Anda di halaman 1dari 48

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,


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

Copyright © 2013 SciRes. OPEN ACCESS


B. Mengistie et al. / Open Journal of Preventive Medicine 3 (2013) 446-453 447

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

Copyright © 2013 SciRes. 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
Factors Associated with Diarrhea
with a response rate of 97.8%. Almost all respondents
were biological mothers (98.4%), married (97.3%) and Multivariate analyses were carried out to identifythe
housewives (96.7%), most had no formal education risk factors associated with diarrhea. In the first block
(82.2%) and were from rural area (85.3%). Mean chil- logistic regression model, diarrhea was significantly
dren age was 26.6 ± 13.5 months. There was slightly higher among children living in the rural than urban area.
more male (51.9%) than female children (51.9% and In the second model, childhood diarrhea was signifi-
48.1%). cantly associated with lack of hand washing facility, do-
Out of 1456 children, 327 had diarrhea two weeks be- mestic water supply from unimproved sources and open
fore the interview, provided a prevalence of 22.5% [95% dumping of refuse around the house. In the third model,
confidence interval (CI) 20.3% - 24.6%]. Children in the diarrhea was significantly associated with age of the
age group 6 - 11 months had the highest prevalence of child and number of under-five children in the house-
diarrhea followed by the age groups 12 - 23 months. The hold.
distribution of prevalence of diarrhea by socio-eco- In the final logistic regression model, diarrhea was in-
nomic, environmental and behavioral characteristics is 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

Copyright © 2013 SciRes. OPEN ACCESS


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

Copyright © 2013 SciRes. OPEN ACCESS


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

Copyright © 2013 SciRes. OPEN ACCESS


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 cial support. We are also thankful for study participants, data collectors
pathogens has been documented [21]. In our study, open and supervisors for their devotion and full participation.
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- REFERENCES
nation might be that inappropriate disposal of refuse pro- [1] Black, R.E., Morris, S.S. and Bryce. J. (2003) Where and
vides breeding site for insects, which may carry diarrhea why are 10 million children dying every year? Lancet,
pathogens from the refuse to water and food. 361, 2226-2234.
Studies showed the importance of hand washing in http://dx.doi.org/10.1016/S0140-6736(03)13779-8
reducing the occurrence of childhood diarrhea [24,25]. [2] Fisher Walker, L.C., Perin, J., Aryee, J.M., Boschi-Pinto,
However, monitoring correct hand washing behavior at C. and Black, R.E. (2012) Diarrhea incidence in low- and
critical times is challenging. Hygiene behavior related middle-income countries in 1990 and 2010: A systematic
review. BMC Public Health, 12.
observational studies showed wide discrepancy between http://dx.doi.org/10.1186/1471-2458-12-220
what people said and did and suggested that reported
[3] UNICEF/WHO (2009) Diarrhoea: Why children are still
hand washing behavior over estimate observed behavior
dying and what can be done. The United Nations Chil-
[26-28] and supported the availability of water and soap dren’s Fund/World Health Organization, Geneva.
in places of hand washing as indicator of hand washing
[4] WHO (2007) Combating waterborne disease at the house-
behavior [29]. In this study, there was a significant posi- hold level. International Network to Promote Household
tive association between the availability of hand washing Water Treatment and Safe Storage, World Health Organi-
facility with childhood diarrhea. zation, Geneva.
The study showed that diarrhea was significantly as- [5] Desalegn, M., Kumie, A. and Tefera, W. (2011) Predictors
sociated with children in the age groups 6 - 11 months of under-five childhood diarrhea: Mecha District, West
and 12 - 23 months compared to children aged above 35 Gojjam, Ethiopia. Ethiopian Journal of Health Develop-
months. This finding is in agreement with other studies ment, 25, 174-232.
[5,9]. The peak prevalence of diarrhea at the age of 6 - 11 [6] Teklemariam, S., Getaneh, T. and Bekele, F. (2000) En-
months can be explained by the introduction of contami- vironmental determinants of diarrheal morbidity in under-
nated weaning foods [30]. In addition, crawling starts at five children, Keffa-Sheka zone, south west Ethiopia.
this age and the risk of ingesting contaminated materials Ethiopian Medical Journal, 38, 27-34.
may cause diarrhea. The risk of diarrhea decreases sub- [7] Mediratta, P.R., Feleke, A., Moulton, H.L., Yifru, S. and
sequently after 6 - 11 months; this is probably because Sack, B.R. (2010) Risk factors and case management of
the children begin to develop immunity to pathogens acute diarrhoea in North Gondar zone, Ethiopia. Journal
of Health, Population and Nutrition, 28, 253-263.
after repeated exposure [31].
The odds of diarrhea were higher among rural children [8] Mekasha, A. and Tesfahun, A. (2003) Determinants of
diarrhoeal diseases: A community based study in urban
than urban ones and this was consistent with the findings
south western Ethiopia. East African Medical Journal, 80,
in Uganda [11] and Egypt [19]. This could be attributed 77-82.
to the fact that the lack of access to water and sanitation
[9] Boadi, K.O. and Kuitunen, M. (2005) Childhood diar-
facilities in the rural areas was more than in the urban
rheal morbidity in the Accra Metropolitan Area, Ghana:
areas [32]. Socio-economic, environmental and behavioral risk de-
In this study, diarrhea was significantly associated terminants. Journal of Health & Population in Develop-
with the presence of two or more under five children in ing Countries. http://www.jhpdc.unc.edu/
the family. This is in agreement with a study done in [10] Siziya, S., Muula, A.S. and Rudatsikira, E. (2009) Diar-
Pakistan [33]. Other study also indicated that number of rhoea and acute respiratory infections prevalence and risk
children born was a predictor of diarrhea among under factors among under-five children in Iraq in 2000. Italian
five children [34]. This might be due to the incapability Journal of Pediatrics, 35.
of the caregiver to care for a large number of children http://dx.doi.org/10.1186/1824-7288-35-8
[19]. It is possible to suggest that child birth spacing might [11] Bbaale, E. (2011) Determinants of diarrhoea and acute re-
have a positive influence on prevention of diarrhea. spiratory infection among under-fives in Uganda. Aus-
tralasian Medical Journal, 4, 400-409.
In conclusion, childhood diarrhea remains an impor-
http://dx.doi.org/10.4066/AMJ.2011.723
tant health concern in the study community. Occurrence
of diarrhea could be decreased by interventions aimed to [12] Chopra, M., Mason, E., Borrazzo, J., Campbell, H., Ru-
dan, I., Liu, L., Black, R.E. and Bhutta, Z.A. (2013) End-
improve sanitation, hygiene and child birth spacing. ing of preventable deaths from pneumonia and diarrhoea:
An achievable goal. The Lancet, 381, 1499-1506.
5. ACKNOWLEDGEMENTS http://dx.doi.org/10.1016/S0140-6736(13)60319-0
The authors would like to thank Haramaya University for its finan- [13] Kersa, D.H.O. (2011) Health service coverage. Kersa

