ABSTRACT

Objective: To describe the clinical-epidemiological characteristics of patients who died from dengue during 2017. Methods: We conducted a retrospective study of the information related to cases of dengue deaths in the department of Piura. Results: We reviewed 24 medical records. Sixty-seven percent were women and 3 (12.5%) were pregnant. Diabetes (12.5%) and hypertension (16.7%) were the most frequent comorbidities. Previous dengue fever was reported in only 12.5%. The time from health care and death was 4.10 ± 5.34 days. Red blood cell transfusions were performed in 45.8%, plasma in 25%, platelets in 16.8% and cryoprecipitate in 16.8% of cases. Crystalloid therapy (91.7%) and treatment with vasoactive drugs (70.8%) were also frequent. In conclusion, mortality from severe dengue fever was predominantly in adult women, and the time of care from the first health facility to a specialized unit was prolonged.

Keywords:
Dengue fever; Mortality; Medical Records; Epidemiology; Peru

KEY MESSAGES

1. Motivation for the study. To describe the characteristics of patients who died from severe dengue fever during the 2017 El Niño in Piura.
2. Main findings. Mortality from severe dengue was higher in adult women. First contact with healthcare took place mostly in higher level hospitals. Admission to a specialized unit was late for severe dengue cases.
3. Implications. Control of dengue fever involves several aspects, such as, access to health, prevention, water availability, vector control and education; therefore, it is important to strengthen public health policies in this regard. In order to achieve this goal, local and central government sectors must be involved.

Keywords:
Dengue fever; Mortality; Medical Records; Epidemiology; Peru

INTRODUCTION

In the Americas, more than 2.7 million cases of dengue were reported during 2019, of which 22,127 were severe cases, with 1206 deaths ¹1. Santos LLM, de Aquino EC, Fernandes SM, Ternes YMF, Feres VC de R. Dengue, chikungunya, and Zika virus infections in Latin America and the Caribbean: a systematic review. Rev Panam Salud Publica. 2023;47:e34. doi: 10.26633/RPSP.2023.34.
https://doi.org/10.26633/RPSP.2023.34... . The number of deaths from dengue increased during the last decade; several countries reported high rates of fatal cases during recent epidemics ²2. Rojas EM, Herrera VM, Miranda MC, Rojas DP, Gómez AM, Pallares C, et al. Clinical indicators of fatal dengue in two endemic areas of Colombia: A hospital-based case-control study. Am J Trop Med Hyg. 2019;100(2):411-9. doi: 10.4269/ajtmh.17-0323.
https://doi.org/10.4269/ajtmh.17-0323... . Dengue has been a growing health problem since its re-entry into Peru in 1990, with reports showing the circulation of all four serotypes ³3. Ramos-Castañeda J, Barreto Dos Santos F, Martínez-Vega R, Galvão de Araujo JM, Joint G, Sarti E. Dengue in Latin America: Systematic review of molecular epidemiological trends. PLoS Negl Trop Dis. 2017;11(1):e0005224. doi: 10.1371/journal.pntd.0005224.
https://doi.org/10.1371/journal.pntd.000... . In Peru, during 2017, epidemiological reports showed 68,290 confirmed and probable cases, of which 27,249 (35.8%) were confirmed by laboratory tests, 79 of the confirmed cases died, and of these 43 (54.4%) were from the Piura region ⁴4. Centro Nacional de Epidemiología, Prevención y Control de Enfermedades [Internet]. CDC MINSA. [citado 27 de marzo de 2023]. Disponible en: https://www.dge.gob.pe/portalnuevo/
https://www.dge.gob.pe/portalnuevo/... .

