Dengue Prediction in Latin America Using Machine Learning and the One Health Perspective: A Literature Review.

Dengue fever is a serious and growing public health problem in Latin America and elsewhere, intensified by climate change and human mobility. This paper reviews the approaches to the epidemiological prediction of dengue fever using the One Health perspective, including an analysis of how Machine Learning techniques have been applied to it and focuses on the risk factors for dengue in Latin America to put the broader environmental considerations into a detailed understanding of the small-scale processes as they affect disease incidence. Determining that many factors can act as predictors for dengue outbreaks, a large-scale comparison of different predictors over larger geographic areas than those currently studied is lacking to determine which predictors are the most effective. In addition, it provides insight into techniques of Machine Learning used for future predictive models, as well as general workflow for Machine Learning projects of dengue fever.

Anticuerpos contra el virus del dengue en pacientes con dislipidemias / Antibodies against dengue virus in patients with dislipidemias

El objetivo fue comparar los anticuerpos IgG e IgM contra el virus del dengue en pacientes con dislipidemias. Tipo de estudio descriptivo, prospectivo de diseño no experimental, de corte transversal. La muestra estuvo constituida por 214 individuos, distribuidos en 169 con dislipidemias y 45 controles. Los lípidos séricos y los anticuerpos anti-dengue se determinaron mediante métodos bioquímicos e inmunológicos convencionales. Se clasificaron en 3 grupos: hipertriacilgliceridemia (279,7±84,2 mg/dl); hipercolesterolemia (252,7±38,5 mg/dl) y el grupo con triacilglicéridos y colesterol elevados (257,3±38,5; 271,6±88,7 mg/dl). El 96% de los pacientes resultó con inmunidad (IgG) contra el virus del dengue, la respuesta primaria (IgM) estuvo presente en un 22%. En cuanto a la positividad de IgM, la mayor frecuencia estuvo en el grupo con hipertriacilgliceridemia (34,2%), mientras que la frecuencia para la IgG estuvo en el grupo con triacilglicéridos y colesterol elevados (31,2%). En este estudio no se observó diferencia entre los anticuerpos IgG e IgM contra virus del dengue en los pacientes con dislipidemias y el grupo control. Se necesitan futuros estudios para evidenciar en áreas de menor endemia para el virus del dengue si efectivamente la alteración del perfil lipídico modifica la intensidad de respuesta ante la infección

The objective was to compare the antibodies against the dengue virus in patients with different types of dyslipidemias. Type of descriptive, prospective study of non-experimental, cross-sectional design. The sample consisted of 214 individuals, distributed in 169 with dyslipidemias and 45 controls. Serum lipids and anti-dengue antibodies were determined by conventional biochemical and immunological methods. They were classified into 3 groups: hypertriacilgliceridemia (279.7 ± 84.2 mg / dl); hypercholesterolemia (252.7 ± 38.5 mg / dl) and the group with high triglycerides and cholesterol (257.3 ± 38.5, 271.6 ± 88.7 mg / dl). 96% of the patients showed immunity (IgG) against dengue virus, the primary response (IgM) was present in 22%. Regarding the positivity of IgM, the highest frequency was in the group with hypertriacilgliceridemia (34.2%), while the frequency for IgG was in the group with triacylglycerides and high cholesterol (31.2%). In this study, no difference was observed between IgG and IgM antibodies against dengue virus in patients with dyslipidemia and the control group. Future studies are needed to demonstrate in areas of lower endemicity for the dengue virus if, in fact, the alteration of the lipid profile modifies the intensity of response to the infection

Increased serum ferritin and interleukin-18 levels in children with dengue.

