Leaky Gut Syndrome Is Associated with Endotoxemia and Serum (1→3)-β-D-Glucan in Severe Dengue Infection

The hallmark of severe dengue infection is the increased vascular permeability and hemodynamic alteration that might be associated with an intestinal permeability defect. However, the mechanisms underlying the gastrointestinal-related symptoms of dengue are not well characterized. A prospective observational study was conducted on patients with dengue who were categorized according to: (i) febrile versus critical phase and (ii) hospitalized patients with versus without the warning signs to evaluate the gut barrier using lactulose-to-mannitol excretion ratio (LEMR). Serum endotoxins, (1→3)-β-D-glucan (BG), and inflammatory parameters were measured. A total of 48 and 38 patients were enrolled in febrile illness and critical phase, respectively, while 22 and 64 patients presented with or without the warning signs, respectively. At enrollment, a positive LEMR test was found in 20 patients (91%) with warning signs, regardless of phase of infection. Likewise, serum endotoxins and BG, the indirect biomarkers for leaky gut, prominently increased in patients who developed severe dengue when compared with the non-severe dengue (endotoxins, 399.1 versus 143.4 pg/mL (p < 0.0001); BG, 123 versus 73.8 pg/mL (p = 0.016)). Modest impaired intestinal permeability occurred in dengue patients, particularly those with warning signs, and were associated with endotoxemia and elevated BG. Thus, leaky gut syndrome might be associated with severity of dengue infection.

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Increased levels of pentraxins protein and cytokines bear good association in patients with severe dengue infection

Scientific Reports ◽

10.1038/s41598-020-80144-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Goutam Patra ◽

Bibhuti Saha ◽

Sumi Mukhopadhyay

Keyword(s):

Dengue Infection ◽

Clinical Manifestations ◽

Blood Parameters ◽

Warning Signs ◽

Severe Dengue ◽

Disease Manifestation ◽

Mild Disease ◽

Tnf Α ◽

The Status ◽

The Tropics

AbstractDengue is an arboviral infection with high rates of morbidity and mortality throughout the tropics and sub-tropics. This work studied the status of pentraxin (CRP/SAP) protein, ferritin, TNF-α and IL-1β levels in Dengue patients of different pathophysiological manifestations. Accordingly, clinically confirmed Dengue cases (n = 97) were enrolled and subsequently blood parameters were studied by Haematology cell counter and Biochemistry Autoanalyser. CRP, SAP, ferritin, TNF-α and IL-1β ELISA were done in all the samples by using standard ELISA kits. Statistical Analysis was done in all the experiments. The levels of CRP (p < 0.0001), SAP (p < 0.0001), ferritin (p < 0.0001), TNF-α (p < 0.0001) and IL-1β (p < 0.0001) were high in patients with Severe Dengue as compared to Dengue without warning signs. High levels of SGOT, SGPT and decreased platelet counts were found in severe patients as compared to Healthy donor. CRP/SAP as well as TNF-α/IL-1β were independently associated with both dengue severity and overall disease manifestation. Statistically significant increased CRP, SAP, ferritin, TNF-α and IL-1β titres were correlated in patients with severe clinical manifestations as compared to mild disease forms of dengue. Elevated levels of pentraxin, TNF-α/IL-1β in blood during dengue infection could act as an early predictor in Severe Dengue infection.

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Clinical profile of dengue fever in children: analysis of 2017 outbreak from Central Kerala, India

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20184293 ◽

2018 ◽

Vol 5 (6) ◽

pp. 2265 ◽

Cited By ~ 1

Author(s):

Senthil Kumar K. ◽

Rajendran N. K. ◽

Ajith Brabhukumar C.

Keyword(s):

Dengue Fever ◽

Dengue Infection ◽

Tertiary Care ◽

Hemorrhagic Fever ◽

Warning Signs ◽

Clinical Profile ◽

Severe Dengue ◽

High Morbidity ◽

Care Hospital ◽

High Grade Fever

Background: In India, dengue epidemics are becoming more frequent (WHO, 2008). The majority of dengue viral infections are self-limiting, but complications may cause high morbidity and mortality. The objective of this study is to assess the clinical profile of the dengue infection in children less than 15 years of age and to evaluate the outcomes of dengue fever from March 2017 to July 2017 at the Pediatric Department of Karuna Medical College, the tertiary care hospital in Palakkad.Methods: In this retrospective study, medical records were reviewed and analyzed. Patients with suspected dengue infection were classified further into 2 groups, Dengue fever (probable dengue, dengue with warning signs) and ‘Severe Dengue’ (dengue hemorrhagic fever and/or dengue shock syndrome (DHF/DSS) according to WHO.Results: A total of 77 cases were classified into 67 (87%) non-severe and 10 (13%) severe dengue cases. The most common age of presentation was above 10 yrs. The mean age of admission was 8.9 yrs. The most common presenting symptom was fever seen in 93% followed by vomiting in 68%. Elevation in Aspartate transaminase (SGOT) and thrombocytopenia were found in 32.4 %.Conclusions: High grade fever, vomiting, abdominal pain and skin rash with normal or low platelet count were the presenting features. Early diagnosis, monitoring and prompt supportive management can reduce mortality.

