Ruchi Pancholy Dengue PPT

Reference:

Teixeira, M. G., Paix, E. S., & Costa, N. (2015). Arterial Hypertension and Skin Allergy Are Risk Factors for Progression from Dengue to Dengue Hemorrhagic Fever : A Case Control Study. PLoS Neglected Tropical Diseases, 9(5), 1–8.

Ruchi Pancholy, MPH, REHSPHC 6002 Infectious Disease Epidemiology

Article Written Critique PresentationFall 2015

Aurora Sanchez-Anguiano, MD, PhD, CPH

Risk Factors for Progression from Dengue to Dengue Hemorrhagic

Fever: A Case Control Study

Presenter

Presentation Notes

Hello everyone. My presentation is a critique of a research article written by Teixiera et al. in 2015 entitled: Arterial Hypertension and Skin Allergy are Risk Factors for Progression from DF to DHF: A Case Control Study.

Dengue Background: A viral disease affecting more than 100 countries worldwide, transmitted primarily by Aedes aegypti mosquitoes.

To date, Brazil reports the world’s largest number of Dengue Fever cases. This study took place in Brazil during Dengue Epidemic Years, 2009-2012 Dengue Fever (DF) is the most common and mildest form Some cases progress to Dengue Hemorrhagic Fever (DHF), a more life

threatening form of the illness. Currently, it is unclear which cases may be more likely to progress from DF

to DHF.

Summary of the Article

Presenter

Presentation Notes

-This study focuses on whether specific comorbidities including: hypertension, allergies, diabetes, and asthma are more likely to be high risk factors for progression of dengue fever cases to become dengue hemorrhagic fever cases. I just want to provide you with some basic background information on Dengue. Dengue is a viral disease and currently affects more than 100 countries throughout the world with 390 million dengue infections occurring annually. It is spread primarily by the aedes aegypti mosquito. Brazil, the county in which this study occurred reports the world’s largest number of DF cases. -Dengue fever is the most common form of illness and symptoms are mild and can be characterized by: a fever, headache, muscle and joint pain, nausea/vomiting, rash, and/or change in mental status. -DHF is the severe form of illness, which is characterized by bleeding and plasma leakage which may lead to life-threatening shock, if unrecognized and not treated in a timely manner (Pang et al., 2012). -To date, it is unclear which DF cases will progress to DHF.

Major Objectives/Hypothesis Determine the major risk factors involved in the progression from DF to

DHF

Understanding risk factors involved in the progression from DF to DHF will allow physicians to initiate early clinical management of cases to limit severity of illness and prevent deaths.

Research Question: Which risk factors (comorbidities due to chronic illness) increase the risk of progression from DF to DHF?

Hypothesis: The study investigators hypothesize that specific comorbidities may increase the likelihood that a DF case will progress to DHF.

Presenter

Presentation Notes

Understanding high risk factors that are significant for DF cases to progress to DHF is critical as it will allow physicians to initiate early detection and treatment of illness, which will prevent severity of the illness and future deaths.

Study Design Study Design: Unmatched Concurrent Case Control study; Four controls

identified per case)

Recruitment: Cases and controls were DF patients in Infectious Disease Reference Hospitals located in one of 6 Brazilian cities during epidemic years, 2009 to 2012

Method: Pre-Tested Standardized Questionnaire

Data Collection: Participants interviewed on demographic and biological data, clinical information, self-reported comorbidities and use of medications to control these illnesses.

Measure of Association: Crude and Adjusted Odds Ratio

Presenter

Presentation Notes

-A case control study was used to assess comorbidities associated with progression from DF to DHF. Four controls per case. -Study was conducted in Brazil , the country with the highest number of DF cases in the world. -Study used a pre-tested standardized questionnaire with sections on demographic and biological data (socioeconomic indicators, years of schooling, etc.), clinical information, other reported health conditions (diabetes, hypertension, allergies, and asthma) and use of medications to control these illnesses. -When the individual reported one of the conditions of interest, he/she was asked who made the diagnosis and the interview asked to see the prescription and/or packaging of material.

Sample Size and Study Sample Study Sample: Total of 1,806 individuals

490 Cases of DF and 1,316 Controls with DF

Case Definition: Patients with DF who progressed to DHF and presented with symptoms including: fever, hemorrhagic manifestations, thrombocytopenia, evidence of plasma leakage, and one positive laboratory diagnosis for dengue.

