Assessing the Role of Ultrasound to Determine the Prognosis and Disease Severity in Pediatric Patients with Dengue Fever
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- Bu səhifədəki naviqasiya:
- Project Schedule and On-Site Support
- Data Analysis and Statistical Techniques
- Incorporation of Results to an Ongoing Prospective Clinical Study
- IV. Human Subjects and Informed Consent
- VII. References
- Appendix 1: Dengue Epidemiology in the Americas
- Appendix 3: Consent Form (English Translation)
- Title of Study
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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 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. 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. 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.6-789 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 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 -1314151617 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. 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 SupportThis 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 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 TechniquesData 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.
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. IV. Human Subjects and Informed ConsentAll 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.
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. 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.18-1920 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.14,21,22 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
Appendix 1: Dengue Epidemiology in the AmericasWHO Dengue Fact Sheet Website: http://www.who.int/mediacentre/factsheets/fs117/en/index.html
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. Appendix 2: Clinical Data Collected from Dengue Patients at the Hospital Infantil Manuel de Jesus Rivera 
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 StudyProspective 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 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 follow-up. 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. 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, cphs@berkeley.edu. 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 Date 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. 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. 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 Jul-Aug;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. 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. Yüklə 76,97 Kb. Dostları ilə paylaş:
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