Copyright © 2013 SciRes. OPEN ACCESS


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

District Health Office, Eastern Hararge, Ethiopia. [25] Mirza, N.M., Caulfield, L.E. and Black, R.E. (1997) Risk
[14] Kelsey, J.L., Whittemore, A.S., Evans, A.S. and Thomp- factors for diarrhoeal diseases duration. American Jour-
son, W.D. (1996) Methods of sampling and estimation of nal of Epidemiology, 146, 776-785.
sample size. In: Kelsey, J.L., Whittemore, A.S., Evans, http://dx.doi.org/10.1093/oxfordjournals.aje.a009354
A.S. and Thompson, W.D., Eds., Methods in Observa- [26] Strina, A., Cairncross, S., Barreto, L.M., Larrea, C. and
tional Epidemiology, Oxford University Press, New York. Prado, S.M. (2003) Childhood diarrhea and observed hy-
[15] CSA (2006) Ethiopian demographic and health survey giene behavior in Salvador, Brazil. American Journal of
2005 Report. Central Statistics Authority, Addis Ababa. Epidemiology, 157, 1032-1038.
http://dx.doi.org/10.1093/aje/kwg075
[16] WHO (2005) The treatment of diarrhea. A manual for
physicians and other senior health workers. World Health [27] Manun’ebo, M.N. (1994) Influence of demographic, so-
Organization, Geneva. cioeconomic and environmental variables on childhood
diarrhoea in a rural area of Zaire. Journal of Tropical
[17] WHO/UNICEF (2010) Progress on sanitation and drink- Medicine and Hygiene, 97, 31-38.
ing-water: 2010 update. World Health Organization/
United Nation Children’s Fund, Geneva. [28] Manun’ebo, M., Cousens, S. and Haggerty, P. (1997) Meas-
uring hygiene practices: A comparison of questionnaires
[18] Vyas, S. and Kumaranayake, L. (2006) Constructing socio- with direct observations in rural Zaire. Tropical Medicine
economic status indices: How to use principal compo- and Internal Health, 2, 1015-1021.
nents analysis. Health Policy Planning, 21, 459-468. http://dx.doi.org/10.1046/j.1365-3156.1997.d01-180.x
http://dx.doi.org/10.1093/heapol/czl029
[29] Halder, A.K., Tronchet, C., Akhter, S., Bhuiya, A., Johns-
[19] El-Gilany, A.H. and Hammad, S. (2005) Epidemiology of ton, R. and Luby, S.P. (2010) Observed hand cleanliness
diarrhoeal diseases among children under age 5 years in and other measures of handwashing behavior in rural
Dakahlia, Egypt. Eastern Mediterranean Health Journal, Bangladesh. BMC Public Health, 10.
11, 762-775 http://dx.doi.org/10.1186/1471-2458-10-545
[20] Stanly, A.M., Sathiyasekaran, B.W.C. and Palani, G. (2009) [30] Dewey, K.G. and Adu-Afarwuah, S. (2008) Systematic re-
A population based study of acute diarrhoea among chil- view of the efficacy and effectiveness of complementary
dren under 5 years in a rural community in South. Sri feeding interventions in developing countries. Maternal
Ramachandra Journal of Medicine, 1, 1-7. & Child Nutrition, 4, 24-85.
[21] Rego, R.F., Moraes, L.R. and Dourado, I. (2005) Diar- http://dx.doi.org/10.1111/j.1740-8709.2007.00124.x
rhoea and garbage disposal in Salvador, Brazil. Royal So- [31] Motarjemi, Y., Käferstein, F., Moy, G. and Quevedo, F.
ciety of Tropical Medicine and Hygiene, 99, 48-54. (1993) Contaminated weaning food: A major risk factor
http://dx.doi.org/10.1016/j.trstmh.2004.02.008 for diarrhoea and associated malnutrition. Bulletin of the
[22] Regassa, G., Birke, W., Deboch, B. and Belachew, T. (2008) World Health Organization, 71, 79-92.
Environmental determinants of diarrhea among under- [32] WHO/UNICEF (2012) Progress on sanitation and drink-
five children in Nekemte town, Western Ethiopia. Ethio- ing-water: 2010 update. World Health Organization, Ge-
pian Journal of Health Sciences, 18, 39-45. neva.
[23] Root, G.P.M. (2001) Sanitation, community environment [33] Shah, M.S., Yousafzai, M., Lakhani, B.N., Chotanp, A.R.
and childhood diarrhea in rural Zimbabwe. Journal of and Nowshad, G. (2003) Prevalence and correlates of di-
Health, Population and Nutrition, 19, 73-82. arrhea. Indian Journal of Pediatrics, 70, 207-211.
[24] Punyaratabandhu, P., Sangchai, R. and Vathanophas, K. [34] Arif, A. and Naheed, R. (2012) Socio-economic determi-
(1993) Risk factors for childhood diarrhoeal diseases in nants of diarrhoea morbidity in Pakistan. Academic Re-
an urban community, Bangkok, Thailand. Journal of the search International, 2, 398-432.
Medical Association of Thailand, 76, 535-541.

Copyright © 2013 SciRes. 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.

References
[1] Ackerknecht, E.H. (1948) Anticontagionism between 1821 and 1867. Bulletin of the History of Medicine, 22, 562-593.
[2] Baldwin, P. (1999) Contagion and the State in Europe, 1830-1930. Cambridge University Press, Cambridge.
http://dx.doi.org/10.1017/CBO9780511497544
[3] Briggs, A. (1961) Cholera and Society in the Nineteenth Century. Past and Present, 19, 76-96.
http://dx.doi.org/10.1093/past/19.1.76
[4] Delaporte, F. (1986) Disease and Civilization: The Cholera in Paris, 1832. MIT Press, Cambridge, MA, and London.
[5] Howard-Jones, N. (1975) The Scientific Background of the International Sanitary Conferences, 1851-1938. World
Health Organization, Geneva.
[6] Pelling, M. (1978) Cholera, Fever and English Medicine, 1825-1865. Oxford University Press, New York.
[7] Rosenberg, C.E. The Cholera Years: The United States in 1832, 1849, and 1866. Chicago and London, University of
Chicago Press, 1962, 1987.
[8] Evans, R. (1987) Death in Hamburg: Society and Politics in the Cholera Years, 1830-1910. Clarendon Press, Oxford.
[9] Frieden, N. (1977) The Russian Cholera Epidemic, 1892-93, and Medical Professionalization. Journal of Social Histo-
ry, 10, 538-559. http://dx.doi.org/10.1353/jsh/10.4.538
[10] Arnold, D. (1986) Cholera and Colonialism in British India. Past and Present, 113, 118-151.
http://dx.doi.org/10.1093/past/113.1.118
[11] Leiker, J. and Powers, R. (1998) Cholera among the Plains Indians: Perceptions, Causes, Consequences. The Western
Historical Quarterly, 29, 317-340. http://dx.doi.org/10.2307/970577

247
Asian Pac J Trop Dis 2015; 5(3): 175-180 175

Contents lists available at ScienceDirect

Asian Pacific Journal of Tropical Disease


journal homepage: www.elsevier.com/locate/apjtd

Document heading doi: 10.1016/S2222-1808(14)60648-4 襃 2015 by the Asian Pacific Journal of Tropical Disease. All rights reserved.

