0.98) 0.99 (0.96-1.02)
of transmission. Typhoid is spread pre- Flooding 1.65 (0.88-3.08) 4.52 (1.90-10.73) 45
dominantly within the household, Eating food from street vendors NA* 3.34 (1.41-7.91) 38
whereas paratyphoid is mainly transmit- Use of iced drinks 1.12 (0.55-2.26) NA*
ted outside the home. No fecal carriers Use of ice cubes 1.34 (0.73-2.44) NA*
among food handlers in the house- Crowding 1.54 (0.88-2.72) NA*
holds were detected and there was no as- Comparison With Fever Controls (n = 289)
sociation between the level of contami- Consumption of ice cubes 2.27 (1.31-3.93) 36 NA*
nation of drinking water and either Female sex 1.79 (1.04-3.06) 26 1.10 (0.43-2.84)
typhoid or paratyphoid fever. Appar- Low income 0.85 (0.49-1.49) 0.28 (0.11-0.71) 49
ently, S typhi is introduced into house- Eating food from street vendors 1.62 (0.88-2.98) 5.17 (2.12-12.60) 48
holds by convalescent cases transiently Flooding NA* 3.25 (1.31-8.02) 42
excreting the bacterium. Consistent with Crowding 1.60 (0.92-2.76) NA*
this, independent risk factors for the in- Abbreviations: CI, confidence interval; OR, odds ratio.
trahousehold spread of typhoid were *Not significantly associated in the bivariate analysis and not included in the multivariate analysis.

poor handwashing hygiene and sharing

of food from the same plate. On the other
hand, risk factors for transmission of
paratyphoid were outside the house-
hold (ie, flooding, consumption of foods
from street vendors). Furthermore, in
this community-based passive surveil-
lance study, paratyphoid comprised 23%
of all enteric fever cases, an apparent rise
in relative incidence of paratyphoid com-
pared with earlier studies.
To reach the conclusion concern-
ing the distinct route of transmission
of paratyphoid and typhoid fever, we
compared characteristics of cases with
those of community controls and fe-
ver controls. Some potential pitfalls that
may affect complete recruitment of pa-
tients in the area, and individual clas-
sification of cases and fever controls,
need to be considered. Not all eligible
fever patients might have been in-
cluded, although we performed blood
cultures free of charge to preclude eco-
nomic barriers for inclusion. Self-
treatment with over-the-counter anti-
biotics and an atypical presentation of
enteric fever (eg, as observed in young
children) may have influenced inclu-
sion.18 Even so, the proportional rep-
©2004 American Medical Association. All rights reserved.
resentation of typhoid fever of 8.6% of
illnesses with fever for 3 or more days
is comparable with rates in other ac-
tive and passive surveillance studies for
typhoid fever using the same inclu-
sion criteria (4.6%-8.5%).19-23 Further-
more, the sensitivity of the microbio-
logical methods never reaches 100%.24
However, because most patients with
fever were included in the first week of
illness, the sensitivity of blood culture
comes close to that of quantitation in
bone marrow and is superior to the
Widal test.25,26 Also, the interference of
antibiotics, which can yield false-
negative results, was limited due to this
short period before inclusion and to the
antibiotic-neutralizing resins in the
blood culture vials. Accordingly, equal
proportions of typhoid and paraty-
phoid fever cases and nonenteric fever
controls had previously taken antibi-
otics. To further minimize misclassifi-
cation of fever controls, stool cultures
were performed 3 to 4 weeks after blood
culture (ie, at a time when bacteria may
still be excreted in feces of patients with
typhoid or paratyphoid fever). The 2 fe-
(Reprinted) JAMA, June 2, 2004—Vol 291, No. 21 2613
brile patients with negative blood cul-
ture results at inclusion, whose stool
cultures yielded S typhi and S para-
typhi A, were accordingly excluded
from the analysis. Another potential
limitation of this study concerns the
screening for Salmonella carriers by a
single stool culture that might not suf-
fice because of intermittent excretion
of the bacteria in stools.12
The use of a representative commu-
nity control group allowed us to deter-
mine the prevalence of risk factors in the
whole population at risk. Our study
demonstrates that risk estimates from
case-control studies could be affected by
the selection of the control-group used
for comparison. For instance, when ty-
phoid fever cases were compared with
community controls, most of the inde-
pendent risk factors for typhoid fever
were intrahousehold factors (ie, no use
of soap for handwashing, sharing of
food, and recent typhoid fever in a
household member), whereas those fac-
tors were not associated in the compari-
son with fever controls. This suggests
that hygiene practices of both cases and

