Download Assessing the Role of Ultrasound to Determine

Assessing the Role of Ultrasound to Determine Prognosis and
Disease Severity in Pediatric Dengue Patients
A Traveling Medical Scholars Proposal:
Clinical Research Concentration
James A. Colbert
Stanford University School of Medicine
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Abstract
Approximately 3 billion people worldwide live in areas at risk for transmission of the dengue
flavivirus by the Aedes aegypti mosquito, and an estimated 100 million people worldwide are
infected with the virus each year. Clinical manifestations of the virus in humans range from
dengue fever (DF), a debilitating though self-limited disease, to dengue hemorrhagic fever
(DHF) and dengue shock syndrome (DSS), severe syndromes that when untreated can lead to
death. A key clinical feature of DHF that distinguishes it from DF is increased vascular
permeability, as evidenced by increased hemoconcentration, pleural effusion, and/or ascites.
Current clinical methods employed in diagnosis of DHF include chest radiography and
hematocrit blood tests. However, these methods both have limitations in the developing world
due to the cost of chest radiography and the invasiveness and cost of numerous blood draws and
hematocrit determinations.
This Traveling Scholars project seeks to analyze the use of portable ultrasound as an alternative
means of assessing disease severity in patients infected with dengue virus. The project will take
place at the Nicaraguan National Pediatric Reference Hospital, the Hospital Infantil Manuel de
Jesus Rivera (HIMJR), in the capital city of Managua, where clinical, virological, and serological
data on dengue cases is systematically collected from all pediatric dengue patients. Over the past
2 years, the team at the Infectious Diseases Unit at the HIMJR has been begun to use ultrasound
as an additional tool in managing cases of dengue. However, since the prognostic capability of
ultrasound has not been validated, there is no established consensus on how to interpret
ultrasound findings in dengue patients. The goal of this project is to first create a database of
dengue patients that incorporates ultrasound findings, clinical data, and virological, serological,
and clinical laboratory results. Once this database has been created it will be possible to
statistically analyze the correlation between sonographic findings and clinical progression of
dengue.
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I. Specific Aims
Goal: To determine the sensitivity of ultrasound in measuring capillary leakage in patients
with dengue fever. Ultrasound will be compared with current clinical standard methods:
palpation, chest radiography, and hematocrit analysis.
Aim 1: To compile a database (Microsoft Access) that incorporates sonographic findings,
clinical and laboratory data in children aged 1-14 admitted to the Hospital Infantil Manuel
de Jesus Rivera (HIMJ) during the 12 months between August 2005 through July 2006.
Because of a sophisticated research effort in collaboration with Dr. Eva Harris at UC Berkeley,
the Infectious Disease Unit at the National Pediatric Reference Hospital (HIMJR) in Nicaragua
has collected a wealth of clinical and laboratory data on hundreds of confirmed cases of dengue.
By combining these data with ultrasound findings collected over the past year, it will be possible
to create a powerful research database.
Aim 2: To analyze the data on ultrasound in dengue patients using the statistical software
package STATA. Once the database has been compiled, it will be possible to ask a number of
questions about the usefulness of ultrasound in the clinical management of dengue. Research
questions to be analyzed include: How does the sensitivity of ultrasound to detect capillary
leakage compare with those of other clinical tools? Does ultrasound provide predictive
information about disease progression? Are there cut-offs that should be applied to the
ultrasound measures in terms of disease severity?
Aim 3: To apply the results of this pilot study to an ongoing prospective study that aims to
create a novel classification algorithm for case management of pediatric dengue patients in
Nicaragua.
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II. Background and Significance
Dengue is the most significant mosquito-borne viral disease in the world today.