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

1. Introduction Trichuris trichiura, Strongyloides stercoralis, Necator


americanus, Ankylostoma duodenale ) are live in the
Helminth infections are the most common infections host’s alimentary canal while trematodes or flukes
in man, and exaggerated worldwide population. It may ( Schistosoma haematobium, Schistosoma mansoni,
cause anemia, eosinophilia, pneumonia and prevalence Schistosoma japonicum), tissue roundworms (Trichinella
of malnutrition [1]. H elminthiasis is the most common spiralis, Dracunculus medinensis) and hydatid tapeworm
infection caused by worms that is contaminant to human ( Echinococcus species ) are live in the host’s tissues [3].
body parts. N ormally, the worms not only live in the Several nematodes that usually live in the gastrointestinal
gastrointestinal tract but may also reside into liver and tract of animals may communicate a disease to humans
other organs. When infected people excrete faeces with and penetrate tissues. A skin infestation, termed
helminth eggs, the soil in the areas with poor sanitation creeping eruption, is caused by the larvae of dog and cat
will be contaminated[2]. There are two clinically important hookworms. Toxocariasis is caused by larvae of cat and
types of worm infections, one is the worms live in the dog roundworms of the Toxocara genus[3].
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, 2. Epidemiology
Diphyllobothrium latum) and intestinal roundworms or
nematodes (Ascaris lumbricoides, Enterobius vermicularis, 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 Technical limitations of currently available diagnostic
methods are the most important problems in the control
T he most evident forms of direct damage are those of helminthiasis. L acking of standard clinical tests
resulting from the blockage of internal organs or from the encourages extensive invasion and poses a hindrance to
effects of pressure exerted by growing parasites (Figure 1). health managements. For basic diagnosis of helminths
Physically blockage of intestine due to large nematodes infection, the specific helminths can be identified from
( Ascaris ) or tapeworms ( Taenia, Diphyllobothrium ) the faeces and their eggs microscopically examined
that produced the formation of granulomas around and established using fecal egg count method. T his
schistosome eggs and the blockage of blood flow through is commonly useful for most species, particularly in
the liver occured, which leads to pathological changes. veterinary investigations[6]. A range of diagnostic tools
C ysts of the tapeworm ( Echinococcus multilocularis ) currently available is (Figure 3): 1) Parasitological tests,
develop in the liver, brain, lungs or other parts of body the parasites are identified microscopically; 2) Serological
cavities can lead to unusal enlargement, organ metastasis assays, the parasite-specific antibodies are detected in
and cause necrosis due to pressure exerted by cysts[5]. 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]
Mahesh Bandappa Manke et al./Asian Pac J Trop Dis 2015; 5(3): 175-180
179
infection 1. The global burden of intestinal nematode disease. of aerial parts of Aerva lanata Linn. Juss. Int J Pharm Sci
Trans R Soc Trop Med Hyg 1994; 8(33): 259-261. Drug Res 2010; 2(4): 269-271.
[2] I dika IK , O konkwo EA , O nah DN , E zeh IO , I heagwam CN , [19] D a n q u a h C A , K o f f u o r G A , A n n a n K , K e t o r E C . T h e
Nwosu CO. Efficacy of levamisole and ivermectin in the control anthelmintic activity of Vernonia amygdalina ( A steraceae )
of bovine parasitic gastroenteritis in the sub-humid savanna and Alstonia boonei De Wild (Apocynaceae). J Med Biomed Sci
zone of Southeastern Nigeria. Parasitol Res 2012; 111(4): 1683- 2012; 1(1): 21-27.
1687. [20] P okale SB , A wate SS , H andibag KD . In vitro anthelmintric
[3] Dale MM, Ritter JM, Fowler RJ, Rang HP. Rang and Dale’s activity of Annona sqamosa ( A nnonaceae ) leaves. Int J
Pharmacology. 6 th ed. E dinburgh: C hurchill L ivingstone; PharmTech Res 2011; 3(3): 1728-1731.
2008, p. 712-713. [21] M ali RG , W adekar RR . In vitro anthelmintic activity of
[4] James WD, Berger TG, Elston DM, Odom RB. Andrews’ diseases Baliospermum montanum Muell. Arg roots. Indian J Pharm
of the skin: clinical dermatology. 10 th ed. P hiladelphia: Sci 2008; 70(1): 131-133.
Saunders Elsevier; 2006, p. 308-311. [22] Ikechukwuogu G. In vitro anthelmintic potentials of Bambusa
[5] Wakelin D. Helminths: pathogenesis and defenses. In: Baron vulgaris ( L . ) leaf extracts using adult african earthworm
S, editor. Medical microbiology. 4th ed. Texas: University of (Eudrilus eugeniae) from Southern Nigeria. Indian J Nov Drug
Texas Medical Branch at Galveston; 1996. Deliv 2012; 4(4): 306-310.
[6] C rompton DWT , S avioli L . Handbook of helminthiasis for [23] Chander PA, Sri HY, Sravanthi NBM, Susmitha UV. In vitro
public health. Boca Raton: CRC/Taylor & Francis; 2007. anthelmintic activity of Barleria buxifolia on I ndian adult
[7] Lustigman S, Prichard RK, Gazzinelli A, Grant WN, Boatin BA, earthworms and estimation of total flavonoid content. Asian
McCarthy JS, et al. A research agenda for helminth diseases Pac J Trop Dis 2014; 4(Suppl 1): S233-S235.
of humans: the problem of helminthiases. PLoS Negl Trop Dis [24] Bhattacharjee C, Debjit B, Tiwari P, Tripathi KK, Dutta AS. In-
2012; doi: 10.1371/journal.pntd.0001582. vitro anthelmintic activity of Benincasa hispida (Petha) Thunb
[8] H unt PW , L ello J . H ow to make DNA count: DNA -based leaves. Int J Pharma Bio Sci 2010 ; 1( 2 ) . [ O nline] A vailable
diagnostic tools in veterinary parasitology. Vet Parasitol 2012; from: http://www.ijpbs.net/issue- 2 / 91 .pdf [ A ccessed on 7 th
186(1-2): 101-108. July, 2014]
[9] Christian P, Khatry SK, West JP Jr. Antenatal anthelminthic [25] Jamkhande PG, Suryawanshi VA, Wattamwar AS, Barde SR.
treatment, birthweight, and infant survival in rural N epal. In vitro anthelmintic efficacy of Borassus flabellifer L inn.
Lancet 2004; 364(9438): 981-983. (Palmae) against Pheretima posthuma. Asian Pac J Trop Dis
[10] Crompton DW, Nesheim MC. Nutritional impact of intestinal 2014; 4(Suppl 1): S199-S203.
helminthiasis during the human life cycle. Annu Rev Nutr [26] B endgude RD , K ondawar MS , P atil SB , H irave RV . In vitro
2002; 22: 35-59. anthelmintic activity of roots of Capparis zeylanica Linn. J
[11] Goodman LS, Hardman JG, Limbird LE, Gilman AG. Goodman Adv Pharm Educ Res 2011; 2: 154-158.
& Gilman’s the pharmacological basis of therapeutics. 10th ed. [27] K ainsa S , K umar P , D ahiya RS . I nvestigation of in vitro
New York: McGraw-Hill; 2001, p. 1121. anthelmintic activity of Cassia auriculata leaves. J Nat Prod
[12] K atzung BG , M asters SB , T revor AJ . Basic and clinical Plant Resour 2012; 2(4): 460-464.
pharmacology. 1 1 th ed. N ew Y ork: the M c G raw- H ill [28] H apse S A , P agar H J , S uruse S D , U gale S S . In-vitro
Companies Inc.; 2009, p. 1223-1237. anthelmintic activity of Croton bonplandianum Baill. J Appl
[13] Tripathi KD. Essentials of medical pharmacology. 6th ed. New Pharm Sci 2012; 2(4): 191-193.
Delhi: Jaypee Brothers Medical Publishers; 2008, p. 810. [29] Bairagi GB, Kabra AO, Mandade RJ. Anthelmintric activity
[14] Rafi KP, Karthikeyan M, Kannan M, Rajasekar S. Anthelmintic of Citrus medica L. leaves in Indian adult earthworm. Int J
activity of Nerium olender flower extract in I ndian adult PharmTech Res 2011; 3(2): 664-667.
earthworm. J Nat Prod Plant Resour 2011; 1(4): 40-46. [30] Shamsul IM, Rahman MMM, Koushik AS, Jamiuddin A, Ariful
[15] Kalia AN. A textbook of industrial pharmacognosy. New Delhi: IM. A study of cytotoxic and anthalmintic activities of crude
Satish Kumar Jain for CBS; 2005, p. 1-9. extracts of leaves of Clerodendrum viscosum. Int Res J Pharm
[16] Tiwari P, Kumar B, Kaur M, Kaur G, Kaur H. Phytochemical 2013; 4(1): 99-102.
screening and extraction: a review. Int Pharm Sci 2011; 1(1): [31] Oliveira LM, Bevilaqua CM, Costa CT, Macedo IT, Barros RS,
98-106. Rodrigues AC, et al. Anthelmintic activity of Cocos nucifera
[17] N aga BM , S ravanthi V , S ujeeth S , K alpana K , S anthoshi L . against sheep gastrointestinal nematodes. Vet Parasitol
P , P avani M , et al. In-vitro anthelmintic activity of 2009; 159(1): 55-59.
methanolic and aqueous extracts of Achyranthes aspera Linn. [32] A leemuddin MA , K arthikeyan M , K rishna PP . Invitro
(Amaranthaceae) stems. Int J Pharm Sci 2013; 3(2): 181-184. anthelmintic activity of different extracts of Coldenia
[18] Rajesh R, Chitra K, Paarakh PM. In vitro anthelmintic activity procumbens. J Nat Prod Plant Resour 2012; 2(2): 267-271.
180 Mahesh Bandappa Manke et al./Asian Pac J Trop Dis 2015; 5(3): 175-180