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 RISK FACTORS FOR TYPHOID AND PARATYPHOID FEVER IN INDONESIA
fever controls were of a standard below
that of community controls. In addi-
tion, partially overlapping routes of
transmission of typhoid fever and other
febrile illnesses could be interdepen-
dent and result in the demonstrated
similar intrahousehold risk profile of ty-
phoid fever cases and fever controls with
similar socioeconomic characteristics.
Food obtained from street vendors
was a likely vehicle for extrahousehold
transmission of paratyphoid fever be-
cause it contributed significantly to
transmission in contrast to hygiene-
related risk factors. This is consistent
with the notion that multiplication of
paratyphoid bacteria in food is re-
quired to reach a number sufficient to
cause disease. Street vendors have only
limited facilities for cooled storage of
foods and for washing of hands, foods,
and dishes. The low hygienic stan-
dards could therefore contribute not
only to the transmission of paraty-
phoid fever but of other foodborne dis-
eases such as typhoid, as well.7,11,27-29 Due
to the Asian economic crisis starting in
1997, the expanding urban population
became even more dependent on inex-
pensive food obtained from street ven-
dors, which may explain the relatively
high proportion of paratyphoid fever in
enteric fever in Jakarta. Low-income
groups more frequently ate food ob-
tained from street vendors than did in-
dividuals with high income, but all in-
come groups who purchase food from
street vendors may be at risk.
In contrast to the largely extra-
household transmission of paraty-
phoid fever, typhoid fever was more of
an intrahousehold affair introduced by
recent typhoid cases in the house-
holds and facilitated by poor hand-
washing hygiene and sharing of food
from the same plate, consistent with an
earlier report.10 The association of poor
handwashing hygiene and typhoid fever
was shown before in Indonesia and
India.6,9,11 A recent review stressed the
importance of the use of soap for the
reduction of the incidence of diarrheal
diseases.30 In our study we also iden-
tified a significant association between
not using soap for handwashing and all
2614 JAMA, June 2, 2004—Vol 291, No. 21 (Reprinted)
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febrile illnesses (OR, 1.40; 95% CI,
1.05-1.88). The combination of poor
handwashing hygiene, eating with
hands, and sharing food from the same
plate can understandably facilitate trans-
mission of typhoid, but apparently the
infective dose to allow transmission of
paratyphoid is only infrequently met.
Because we observed no intrahouse-
hold outbreaks and detected no fecal
carriers among the food handlers in the
households of cases, intrahousehold
person-to-person spread through
convalescent patients observing poor
hygiene seems a more likely scenario
than transmission by chronic carriers
among food handlers in households.
Apart from the above-mentioned risk
factors, some additional observations
should be considered. First, the total
number of interviewed patients with
typhoid and paratyphoid fever in our
study was limited, which may have influ-
enced the statistical power of the analy-
sis, especially in small subgroups, and
the demonstrated associations of spe-
cific risk factors. Second, food pur-
chased from street vendors could be
implicated as a vehicle for transmission
of typhoid as well, as shown in the bivar-
iate analysis. Also, the consumption of
ice cubes obtained from street vendors
might expose clients to Salmonella bac-
teria because these bacteria can survive
in ice.31 Another extrahousehold loca-
tion of acquisition of typhoid fever could
be public toilets, which generally lack
handwashing facilities. Third, there was
an association between flooding and
paratyphoid fever. Two hypotheses may
explain this association: flooding could
introduce bacteria from contaminated
surface water into sources of drinking
water. However, since most cases of
typhoid and paratyphoid fever occurred
during the dry season, flood-related
waterborne transmission seemed not to
play a major role. Alternatively, flood-
ing may be an income-associated geo-
graphic marker that coincides with the
distribution of carriers among food ven-
dors in the area. This could also explain
the clustering of paratyphoid fever cases
in some regions, but since community
controls were nonmatched for subdis-
©2004 American Medical Association. All rights reserved.
trict neighborhood residence, this
assumption could not be verified. Finally,
although a considerable proportion of
the sources of drinking water con-
tained fecal coliforms that were used as
indicator organisms, contamination itself
was not associated with enteric fever.
Dilution of S typhi or S paratyphi in water
might generate too low a dose to infect
partially immune residents. More likely,
however, the entrenched habit of boil-
ing drinking water from the water mains
or groundwater pumps explains the lack
of an association between water con-
tamination and enteric fever and should
certainly be continued to prevent pos-
sible outbreaks of disease, in combina-
tion with proper storage of boiled water
to prevent domestic contamination.
In conclusion, the present findings
suggest that public health policies for
control of typhoid and paratyphoid fe-
ver in Jakarta should focus on hygiene
education as well as monitoring of the
street-food trade, although such strat-
egies would have to be tested in inter-
vention trials to prove their value. First,
instruction on proper handwashing hy-
giene using soap could reduce the over-
all incidence of infectious diseases in
Jakarta and especially preclude trans-
mission of typhoid fever among con-
tacts of cases. Second, prevention of
bacterial contamination of street food
and ice cubes could contribute to con-
tainment of enteric fever, paratyphoid
in particular. Follow-up of enteric fe-
ver cases, especially among food ven-
dors, should be prioritized to reduce the
role of transient or chronic carriers in
the foodborne transmission.
If vaccination were to be consid-
ered as a means of controlling ty-
phoid, an individualized approach
rather than mass vaccination (ie, tar-
geted vaccination of young household
contacts of cases) may be a cost-
effective approach when public health
resources are scarce.32 But, because of
the increasing incidence of paraty-
phoid fever in Jakarta, as well as readily
available antibiotic treatment and the
potentially effective intervention of edu-
cation to increase appropriate hand-
washing, mass immunization pro-

grams for typhoid fever in Jakarta may
not be appropriate at this time.
Author Contributions: Dr van Dissel, as principal in-
vestigator, had full access to all of the data in this study
and takes full responsibility for the integrity of the data
and accuracy of the data analysis.
Study concept and design; critical revision of the manu-
script for important intellectual content: Vollaard, Ali,
van Asten, Widjaja, Visser, Surjadi, van Dissel.
Acquisition of data: Vollaard, Ali.
Analysis and interpretation of data: Vollaard, Ali,
van Dissel.
Drafting of the manuscript: Vollaard.
Statistical expertise: Vollaard, van Asten, van Dissel.
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