Approximately 3 billion people worldwide live in areas at risk for transmission of the dengue
flavivirus by the Aedes aegypti mosquito, and an estimated 100 million people worldwide are
infected with the virus each year.1 Clinical manifestations of the virus include dengue fever
(DF), dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). The classic
symptoms of DF include high fever, headache, musculo-skeletal pain, retro-orbital pain, and
rash. The principal requirements for a DHF classification are hemorrhagic manifestations,
plasma leakage, and thrombocytopenia (platelet count <100,000/mm3); the additional presence of
hypotension or narrow pulse pressure along with clinical signs of shock designates DSS. Four
serotypes of the dengue virus exist (DEN-1, DEN-2, DEN-3, and DEN-4); all are pathogenic,
although studies suggest that differences do exist between clinical manifestations of the various
serotypes.2,3
Over the past twenty years dengue has emerged as a very significant public health
problem in the Americas. Much of the spread in dengue can be attributed to expansion in the
range of the Ae. aegypti mosquito following an eradication program that was abandoned in the
1970s (See Figure 1). Similarly, in 1970 only the Dengue-2 viral serotype existed in the
Americas, while today all four serotypes of the virus are now endemic to the Western
Hemisphere.4 This is significant because risk for severe disease (DHF or DSS) is much higher in
individuals with secondary infection caused by exposure to a different DEN serotype than their
first infection (See Figure 2).5
Dengue has been endemic in Nicaragua since 1985, and all four DEN serotypes have
circulated, usually with one dominant serotype per epidemic season.6-9 Cases are reported
throughout the year, with an increase during the rainy months (Jun-Oct), and the burden of
disease lies mainly in children 5-14 years of age and in infants.10 Dengue in Managua causes
anywhere from 200 to 700 hospitalizations per year at the Hospital Infantil Manuel de Jesus
Rivera. Since 1998, collaboration between the Nicaraguan Ministry of Health and Dr. Eva
Harris at UC Berkeley has established longitudinal hospital–and health center-based studies of
pediatric dengue patients to characterize clinical features of dengue in Nicaragua and to
investigate risk factors for severe dengue. The sophistication of the data collection and dengue
monitoring methods at the Hospital Infantil Manuel de Jesus Rivera makes it an ideal site for this
clinical research study.
Laboratory diagnosis of dengue involves either detection of anti-DEN antibodies
(serology) or detection of the virus itself (virology). Serological tests include hemagglutination
inhibition (HI) assay and IgG or IgM enzyme immunoassays. Virological testing involves
isolation of the virus from the patient’s blood and/or amplification of the viral RNA via the
reverse transcriptase-polymerase chain reaction. In Nicaragua the laboratory diagnosis is
performed at the National Virology Laboratory of the Ministry of Health in Managua.
While laboratory diagnosis of dengue is the gold standard, results may not always be
obtained in time to be clinically useful. Also, laboratory diagnosis may not be possible in
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regions of the world without extensive medical infrastructure. In many parts of the developing
world, diagnosis of DHF is made solely on the basis of the clinical case definition: hemorrhagic
manifestations, plasma leakage, thrombocytopenia, and signs of shock. Capillary leakage
usually manifests itself clinically through pleural effusion and ascites, which can be detected by
palpation and radiography. Assessment of increased vascular permeability also relies heavily on
repeated measurements of hematocrit to detect hemoconcentration.
A major problem with managing dengue in Nicaragua is the difficulty of predicting
which patients will develop severe disease. Recent studies have shown that the distinction
between DF and DHF may not be sufficient, as some patients who do not meet the criteria for
DHF may actually enter a critical phase from which they can die if not treated with appropriate
fluids. Similarly, some patients who meet the criteria for DHF resolve on their own without
treatment.11 Hospitalization of dengue patients in Nicaragua is mostly a preventative measure;
criteria for admission are very broad, and once in the hospital patients are carefully monitored for
increased vascular permeability, severe thrombocytopenia (platelets<50,000), and intestinal or
vaginal bleeding. Once these signs manifest, this is the “critical phase” during which the patient
can die within 24-48 hours if not treated with appropriate fluids.
Ultrasound may be a promising alternative to radiography in the management of dengue
in developing nations. Advantages of ultrasound include its non-invasive nature as well as lower
cost and greater portability compared with X-rays. Ultrasound allows a clinician to detect
capillary leakage as well as hepatomegaly, splenomegaly, and thickening of the gallbladder wall
in patients with dengue.12 -17 However, an analysis of the predictive value of ultrasound for
dengue diagnosis and case management based on data collected in the Western Hemisphere has
not yet been published.