[33] H ussain A , S onkar AK , A hmad MP , W ahab S . In-vitro potential medicinal plant. J Chem Pharm Res 2013; 5(2): 345-
anthelmintic activity of Coleus aromaticus root in I ndian 348.
adult earthworm. Asian Pac J Trop Dis 2012; 2(Suppl 1): S425- [48] Partap S, Kumar S, Kumar A, Sharma NK, Jha KK. In-vitro
S427. anthelmintic activity of Luffa cylindrica leaves in I ndian
[34] Molefe NI, Tsotetsi AM, Ashafa AOT, Thekisoe OMM. In vitro adult earthworm. J Pharmacogn Phytochem 2012; 1(2): 27-30.
anthelmintic activity of Cotyledon orbiculata, Hermannia [49] N agaraja MS , Paarakh PM . In vitro anthelmintic activity of
depressa and Nicotiana glauca extracts against parasitic stem bark of Millingtonia hortensis Linn. Int J Pharm Biol
gastrointestinal nematodes of livestock. J Med Plants Res Sci 2011; 2(2): 15-19.
2013; 7(9): 536-542. [50] Dhamija HK, Gupta D, Parashar B, Kumar S, Shashipal. In-
[35] Rakh MS, Pawar RV, Khedkar AN. Anthelmintic potential of vitro anthelmintic activity of aqueous and ethanol extracts
various extracts of the rhizomes of Curcuma amada R oxb. of Mimusops elengi Linn. bark. Pharmacologyonline 2011; 3:
Asian Pac J Trop Dis 2014; 4(Suppl 1): S276-S278. 740-746.
[36] Amit S, Singh FM. In-vitro anthelmintic activity of Diplazium [51] Pagariya A, Chatur S, Nawab F. In vitro anthelmintic activity
esculentum ( R etz. ) S wiss rhizome extract. J Pharmacogn of root extract of Murraya koenigii ( L inn. ) S preng. Int J
Phytochem 2012; 1(4): 85-87. Pharm Innov 2013; 3(1): 111-114.
[37] Gadamsetty G, Lakshmipathy R, Sarada NC. Phytochemical [52] D ahiya SS , K aur R , S harma SK . E valuation of in vitro
analysis and in-vitro anthelmintic activity of Mimusops elengi anthelmintic activity of Oenothera rosea L’Hér. ex Aiton. stem
Linn. and Drypetes sepiaria. Int J Pharm Pharm Sci 2013; 5(1): and root. J Nat Prod Plant Resour 2012; 2(4): 534-539.
126-128. [53] P al MK . E valuation of anthelmintic activity of leaves of
[38] Sawarkar HA, Singh MK, Pandey AK, Bharadwaj D, Kashyap Paederia foetida. Int J Pharm Biol Sci 2011; 2(1): 227-231.
P . C omparative in vitro anthelmintic activity of Ficus [54] Asha K, Latha KP, Vagdevi HM, Shwetha C, Pushpa B, Shruthi
benghalensis, Ficus carica & Ficus religiosa. Int J PharmTech A. In vitro anthelmintic activity of bark extracts of Pajanelia
Res 2011; 3(1): 157-159. longifolia K. Schum. Int Res J Pharm Plant Sci 2013; 1(2): 1-5.
[39] S reejith M , K annappan N , S anthiagu A , M athew A P . [55] R ao BM , N aseeruddin SD , R ao NJ . In-vitro anthelmintic
P hytochemical, anti-oxidant and anthelmintic activities of activity of pet-ether extract of Portulaca oleracea ( L inn. )
various leaf extracts of Flacourtia sepiaria Roxb. Asian Pac J against Pheretima posthuma. Int J Appl Biol Pharm Technol
Trop Biomed 2013; 3(12): 947-953. 2013; 4(1): 34-37.
[40] Raj L, Gadamsetty G, Sarada NC. Comparative studies on in- [56] S harma A , G upta S , S achan S , M ishra A , B anarji A .
vitro anthelmintic activity of Gymnema sylvestre and Acalypha Anthelmintic activity of the leaf of Saraca indica Linn. Asian
fruticosa Forssk. Int J Pharm Pharm Sci 2012; 4(1): 107-109. J Pharm Life Sci 2011; 1(4): 391-395.
[41] G oswami S , P andey A , T ripathi P , S ingh A , R ai A . A n in [57] P arhi PK , M ohapatra P . In-vitro anthelmintic activty of
vitro evaluation of the anthelmintic activity of Hedychium galenicals of Spermacoce ocymoides (Burm. F) DC. Cent Eur J
spichatum rhizomes and Zingiber zerumbet rhizomes on Exp Biol 2012; 1(3): 100-106.
the Pheretima posthuma model: a comparative study. [58] D as SS , D ey M , G hosh AK . D etermination of anthelmintic
Pharmacognosy Res 2011; 3(2): 140-142. activity of the leaf and bark extract of Tamarindus indica
[42] Amit K, Pravina G, Ganesh D. In-vitro anthelmintic activity Linn. Indian J Pharm Sci 2011; 73(1): 104-107.
of Helicteres isora seeds. Deccan J Nat Prod 2011; 2(1): 34-41. [59] M anjula RR , S pandana U , A nand TJ , S udheer M . In vitro
[43] Mahato K, Kakoti BB, Borah S, Kumar M. Evaluation of in- anthelmintic activity of aqueous and methanolic leaf extract
vitro anthelmintic activity of Heliotropium indicum L inn. of Tephrosia purpurea Linn. Int J Res Pharm Chem 2013; 3(1):
leaves in Indian adult earthworm. Asian Pac J Trop Dis 2014; 12-14.
4(Suppl 1): S259-S262. [60] Bachaya HA, Iqbal Z, Khan MN, Jabbar A, Gilani AH, Islam-
[44] D ullu V . A nthelmintic activity of ethanolic leaf extract of U d- D in I . In vitro and in vivo anthelmintic activity of
Jasminum mesnyi. Asian Pac J Trop Dis 2014 ; 4 ( S uppl 1 ) : Terminalia arjuna bark. Int J Agric Biol 2009; 11(3): 273-278.
S273-S275. [61] Patil SH, Deshmukh PV, Sreenivas SA, Sankeertana V, Rekha
[45] Kale AA, Gaikwad SA, Kamble GS, Deshpande NR, Salvekar V, Anjaiah B. Evaluation of anthelmintic activity of Uncaria
JP . In vitro anthelmintic activity of stem bark of Juglans gambier Roxb. against Pheretima posthuma. Int J Drug Dev
regia L. J Chem Pharm Res 2011; 3(2): 298-302. Res 2012; 4(4): 234-238.
[46] Sen S, De B, Devanna N, Chakraborty R. Anthelmintic and in [62] P atil DA , M anke MB , S hisode BT , S avke SJ . In-vitro
vitro antioxidant evaluation of fractions of methanol extract of anthelmintic activity of ethanolic extract of Ziziphus
Leea asiatica leaves. Anc Sci Life 2012; 31(3): 101-106. mauritiana leaves. Inventi Rapid: Ethnopharmacology
[47] G naneswari K , P adma Y , V enkata RRR , J ayaveera KN . In 2013 . [O nline] A vailable from: http://www.inventi.in/Article/
vitro anthelmintic activity of Leonotis nepetiifolia (L.) R. Br., a pep/873/13.aspx [Accessed on 7th July, 2014]
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

https://doi.org/10.4236/jbise.2018.1110023 275 J. Biomedical Science and Engineering


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

https://doi.org/10.4236/jbise.2018.1110023 276 J. Biomedical Science and Engineering


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].

https://doi.org/10.4236/jbise.2018.1110023 277 J. Biomedical Science and Engineering


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

https://doi.org/10.4236/jbise.2018.1110023 278 J. Biomedical Science and Engineering


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].

https://doi.org/10.4236/jbise.2018.1110023 279 J. Biomedical Science and Engineering


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

https://doi.org/10.4236/jbise.2018.1110023 280 J. Biomedical Science and Engineering


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-

https://doi.org/10.4236/jbise.2018.1110023 281 J. Biomedical Science and Engineering


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.

https://doi.org/10.4236/jbise.2018.1110023 282 J. Biomedical Science and Engineering


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.

REFERENCES
1. Ding, N. (2017) Hepatitis E Is a Liver Disease Caused by Hepatitis E Virus (HEV) Transmitted through the
Faecal-Oral Route.
http://www.drhealthtopics.com/hepatitis-e-liver-disease-caused-hepatitis-e-virus-hev-transmitted-faecal-oral-ro
ute/
2. Kadir, S.M., Saleem-ur-Rehman, K., Benetou, K., Ahmad, D. and Abdullah, A. (2016) Ten Years of Disease Sur-
veillance in Kashmir, India under Integrated Disease Surveillance Programme (IDSP) during 2006-2016.
https://www.amhsr.org/articles/ten-years-of-disease-surveillance-in-kashmir-india-under-integrated-disease-su
rveillance-programme-idsp-during-20062016-4186.html
3. Leonad, N. (2016) Mikhail Balayan and the Bizarre Discovery of Hepatitis E Virus.
https://norkinvirology.wordpress.com/2016/05/03/mikhail-balayan-and-the-bizarre-discovery-of-hepatitis-e-vir
us/
4. WHO, K. (2017) Hepatitis E. http://www.who.int/news-room/fact-sheets/detail/hepatitis-e
5. Daniel, C. and Olender, S. (2018) How Can You Prevent Diseases Spread by the Fecal-Oral Route?
https://www.verywellhealth.com/what-is-the-fecal-oral-route-1760046
6. Kamar, N., Izopet, J., Pavio, N., Aggarwal, R., Labrique, A., Wedemeyer, H. and Dalton, H.R. (2017) Hepatitis E
Virus Infection. https://www.ncbi.nlm.nih.gov/pubmed/29154369
7. de Alencar Arrais Guerra, J.A., Kampa, K.C., Morsoletto, D.G., Junior, A.P. and Ivantes, C.A. (2017) Hepatitis
E: A Literature Review. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719195/
8. Pelosi, E. and Clarke, I. (2008) Hepatitis E: A Complex and Global Disease.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3167588/
9. Ding, Q., Heller, B., Capuccino, J.M., Song, B., Nimgaonkar, I., Hrebikova, G., et al. (2017) Hepatitis E Virus
ORF3 Is a Functional Ion Channel Required for Release of Infectious Particles.
http://www.pnas.org/content/114/5/1147
10. Cao, D. and Meng, X. (2012) Molecular Biology and Replication of Hepatitis E Virus.
https://www.nature.com/articles/emi20127
11. Song, Y. (2010) Studies of Hepatitis E Virus Genotypes.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3028963/
12. Pischke, S., Behrendt, P., Bock, C., Jilg, W., Manns, M. and Wedemeyer, H. (2014). Hepatitis E in Germany—An
Under-Reported Infectious Disease. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174681/
13. Cornelia, A., Alexander, W., Helga, M., Marco, K., Heinz, E. and Georg, P. (2009) High HEV Presence in Four
Different Wild Boar Populations in East and West Germany.
https://www.sciencedirect.com/science/article/pii/S0378113509003174
14. Szabo, K. and ReimarJohneb, R. (2015) Detection of Hepatitis E Virus RNA in Raw Sausages and Liver Sausages
from Retail in Germany Using an Optimized Method.
https://www.sciencedirect.com/science/article/pii/S0168160515301264
15. Krumbholz, A., Joel, S., Dremsek, P., et al. (2014) Seroprevalence of Hepatitis E Virus (HEV) in Humans Living
in High Pig Density Areas of Germany. Medical Microbiology and Immunology, 203, 273-282.
https://link.springer.com/article/10.1007/s00430-014-0336-3