Control Definition: Patients from the same hospital as cases presenting with symptoms of DF including: fever, headache, myalgia, and positive laboratory diagnosis for dengue.

Presenter

Presentation Notes

- The study sample consisted of a total of 1,806 individuals: 490 cases with DHF and 1,316 controls with DF. Approximately 60% of cases were female, 55% considered themselves mixed race. Cases were defined as patients with DF who progressed to DHF and presented with one or more of the following symptoms: fever, hemorrhagic manifestations, thrombocytopenia, evidence of plasma leakage, hypoproteinemia or clinical fluid accumulation, and one positive specific laboratory diagnosis for dengue. Controls were defined as patients from the same hospital as cases with signs and symptoms of DF including: fever, headache or retroorbital pain, myalgia, arthralgia, prostration, and positive specific laboratory diagnosis for dengue who did not progress to DHF

Study Population

Source Population: 1,806 Patients hospitalized and diagnosed with DF in an Infectious Disease Reference Hospital located in one of the 6 Brazilian cities during epidemic years, 2009 to 2012.

Target Population: Patients diagnosed and hospitalized with DF throughout the world.

Presenter

Presentation Notes

Target Pop: Pop to which results can be generalized to. (Patients with DF)- All patients diagnosed with DF throughout the world Source Pop: Patients hospitalized and diagnosed with DF in one of the Infectious Disease Reference Hospitals located in one of the 6 Brazilian cities (Campo Grande/MS, Fortaleza/CE, Itabuna/BA, Jequie/BA, Ilheus/BA, and Salvador/BA) during epidemic years, 2009 to 2012.

Exposure & Outcome Research Question: Do DF patients with pre-existing comorbidities increase the likelihood that

they will progress to DHF?

Pre-Existing Comorbidities DHF Diabetes, hypertension, allergies, asthma

Exposure Outcome

Identification of Exposed Individuals: Administration of a standardized questionnaire by trained interviewers at one of the International Disease Reference Hospitals in one of the 6 Brazilian cities during epidemic years, 2009-2012.

How Exposure were Defined and Measured: Upon arrival to the hospital, DF patients and/or relatives were interviewed on demographic info, socioeconomic indicators, clinical information including signs and symptoms of dengue, self-reported comorbidities, and use of medication to control these illnesses.

Assessing Self-Reported Comorbidities: Only DF patients able to show proof of using prescription medications to treat their self-reported illnesses were considered by investigators to have the condition.

Presenter

Presentation Notes

-Exposure Variables of Prime Interest: Risk Factors Associated with Dengue/ Self-Reported Comorbidities including: Hypertension, Allergies (Food, Respiratory & Skin), Diabetes, and Asthma/Outcome: Progression to DHF -

Confounding

Pre-Existing Comorbidities DHF Diabetes, hypertension, allergies, asthma

Exposure Outcome

Confounding FactorsMajority of Cases and Controls were Mixed Race & Female

Secondary InfectionAge Related Differences

Nutritional Status (Over or Under Nutrition)Pregnancy

Presenter

Presentation Notes

-Overall, individuals of mixed race were more likely to participate in this study, as 55% (173/316) of DHF cases were mixed race and 44% of DF controls were mixed race. -59% of DHF cases and 63% of DF controls were female. Are females more likely to see treatment/remain hospital longer? Were there untreated controls that progressed to DHF and went undetected?. However, based on my research, according to findings by Yacoub et al. (2014), predicting outcome from dengue, females sex has been associated with more severe disease. -The investigators did not have information on previous history of dengue so they could not control for secondary re-infection. Previous epidemiological studies have identified secondary infection as a significant risk factor associated with progression to DHF. -Age related difference is another confounding factor. Documented epidemiological studies point to age-related difference in dengue progression between adults and children. This study may have been limited in power for children less than 15 years of age./Results were not significant in those 15 years of age or less. -The investigators did take the following factors into account: nutritional status including over or under nutrition, pregnancy, and secondary infection. Documented studies have supported evidence that these factors are risk factors for progression from DF to DHF.

Information Bias: Investigators prevent this by conducting a concurrent case control study by recruiting incident rather than past cases and collected data from cases as they were diagnosed.