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A clinical corelation study of dengue fever with hepatic dysfunction in children and their outcome

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20211081 ◽

2021 ◽

Vol 8 (4) ◽

pp. 706

Author(s):

Srividya G. M. ◽

Poornima Lakshmi

Keyword(s):

Hepatic Dysfunction ◽

Total Bilirubin ◽

Complete Blood Count ◽

Dengue Infection ◽

Liver Function Tests ◽

Significant Rise ◽

Warning Signs ◽

Severe Dengue ◽

Serum Total Bilirubin ◽

Life Threatening

Background: The study was hepatic dysfunction in childhood dengue infection and to study clinical co-relation like severity, clinical features, and outcome.Methods: Dengue sero positive patients of 100 were admitted during the study period and examined for hepatomegaly and jaundice and subjected to complete blood count, liver function tests, ultrasound abdomen, PT, APTT, HBsAg, HCV, Widal and analysed.Results: All patients presented with fever, most commonly occurred in age group of 5 to 7 years, hepatomegaly was the commonest clinical sign seen, thrombocytopenia was seen in 88% of cases, serum total bilirubin was raised in 10% of subjects with severe dengue infection. Serum SGOT was raised in 74 % of patients with dengue. When compared between the groups, rise in SGOT occurred in 74% of patients with probable dengue, 98% with warning signs and 100% in severe dengue. SGPT was raised in 58% of patients with dengue infection. When compared between the groups, rise in SGPT occurred in 42% of patients with probable dengue, 66% with warning signs and 81% in severe dengue. SGPT was raised in 28% of patients with dengue infection. When compared between the groups, rise in SGOT occurred in 9.5% of patients with probable dengue, 32% with warning signs and 82% in severe dengue. Prothrombin time was raised in 11% of patients. When compared between the groups, rise in PT occurred in 6.4% with warning signs and 72% in severe dengue. When compared between the groups, rise in APTT occurred in 6.4% of patients with warning signs and 72% in severe dengue. When compared between the groups fall in serum protein occurred in 12.7% with warning signs and 54.5% in severe dengue. 2 cases of severe dengue expired, in which the enzyme levels were highly elevated.Conclusions: Significant rise of liver enzymes helps in recognition of severe forms of dengue infection. As hepatic dysfunction in dengue is transient and reversible, early identification of the same should help to reduce life threatening complications. This can help to reduce the morbidity and mortality due to dengue infection.al population.

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The association of lipopolysaccharide and inflammatory markers with severe dengue infection

10.21203/rs.2.19143/v1 ◽

2019 ◽

Author(s):

N.L Ajantha Shyamali ◽

Sameera D. Mahaputuna ◽

Laksiri Gomes ◽

Ananda Wijewickrama ◽

Graham Ogg ◽

...

Keyword(s):

Inflammatory Markers ◽

Metabolic Diseases ◽

Dengue Infection ◽

Severe Dengue ◽

Atopic Diseases ◽

Disease Pathogenesis ◽

Critical Phase ◽

Plasma Leakage ◽

Detectable Serum

Abstract Background Although serum lipopolysaccharide (LPS) was shown to associate with development of severe dengue, the reasons for high LPS and its subsequent involvement in disease pathogenesis are not known. Methods: We assessed LPS, lipopolysaccharide binding protein (LBP), CRP, IL-18, procalcitonin in patients with acute dengue fever (DF=129) and dengue haemorrhagic fever (DHF=64) and correlated these observations with the presence of comorbid illnesses, concurrent bacteraemia and clinical disease severity. Results: LPS levels were significantly (p=0.01) higher in patients with DHF, compared to those with DF. 45 (70%) of those with DHF and 63 (49%) of those with DF had detectable LPS and therefore, presence of LPS was significantly associated with DHF (p=0.005, OR=2.48, 95% CI: 1.29 to 4.64). Those with metabolic diseases, 22/29 (75.9%) and those with atopic diseases 17/22 (77.3%) were significantly more likely to have detectable LPS (p=0.025, OR=2.9, 95% CI- 1.17 to 7.59) and (p=0.039, OR=3.06, 95% CI-1.07 to 7.81) respectively, than others. LPS, LBP and CRP levels were high at the febrile phase, before onset of plasma leakage and reduced towards to the critical phase. The CRP levels were significantly higher (p=0.03) in early illness (≤3 days of illness) in those who progressed to develop DHF when compared to those who developed DF. Those who had detectable serum LPS also had a significantly higher CRP (p=0.01). Although there was no difference in procalcitonin (PCT) levels in patients with DF and DHF, the PCT levels were significantly higher in those who had detectable serum LPS (p=0.02). Conclusions: LPS levels were higher in patients with DHF and associated with high levels of other inflammatory markers. Since LPS levels were highest during early infection and were significantly more likely to be present in those with comorbid illnesses, the possible role of LPS in disease pathogenesis, should be further investigated.