https://doi.org/10.4236/jbise.2018.1110023 285 J. Biomedical Science and Engineering


16. Bettinger, D.E.H.H., Kappert, O.M. and Wenzel, J. (2014) Transfusion-Transmitted Hepatitis E in Germany,
2013. Eurosurveillance, 19, pii: 20812.
https://www.eurosurveillance.org/content/10.2807/1560-7917.ES2014.19.21.20812
17. Vollmer, T., Diekmann, J., Johne, R., Eberhardt, M., Knabbe, C. and Dreier, J. (2012) Novel Approach for De-
tection of Hepatitis E Virus Infection in German Blood Donors. Journal of Clinical Microbiology, 50,
2708-2713.
18. Vollmer, T., Diekmann, J., Eberhardt, M., Knabbe, C. and Dreier, J. (2016) Hepatitis E in Blood Donors: Inves-
tigation of the Natural Course of Asymptomatic Infection, Germany, 2011. Eurosurveillance, 21.
https://www.ncbi.nlm.nih.gov/pubmed/27608433
19. Jain, P., Prakash, S., Gupta, S., Singh, K.P., Shrivastava, S., Singh, D.D. and Jain, A. (2013) Prevalence of Hepati-
tis A Virus, Hepatitis B Virus, Hepatitis C Virus, Hepatitis D Virus and Hepatitis E Virus as Causes of Acute
Viral Hepatitis in North India: A Hospital Based Study. Indian Journal of Medical Microbiology, 31, 261-265.
https://www.ncbi.nlm.nih.gov/pubmed/23883712/
20. Tnn, N. (2013) Around 80% of Sewage in Indian Cities Flows into Water System.
https://timesofindia.indiatimes.com/home/environment/pollution/Around-80-of-sewage-in-Indian-cities-flows
-into-water-systems/articleshow/18804660.cms
21. Ippagunta, S., Sharma, B. and Aggarwal, R. (2007) Presence of Hepatitis E Virus in Sewage in Northern India:
Frequency and Seasonal Pattern. Journal of Medical Virology, 79, 1827-1831.
https://onlinelibrary.wiley.com/doi/abs/10.1002/jmv.21017
22. Helen, W. (2017) Seroprevalence and Risk Factors Associated with Hepatitis E Virus Infections among People
and Pigs in Tibet, China. Acta Tropica, 172, 102-106.
https://www.sciencedirect.com/science/article/pii/S0001706X17302875?via=ihub
23. Jia, Z., Yi, Y., Liu, J., Cao, J., Zhang, Y., Tian, R., Bi, S., et al. (2014) Epidemiology of Hepatitis E Virus in China:
Results from the Third National Viral Hepatitis Prevalence Survey, 2005-2006. PLoS ONE, 9, e110837.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4215996/
https://doi.org/10.1371/journal.pone.0110837
24. Dong, C., Dai, X., Liang, J., Dong, M. and Meng, J. (2012) Seroprevalence of Hepatitis E Virus Varies Consider-
ably among Chinese Provinces. Hepatitis Monthly, 12, 386-390.
http://hepatmon.com/en/articles/70416.html
25. Worm, H.C. and Wirnsberger, G. (2004) Hepatitis E Vaccines: Progress and Prospects. Drugs, 64, 1517-1531.
https://doi.org/10.2165/00003495-200464140-00002
26. Ahmad, I., Holla, R.P. and Jameel, S. (2011) Molecular Virology of Hepatitis E Virus. Virus Research, 161,
47-58. https://doi.org/10.1016/j.virusres.2011.02.011
27. Makar, G. (2007) Safety and Efficacy of a Recombinant Hepatitis E Vaccine. The New England Journal of Medi-
cine, 356, 895-903. https://doi.org/10.1016/S0739-5930(08)70198-3
28. Zhang, J. (2015) Long-Term Efficacy of a Hepatitis E Vaccine. New England Journal of Medicine, 372,
1478-1478. https://doi.org/10.1056/NEJMoa1406011
29. Wut, T. (2015) Zhongguo Wuganyimian - Weiyufang Dailai Xiwang.
http://news.medlive.cn/all/info-progress/show-45099_35.html
30. Us, C. (2018) Vaccines for Children Program (VFC).
https://www.cdc.gov/vaccines/programs/vfc/awardees/vaccine-management/price-list/index.html
31. (2018) Germany GDP per Capita PPP 1990-2018.
https://tradingeconomics.com/germany/gdp-per-capita-ppp

https://doi.org/10.4236/jbise.2018.1110023 286 J. Biomedical Science and Engineering


32. Vivek, R., Zachariah, U., Ramachandran, J., Eapen, C., Rajan, D. and Kang, G. (2013) Characterization of Hepa-
titis E Virus from Sporadic Hepatitis Cases and Sewage Samples from Vellore, South India. Transactions of the
Royal Society of Tropical Medicine and Hygiene, 107, 363-367. https://doi.org/10.1093/trstmh/trt030
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454524/
33. (2018) Deguo Juanxian Qiguan Renshu Chuangxindi - Xinhuawang.
http://www.xinhuanet.com/world/2018-01/16/c_1122266247.htm
34. (2018) 2018 Nian Zhongguo Qiguan Juanxian Youwang Tupo 6000 li - Xinhuawang.
http://www.xinhuanet.com/politics/2018-07/14/c_129913433.htm
35. Domanović, D., Tedder, R., Blümel, J., Zaaijer, H., Gallian, P., Niederhauser, C., Hewitt, P., et al. (2017) Hepati-
tis E and Blood Donation Safety in Selected European Countries: A Shift to Screening? Eurosurveillance, 22,
30514. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404480/
https://doi.org/10.2807/1560-7917.ES.2017.22.16.30514
36. Guo, Q., Yan, Q., Xiong, J., Ge, S., Shih, J., Ng, M., Xia, N., et al. (2009) Prevalence of Hepatitis E Virus in Chi-
nese Blood Donors. Journal of Clinical Microbiology, 48, 317-318.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812292/
https://doi.org/10.1128/JCM.01466-09
37. Gajjar, M., Bhatnagar, N., Sonani, R., Gupta, S. and Patel, T. (2014) Hepatitis E Seroprevalence among Blood
Donors: A Pilot Study from Western India. Asian Journal of Transfusion Science, 8, 29-31.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943141/
https://doi.org/10.4103/0973-6247.126685
38. Wang, M., Yin, Y., He, M. and Liu, Y. (2016) Acute, Recent and Past HEV Infection among Voluntary Blood
Donors in China: A Systematic Review and Meta-Analysis. PLoS ONE, 11, e0161089.
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0161089
https://doi.org/10.1371/journal.pone.0161089
39. Wen, G., Chen, C., Song, X., Tang, Z., Ji, W., Wang, S., Xia, N., et al. (2018) Long-Term HEV Carriers without
Antibody Seroconversion among Eligible Immunocompetent Blood Donors. Emerging Microbes & Infections,
7, 125. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033859/
https://doi.org/10.1038/s41426-018-0125-y
40. BioPharm, W. (2013) HEV-IgM Testing Paper Box.
http://www.ystwt.com/product/276519599
41. BioPharm, W. (2015) Hepatitis E Virus IGM Detection Reagent.
http://www.wondfo.com.cn/product-165.html
42. (2017) Ribavirin—FDA Prescribing Information, Side Effects and Uses.
https://www.drugs.com/pro/ribavirin.html
43. Goldszmid, R., Dzutsev, A. and Trinchieri, G. (2014) Host Immune Response to Infection and Cancer: Unex-
pected Commonalities. Cell Host & Microbe, 15, 295-305.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3996827/
https://doi.org/10.1016/j.chom.2014.02.003
44. Kamar, N., et al. (2014) Ribavirin for Chronic Hepatitis E Virus Infection in Transplant Recipients. The New
England Journal of Medicine, 370, 1111-1120. https://www.nejm.org/doi/full/10.1056/NEJMoa1215246
https://doi.org/10.1056/NEJMoa1215246
45. Yeh, M., Hsieh, M., Huang, C., Huang, C., Hsieh, M., Huang, J., Yu, M., et al. (2016) Long-Term Efficacy of
Peg-Interferon/Ribavirin with and without Lamivudine Therapy for HBeAg-Positive Hepatitis B and C Dual
Infection. Journal of Gastroenterology and Hepatology, 31, 835-841.