Ultrasound has two potential uses in the management of dengue in Nicaragua. As a
prognostic indicator, ultrasound could potentially be used to assess which patients are at severe
risk of entering the critical phase. By identifying these patients early, hospital resources could be
more efficiently allocated, and patients who are not at high risk could be discharged earlier.
Secondly, ultrasound could be used as a cheaper, less invasive means of monitoring for plasma
leakage. The goal of this study is to analytically investigate these two potential uses of
ultrasound.
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III. Experimental Design
Aim 1: To compile a database that incorporates sonographic findings, clinical and
laboratory data in children aged 1-14 admitted to the Hospital Infantil Manuel de Jesus
Rivera during the 12 months between August 2005 through July 2006.
Project Schedule and On-Site Support
This will be a six-week project in Managua, Nicaragua that will run from the last week of
June through the first week of August. The project will be based in the Infectious Disease Unit
(IDU) of the Hospital Infantil Manuel de Jesus Rivera, the premier children’s hospital in
Nicaragua. The Infectious Diseases Unit (IDU) is headed by Dr. Crisanta Rocha and is the site
of primary admission of dengue patients with hospitalization criteria, with 24 beds. Dr. Sheyla
Silva and Dr. Javier Silva are pediatric infectious disease specialists at the hospital who are
willing to supervise and provide assistance with the project. William Avilés is an informatics
engineer who will be available for supervision of the data management aspects of the project.
Dr. Rigoberto Roxeline is a radiologist who examines patients in the IDU with ultrasound.
Samantha Hammond is the on-site coordinator for Dr. Harris’s dengue program in Managua,
which consists of a number of projects including the clinical study with which this summer
project is associated. Finally, Dr. Eva Harris will serve as the project advisor and will supervise
the progress of the research study.
Sources of Data
Clinical data on hospitalized patients with dengue is collected systematically at the
Hospital Infantil Manuel de Jesus Rivera as part of an ongoing prospective study on the clinical
management of dengue fever (See Appendix 3). This data is stored in both hard copy and
electronically. At enrollment, all patients complete a clinical history and epidemiologic
questionnaire. Vital signs are measured and recorded several times a day; these include:
temperature, blood pressure, pulse, and respiratory rate. Additionally, information is recorded on
all bleeding symptoms, vascular permeability indicators, signs of circulatory compromise
(shock), respiratory problems, renal functioning, gastrointestinal symptoms, skin rashes,
neurological symptoms, and musculoskeletal pain.
Clinical laboratory results include blood samples processed for CBC with platelets and
atypical lymphocytes. Transaminase and glucose tests, as well as cholesterol (LDL, HDL) are
processed on the day of admission for all patients, on the day of convalescent visit for all
patients, and as necessary for patients with severe disease. PT, PTT, creatinine, and total protein
including albumin are assessed as needed for all patients. Microhematocrit readings are obtained
using microcentrifuge/ microcapillaries at regular time intervals.
Laboratory data includes serological and virological data from samples collected on the
day of hospital admission and at convalescence (at least six days after onset of symptoms). IgM
antibodies are measured using a MAC ELISA, and the level of anti-DEN IgG antibodies are
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determined by Inhibition ELISA. Virus isolation and immunofluorescent serotyping is
performed, and viral RNA is detected by RT PCR.
Radiography data includes pleural effusion and pulmonary edema. Sonography data
includes measurements of pleural effusion, ascites, gallbladder wall thickening, hepatomegaly,
and splenomegaly.
Aim 2: To analyze the database in order to investigate: 1) the role of ultrasound to provide
predictive information about disease progression, and 2) whether there are specific disease
severity cut-offs that should be applied when using ultrasound.