In Peru, the 2017 Coastal El Niño was quite destructive, particularly for the northern region during almost three months ⁵5. Learning from El Niño Costero 2017: Opportunities for building resilience in PeruLearning from El Niño Costero 2017: Opportunities for building resilience in Peru [Internet]. ISET; 2017.[citado 6 de marzo de 2023]. Disponible en: https://www.i-s-e-t.org/publications-and-resources-1/learning-from-el-niño-costero-2017:-opportunities-for-building-resilience-in-peru.
https://www.i-s-e-t.org/publications-and... . According to the World Health Organization, it is essential to have global epidemiological data to predict and identify severe cases of dengue ⁶6. Dengue guidelines, for diagnosis, treatment, prevention and control [Internet]. World Health Organization; 2009 [citado 27 de marzo de 2023]. Disponible en: https://www.who.int/publications/i/item/9789241547871.
https://www.who.int/publications/i/item/... . For this reason, this study aimed to describe the clinical and epidemiological characteristics of patients who died from dengue in healthcare facilities in the Piura region, northern Peru, in 2017.

THE STUDY

Population and study design

A retrospective study was conducted to review the medical records of patients who died of dengue in the Piura region up to epidemiological week 42 of 2017, which includes a dengue outbreak. The Epidemiology Area of the Regional Health Directorate of Piura (DIRESA-Piura), provided 32 medical records, eight of which were excluded (duplicate records, no medical death certificate, illegible information and incomplete information), therefore 24 were finally included.

Dengue case definition

Dengue was diagnosed according to the clinical and epidemiological criteria established by the technical guideline of the Peruvian Ministry of Health (MINSA) ⁷7. Ministerio de Salud. Resolución Ministerial N.° 071-2017-MINSA [Internet]. [citado 27 de marzo de 2023]. Disponible en: https://www.gob.pe/institucion/minsa/normas-legales/190341-071-2017.
https://www.gob.pe/institucion/minsa/nor... . All cases had positive results in one or more of the diagnostic tests, either the enzyme-linked immunosorbent assay (ELISA) for the nonstructural glycoprotein NS1, or the detection of IgM or IgG antibodies with the Peruvian TARIKI-DENGUE kit and Standard Diagnostics BIOLINE Dengue Duo, respectively.

Data collection

All cases were from the Piura region. The physicians in charge filled the MINSA forms and the registry. A data collection instrument was used to obtain information from the medical records. We obtained epidemiological data such as age, sex, pathological history, history of dengue, time of illness, place of care, characteristics of the time of care between admissions to healthcare facilities; signs and symptoms such as fever (axillary temperature higher than 38°C), headache, retroorbital pain, myalgia, arthralgia, malaise, others; vital functions; fluid management; life and hematological support; laboratory tests (automated equipment was used to assess blood gases) and use of antipyretic drugs and antibiotics.

Statistical analysis

Continuous variables were reported with mean and standard deviation (SD) or median and interquartile range (IQR), depending on their normal distribution. Categorical variables were reported with frequencies and percentages. All statistical analyses were performed with the SPSS 21 statistical program.

Ethical aspects

This study was approved by the Research Ethics Committee of the Universidad Peruana Unión (UPeU) (code: 2022-CEUPeU-001).

FINDINGS

Diagnosis and care of dengue cases

Of the 24 cases, 62.5%, 70.8% and 41.7% were positive by NS1 (ELISA), IgM (ELISA) and IgG (ELISA), respectively. According to medical records, 8 (33.3%) deaths occurred at MINSA’s Santa Rosa II-2 Hospital, 6 (25.0%) at EsSalud’s Cayetano Heredia III Hospital, 5 (20.8%) at other EsSalud hospitals, 1 (4.2%) at the Armed Forces health facility, and 4 (16.7%) occurred at a primary care center.