Activated monocytes/macrophages that produce a cytokine storm play an important role in the pathogenesis of dengue. Interleukin-18 (IL-18) is a proinflammatory cytokine produced by monocyte/macrophages that is increased during dengue. Ferritin is an acute-phase reactant and expressed by cells of the reticulo-endothelial system in response to infection by dengue virus. The aims of this study were to analyze the simultaneous expression of both IL-18 and ferritins in children infected by diverse serotypes of dengue virus (DENV) and determine their association with dengue severity. In this regard, children with dengue (n = 25) and healthy controls with similar age and sex (n = 20) were analyzed for circulating ferritin and cytokines. Monocytes were isolated by Hystopaque gradient and co-cultured with DENV-2. IL-18 and ferritin contents in blood, and IL-18 in culture supernatants were determined by ELISA. Increased levels of ferritin and IL-18 (p < 0.0001) were observed in dengue patients, not associated to NS1expression or type of infection (primary or secondary). Highest values of both molecules (p < 0.001) were observed in dengue with warning signs and severe dengue. Differential effect on IL-18/ferritin production was observed associated to viral serotype infection. There were no correlations between ferritin vs. IL-18 production, ferritin vs. NS1 status, and IL-18 vs. NS1 status. Viral-infected monocyte cultures showed increased production of IL-18 (p < 0.001). In conclusion, increased circulating ferritin and IL-18 are expressed in children infected by different serotypes of DENV associated with dengue severity.

Gefitinib and pyrrolidine dithiocarbamate decrease viral replication and cytokine production in dengue virus infected human monocyte cultures.

AIMS: The epidermal growth factor receptor (EGFR) and nucleotide-binding and oligomerization-domain containing 2 (NOD2) are important in cancer and in microbial recognition, respectively. These molecules trigger intracellular signaling pathways inducing the expression of inflammatory genes by NF-kB translocation. Gefitinib (GBTC) and pyrrolidine dithiocarbamate (PDTC) are capable of inhibiting EGFR/NOD2 and NF-kB, respectively. In earlier stages of dengue virus (DENV) infection, monocytes are capable of sustaining viral replication and increasing cytokine production, suggesting that monocyte/macrophages play an important role in early DENV replication. GBTC and PDTC have not been used to modify the pathogenesis of DENV in infected cells. This study was aimed to determine the effect of GBTC and PDTC on viral replication and cytokine production in DENV serotype 2 (DENV2)-infected human monocyte cultures. MAIN METHODS: GBTC and PDTC were used to inhibit EGFR/NOD2 and NF-kB, respectively. Cytokine production was measured by ELISA and viral replication by plaque forming unit assay. KEY FINDINGS: Increased DENV2 replication and anti-viral cytokine production (IFN-α/ß, TNF-α, IL-12 and IL-18) in infected cultures were found. These parameters were decreased after EGFR/NOD2 or NF-kB inhibitions. SIGNIFICANCE: The inhibitory effects of GBTC and PDTC on viral replication and cytokine production can be beneficial in the treatment of patients infected by dengue and suggest a possible role of EGFR/NOD2 receptors and NF-kB in dengue pathogenesis.

Role of the myeloid differentiation primary response (MYD88) and TIR-domain-containing adapter-inducing interferon-ß (TRIF) pathways in dengue.

AIMS: Dengue disease courses with high viremia titers and high cytokine production suggesting viral replication and active immune response that could be related to viral evasion. One of the main targets of dengue virus (DENV) is monocyte/macrophage cells; however, little information regarding viral evasive mechanisms and pathway activation in monocytes infected by DENV is available. The aim of this study was to determine the role of myeloid differentiation primary response (MyD88), TIR-domain-containing adapter- inducing interferon-ß (TRIF) and NF-kB pathways in viral replication and cytokine production in human monocyte cultures infected by DENV2. MAIN METHODS: In this regard Pepinh- TRIF, Pepinh- MYD and pyrrolidine dithiocarbamate (PDTC) were used to inhibit TRIF, MYD88 and NF-kB pathways. Cytokine production was measured by ELISA. KEY FINDINGS: Increased DENV replication and IFNα/ß, TNF-α, IL-12 and IL-18 in infected cultures at 24h were found. All of these parameters were significantly decreased after TRIF, MYD88 or NF-kB inhibition. Association analysis between viral replication and cytokine production showed high significant positive correlation in TRIF and MYD88 treated cultures. SIGNIFICANCE: This study shows that DENV2 induces activation of innate-immune response and transcription factors to drive viral expression and replication in the face of pro-inflammatory antiviral responses in vitro.

