ABSTRACT

Objective

To evaluate the association of several clinical markers with acute laboratory-positive Dengue Virus infection.

Methods

A hospital-based case-control study was conducted in the state of Colima, Mexico, by using information from the National System of Epidemiological Surveillance (Sistema Nacional de Vigilancia Epidemiológica [SINAVE]) for Dengue. Data from 2 732 cases and 2 775 frequency-matched controls were analyzed. Odds Ratio (OR) and the 95 % Confidence Interval (CI), estimated by means of logistic regression models, were used.

Results

The presence of skin rash (OR=1,7; 95 % CI 1,5-2,1), persisting vomiting (OR=1,8; 95 % CI 1,5-2,3) and increased capillary fragility (petechiae, ecchymosis, hematoma or positive tourniquet test; OR=1,8; 95 % CI 1,2-2,6) were associated with laboratory-positive infection.

Conclusions

Three clinical markers were significantly associated with an increased risk of acute laboratory-confirmed dengue infection. These findings would support accurate and timely diagnosis of dengue in laboratory-limited settings.

Key Words:
Dengue; epidemiology; population surveillance; communicable diseases; case-control studies (source: MeSH, NLM)

RESUMEN

Objetivo

Evaluar la asociación de distintos marcadores clínicos con la infección por virus de Dengue, confirmada por laboratorio.

Métodos

Se condujo un estudio hospitalario de casos y controles, en el estado de Colima, México, usando información del Sistema Nacional de Vigilancia Epidemiológica (SINAVE) para dengue. Se analizó la información de 2 732 casos y 2 775 controles de frecuencia compatible/pareada. Se utilizó la Razón de Momios (RM) y el Intervalo de Confianza de 95 % (IC), estimado con modelos de regresión logística.

Resultados

La presencia de exantema (OR=1,7; 95 % CI 1,5-2,1), vómito persistente (OR=1,8; 95 % CI 1,5-2,3) y fragilidad capilar aumentada (petequias, equimosis, hematomas o prueba del torniquete positiva; OR=1,8; 95 % CI 1,2-2,6) se asociaron con la infección por dengue confirmada por laboratorio.

Conclusiones

Tres marcadores clínicos se asociaron significante con un riesgo incrementado de la infección aguda por dengue confirmada por laboratorio. Estos hallazgos pueden apoyar al preciso y oportuno diagnóstico de la infección en sitios con acceso limitado a laboratorios.

Palabras Clave:
Dengue; epidemiología; vigilancia de la población; enfermedades transmisibles; estudios de casos y controles (fuente; DeCS, BIREME)

Dengue is an epidemic disease transmitted to humans by the bite of infected mosquitoes (Aedes aegypti and Aedes albopictus) and it is caused by Dengue Virus (DENV) ¹1. Simmons CP, Farrar JJ, Nguyen V, Wills B. Dengue. N Engl J Med. 2012; 366(15): 1423-32.. Approximately 40 % of the population of the world is at risk of pathogen transmission ²2. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. The global distribution and burden of dengue. Nature. 2013; 496(7446): 504-7.. In Mexico, all DENV serotypes (DENVI - 4) have been isolated. Additionally, disease transmission in most of Mexican states has been reported ³3. Hernandez-Avila JE, Rodriguez MH, Santos-Luna R, Sanchez-Castaneda V, Roman-Perez S, Rios-Salgado VH, et al. Nation-wide, web-based, geographic information system for the integrated surveillance and control of dengue fever in Mexico. PLoS One. 2013; 8(8): e70231..

Mexican health services are obligated to report suspected cases of dengue using a web-based platform from the National Epidemiological Surveillance System (SINAVE) ⁴4. Dirección General de Epidemiología. Lineamientos para la vigilancia epidemiológica de dengue por laboratorio. Disponible en: Disponible en: https://goo.gl/qDH4k7 . Consultado en enero de 2017.
https://goo.gl/qDH4k7... ^,55. Hernández-Suárez CM, Mendoza-Cano O. Empirical evidence of the effect of school gathering on the dynamics of dengue epidemics. Global health action. 2016; 9: 28026.. The 1997 World Health Organization (WHO) dengue case definition was used during 2014 and suspected cases were classified as dengue fever (DF), dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) ⁶6. World Health Organization. Dengue Haemorrhagic Fever: Diagnosis, Treatment, Prevention and Control, 2nd edn, Geneva, Switzerland, WHO, 1997..