https://doi.org/10.4236/jbise.2018.1110023 287 J. Biomedical Science and Engineering


https://www.ncbi.nlm.nih.gov/pubmed/26478984
https://doi.org/10.1111/jgh.13203
46. Kamar, N., Lhomme, S., Peron, O.M., Alric, L. and Izopet, J. (2016) Treatment of HEV Infection in Patients
with a Solid-Organ Transplant and Chronic Hepatitis. Viruses, 8, 222.
http://www.mdpi.com/1999-4915/8/8/222/htm
https://doi.org/10.3390/v8080222
47. (2018) Ribavirin Side Effects in Detail—Drugs.com.
https://www.drugs.com/sfx/ribavirin-side-effects.html

https://doi.org/10.4236/jbise.2018.1110023 288 J. Biomedical Science and Engineering


ORIGINAL CONTRIBUTION

Risk Factors for Typhoid and


Paratyphoid Fever in Jakarta, Indonesia
Albert M. Vollaard, MD Context The proportion of paratyphoid fever cases to typhoid fever cases may change
Soegianto Ali, MD, MSc 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-
Henri A. G. H. van Asten, MD, MPH phoid, because risk factors for disease may not coincide and current typhoid vaccines
Suwandhi Widjaja, MD, PhD do not protect against paratyphoid fever.
Leo G. Visser, MD, PhD Objective To determine risk factors for typhoid and paratyphoid fever in an en-
demic area.
Charles Surjadi, MD, PhD
Design, Setting, and Participants Community-based case-control study con-
Jaap T. van Dissel, MD, PhD 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-

T
YPHOID FEVER, A FOOD- AND WA-
phoid cases, 24 confirmed paratyphoid cases, and 289 control patients with fever but
terborne disease caused by Sal- without Salmonella bacteremia were interviewed, plus 378 randomly selected com-
monella enterica serotype typhi munity controls.
(S typhi), is a serious public
Main Outcome Measures Blood culture–confirmed typhoid or paratyphoid fe-
health problem in developing coun-
ver; risk factors for both diseases.
tries that claims 600000 lives every year.1
Paratyphoid fever, caused by Salmo- Results In 1019 fever patients we identified 88 (9%) Salmonella typhi and 26 (3%)
Salmonella paratyphi A infections. Paratyphoid fever among cases was indepen-
nella paratyphi A, B, or C, has a disease
dently associated with consumption of food from street vendors (comparison with com-
presentation similar to that of typhoid munity controls: odds ratio [OR], 3.34; 95% confidence interval [CI], 1.41-7.91; with
fever, but its incidence is reportedly fever controls: OR, 5.17; 95% CI, 2.12-12.60) and flooding (comparison with com-
about one tenth that of typhoid (ratio, munity controls: OR, 4.52; 95% CI, 1.90-10.73; with fever controls: OR, 3.25; 95%
1:10-20).2,3 In developing countries the CI, 1.31-8.02). By contrast, independent risk factors for typhoid fever using the com-
identification of risk factors and rel- munity control group were mostly related to the household, ie, to recent typhoid fe-
evant route of transmission for a dis- ver in the household (OR, 2.38; 95% CI, 1.03-5.48); no use of soap for handwashing
ease such as typhoid fever is essential for (OR, 1.91; 95% CI, 1.06-3.46); sharing food from the same plate (OR, 1.93; 95% CI,
the development of rational control strat- 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).
egies. Resources could consequently be
In comparison with fever controls, risk factors for typhoid fever were use of ice cubes
allocated to where they count most, eg, (OR, 2.27; 95% CI, 1.31-3.93) and female sex (OR, 1.79; 95% CI, 1.04-3.06). Fecal
to the construction or expansion of contamination of drinking water was not associated with typhoid or paratyphoid fe-
water distribution networks or sewage ver. We did not detect fecal carriers among food handlers in the households.
systems, chlorination of drinking wa- Conclusions In Jakarta, typhoid and paratyphoid fever are associated with distinct
ter, ensurance of food safety, hygiene routes of transmission, with the risk factors for disease either mainly within the house-
education, mass vaccination cam- hold (typhoid) or outside the household (paratyphoid).
paigns, and/or the identification of car- JAMA. 2004;291:2607-2615 www.jama.com
riers within or outside the households
of patients. of bacteria is required for infection than Author Affiliations: Department of Infectious Dis-
eases, Leiden University Medical Center, Leiden, the
Risk factors for typhoid fever have in typhoid fever; consequently, food is Netherlands (Drs Vollaard, Visser, and van Dissel); De-
been identified in several epidemio- implicated as the major vehicle for partment of Biology, Medical Faculty (Dr Ali), Depart-
ment of Internal Medicine (Dr Widjaja), and Center
logic studies suggesting either water- transmission of paratyphoid fever, since for Health Research (Dr Surjadi), Atma Jaya Catholic
borne 4 - 8 or foodborne transmis- Salmonella bacteria can multiply in University, Jakarta, Indonesia; and Institute for Inter-
national Health, University Medical Center Nijme-
sion.7,9-11 Whether these factors coincide food.12 Comparison of the transmis- gen, Nijmegen, the Netherlands (Dr van Asten).
with those for paratyphoid fever has not sion of both diseases is becoming in- Corresponding Author: Jaap T. van Dissel, MD, PhD,
Department of Infectious Diseases, C5-P, Leiden Uni-
been determined. The assumption is creasingly relevant, because recent re- versity Medical Center, PO Box 9600, 2300 RC Leiden,
that in paratyphoid fever, a higher dose ports have demonstrated an increasing the Netherlands (j.t.van_dissel@lumc.nl).

©2004 American Medical Association. All rights reserved. (Reprinted) JAMA, June 2, 2004—Vol 291, No. 21 2607

Downloaded From: https://jamanetwork.com/ on 10/20/2019


RISK FACTORS FOR TYPHOID AND PARATYPHOID FEVER IN INDONESIA

occurrence of paratyphoid fever.3,13 It Jakarta, Indonesia, we compared case METHODS


is not clear whether this is due to in- patients having paratyphoid and ty- Study Area and Population
completeness of epidemiologic data in phoid fever with random community The Jatinegara district in East Jakarta, a
endemic countries or to a downward controls to identify hygienic prac- 10.6-km2 area with 262699 registered
trend in the incidence of typhoid fe- tices, eating habits, and environmen- inhabitants (as of March 2002), was se-
ver1,14 and a consequent relative or tal and household characteristics that lected as the study area (FIGURE 1) be-
absolute increase in the incidence of could elucidate prevailing transmis- cause of its varied socioeconomic con-
paratyphoid fever. In consequence, sion routes. For this purpose we also ditions and good access to puskesmas
however, public health measures may examined the microbiological quality (ie, public community health centers
well be refocused. In particular, re- of drinking water and cultured stools providing medical care for low-income
cent interest in mass immunization as of intrahousehold food handlers to de- residents of Indonesia). The local cli-
a control strategy in regions of ende- tect transient or chronic carriers. A sec- mate has 2 distinctive seasons: a rainy
micity needs to be reconsidered if the ond control group composed of pa- season (December-April) and a dry sea-
incidence of typhoid fever is decreas- tients with nonenteric fever was used son (May-November). Three rivers cross
ing and paratyphoid fever is on the rise, for comparison and confirmation of the area, making the adjacent subdis-
because current typhoid fever vac- the results. Patients with typhoid fe- tricts prone to flooding. There is no sew-
cines (ie, parenteral Vi and oral Ty21a ver, paratyphoid fever, and nonen- age system in the area. Vaccination cam-
vaccine) do not protect against paraty- teric fever were identified in a prospec- paigns have not been initiated in the area.
phoid fever.2 tive passive-surveillance study involving
In this community-based case- hospitals and outpatient health cen- Study Design and Selection Criteria
control study in an endemic area in East ters in the study area. The study was approved by the Indone-
sian National Institute of Health Re-
Figure 1. Study Area ( Jatinegara, Jakarta, Indonesia), Showing Households of Cases search and Development (Litbangkes)
With Typhoid and Paratyphoid Fever and Fever Controls and provincial authorities. A passive sur-
veillance system was established from
INDIA CHINA N June 11, 2001, to February 4, 2003.
Teluk
MYANMAR
LAO PDR TAIWAN
PACIFIC
Jakarta Health care facilities in the study area
OCEAN were approached for the surveillance
THAILAND PHILIPPINES study. Those participating included all
VIETNAM 4 hospitals in the immediate vicinity, 8
CAMBODIA JAKARTA
Jakarta of the 13 additional small private out-
BRUNEI
MALAYSIA
patient clinics in the area, and all 12
PAPUA
NEW GUINEA Area of Detail puskesmas. A fee of US $0.35 covers 3
INDONESIA
days of antibiotic treatment, but cul-
Jakarta
tures or Widal tests are not part of the
0 10
km
usual diagnostic practice in puskesmas.
Eligible patients were individuals living
N Jatinegara Area 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-
er
Cili w u n g