Data Analysis and Statistical Techniques
Data management will be performed using Microsoft Access. Primary data points
include measurements of hemoconcentration, thrombocytopenia, capillary leakage and internal
bleeding. Hemoconcentration and thrombocytopenia data will be obtained from laboratory blood
analysis; capillary leakage and internal bleeding will be obtained from multiple sources: physical
exam, X-ray, and ultrasound. Rather than just classify capillary leakage as a yes/no category, it
will be important in this study to note such factors as quantity of fluid leakage and tissues
affected by this leakage.
Data analysis will be performed using STATA (STATA Corp). Sensitivity of ultrasound
to detect capillary leakage will be compared to the customary methods that include X-ray and
hematocrit analysis. Patients will be classified on a severity scale based on the number of severe
symptoms: thrombocytopenia, hepatitis, hemorrhagic manifestations, shock, and neurological
symptoms. The severity score will be used in regression analysis to investigate the predictive
value of ultrasound. ROC analysis will be used to obtain cut-off values and sensitivity and
specificity of ultrasound as a measure of disease severity. A regression analysis will be
performed to detect if there are serotype-specific differences in disease severity and capillary
leakage. The main outcome endpoint for data analysis will be progression to critical phase (as
measured by increased capillary leakage, platelet count<50,000, and internal bleeding).
In order to answer the question of a cut-off for “severe” capillary leakage, it will be
necessary to compare the outcome differences between cases of dengue in which ascites are
detected by both physical exam and ultrasound versus cases in which ascites are detected by
ultrasound only.
As this is a retrospective analysis, the study will not be able to definitively determine
ultrasound cut-off values, but rather the goal is to generate hypotheses that can then be tested
prospectively in the following year. The number of dengue patients analyzed in this study will
be approximately 150.
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Aim 3: To apply the results of this pilot study to an ongoing prospective study that aims to
create a novel classification algorithm for case management of pediatric dengue patients in
Nicaragua.
Incorporation of Results to an Ongoing Prospective Clinical Study
The Hospital Infantil Manuel de Jesus Rivera (HIMJR) is the site of an ongoing three
year clinical study entitled “Prospective hospital-based study of dengue classification and case
management in Nicaragua.” Between 2005 and 2008 this study aims to recruit approximately
2000 pediatric dengue patients, although the actual number will be determined by the number of
suspected dengue cases that attend the HIMJR during the study period each year. As this is a
pediatric hospital, the study population is children up to 14 years of age. The population is
comprised of suspected dengue cases seen at the HIMJR as outpatients, hospitalized in the
infectious disease unit (IDU), hospitalized in other units, or under long-term observation in the
Emergency Department (ED). The population includes both primary and secondary DEN
infections. A principle aim of this prospective study is
To identify warning signs and design an algorithm useful for detecting severe dengue for
case management at different levels of the health system, and to establish differences in
type or utility of such warning signs/algorithms between regions, age groups, patients
with and without chronic diseases and/or different nutritional levels.
Thus, a goal of this Travel Scholars Proposal is to establish ultrasound guidelines that can be
validated by patients who enroll in this study during the next two years. Ultrasound cut-offs for
capillary leakage and disease severity proposed by this Travel Scholars Project will be rigorously
tested over the next two years as hundreds of new patients will be enrolled and followed.
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IV. Human Subjects and Informed Consent
All data involved in this study will be collected from pediatric patients who are enrolled
in a prospective study entitled “Prospective hospital-based study of dengue classification and
case management in Nicaragua.” This study has been approved by the following human subjects
ethics committees: The World Health Organization, University of California at Berkeley, Centro
Nacional de Diagnostico y Referencial del Ministerio de Salud Nicaragua, and Hospital Infantil
Manuel de Jesus Rivera (HIMJR). Recruitment occurs through invitation of parents/guardians of
children seen at the HIMJR who are suspected of dengue in the ED or, for transferred
hospitalized patients, upon admission to the IDU. Patients are recruited in the ED or hospital
units by trained study personnel. Nurses or physicians screen patients referred from other
hospitals. One-on-one or in small groups, information regarding the study is provided to the
adult(s) responsible for the child suspected of dengue. The discussion begins with a preliminary
explanation of the study, and the consent form is reviewed together, providing a more detailed
explanation of all of the aspects of the study. Only patients whose parents have consented to
their participation and children over age 5 who have assented are permitted to enter the study
(See Appendix 3 for English translation of consent form).