Serum level of C-reactive protein is not a parameter to determine the difference between viral and atypical bacterial infections.

C-reactive protein (CRP) is an acute-phase reactant that increases in the circulation in response to a variety of inflammatory stimuli. Elevated levels in serum during several infectious diseases have been reported. In this study, a highly sensitive CRP enzyme immunoassay was used to evaluate serum CRP values in patients with viral and atypical bacterial infections. Patients (n = 139) with different viral or atypical bacterial infections (systemic or respiratory) and healthy controls (n = 40) were tested for circulating CRP values. High levels of IgM antibodies against several viruses: Dengue virus (n = 36), Cytomegalovirus (n = 9), Epstein Barr virus (n = 17), Parvovirus B19 (n = 26), Herpes simplex 1 and 2 virus (n = 3) and Influenza A and B (n = 8) and against atypical bacteria: Legionella pneumophila (n = 15), Mycoplasma pneumoniae (n = 21) and Coxiella burnetii (n = 4) were found. High values of CRP in infected patients compared with controls (P < 0.001) were found; however, no significant differences between viral and atypical bacterial infections were found. Low levels of CRP in respiratory and Coxiella burnetii infections compared with exanthematic viral and other atypical bacterial infections were found. This study suggests that CRP values are useful to define viral and atypical bacterial infections compared with normal values, but, it is not useful to define type of infection.

Increased C-reactive protein and decreased Interleukin-2 content in serum from obese individuals with or without insulin resistance: Associations with leukocyte count and insulin and adiponectin content.

AIMS: Chronic inflammation in obesity is associated with co-morbidities such as, hyperglycemia, hypertension and hyperlipidemia. Leukocytes play an important role in this inflammation and C-reactive protein (CRP) and Interleukin-2 (IL-2) can be important effectors during the immune response in obesity; however, the initial inflammatory events in obesity remain unclear. The aim of this study was to determine the circulating levels of CRP, IL-2, insulin and adiponectin, their association and the association with leukocyte count in obese individuals without co-morbidities and with or without insulin resistance (IR). MATERIALS AND METHODS: Nineteen obese non-diabetic and 9 lean subjects were studied for serum levels of CRP, IL-2, insulin, adiponectin, lipids, glycated hemoglobin, glycemia, for homeostasis model assessment of insulin resistance (HOMA-IR), arterial pressure and anthropometric parameters, and for leukocyte counts. Neutrophil/lymphocyte ratio (N/L) was calculated using the loge of leukocyte counts. Associations were determined by Pearson's correlation. RESULTS: None of the studied groups presented co-morbidities and two groups of obese individuals with normal or high levels of insulin (IR) were found. Increased CRP concentration and decreased IL-2 and adiponectin concentrations in obese were observed. Positive correlation between leukocyte type counts with CRP in obese with IR was found; however, no correlations with IL-2 in obese were observed. Insulin in obese were positively correlated with CRP and negatively correlated with IL-2 in IR obese individuals. Adiponectin in obese was negatively correlated with CRP. CONCLUSION: CRP and IL-2 may represent two important effectors in the early inflammatory events in obese individuals without co-morbidities. Adiponectin and insulin may be involved in anti-inflammatory events.

[Zika virus: Another emerging arbovirus in Venezuela?]. / Virus Zika: Otro arbovirus emergente en Venezuela?

Current health conditions of Venezuela, together with the tropical proliferation of different types of Aedes (aegypti and albopictus), suggest the arrival to this country of ZIKA virus (ZIKV). The Pan American Health Organization urges Latin American countries to take measures to prevent the ZIKV entry and advises that these measures must be designed to detect the introduction of ZIKV in an area, track its spread and actively monitor the disease. In Venezuela and other Latin-American countries, where endemicity is high for other arboviruses such as dengue arid chikungunya, health authorities should strengthen their surveillance systems to detect early and timely introduction of ZIKV ap.d refine diagnostic methods to confirm the infection rate; however, the high incidence of cases due those viral agents reflects weakened and poorly timed insensitive monitoring systems, as well as, poor vector control measures, arising the questions: will this arbovirus pop in our country, will it set as the other as edemicepidemic and lead to alter their clinical behavior and severity of the disease?