Timely diagnosis and supportive initial treatment reduce dengue mortality and may potentially prevent additional cases among contacts ⁷7. Mayurasakorn S, Suttipun N. The impact of a program for strengthening dengue hemorrhagic fever case management on the clinical outcome of dengue hemorrhagic fever patients. Southeast Asian J Trop Med Public Health. 2010; 41(4): 858-63.. Since the spectrum of clinical manifestations of dengue is wide, early diagnosis may be difficult to detect ⁸8. Gregory CJ, Santiago LM, Arguello DF, Hunsperger E, To-mashek KM. Clinical and laboratory features that differentiate dengue from other febrile illnesses in an endemic area--Puerto Rico, 2007-2008. Am J Trop Med Hyg. 2010; 82(5): 922-9.^,99. Mishra B, Gupta PK, Dhiman V, Pujhari SK, Sharma M, Ratho RK. Clinical applicability of various dengue diagnostic tests in resource-limited endemic settings. J Glob Infect Dis. 2014; 6(3): 109-13.. This study aimed to evaluate the association of clinical markers with acute laboratory-positive dengue infection using data from large case-control study conducted in an endemic area.

MATERIALS AND METHODS

Study population

A hospital-based case-control study was conducted in the state of Colima, Mexico, by using data from the SI-NAVE. Incident cases (n=2 732) -included individuals aged from 3 years old and on- were reported, from January to December in 2014, as clinically suspected cases of dengue (fever>2 of the following: headache, myalgia, arthralgia, retro-orbital pain or skin rash) that were subsequently and serologically confirmed as dengue infection cases. A multistage probabilistic sampling, according to age distribution of total confirmed cases from the database, was used in the selection of cases. Dengue serologic tests included ELISA (Enzyme-Linked Immunosorbent Assay), NSI (nonstructural protein 1), and igG/igM (immunoglobulin G/M); and were performed by staff from the State Laboratory of Public Health in accordance with normative standards ⁴4. Dirección General de Epidemiología. Lineamientos para la vigilancia epidemiológica de dengue por laboratorio. Disponible en: Disponible en: https://goo.gl/qDH4k7 . Consultado en enero de 2017.
https://goo.gl/qDH4k7... .

Controls (n=2775) -included subjects notified as suspected dengue cases with a subsequent negative serology test- were matched to the cases (frecuency-matching) according to sex, five years old age groups, membership to a health care institution, and health jurisdiction of residence. Controls were randomly selected from individuals fulfilling the eligibility criteria.

Data regarding the clinical manifestations of study subjects were collected and included the initial disease classification (suspected DF, DHF or DSS); fever (yes/no); headache (yes/no); myalgia (yes/no); arthralgia (yes/no); retro-ocular pain (yes/no); skin rash (yes/no); persisting vomiting (yes/no); abdominal pain or tenderness (yes/ no); clinical fluid accumulation (ascites, edema or pleural effusion; yes/no); increased capillary fragility (petechiae, ecchymosis, hematoma or positive tourniquet test; yes/ no) and mucosal bleeding (gingival bleeding, epistaxis, hematemesis or melena; yes/no). Results of serology tests were also extracted from the database.

This study was approved by the National Commission for Clinical Research.

Statistical analysis

Summary statistics were used to compare cases and controls. To determine statistical association between the clinical manifestations and dengue, odds ratios (OR) and 95 % confidence intervals (CI) were estimated by means of unconditional logistic regression models. All analyses were conducted using Stata SE 11.0 (StataCorp, College Station, TX) and significance level was set at 5 %.

RESULTS

Table 1 shows the study population characteristics for selected variables. The mean age of cases and controls was 27, 8±18,0 and 26,9±17,8 years respectively, and this difference did not reach statistical significance. When compared with controls, cases were more likely to be classified at first healthcare contact as DHF/DSS patients requiring hospital admission. Cases also had a significant higher prevalence of retroocular pain (85,3 % vs. 83,0 %), skin rash (17,1 % vs. 9,1 %), persisting vomiting (15,3 % vs. 5,9 %), abdominal pain (14,3 % vs. 6,5 %), clinical fluid accumulation (2,4 % vs. 0,3 %), increased capillary fragility (9,1 % vs. 1,5 %) and mucosal bleeding (5,6 % vs. 1,3 %).

In multiple analyses (Table 2), clinical markers associated with laboratory-positive dengue infection were skin rash (OR=I,7; 95 % CI 1,5-2,1), persisting vomiting (OR=I,8; 95 % CI 1,5-2,3) and increased capillary fragility (OR=I,8; 95 % CI 1,2-2,6).

DISCUSSION

We found that three clinical markers were associated with laboratory-confirmed dengue virus infection: skin rash, persisting vomiting and increased capillary fragility. Acute dengue illness is characterized by nonspecific signs and symptoms that are difficult to distinguish from other febrile illnesses ¹⁰10. Halstead SB. More dengue, more questions. Emerg Infect Dis. 2005; 11(5): 740-1.. Moreover, in laboratory limited health care settings, a diagnostic algorithm based on clinical markers could improve early medical management and disease outcomes.

Previously published studies have described variations in clinical dengue features between them ¹¹11. Hammond SN, Balmaseda A, Perez L, Tellez Y, Saborio SI, Mercado JC, et al. Differences in dengue severity in infants, children, and adults in a 3-year hospital-based study in Nicaragua. Am J Trop Med Hyg. 2005; 73(6): 1063-70.^,1212. Kittigul L, Pitakarnjanakul P, Sujirarat D, Siripanichgon K. The differences of clinical manifestations and laboratory findings in children and adults with dengue virus infection. J Clin Virol. 2007; 39(2): 76-81.. Differences may be secondary to host response to infection ¹³13. Whitehorn J, Farrar J. Dengue. Br Med Bull. 2010;95:161-73..