u nt

lected into blood culture vials (aerobic)


li S

containing antibiotic-absorbing resins


Ka

(Bactec; Becton Dickinson, Franklin


Lakes, NJ) that were provided to the cen-
ters by the study group free of charge.
Household Cases were eligible patients with
Typhoid Fever Case blood culture–confirmed S typhi or
Cipinang

Paratyphoid Fever Case S paratyphi infection. All cases were


0 1
Fever Control
km subject to a household visit within a
month after the febrile episode that
prompted the blood culture.
2608 JAMA, June 2, 2004—Vol 291, No. 21 (Reprinted) ©2004 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 10/20/2019


RISK FACTORS FOR TYPHOID AND PARATYPHOID FEVER IN INDONESIA

Blood cultures of patients with non- a participant in the 12 months preced- tericidal effect of chlorine during trans-
enteric fever showed either no growth ing the interview. Intrahousehold food port was neutralized by 0.1 mL of 10%
or bacteria other than S typhi or S para- handlers were defined as individuals sodium thiosulphate. Water samples
typhi as cause of fever. Malaria could preparing meals for cases or controls were examined for total and fecal co-
be excluded in the differential diagno- 3 or more times a week. A single stool liforms by use of most probable num-
sis of prolonged fever, because trans- sample of 2 g was collected from all ber method.15 Fecal contamination was
mission does not occur in Jakarta. Ev- cases, controls, and their intrahouse- defined as a most probable number in-
ery second consecutive patient with hold food handlers in a vial with Cary- dex for fecal coliforms of 1⁄100 mL or
nonenteric fever was selected as a fe- Blair transport medium and samples greater.
ver control and visited. Also, during the were processed within 24 hours after
surveillance, community controls were collection. Water samples of 150 mL di- Statistical Methods
randomly selected within a random rectly from the source of running drink- Data from the questionnaires were en-
household in every third rukun tet- ing water were collected in the house- tered twice using EpiInfo 6.04b soft-
angga (ie, the smallest administrative holds of 62 typhoid and 20 paratyphoid ware (US Centers for Disease Control
unit of 40-60 area households) of a total cases, 341 community controls, and 233 and Prevention, Atlanta, Ga), vali-
of 1140 rukun tetanggas. When a com- fever controls using World Health Or- dated, and imported into SPSS version
munity control reported fever in the 30 ganization guidelines.15 11.5 (SPSS Inc, Chicago, Ill) for statis-
days preceding the interview or re- tical analysis. After the first 3 months of
fused participation, the house on alter- Laboratory Methods surveillance, an interim analysis was per-
nating sides of the initially selected Blood culture vials from outpatient fa- formed and the needed sample size was
household was approached. The selec- cilities were transported on the day of calculated; a minimum sample size of 80
tion of both groups of controls was collection to Mitra Internasional, one of enteric fever cases (assuming 4 times as
nonmatched for age, sex, or neighbor- the participating private hospitals with many fever controls) was required to de-
hood (ie, residence in 1 of the 8 sub- a microbiology laboratory certified by the tect significant associations (P⬍.05) be-
districts of Jatinegara) to limit selec- International Organization for Standard- tween key exposure variables and out-
tion bias and prevent overmatching. ization. Blood cultures were incubated come, with a power of 0.80. Normally
Four controls from both groups for for up to 7 days. Samples demonstrat- and nonnormally distributed numeri-
every case of enteric fever were se- ing growth were plated on blood agar cal variables were analyzed using t tests
lected to increase statistical power. medium. Salmonella typhi or S para- and Mann-Whitney U tests, respec-
typhi A were identified by use of agglu- tively. Measures for association were ex-
Household Visits tination antisera (Polyvalent, D, Vi, H, pressed as odds ratios (ORs) for dis-
and Sample Collection and Paratyphi A; Murex Biotech Ltd, ease with their 95% confidence intervals
Cases and controls were interviewed by Dartford, England) and biochemical tests (CIs) for categorical variables. To con-
trained medical school graduates, us- (Microbact; Medvet Diagnostics, Ad- trol for confounding, a multivariate
ing a standardized questionnaire that elaide, Australia). Susceptibility against analysis was performed using logistic re-
included the known risk factors from chloramphenicol, ampicillin, cotrimoxa- gression with a forward likelihood ra-
previous studies and questions from a zole, and ciprofloxacine was tested by tio test with the significantly associ-
questionnaire that was used in a simi- disk diffusion on Mueller-Hinton agar. ated variables from the bivariate analysis
lar risk factor study, which had been lo- Stool samples were cultured for Salmo- and potential confounders (eg, age,
cally tested and validated.6 Written in- nella bacteria using selenite enrich- sex, income, and neighborhood resi-
formed consent was provided by all ment broth (Oxoid Ltd, Hampshire, dence).16 Sex and income were also in-
participants at the household visit. To England). Suspected colonies as iden- cluded in the bivariate analysis; age and
prevent the overrepresentation of mul- tified by visual inspection were plated neighborhood residence were not. Effect
tiple-case households, only 1 patient on xylose-lysine-desoxycholate agar and modification by interaction of age, sex,
(ie, the first reported case or fever con- Salmonella-Shigella agar, and on triple or income was tested, but these terms
trol) per household was interviewed. If sugar iron agar, SIM (sulphide and in- were not significantly associated and did
cases or controls were younger than 13 dole production and motility) me- not change the ORs of associated vari-
years, the mother or guardian was in- dium, and Simmons citrate (Oxoid). ables. The attributable risk of each in-
terviewed. No time frame for hygiene Bacterial identification was identical to dependently associated variable from the
behavior and food habits was men- that for bacteria from blood cultures. multivariate analysis was calculated.17
tioned, because it aimed at the descrip- Samples from the sources of drink-
tion of usual practice. A household was ing water were transported on ice and RESULTS
defined as a dwelling whose inhabit- processed within 6 hours after collec- Surveillance Study
ants ate from the same pot. Flooding was tion at the Nusantara Water Centre.15 During the study period 1019 consecu-
defined as inundation of the house of In samples from piped water the bac- tive patients with fever lasting 3 or more
©2004 American Medical Association. All rights reserved. (Reprinted) JAMA, June 2, 2004—Vol 291, No. 21 2609

Downloaded From: https://jamanetwork.com/ on 10/20/2019


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.