This Traveler Scholars Proposal is in the process of IRB approval through the Stanford
Human Subjects Research Office. It is being submitted as a Medical Expedited Review,
classification five.
V. Learning Objectives
Besides performing data analysis, the Traveling Scholar grant recipient will assist
members of the Infectious Disease Unit of Hospital Infantil Manuel de Jesus Rivera to care for
pediatric patients who present to the hospital with symptoms of dengue. The Traveling Scholar
grant recipient will also assist Dr. Rigoberto Roxelin to perform ultrasound on patients with
suspected dengue infection. These clinical interactions will allow the grant recipient to gain a
comprehensive understanding of the presentation and management of both DF and DHF.
A broader goal of this project will be to give the grant recipient exposure to the methods
involved in epidemiological research in developing countries. The author of this grant proposal
has a strong interest in infectious disease and international health. Through this summer
experience the grant recipient will be able to explore the possibility of building a career that
focuses on these aspects of medicine.
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VI. Relevance to Medicine
This project will be the first study that uses data collected in the Americas to
quantitatively examine the role of ultrasound as a means of assessing dengue fever. A number of
recent studies have definitively established ultrasound as an effective tool for detecting pleural
effusions in hospitalized patients.18-20 Since pleural effusion is a major finding in dengue
hemorrhagic fever, these findings are promising for the role of ultrasound in dengue assessment.
Likewise, the role of thickening of gallbladder wall has been associated with dengue but needs to
be further validated.15,21,22
As a prognostic indicator, ultrasound could potentially be used to assess which patients
are at severe risk of entering the critical phase of dengue infection. Secondly, ultrasound could
be used as a cheaper, less invasive means of monitoring for plasma leakage. Thus, as a low cost,
portable and non-invasive procedure, ultrasound has the potential to be a major tool in the
clinical management of dengue worldwide.
VII. References
1. Burke, D. S., and T. P. Monath. 2001. Flaviviruses, p. 1043-1126. In D. M. Knipe and P.
M. Howley (ed.), Fields Virology, 4th ed, vol. 1. Lippincott Williams and Wilkins,
Philadelphia.
2. Balmaseda, A., S. N. Hammond, Y. Tellez, L. Imhoff, Y. Rodriguez, S. Saborio, J. C.
Mercado, L. Perez, E. Videa, E. Almanza, G. Kuan, M. Reyes, L. Saenz, J. J. Amador,
and E. Harris. 2006. High seroprevalence of antibodies against dengue virus in a
prospective study of schoolchildren in Managua, Nicaragua. Trop. Med. Int. Health. In
press.
3. Nisalak, A., T. P. Endy, S. Nimmanniya, S. Kalayanarooj, U. Thisayakorn, R. M. Scott,
D. S. Burke, C. H. Hoke, B. L. Innis, and D. W. Vaughn. 2003. Serotype-specific dengue
virus circulation and dengue disease in Bangkok, Thailand from 1973-1979. Am. J. Trop.
Med. Hyg. 68:191-202.
4. Organization, P. A. H. 1994. Dengue and Dengue Hemorrhagic Fever in the Americas:
Guidelines for prevention and control, vol. Scientific Publication #548.
5. Rothman, AL. Dengue: defining protective versus pathologic immunity. J Clin Invest
2004; 113:946.
6. Kouri, G., M. Valdez, L. Arguello, M. G. Guzmán, L. Valdes, M. Soler, and J. Bravo.
1991. Dengue epidemic in Nicaragua, 1985. Rev. Inst. Med. Trop. Sao Paulo 33:365-371.
7. Guzmán, M. G., S. Vásquez, E. Martínez, M. Alvarez, R. Rodríguez, G. Kourí, J. de los
Reyes, and F. Acevedo. 1996. Dengue en Nicaragua, 1994: reintroducción del serotipo 3
en las Américas. Bol. Oficina Sanit. Panam. 121:102-110.