Selection Bias: Investigators prevent this by recruiting cases and controls from the same population (or hospital).

Medical Surveillance Bias: In this study, hospitalization with DF was related to the exposure; therefore it is possible that individuals presenting with signs and symptoms of Dengue that were not hospitalized could have later been at risk for developing DHF.

Chance: 95% CI, Alpha set at 0.05, Power: 80%

Bias & Chance

Presenter

Presentation Notes

-Power may have been limited in those 15 years of age or less and in each of the 6 cities.

Study Limitations No Information on Previous History of Dengue- Investigators could not

control for whether DHF cases had a heterologous re-infection.

Immunological Mechanisms were not explored in this study

Comorbidity data was self-reported rather than abstracted from medical records; since the study required proof of medication to treat the illness there is a possibility that those with pre-existing illnesses may not have been reported.

Findings may not be generalizable to DF patients in wealthier nations

Causality Criteria Strength of the Association- Criteria is met by reporting adjusted odds ratios for self-reported

chronic diseases. Hypertension (OR=1.6; 95% CI 1.1-2.1) and Skin Allergy (OR= 1.8; CI 1.1-3.2) showed statically significant associations.

Biologic plausibility- This study demonstrates this criteria by referencing two other studies that provided supporting evidence that pre-existing comorbidities including: diabetes, allergies, and hypertension are related to progression from DF to DHF. In addition, the investigators discuss possible biological mechanisms explaining how arterial hypertension may be linked to progression from DF to DHF.

Dose-response- Not demonstrated in this study because it is unclear how much of the exposure (pre-existing disease) is required to result in progression from DF to DHF.

Temporality- This study meets this criteria as the investigators used a concurrent case study and it is clear that interviewers assessed self-reported comorbidities in DF cases prior to progression to DHF. Self-reported illnesses were only assessed prior to becoming diagnosed with DHF.

Consistency- Investigators cite two studies that support the hypothesis that pre-existing comorbidities increase the likelihood of progression from DF to DHF. Two of the studies were conducted retrospectively and took place by the same investigators in Brazil and Singapore.

Presenter

Presentation Notes

Strength of Association- Both measures are statically significant at the 95% Confidence Interval.

ResultsTable 1. Socioeconomic and Demographic Characteristics of DHF Cases

(N=316) and DF Controls (N=912) > 15 years of age,Living in Six Municipalities of Brazil, 2009-2012

Characteristics Cases N=316 Controls N=912 p valueSex

Female 188 (59%) 579 (63%) 0.206Male 128 (41%) 333 ((37%)

Skin ColorBlack 40 (13%) 132 (15%) 0.003White 102 (32%) 373 (41%)Mixed 173 (55%) 395 (44%)

Income> 1 144 (48%) 286 (34%) 0.0001-3 103 (34%) 345 (40%)> 3 54 (18%) 222 (26%)

Schooling0-3 39 (13%) 83 (10%) 0.1463-7 39 (13% 143 (18%)

7-10 49 (17%) 151 (19%)> 10 166 (57%) 425 (53%)

Presenter

Presentation Notes

- This table depicts the socioeconomic and demographic characteristics of 313 DHF cases and 912 DF controls, greater than or equal to 15 years of age, residing in one of the 6 Municipalities of Brazil between the years 2009 to 2012. -According to Table 1, 59% of adult cases (> 15 years of age) were female, 55% considered themselves mixed race, about 48% had an income equivalent to > 1 minimum monthly salary of approximately (USD 239–306), and 57% had at least ten years of schooling. - Skin color (P Value: 0.003) and Income (P Value 0.000) showed a statistically significant association with progression to DHF among subjects over 15 years of age.

Results Table 2. Odds ratio crude and adjusted obtained by logistic regression for the association

between DHF and socioeconomics and demographic variables of residents in six municipalities of Brazil, according to age group, 2009-2012.