Headache and retro-ocular pain are grouped in the WHO 2009 dengue case definition ¹⁴14. Beatty ME, Stone A, Fitzsimons DW, Hanna JN, Lam SK, Vong S, et al. Best practices in dengue surveillance: a report from the Asia-Pacific and Americas Dengue Prevention Boards. PLoS Negl Trop Dis. 2010; 4(11): e890.. The association of headache and retro-ocular pain with confirmed disease was not significant when they were analyzed combined (OR=I,6; 95 % CI 0,8-3,2; data not presented), which is consistent with a previously published study ¹⁵15. Farrar J, Focks D, Gubler D, Barrera R, Guzman MG, Simmons C, et al. Towards a global dengue research agenda. Trop Med Int Health. 2007; 12(6): 695-9.. Dengue-related ocular manifestations have been described in 10-40 % of confirmed cases ¹⁶16. Su DH, Bacsal K, Chee SP, Flores JV, Lim WK, Cheng BC, et al. Prevalence of dengue maculopathy in patients hospitalized for dengue fever. Ophthalmology. 2007; 114(9): 1743-7.^,1717. Kapoor HK, Bhai S, John M, Xavier J. Ocular manifestations of dengue fever in an East Indian epidemic. Can J Ophthalmol. 2006; 41(6): 741-6..

Hospital admission rate was 25,7 % and 5,9 % in cases and controls respectively. This finding is lower to rates reported in other American or Asian populations (45 % - 80 %) ¹⁸18. Suaya JA, Shepard DS, Siqueira JB, Martelli CT, Lum LC, Tan LH, et al. Cost of dengue cases in eight countries in the Americas and Asia: a prospective study. Am J Trop Med Hyg. 2009; 80(5): 846-55.^,1919. Lee VJ, Lye DC, Sun Y, Fernandez G, Ong A, Leo YS. Predictive value of simple clinical and laboratory variables for dengue hemorrhagic fever in adults. J Clin Virol. 2008; 42(1): 34-9.. DENV-2 was the most frequent se-rotype isolated (87,8 %) and it has been associated with increased risk of developing DHF or DSS ²⁰20. Chaiyaratana W, Chuansumrit A, Pongthanapisith V, Tangna-raratchakit K, Lertwongrath S, Yoksan S. Evaluation of dengue nonstructural protein 1 antigen strip for the rapid diagnosis of patients with dengue infection. Diagn Microbiol Infect Dis. 2009; 64(1): 83-4.. In the study sample, 68,1 % and 31,9 % of cases were classified as DF and DHF as corresponding; no DSS cases were registered.

The autochthonous transmission of chikungunya virus and zika virus was first observed in Mexico on 2014 and 2015 respectively ²¹21. Diaz-Gonzalez EE, Kautz TF, Dorantes-Delgado A, Malo-Garcia IR, Laguna-Aguilar M, Langsjoen RM, et al. First Report of Aedes aegypti Transmission of Chikungunya Virus in the Americas. Am J Trop Med Hyg. 2015; 93(6): 1325-9.^,2222. Guerbois M, Fernandez-Salas I, Azar SR, Danis-Lozano R, Alpuche-Aranda CM, Leal G, et al. Outbreak of Zika Virus Infection, Chiapas State, Mexico, 2015, and First Confirmed Transmission by Aedes aegypti Mosquitoes in the Americas. The Journal of infectious diseases. 2016; 214(9): 1349-1356.. There are clinical characteristics that may be helpful to distinguish between acute cases of dengue, chikungunya or zika infection in limited health-care settings ²³23. Thiberville SD, Moyen N, Dupuis-Maguiraga L, Nougairede A, Gould EA, Roques P, et al. Chikungunya fever: epidemiology, clinical syndrome, pathogenesis and therapy. Antiviral research. 2013; 99(3): 345-70.^,2424. Sampathkumar P, Sanchez JL. Zika Virus in the Americas: A Review for Clinicians. Mayo Clinic proceedings. 2016; 91(4): 514-21..

There are some limitations in this study. First, cases and controls were selected from health services users and might not reflect the whole dengue-infected group. However, our results are useful in health care settings from dengue endemic areas. Second, data regarding dengue all warning signs -included in the 2009 WHO case definition- were not collected systematically by the analyzed surveillance system. In Mexico, the 1997 WHO case definition is used for epidemiological purposes. Third, this study was conducted in a population with high incidence of dengue infection, which means our findings may not be reproducible in a non-endemic area.

The results of this study suggest that clinical data may be used to identify acute dengue infection. To our knowledge, this is the first evaluation of interactions between age and clinical markers; further research is needed to understand better our findings ♦

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