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Epidemiological and Clinical Features of Dengue Infection in Adults in the 2017 Outbreak in Vietnam

BioMed Research International ◽

10.1155/2019/3085827 ◽

2019 ◽

Vol 2019 ◽

pp. 1-6 ◽

Cited By ~ 5

Author(s):

Bui Vu Huy ◽

Le Nguyen Minh Hoa ◽

Dang Thi Thuy ◽

Nguyen Van Kinh ◽

Ta Thi Dieu Ngan ◽

...

Keyword(s):

Elderly Patients ◽

Dengue Fever ◽

Clinical Features ◽

Dengue Infection ◽

Clinical Manifestations ◽

Warning Signs ◽

Severe Dengue ◽

Severe Bleeding ◽

Cross Sectional ◽

Number Of Patients

Purpose. The clinical features and laboratory results of dengue-infected adult patients admitted to the hospital during the 2017 outbreak were analyzed in this study. Method. This is a cross-sectional study. 2922 patients aged 18 years or more with dengue fever in National Hospital for Tropical Diseases (NHTD) in the North and Hospital for Tropical Disease (HTD) in the South of Vietnam were recruited in this study. Result. Patients were admitted in the hospital around the year and concentrated from August to December, in 53/63 (84.0%) provinces in Vietnam, and patients in all ages were affected. The number of patients with dengue fever was 1675 (57.3%), dengue with warning signs 914 (31.3%), and severe dengue 333 (11.4%), respectively. Among patients with severe dengue, severe plasma leakage and dengue shock account for 238 (8.1%), severe organ impairment 73 (2.5%), and severe bleeding 22 (0.75%). The rate of mortality was 0.8%, and the outcome of dengue patients is worse in the elderly and people with underlying diseases. Conclusion. The 2017 dengue outbreak occurred in a larger scale than in the previous years in terms of time, location, and number of patients. More elderly patients were infected by dengue in this outbreak, and this may contribute to the mortality rate. Clinical manifestations of dengue patients in Southern Vietnam are more typical than the northern, but the rate of severe dengue is not different. The mortality risk and underlying conditions associated with dengue-infected elderly patients are worthy of further investigations in the future.

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2654. Myocarditis in Dengue: A Prospective Observational Study

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.2332 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S928-S929

Author(s):

Manish Soneja ◽

Manasvini Bhatt ◽

Faraz A Farooqui ◽

Naval K Vikram ◽

Ashutosh Biswas ◽

...

Keyword(s):

Observational Study ◽

Prospective Observational Study ◽

Fluid Overload ◽

Fluid Management ◽

Clinical Signs ◽

Clinical Manifestations ◽

Hemodynamic Instability ◽

Warning Signs ◽

Severe Dengue ◽

Cardiac Enzymes

Abstract Background Cardiac involvement in dengue fever is underdiagnosed due to low index of suspicion and overlapping clinical manifestations of capillary leak associated with dengue. The frequency of subclinical dengue myocarditis and its relative contribution to the hemodynamic instability in severe dengue needs to be explored. We studied the prevalence of myocarditis and clinical outcomes among admitted patients with dengue. Methods A prospective observational study was carried out in admitted patients with age between 18 and 65 years having confirmed dengue (NS1/IgM ELISA). Patients with electrolyte abnormalities or on medications affecting heat rhythm/ rate, pre-existing heart disease were excluded. The baseline demographic, clinical and laboratory parameters were collected. A baseline ECG was done and repeated every second day. Trop-I and NT-proBNP were done at baseline and repeated only if elevated at baseline or there were ECG changes. The cardiac enzymes were measured using enzyme-linked ﬂuorescent assay (VIDAS, bioMérieux, France). Patients with elevated enzymes underwent 2-dimensional echocardiography. Diagnosis of myocarditis was as per ESC 2013 criteria. Fluid management was as per WHO guidelines (2009). Results A total of 183 patients were recruited with median age of 29 years (IQR 21, 37) and 31% were females. Dengue with warning signs was present in 80 (44%) and severe dengue in 45 (25%) patients. Cardiac enzymes were elevated in 27 (15%) patients (cTnI in 25, NT-proBNP in 22). Among these 27 patients, 11 [6% (2.6–9.4, 95% CI)] had echo evidence and diagnosed as having myocarditis according to ESC 2013 criteria (Figure 1). Clinical features of fluid overload were more common in myocarditis group [8 (73%) vs 4 (2%), P = Overall, 5 (2.7%) patients expired, all of them had myocarditis (5/11 = 45%). These patients had severe dengue, 2 patients developed hospital-acquired pneumonia and 1 had malaria co-infection. Among patients with raised enzymes and normal echo (n = 16), 3 patients developed clinical signs of fluid overload compared with only 1 out of 156 patients without raised enzymes (P < 0.01). Conclusion Myocarditis in admitted patients with dengue is not uncommon [6% (2.6–9.4, 95% CI)] and may lead to a complicated disease course. Disclosures All authors: No reported disclosures.