Clinical and epidemiological characteristics of dengue deaths

The epidemiological characteristics of the patients who died from dengue are described in Table 1. Mortality in female patients was higher; 3 (12.5%) of the deceased were pregnant. Comorbidities such as diabetes mellitus and arterial hypertension were reported in 12.5% and 16.7%, respectively; corticosteroids were not used prior to admission in any case. Four participants (16.7%) were identified as having possible previous contact with a patient with dengue fever (1 case with febrile syndrome and 3 cases with a previous history of dengue fever). According to the clinical diagnoses at admission, 6 (25%) had dengue with warning signs and 10 (42%) had severe dengue. The mean time elapsed between the first admission to a healthcare facility and death was 4.10 (SD 5.34) days (Table 1).

The clinical characteristics on admission are described in Table 2. The most frequent clinical manifestations were related to the febrile phase of dengue fever: fever (87.5%) and systemic symptoms such as headache (33.3%), nausea/vomiting (58.3%), abdominal pain (45.8%), arthralgia (33.3%) among others. In addition, vital signs on admission revealed tachycardia (mean heart rate of 108 beats per min), and polypnea (mean respiratory rate of 25).

Laboratory results are described in Table 3. The hemogram was performed within 48 hours of admission and showed wide variability, this may have been due to the fact that the data from peripheral healthcare facilities were obtained manually and data from greater complexity facilities were obtained using systematized methods. The results showed a decreasing trend of the platelet count. Lactate levels were found to be high. Results showed that transaminase enzymes (AST and ALT) were high, suggesting hepatic alterations; INR levels were also high. Half of the patients had thrombocytopenia.

Management of dengue cases

Patient management at the onset of signs and symptoms included mainly crystalloid fluids, sodium chloride solution 9°/00 (91.7%); the use of vasoactive drugs and mechanical ventilation was frequent (70.8%), analgesics (58.3%) and doses <300mg/24h of intravenous corticosteroids (45.8%) were also reported. Transfusion of blood derivatives or more than one blood product at the same time was reported in 46% of patients (Table 4).

The use of analgesics such as paracetamol was reported in 25% and metamizole in 17% of patients who died of dengue. Physical means were not used in any case. Antibiotics were widely used, 71% of patients received more than two classes of antibiotics (Table 4). Regarding transfusion, 45.8% of the patients received blood and 25% fresh frozen plasma. Platelet units and cryoprecipitate were also transfused in 16.8% of cases.

Aspects related to the causes of death

PaO₂/FiO₂ values of 220 indicate pulmonary involvement; the pH was 7.22 which suggests severe acidosis. High lactate levels were reported with a median of 11.1 mmol/L (Table 3). Finally, 100% of the deaths presented neurological, respiratory and cardiovascular disorders. Hematologic disorders were reported in 58.3% and gastrointestinal and renal dysfunction in 50% of the cases.

DISCUSSION

Of the 24 cases, most were women who had a history of diabetes mellitus and arterial hypertension. The time to admission in severe cases was long and the most frequent symptoms were fever, nausea and vomiting. The most frequent laboratory findings were leukocytosis, metabolic acidosis and hyperlactatemia. Treatment in a specialized unit was late and antibiotics were used empirically.

Our findings are consistent with the strong association of the female sex with dengue shock syndrome previously reported ⁸8. Huy NT, Van Giang T, Thuy DHD, Kikuchi M, Hien TT, Zamora J, et al. Factors associated with dengue shock syndrome: a systematic review and meta-analysis. PLoS Negl Trop Dis. 2013;7(9):e2412. doi: 10.1371/journal.pntd.0002412.
https://doi.org/10.1371/journal.pntd.000... and may be explained by gender differences in seeking medical care, as well as physical characteristics ⁹9. Anders KL, Nguyet NM, Chau NVV, Hung NT, Thuy TT, Lien LB, et al. Epidemiological factors associated with dengue shock syndrome and mortality in hospitalized dengue patients in Ho Chi Minh City, Vietnam. Am J Trop Med Hyg [Internet]. enero de 2011;84(1):127-34. Disponible en: http://dx.doi.org/10.4269/ajtmh.2011.10-0476.
http://dx.doi.org/10.4269/ajtmh.2011.10-... . Three cases of dengue were reported in pregnant women, which were not categorized as dengue cases at hospital admission. Therefore, a correct diagnosis is important, especially to avoid perinatal involvement with high morbidity in pregnant women, especially during the first two trimesters ¹⁰10. Romero-Santacruz E, Lira-Canul JJ, Pacheco-Tugores F, Palma-Chan AG. Dengue neonatal. Presentación de casos clínicos. Ginecol Obstet Mex. 2015;83(05):308-15..