Age Group >15 years < 15 YearsCharacteristics Crude

ORCI 95% Adjusted OR CI95% Crude OR CI 95% Adjusted

ORCI95%

Skin ColorWhite 1.0 1.0 1.0 1.0Mixed 1.6 1.2-0.8 1.2 0.9-1.7 1.5 0.9-2.5 1.4 0.9-2.3Black 1.1 0.7-1.7 0.8 0.5-1.2 1.7 0.9-3.2 1.3 0.7-2.5Income< 1 1.0 1.0 1.0 1.02 < -3 0.6 0.4-0.8 0.6 0.4-0.8 1.1 0.7-1.7 1.1 0.7-1.8> 3 0.5 0.3-0.7 0.5 0.3-0.8 0.8 0.4-1.7 0.8 0.4-1.7Schooling0-3 1.0 1.0 - - - -4-7 0.6 0.3-1.0 0.6 0.3-1.0 - - - -8-10 0.7 0.4-1.1 0.8 0.5-1.3 - - - -> 10 0.8 0.5-1.2 1.0 0.6-1.6 - - - -

Presenter

Presentation Notes

Table 2. Self-reported skin color, family income and skin allergy showed a statistically significant association with DHF (p<0.05) among subjects aged over 15 years.

Results Table 3. Odds ratio crude* and adjusted obtained by logistic regression for the association between DHF and select comorbidities of > 15 years old residents in six municipalities of

Brazil 2009-2012

Chronic Disease OR Crude (IC a 95%) OR Adjusted (IC a 95%)Hypertension

No 1.0 1.0Yes 1.3 (0.9-1.7) 1.6 (1.1-2.1)

AllergyNo 1.0 1.0Yes 1.2 (0.8-1.6) 1.1 (0.8-1.6)

Food AllergyNo 1.0 1.0Yes 1.3 (0.7-2.5) 1.0 (0.5-2.2)

Respiratory AllergyNo 1.0 1.0Yes 1.0 (0.7-1.5) 1.1 (0.7-1.6)

Skin AllergyNo 1.0 1.0Yes 1.8 (1.1-3.0) 1.8 (1.1-3.2)

DiabetesNo 1.0 1.0Yes 1.0 (0.6-1.8) 1.2 (0.7-2.3)

Diabetes with Hypertension

No 1.0 1.0Yes 1.0 (0.5-2.0) 1.2 (0.6-2.5)

AsthmaNo 1.0 1.0Yes 1.4 (0.7-3.1) 1.1 (0.4-2.6)

Presenter

Presentation Notes

Table 3. When each self-reported chronic disease was adjusted for ethnic and social variables, only hypertension (OR=1.6; 95% CI 1.1-2.1) and skin allergy (OR=1.8; 95% CI 1.1-3.2) were associated with progression to DHF.

Implications of the Study During dengue outbreaks, close monitoring and observation of DF cases

should be conducted for patients with the following comorbidities: arterial hypertension, skin allergy, and diabetes.

In epidemics where healthcare resources are limited, risk factors for DHF can be used to prioritize hospitalization of DF patients. Potential DHF cases should remain in the hospital during outbreaks and monitored for early detection of signs and symptoms related to DHF.

Early detection and clinical management of potential DHF cases is critical in order to eliminate severity associated with illness and prevent future deaths.

Finally, policy makers can prioritize high risk DHF patients for vaccination when dengue vaccines are available, especially in developing countries.

Future Research Further clinical studies to define new protocols on the evolution of dengue

infections in patients with diabetes, allergies, and hypertension (particularly with respect to drugs used) and appropriate medical management.

Investigators of this study recommend future research should examine the influence of the immune system in order to identify immunological biomarkers that can function as indictors of progression from DF to DHF.

Similar studies assessing risk factors and progression to DHF should be conducted in other limited resource countries and developed countries to determine if differences exist.

QUESTIONS?

Presenter

Presentation Notes

Thank you for listening everyone. My take home message is that further research needs to be conducted in Brazil, other limited income countries, and wealthier nations to fully understand which pre-existing illnesses or high risk factors for the progression from DF to DHF. Understanding risk factors will help eliminate the severity of DHF and prevent future deaths. Do you have any questions for me?

References

Teixeira, M. G., Paix, E. S., & Costa, N. (2015). Arterial Hypertension and Skin Allergy Are Risk Factors for Progression from Dengue to Dengue Hemorrhagic Fever : A Case Control Study. PLoS Neglected Tropical Diseases, 9(5), 1–8.

Yacoub, S. & Wills, B. (2014). Predicting outcome from dengue. BMC Medicine, 12 (147), 1-10.

Ruchi Pancholy Dengue PPT

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