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8. Harris, E., E. Videa, L. Perez, E. Sandoval, Y. Tellez, M. L. Perez, R. Cuadra, J. Rocha,
W. Idiaquez, R. E. Alonso, M. A. Delgado, L. A. Campo, F. Acevedo, A. Gonzalez, J. J.
Amador, and A. Balmaseda. 2000. Clinical, epidemiologic, and virologic features of
dengue in the 1998 epidemic in Nicaragua. Am J Trop Med Hyg 63:5-11.
9. Balmaseda, A., S. Hammond, L. Pérez, Y. Tellez, S. Saboria, J. Mercado, M. Pérez, S.
Silva, C. Rocha, and E. Harris. 2006. Serotype-specific differences in clinical
manifestations of dengue. Am. J. Trop. Med. Hyg. 74:449-456.
10. Hammond, S. N., A. Balmaseda, L. Perez, Y. Tellez, S. I. Saboría, J. C. Mercado, E.
Videa, Y. Rodríguez, M. A. Perez, R. Cuadra, S. Solano, J. Rocha, W. Idiaquez, A.
Gonzalez, and E. Harris. 2005. Differences in dengue severity in infants, children, and
adults in a three-year hospital-based study in Nicaragua. Am. J. Trop. Med. Hyg.
73:1063-1070.
11. Balmaseda A, Hammond SN, Perez MA, Cuadra R, Solano S, Rocha J, Idiaquez W,
Harris E. Assessment of the World Health Organization scheme for classification of
dengue severity in Nicaragua. Am J Trop Med Hyg. 2005 Dec;73(6):1059-1062.
12. Thulkar S, Sharma S, Srivastava DN, Sharma SK, Berry M, Pandey RM. Sonographic
findings in grade III dengue hemorrhagic fever in adults.J Clin Ultrasound. 2000
Jan;28(1):34-7.
13. Setiawan MW, Samsi TK, Wulur H, Sugianto D, Pool TN. Epigastric pain and
sonographic assessment of the pancreas in dengue hemorrhagic fever.J Clin Ultrasound.
1998 Jun;26(5):257-9.
14. Setiawan MW, Samsi TK, Wulur H, Sugianto D, Pool TN. Dengue haemorrhagic fever:
ultrasound as an aid to predict the severity of the disease. Pediatr Radiol. 1998
Jan;28(1):1-4.
15. Setiawan MW, Samsi TK, Pool TN, Sugianto D, Wulur H. Gallbladder wall thickening in
dengue hemorrhagic fever: an ultrasonographic study. J Clin Ultrasound. 1995 JulAug;23(6):357-62.
16. Pramuljo HS, Harun SR. Ultrasound findings in dengue haemorrhagic fever. Pediatr
Radiol. 1991;21(2):100-2.
17. Pelupessy JM, Allo ER, Jota S. Pericardial effusion in dengue haemorrhagic fever.
Paediatr Indones. 1989 Mar-Apr;29(3-4):72-5.
18. Piccoli M, Trambaiolo P, Salustri A, Cerquetani E, Posteraro A, Pastena G, Amici E,
Papetti F, Marincola E, La Carruba S, Gambelli G. Bedside diagnosis and follow-up of
patients with pleural effusion by a hand-carried ultrasound device early after cardiac
surgery. Chest. 2005 Nov; 128(5):3413-20.
19. Rozycki GS, Pennington SD, Feliciano DV. Surgeon-performed ultrasound in the critical
care setting: its use as an extension of the physical examination to detect pleural effusion.
J Trauma. 2001 Apr;50(4):636-42.
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20. Vignon P, Chastagner C, Berkane V, Chardac E, Francois B, Normand S, Bonnivard M,
Clavel M, Pichon N, Preux PM, Maubon A, Gastinne H Quantitative assessment of
pleural effusion in critically ill patients by means of ultrasonography. Crit Care Med.
2005 Aug;33(8):1757-63.
21. Zulkarnain I. Gallbladder edema in Dengue hemorrhagic fever and its association with
haematocrit levels and type of infections. Acta Med Indones. 2004 Apr-Jun;36(2):84-6.