First contact with a healthcare facility was with a high complexity hospital in Piura in 58% of the cases; it is important to note that 16.7% of the cases began receiving treatment in a primary care center. Fatal cases of dengue vary between 1% and 3% in countries near to Peru⁶6. Dengue guidelines, for diagnosis, treatment, prevention and control [Internet]. World Health Organization; 2009 [citado 27 de marzo de 2023]. Disponible en: https://www.who.int/publications/i/item/9789241547871.
https://www.who.int/publications/i/item/... .

The highest mortality rate was found in the age group 19 to 35 years and in those older than 65 years, totaling 75%. On the other hand, greater incidence has been reported in children and young adults ¹¹11. Fonseca SNS. Changing epidemiology of dengue fever in children in South America. Curr Opin Pediatr [Internet]. 1 de abril de 2023;35(2):147-54. doi: 10.1097/MOP.0000000000001220.
https://doi.org/10.1097/MOP.000000000000... , which differs from our results. The time elapsed between the first contact to healthcare and death had a mean of 4.10 (SD: 5.34) days, which shows the late start of treatment in these cases.

Fever, vomiting and abdominal pain were the most frequent signs and symptoms in the deceased patients. Severe forms of dengue infection are characterized by hemorrhage, hypotension, thrombocytopenia and plasma leakage, and may be accompanied by some neurological alterations. These signs can lead to shock and subsequent multisystem failure, which may have increased mortality, especially if comorbidities are present ¹²12. World Health Organization. Global strategy for dengue prevention and control 2012-2020 [Internet]. Genève, Switzerland: World Health Organization; 2012 [citado 6 de marzo de 2023]. Disponible en: https://apps.who.int/iris/handle/10665/75303.
https://apps.who.int/iris/handle/10665/7... . Temperature during the febrile phase is usually ≥38.5°C and our results showed an average temperature of ≥37.8°C, this difference could be explained by the fact that patients could be transitioning from the febrile phase to the critical phase ¹³13. Simmons CP, Farrar JJ, Nguyen van VC, Wills B. Dengue. N Engl J Med. 2012;366(15):1423-32. doi: 10.1056/NEJMra1110265.
https://doi.org/10.1056/NEJMra1110265... ⁾ or by the antipyretic effect.

The daily platelet count appears to be a promising predictor for dengue shock syndrome ¹⁴14. Lam PK, Van Ngoc T, Thu Thuy TT, Hong Van NT, Nhu Thuy TT, Hoai Tam DT, et al. The value of daily platelet counts for predicting dengue shock syndrome: Results from a prospective observational study of 2301 Vietnamese children with dengue. PLoS Negl Trop Dis. 2017;11(4):e0005498. doi: 10.1371/journal.pntd.0005498.
https://doi.org/10.1371/journal.pntd.000... , although only half of the patients showed this finding. Serum lactate was high in this sample.