Losartan and enalapril decrease viral absorption and interleukin 1 beta production by macrophages in an experimental dengue virus infection.

The role of angiotensin II (Ang II) in dengue virus infection remains unknown. The aim of this study was to determine the effect of losartan, an antagonist of the angiotensin II type 1 receptor (AT1 receptor), and enalapril, an inhibitor of angiotensin I-converting enzyme (ACE), on viral antigen expression and IL-1ß production in peritoneal macrophages infected with dengue virus type 2. Mice treated with losartan or enalapril and untreated controls were infected intraperitoneally with the virus, and macrophages were analyzed. Infection resulted in increased IL-1ß production and a high percentage of cells expressing viral antigen, and this was decreased by treatment with anti-Ang II drugs, suggesting a role for Ang II in dengue virus infection.

Role of angiotensin II in experimental Venezuelan equine encephalitis in rats.

Venezuelan equine encephalitis (VEE) is a viral disease transmitted by mosquitoes. The inflammation induced by the VEE virus is associated with a high mortality rate in mice. Angiotensin II (Ang II), a pro-inflammatory molecule, is produced in the normal rat brain. There is no information about the role of this molecule in the inflammatory events occurring during VEE and the effect of inflammation on the mortality rate in VEE-virus-infected rats. This study was designed to determine the role of Ang II in VEE and to analyze the effect of inflammation on mortality in infected rats. Two groups of rats were studied: 1) Virus-infected animals and controls (n = 60) were treated with losartan (a blocker of the Ang II-AT1 receptor) or with pyrrolidine dithiocarbamate (PDTC, an inhibitor of NF-κB) or left untreated and analyzed for morbidity and mortality. 2) Animals treated using the same protocol (n = 30) were sacrificed at day 4 postinfection and analyzed by immunohistochemistry and histopathology and for cytokine production. Increased expression of Ang II, ICAM-1, ED-1 and cytokines (IL-1α, MCP-1, IL-6 and IL-10) in infected animals was observed. The main histopathology findings were dilated capillaries and capillaries with endothelial detachment. Losartan and PDTC reduced the expression of IL-1α, MCP-1, and IL-10, and the number of dilated capillaries and capillaries with endothelial detachment. Survival analysis showed that 100% mortality was reached earlier in infected rats treated with losartan (day 14) or PDTC (day 11) than in untreated animals (day 19). These findings suggest that Ang II plays a role in VEE and that brain inflammation is protective against viral infection.

Melatonin, minocycline and ascorbic acid reduce oxidative stress and viral titers and increase survival rate in experimental Venezuelan equine encephalitis.

Venezuelan equine encephalitis (VEE) virus causes an acute central nervous system infection in human and animals. Melatonin (MLT), minocycline (MIN) and ascorbic acid (AA) have been shown to have antiviral activities in experimental infections; however, the mechanisms involved are poorly studied. Therefore, the aim of this study was to determine the effects of those compounds on the viral titers, NO production and lipid peroxidation in the brain of mice and neuroblastoma cultures infected by VEE virus. Infected mouse (10 LD50) were treated with MLT (500 µg/kg bw), MIN (50mg/kg bw) or AA (50mg/kg bw). Infected neuroblastoma cultures (MOI: 1); MLT: 0.5, 1, 5mM, MIN: 0.1, 0.2, 2 µM or AA: 25, 50, 75 µM. Brains were obtained at days 1, 3 and 5. In addition, survival rate of infected treated mice was also analyzed. Viral replication was determined by the plaque formation technique. NO and lipid peroxidation were measured by Griess׳ reaction and thiobarbituric acid assay respectively. Increased viral replication, NO production and lipid peroxidation were observed in both, infected brain and neuroblastoma cell cultures compared with uninfected controls. Those effects were diminished by the studied treatments. In addition, increased survival rate (50%) in treated infected animals compared with untreated infected mice (0%) was found. MLT, MIN and AA have an antiviral effect involving their anti-oxidant properties, and suggesting a potential use of these compounds for human VEE virus infection.