22. Sehgal A, Gupta S, Tyagi V, Bahl S, Singh SK, Puliyel JM. Gall bladder wall edema is
not pathogenic of dengue infection. J Trop Pediatr. 2002 Oct;48(5):315-6.
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Appendix 1: Dengue Epidemiology in the Americas
WHO Dengue Fact Sheet Website:
http://www.who.int/mediacentre/factsheets/fs117/en/index.html
CDC Dengue Fact Sheet Website:
http://www.cdc.gov/ncidod/dvbid/dengue/
2002
1971
Figure 1. Distribution of the Ae. aegypti mosquito in 1970 and in 2002
Source: CDC Dengue Fever Fact Sheet
Figure 2. Laboratory confirmed cases of Dengue Hemorrhagic Fever in the Americas before and
after 1981.
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Appendix 2: Clinical Data Collected from Dengue Patients at the Hospital Infantil Manuel de Jesus Rivera
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Appendix 3: Consent Form (English Translation)
Consent to Participate in a Research Study
Project Coordinators
Dr. Eva Harris, School of Public Health, University of California, Berkeley
Dr. Angel Balmaseda, Centro Nacional de Diagnóstico y Referencia, Ministerio de Salud
(MINSA), Nicaragua
Dr. Crisanta Rocha, Hospital Infantil Manuel de Jesús Rivera (HIMJR) “La Mascota”, Managua,
Nicaragua
Dr. Juan José Amador, Dirección de Epidemiología y Salud Ambiental, Ministerio de Salud
(MINSA), Nicaragua
Dr. Alcides González, Centro Nacional de Diagnóstico y Referencia, Ministerio de Salud
(MINSA), Nicaragua
Title of Study
Prospective hospital-based study of dengue classification and case management in Nicaragua
You and your child are being invited to participate in a research study, which is a collaboration
between the Hospital Infantil Manuel de Jesús Rivera “La Mascota”, the Ministry of Health of
Nicaragua, the World Health Organization, and the University of California, Berkeley, designed
to learn more about the symptoms of dengue fever. Information from this study will be used to
help improve understanding of the disease, allow provision of better care for patients with
dengue, and contribute to the development a vaccine for dengue. Your child has been selected
because he/she is a suspected of having dengue at the “La Mascota” hospital. The choice to
participate in this study is yours and will not affect the medical care that your child receives. At
any point during this study, you may choose to have your child stop taking part in the study
without penalty.
If you agree for your child to take part in this research, we will collect some background
information and medical history on your child. This information will help the doctor follow the
history of this illness. A doctor will perform a routine medical examination of your child, and
this information will be recorded. Whether your child is hospitalized or followed as an
outpatient, each day tests will be performed to better follow his/her illness. Participation in this
study does not require any extra needle sticks during the course of the illness. However, a small
amount of extra blood (5 cc) will be taken while your child is being treated for dengue. One
week after your child leaves the hospital or recovers from illness, we ask that he/she return for a
medical check-up during which a blood sample (5 cc) will be collected. We need this extra
sample to verify that your child had dengue. Therefore, the length of participation in this study is
during your child’s illness, usually 5 days, and then one visit one week later. All study-related
examinations and medical treatment will be provided at no charge.
To increase the information available about dengue illness, we would like to follow your child
for a period of 18 months following your child’s acute illness. This part of the study would
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involve 4 blood draws (6 cc each), at 3 months, 6 months, 1 year, and 1 and a half years after
your child’s dengue illness. The blood collected during this time will be used to study what
protects the body from getting dengue again. This work is very important for making a vaccine
against dengue and for developing new ways to measure what protects against dengue.
The blood collected in this study will be used both for routine clinical tests and for some specific
research tests. The routine clinical tests include complete blood count, dengue virus detection,
measurement of cholesterol level, and other routine tests. The research tests will let us find out
how your child’s body responds to dengue and learn more about the virus itself.