Intensive monitoring and good supportive care can reduce mortality rates to below 1%. The sepsis survival campaign is based on the sepsis and septic shock survival guidelines ¹⁵15. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: International guidelines for management of sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-77. doi: 10.1007/s00134-017-4683-6.
https://doi.org/10.1007/s00134-017-4683-... ; this program has not been validated and often cannot be applied to low- and middle-income countries, where the frequency of sepsis is high and sepsis outcomes are often poor ¹⁶16. Shrestha GS, Kwizera A, Lundeg G, Baelani JI, Azevedo LCP, Pattnaik R, et al. International Surviving Sepsis Campaign guidelines 2016: the perspective from low-income and middle-income countries. Lancet Infect Dis. 2017;17(9):893-5. doi: 10.1016/S1473-3099(17)30453-X.
https://doi.org/10.1016/S1473-3099(17)30... . Cases of severe dengue require treatment with fluids, according to the MINSA technical guideline⁷7. Ministerio de Salud. Resolución Ministerial N.° 071-2017-MINSA [Internet]. [citado 27 de marzo de 2023]. Disponible en: https://www.gob.pe/institucion/minsa/normas-legales/190341-071-2017.
https://www.gob.pe/institucion/minsa/nor... ⁾⁽¹⁶16. Shrestha GS, Kwizera A, Lundeg G, Baelani JI, Azevedo LCP, Pattnaik R, et al. International Surviving Sepsis Campaign guidelines 2016: the perspective from low-income and middle-income countries. Lancet Infect Dis. 2017;17(9):893-5. doi: 10.1016/S1473-3099(17)30453-X.
https://doi.org/10.1016/S1473-3099(17)30... . Therapy with blood products is indicated in patients with major bleeding, but there is controversy regarding platelet transfusions for thrombocytopenia without bleeding ¹⁷17. Rajapakse S, de Silva NL, Weeratunga P, Rodrigo C, Fernando SD. Prophylactic and therapeutic interventions for bleeding in dengue: a systematic review. Trans R Soc Trop Med Hyg. 2017;111(10):433-9. doi: 10.1093/trstmh/trx079.
https://doi.org/10.1093/trstmh/trx079... .

On the other hand, previous antibiotic treatment and empirical use of antipyretics are common in patients with clinical symptoms compatible with dengue, which could delay the diagnosis, care or management of dengue cases. On the other hand, although guidelines suggest avoiding the use of metamizole ¹⁸18. Díaz-Quijano FA, Villar-Centeno LA, Martínez-Vega RA. Effectiveness of early dipyrone administration on severity of dengue virus infection in a prospective cohort. Enferm Infecc Microbiol Clin. 2005;23(10):593-7. doi: 10.1157/13081567.
https://doi.org/10.1157/13081567... , we found that 17% of the cases used this analgesic. Likewise, the use of paracetamol as an antipyretic was reported in only 21% of cases. It should be noted that, although prophylactic antibiotic treatment is not recommended without evidence of bacterial infections ¹⁹19. Thein T-L, Lye DC, Leo Y-S, Wong JGX, Hao Y, Wilder-Smith A. Severe neutropenia in dengue patients: prevalence and significance. Am J Trop Med Hyg. 2014;90(6):984-7. doi: 10.4269/ajtmh.14-0004.
https://doi.org/10.4269/ajtmh.14-0004... , most patients (87.5%) had received some dose of antibiotics.

The mortality rate of dengue cases with untreated shock is 20%, this can decrease between 1% and 2.5% with adequate treatment ²⁰20. Byard RW. Lethal dengue virus infection: A forensic overview. Am J Forensic Med Pathol. 2016;37(2):74-8. doi: 10.1097/PAF.0000000000000236.
https://doi.org/10.1097/PAF.000000000000... , while, in Peru during 2017 it exceeded 35%. In this sample, 100% of the cases had shock with multiorgan failure. Shock is a medical emergency, and resuscitation with fluids as well as hemodynamic assessments are recommended within the first three hours ¹⁵15. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: International guidelines for management of sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-77. doi: 10.1007/s00134-017-4683-6.
https://doi.org/10.1007/s00134-017-4683-... .

A limitation of this study was that some medical records were missing and others had incomplete data.

In conclusion, mortality from severe dengue fever was higher in adult women with classic symptomatology; likewise, the time of admission to the first healthcare facility to a specialized center was long.

Acknowledgements.

To all DIRESA-Piura staff for providing access to the information.

References

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History