Association of lipid profile alterations with severe forms of dengue in humans.

Previous studies have shown a relationship between circulating lipids and dengue virus infection; however, the association of altered lipid profiles with severe dengue remains little studied. The aim of this study was to determine the association between circulating lipid content and severe dengue and/or platelet counts. Ninety-eight patients (2-66 years old) classified as having dengue without warning signs (DNWS), dengue with warning signs (DWWS), or severe dengue (SD) and 62 healthy individuals were studied. Blood samples were tested for NS1, anti-dengue IgM, platelet content, total cholesterol (TC), triglycerides (T), high-density lipoproteins (HDL), low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL). Lipid alterations were observed mainly in patients with SD. Increased T and VLDL was observed in SD, and increased HDL was observed in DWWS and SD. Decreased TC was found in all forms of dengue, and the lowest LDL values were found in SD. Platelet counts were significantly decreased in DWWS and SD when compare to DNWS. A positive correlation (p = 0.019) between LDL values and platelet counts and a negative correlation (p = 0.0162) between VLDL values and platelet counts were found. Lipid profile alterations were associated with severe dengue.

Melatonin decreases brain apoptosis, oxidative stress, and CD200 expression and increased survival rate in mice infected by Venezuelan equine encephalitis virus.

BACKGROUND: Pro-inflammatory and oxidative events during brain Venezuelan equine encephalitis virus infection could lead to apoptosis and induce anti-inflammatory responses (increased expression of CD200). The aim of this study was to determine the effect of melatonin on brain apoptosis, oxidative stress, and CD200 molecule in mice and neuroblastoma cultures infected by Venezuelan equine encephalitis virus. METHODS: Mice were infected with 10 median lethal doses (LD50) of Venezuelan equine encephalitis virus, treated with melatonin (500 µg/kg bw; three days before infection and during all experimental time) and sacrificed on days 1, 3, and 5 postinfection. Brain samples were obtained at those periods of time. In addition, infected neuroblastoma cell cultures (multiplicity of infection [MOI]: 1) were treated with 0, 0.1, 0.5, and 1 mM of melatonin and analyzed at 2, 4, and 6 h. CD200 and apoptosis expressions were analyzed by immunohistochemistry and TUNEL assay, respectively. Nitrites and malondialdehyde were determined by appropriate biochemical methods. RESULTS: Increased brain expression of apoptosis, nitrite, and malondialdehyde productions and CD200 of infected mice were found. Melatonin diminished those expressions. Similarly, high apoptosis expression and nitrite and malondialdehyde productions on infected neuroblastoma cultures were diminished by melatonin. Melatonin increased the survival rate (25%) in Venezuelan equine encephalitis virus-infected animals compared with untreated infected mice (0%). CONCLUSIONS: Neurological damage during brain Venezuelan equine encephalitis virus infection could be mediated by apoptosis and oxidative stress and CD200 molecule could be an important anti-inflammatory response. Melatonin could be beneficial reducing apoptosis and oxidative stress.

[Allergic rhinitis in asthmatic patients]. / Rinitis alérgica en pacientes asmáticos.