Your child’s doctor will give you information about the results of the clinical tests, but since the
research tests take much longer to perform you will only be informed of these results if it is
medically important for you to know. We estimate that our study will take 5 years to complete.
We are asking you to choose one of two options: 1) that your child’s samples are stored for
future studies or 2) that your child’s samples are destroyed by adding bleach after the completion
of this study. We will also later explain and ask for additional permission to store your child’s
blood for future use in genetic studies and share your child’s clinical information, but not
personal information, with our research partners. If you decide that you do not want your child’s
DNA used in genetic studies, your child can still participate in this study. The rest of this consent
form pertains to this study.
If you choose to have your child participate in the study there are several risks and benefits. The
risk in drawing blood is temporary soreness and bruising; rarely, it may result in infection.
These risks are minimized by having experienced nurses do the procedures and by using sterile
technique. The benefits of this study are that your child will receive a one month’s supply of
vitamins. All study-related treatment, including diagnostic tests, will be provided free of cost.
Additionally, the knowledge gained from this study will help doctors give better care to children
with dengue in Nicaragua and the rest of the world, will allow testing of important new assays,
and will help in the development of a new vaccine that would prevent dengue in children.
You will also receive 50 cordobas to cover your transportation costs for each outpatient visit
during the period of illness and for each of the 4 appointments during the 18 months of followup. If you do not come to the appointment, study personnel will visit you in your home.
Information collected during this study will be kept confidential. Your child’s name or
identifying information will not be used in any reports of the study. All the information will be
processed using codes and stored in a database that only the project coordinator and key study
personnel have access to. There is the unlikely possibility that your child’s confidentiality will
be compromised; however, we have taken measures to minimize this risk.
If you have any questions, concerns, or problems related to this study, please contact Dr. Angel
Balmaseda at the Centro Nacional de Diagnóstico y Referencia at the following numbers: 289 77
23 or 289 46 04. If you have any questions about your rights as a research subject, please
contact Dr. Alberto Montoya of the Ministry of Health at 289 77 23, parasitologia@
minsa.gob.ni. If you wish to stop participating in this study, please communicate with a study
doctor or nurse.
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In the unlikely event that your child is injured as a result of taking part in this study, medical care
will be made available to him/her. The costs of this care may be covered by the University of
California depending on a number of factors. If you have any questions regarding this assurance,
you may consult the Committee for Protection of Human Subjects, 101 Wheeler Hall, University
of California, Berkeley, CA 94720-1340, telephone number 510-642-7461, [email protected].
Once again, participation in this study is voluntary and you may choose to stop taking part in this
study at any time.
Do you have any questions?
Part 2: Certificate of Consent
I have had the consent form read to me. My questions were answered to my satisfaction. I
recognize that my/my child’s participation in this study is voluntary. I/my child can
participate or withdraw at any moment without affecting my/my child’s medical care.
Choose one of the following
I permit my child to participate in the study for 1 and a half years after he/she recovers from
dengue.
I do not permit my child to participate in the study for 1 and a half years after he/she recovers
from dengue.
Choose one of the following
I permit my child’s samples and clinical information to be used in the study and to be stored
after the completion of the studies for future use.
I permit my child’s samples and clinical information to be used in the study and to be
destroyed when the study is finished.
_______________________________________
Name of Subject
_______________
Study code
__________________________________________________________
Name of Parent of Guardian
_______________________________________
Signature of Parent or Guardian
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_______________
Date
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If illiterate:
I have witnessed the accurate reading of the consent form to the potential participant, and the
individual has had the opportunity to ask questions. I confirm that the individual has given
consent freely.
________________________________________
Name of Witness
_________________________________________
Signature
_____________________
Date
Thumb print of parent
I have accurately read or witnessed the accurate reading of the consent form to the
potential participant, and the individual has had the opportunity to ask questions. I
confirm that the individual has given assent freely.
_____________________________________
Name of Researcher
_____________________________________
Signature
______________________
Date
A copy of this Informed Consent Form has been provided to the parent or guardian of the
participant_______(initialed by researcher/assistant)
An Informed Assent Form will________ OR will not_________ be completed.
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