Downloaded From: https://jamanetwork.com/ on 10/20/2019


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

Downloaded From: https://jamanetwork.com/ on 10/20/2019


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

Downloaded From: https://jamanetwork.com/ on 10/20/2019


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

Downloaded From: https://jamanetwork.com/ on 10/20/2019


RISK FACTORS FOR TYPHOID AND PARATYPHOID FEVER IN INDONESIA

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

Downloaded From: https://jamanetwork.com/ on 10/20/2019


RISK FACTORS FOR TYPHOID AND PARATYPHOID FEVER IN INDONESIA

grams for typhoid fever in Jakarta may Administrative, technical, or material support: Vollaard, ment of Medical Statistics for critically reviewing the
Ali, Widjaja, Surjadi. document and Wil Dolmans, MD, PhD, for his help
not be appropriate at this time. Study supervision: Vollaard, Ali, Widjaja, Visser, Surjadi, in the preparatory stage of this project. We thank
van Dissel. the physicians, nurses, and technicians of the par-
Author Contributions: Dr van Dissel, as principal in- Funding/Support: This study was supported by the ticipating health centers in Jakarta for their coop-
vestigator, had full access to all of the data in this study Royal Netherlands Academy of Arts and Sciences eration: Mitra Internasional hospital and micro-
and takes full responsibility for the integrity of the data (KNAW). biology laboratory, Budhi Asih, St Carolus and
and accuracy of the data analysis. Role of the Sponsor: The Royal Netherlands Acad- Persahabatan hospital, all puskesmas in Jatinegara,
Study concept and design; critical revision of the manu- emy of Arts and Sciences had no role in the design the local private practitioners, as well as the micro-
script for important intellectual content: Vollaard, Ali, and conduct of the study; the collection, manage- biology department of Atma Jaya University Hospi-
van Asten, Widjaja, Visser, Surjadi, van Dissel. ment, analysis, and interpretation of the data; or the tal and Nusantara Water Centre, West Jakarta. This
Acquisition of data: Vollaard, Ali. preparation, review, or approval of the manuscript. study could not have been done without our
Analysis and interpretation of data: Vollaard, Ali, Acknowledgment: We thank J. P. Vandenbroucke, research assistants: Billy Hunsinger, Ferry Kandaw,
van Dissel. MD, PhD, from the Leiden University Medical Cen- Rinny Listyani, Meily, Vea Noveria, Carmelita Rid-
Drafting of the manuscript: Vollaard. tre (LUMC) Department of Clinical Epidemiology wan, Min Ali Sugiharto, Lidwina Sutikno, Mariana
Statistical expertise: Vollaard, van Asten, van Dissel. and Nico Nagelkerke, PhD, from the LUMC Depart- Tasman, and Lily Yaputra.

REFERENCES
1. Pang T, Levine MM, Ivanoff B, Wain J, Finlay BB. 12. Christie AB. Infectious Diseases: Epidemiology and 23. Bodhidatta L, Taylor DN, Thisyakorn U, Eche-
Typhoid fever—important issues still remain. Trends Clinical Practice. 4th ed. Edinburgh, Scotland: Churchill verria P. Control of typhoid fever in Bangkok, Thai-
Microbiol. 1998;6:131-133. Livingstone; 1987. land, by annual immunization of schoolchildren with
2. Arya SC, Sharma KB. Urgent need for effective vac- 13. Tankhiwale SS, Agrawal G, Jalgaonkar SV. An un- parenteral typhoid vaccine. Rev Infect Dis. 1987;9:
cine against Salmonella paratyphi A, B and C. Vac- usually high occurrence of Salmonella enterica sero- 841-845.
cine. 1995;13:1727-1728. type paratyphi A in patients with enteric fever. In- 24. Parry CM, Hien TT, Dougan G, White NJ, Farrar
3. Sood S, Kapil A, Dash N, Das BK, Goel V, Seth P. dian J Med Res. 2003;117:10-12. JJ. Typhoid fever. N Engl J Med. 2002;347:1770-
Paratyphoid fever in India: an emerging problem. Emerg 14. Saha MR, Dutta P, Niyogi SK, et al. Decreasing 1782.
Infect Dis. 1999;5:483-484. trend in the occurrence of Salmonella enterica sero- 25. Wain J, Pham VB, Ha V, et al. Quantitation of bac-
4. Swaddiwudhipong W, Kanlayanaphotporn J. A type typhi amongst hospitalised children in Kolkata, teria in bone marrow from patients with typhoid fe-
common-source water-borne outbreak of multidrug- India during 1990-2000. Indian J Med Res. 2002; ver: relationship between counts and clinical fea-
resistant typhoid fever in a rural Thai community. 115:46-48. tures. J Clin Microbiol. 2001;39:1571-1576.
J Med Assoc Thai. 2001;84:1513-1517. 15. World Health Organization. Guidelines for Drink- 26. Parry CM, Hoa NT, Diep TS, et al. Value of a single-
5. King CC, Chen CJ, You SL, Chuang YC, Huang HH, ing-Water Quality. 2nd ed. Geneva, Switzerland: tube Widal test in diagnosis of typhoid fever in Viet-
Tsai WC. Community-wide epidemiological investi- World Health Organization; 1997. nam. J Clin Microbiol. 1999;37:2882-2886.
gation of a typhoid outbreak in a rural township in 16. Sun GW, Shook TL, Kay GL. Inappropriate use of 27. Castillo MTG, Superable JT, Magpantay RL, White
Taiwan, Republic of China. Int J Epidemiol. 1989;18: bivariable analysis to screen risk factors for use in mul- ME, Dayrit MM, Saniel MC. Case-control study of re-
254-260. tivariable analysis. J Clin Epidemiol. 1996;49:907- sistant Salmonella typhi in metro Manila, Philip-
6. Gasem MH, Dolmans WM, Keuter MM, Djoko- 916. pines. Southeast Asian J Trop Med Public Health. 1995;
moeljanto RR. Poor food hygiene and housing as risk 17. Bruzzi P, Green SB, Byar DP, Brinton LA, Schairer 26(suppl):39-41.
factors for typhoid fever in Semarang, Indonesia. Trop C. Estimating the population attributable risk for mul- 28. Estrada-Garcia T, Cerna JF, Thompson MR, Lopez-
Med Int Health. 2001;6:484-490. tiple risk factors using case-control data. Am J Epide- Saucedo C. Faecal contamination and enterotoxi-
7. Luby SP, Faizan MK, Fisher-Hoch SP, et al. Risk fac- miol. 1985;122:904-914. genic Escherichia coli in street-vended chili sauces in
tors for typhoid fever in an endemic setting, Karachi, 18. Ferreccio C, Levine MM, Manterola A, et al. Be- Mexico and its public health relevance. Epidemiol In-
Pakistan. Epidemiol Infect. 1998;120:129-138. nign bacteremia caused by Salmonella typhi and para- fect. 2002;129:223-226.
8. Mermin JH, Villar R, Carpenter J, et al. A massive typhi in children younger than 2 years. J Pediatr. 1984; 29. Koo D, Aragon A, Moscoso V, et al. Epidemic chol-
epidemic of multidrug-resistant typhoid fever in 104:899-901. era in Guatemala, 1993: transmission of a newly in-
Tajikistan associated with consumption of municipal 19. Lin FY, Vo AH, Phan VB, et al. The epidemiology troduced epidemic strain by street vendors. Epide-
water. J Infect Dis. 1999;179:1416-1422. of typhoid fever in the Dong Thap Province, Mekong miol Infect. 1996;116:121-126.
9. Bhan MK, Bahl R, Sazawal S, et al. Association be- Delta region of Vietnam. Am J Trop Med Hyg. 2000; 30. Curtis V, Cairncross S. Effect of washing hands
tween Helicobacter pylori infection and increased risk 62:644-648. with soap on diarrhoea risk in the community: a
of typhoid fever. J Infect Dis. 2002;186:1857-1860. 20. Simanjuntak CH, Paleologo FP, Punjabi NH, et al. systematic review. Lancet Infect Dis. 2003;3:275-
10. Black RE, Cisneros L, Levine MM, Banfi A, Lobos Oral immunisation against typhoid fever in Indonesia 281.
H, Rodriguez H. Case-control study to identify risk fac- with Ty21a vaccine. Lancet. 1991;338:1055-1059. 31. Dickens DL, DuPont HL, Johnson PC. Survival of
tors for paediatric endemic typhoid fever in Santiago, 21. Sinha A, Sazawal S, Kumar R, et al. Typhoid fe- bacterial enteropathogens in the ice of popular drinks.
Chile. Bull World Health Organ. 1985;63:899-904. ver in children aged less than 5 years. Lancet. 1999; JAMA. 1985;253:3141-3143.
11. Velema JP, van Wijnen G, Bult P, van Naerssen 354:734-737. 32. Luxemburger C, Chau MC, Mai Nl, et al. Risk fac-
T, Jota S. Typhoid fever in Ujung Pandang, Indonesia— 22. Saha SK, Baqui AH, Hanif M, et al. Typhoid fe- tors for typhoid fever in the Mekong delta, southern
high-risk groups and high-risk behaviours. Trop Med ver in Bangladesh: implications for vaccination policy. Viet Nam: a case control study. Trans R Soc Trop Med
Int Health. 1997;2:1088-1094. Pediatr Infect Dis J. 2001;20:521-524. Hyg. 2001;95:19-23.

©2004 American Medical Association. All rights reserved. (Reprinted) JAMA, June 2, 2004—Vol 291, No. 21 2615

Downloaded From: https://jamanetwork.com/ on 10/20/2019

Anda mungkin juga menyukai