BACKGROUND: Allergic rhinitis and bronchial asthma are airways chronic inflammatory processes, with a correlation of 28-78%. OBJECTIVES: To determine the prevalence and classification of allergic rhinitis on asthmatic patients, according to the workshop Allergic Rhinitis and its Impact on Asthma (ARIA), and to assess the total serum concentrations of IgE and the presence of nasal and blood eosinophilia. MATERIAL AND METHOD: A study was done with asthmatic patients ages 7 to 14, attending the Pediatric Service at the Hospital General del Sur Dr. Pedro Iturbe, Maracaibo, Estado Zulia, Venezuela. Subjects were polled for signs and symptoms suggesting allergic rhinitis and its impact on quality of life. Blood and nasal swab samples were taken to perform laboratory tests in study. RESULTS: There were 60 asthmatic patients, 73.3% males and 70% scholar age patients. The prevalence of allergic rhinitis was 93.3%, according to ARIA classification. Mild intermittent group was the most frequent type, with 42.8% the most frequent clinic sign was the allergic shiners (86.6%), and the predominant symptom was the nasal aqueous trickle (83.3%), while sleep disorders were the most common affection of quality of life (39.2%). In 85.7% of patients eosinophil percentage was higher than 3%, whereas in 75% total serum IgE values were higher than 100 Ul/mL. In patients with rhinitis, 61.9% of the nasal mucus showed altered eosinophils percentage higher than 10%. CONCLUSION: A high prevalence of allergic rhinitis is present in asthmatic patients, confirmed by laboratory tests, which proves an inflammatory response mediated by IgE.

Antecedentes: la rinitis alérgica y el asma bronquial son procesos inflamatorios crónicos de las vías respiratorias, con una correlación que varía entre 28 y 78%. Objetivos: determinar la prevalencia de rinitis alérgica en pacientes asmáticos y clasificarla según las guías Rinitis Alérgica y su Impacto en Asma (ARIA), así como detectar las concentraciones séricas de IgE total y la existencia de eosinofilia nasal y en sangre periférica. Material y método: estudio en el que pacientes asmáticos entre 7 y 14 años de edad, consultantes del servicio de Pediatría del Hospital General del Sur Dr. Pedro Iturbe, Maracaibo, Estado Zulia, Venezuela, fueron encuestados acerca de signos y síntomas sugerentes de rinitis alérgica y su efecto en la calidad de vida. Se tomaron muestras sanguíneas e hisopado nasal para hacer las determinaciones objeto de estudio. Resultados: se evaluaron 60 pacientes asmáticos, 73.3% del sexo masculino y 70% escolares. La prevalencia de rinitis alérgica se estableció en 93.3%, el tipo más frecuente según ARIA fue el intermitente leve, con 42.8%. El signo clínico más frecuente fueron las ojeras alérgicas (86.6%) y el síntoma predominante fue el goteo nasal acuoso (83.3%), la afectación en cuanto a calidad de vida estuvo representada por trastornos del sueño (39.2%). El 85.7% de los encuestados tuvo porcentajes de eosinófilos mayores a 3% y 75% tuvo valores mayores de 100 UI de IgE total sérica. El 61.9% de las muestras de moco nasal de pacientes con rinitis mostró porcentajes de eosinófilos mayores a 10%. Conclusión: existe alta prevalencia de rinitis alérgica en asmáticos confirmada mediante pruebas de laboratorio que evidencian una respuesta inflamatoria mediada por IgE.

[Is the fight against dengue complicated with the emergence of a new viral serotype?]. / Se complica la lucha contra el dengue ante el surgimiento de un nuevo serotipo viral?

Dengue is a viral acute febrile illness, currently considered one of the most important arbovirosis worldwide in terms of morbidity, mortality and economic impact. Various theories have been proposed to explain the pathogenesis of severe forms of dengue, involving among other factors, features related to the virus, such as the presence of more virulent strains and/or strains with increased replicative capacity. A crucial point at this time is the discovery of a new viral type, dengue 5, from nonhuman primates in Malaysia-Borneo, which could result in greater difficulties for control and vaccine production (currently in efficacy tests). Once the circulation of this viral type has been demonstrated in the human population, the high risk of infection will have extreme or controversial public health implications. Therefore, a worldwide program to combat dengue should include an urgent need to implement continuous vector elimination, community education and prevention and control of the disease. Only then, we will be aiming to reduce the morbidity and transmission risk of dengue, while new technological and effective alternatives come about.