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Factors predicting the severity of dengue in patients with warning signs in Rio de Janeiro, Brazil (1986–2012)

Transactions of the Royal Society of Tropical Medicine and Hygiene ◽

10.1093/trstmh/trz066 ◽

2019 ◽

Vol 113 (11) ◽

pp. 670-677 ◽

Cited By ~ 1

Author(s):

Bianca De Santis Gonçalves ◽

Rita Maria Ribeiro Nogueira ◽

Ana Maria Bispo de Filippis ◽

Marco Aurélio Pereira Horta

Keyword(s):

Rio De Janeiro ◽

Dengue Infection ◽

Warning Signs ◽

Severe Dengue ◽

Enzyme Linked Immunosorbent Assay ◽

Infection Status ◽

Viral Loads ◽

Dengue Virus Type 3 ◽

Dengue With Warning Signs ◽

Type 3

AbstractBackgroundSince 1981, >12 million cases of dengue have been reported in Brazil. Early prediction of severe dengue with no warning signs is crucial to avoid progression to severe dengue. Here we aimed to identify early markers of dengue severity and characterize dengue infection in patients in Rio de Janeiro.MethodsWe evaluated early severity markers, serotypes, infection status, number of days of illness and viral loads associated with dengue fever in patients from Rio de Janeiro, Brazil through an observational retrospective study (1986–2012). We compared dengue without warning signs and dengue with warning signs/severe dengue (DWWS/SD). Infection status was classified by enzyme-linked immunosorbent assay and viraemia was quantified by quantitative real-time reverse transcription polymerase chain reaction.ResultsThe presence of DWWS/ SD was significantly associated with younger age; patients 13–19 y of age had a significantly greater chance of presenting warning signs. Dengue virus type 3 (DENV3) was more likely to induce DWWS/SD, which was more frequent on days 4–5 of illness.ConclusionsDENV3, 4–5 d of illness and 13–19 y of age were early biomarkers of dengue severity. To our knowledge, this was the first study to analyse the characteristics of dengue severity in the state of Rio de Janeiro over 27 y of epidemics since the introduction of DENV.

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2565. A Novel Prognostic Gene Set for the Prediction of Severe Dengue

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy209.173 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S72-S72

Author(s):

Makeda L Robinson ◽

Timothy E Sweeney ◽

Rina Barouch-Bentov ◽

Malaya K Sahoo ◽

Ana Maria Sanz ◽

...

Keyword(s):

Gene Expression ◽

In Silico ◽

Dengue Infection ◽

Differentially Expressed Gene ◽

Warning Signs ◽

Severe Dengue ◽

Blood Samples ◽

Gene Set ◽

Severity Scores ◽

Pcr Assays

Abstract Background There is an urgent need for the identification of biomarkers predictive of severe dengue. Single cohort transcriptomic studies have not yielded a parsimonious gene set predictive of severe dengue. We hypothesized that integration of gene expression data from heterogeneous patient populations with dengue infection would yield a set of conserved genes that is predictive of severe dengue and generalizable across cohorts. Methods Ten dengue gene expression datasets were identified in publicly available microarray repositories. A novel integrated multicohort platform was used to detect differentially expressed gene transcripts between uncomplicated and severe dengue patients and validate the identified putative signature in silico and prospectively in a new cohort of 34 dengue patients in Colombia. Dengue diagnosis was made by NS1 antigen and anti-DENV IgM antibody and confirmed by RT-PCR assays, ELISA, and IgG avidity measurements. The expression level of the signature genes was measured via microfluidic qRT-PCR assays in blood samples collected longitudinally during the course of illness. Results Using the multicohort analysis to analyze 446 peripheral blood samples of patients with dengue infection from 7 publicly available gene expression datasets, we identified a 20 gene set that predicts the development of severe dengue. We in silico validated the diagnostic power of this gene set to separate severe dengue from dengue with or without warning signs in 3 independent datasets composed of 84 samples with a global area under the ROC curve (AUC) of 0.80 [95% CI 0.68–0.88]. We prospectively validated the gene set in a new cohort composed of 34 dengue patients from Colombia with an AUC of 0.89 [95% CI 0.81–0.97]. The severity scores measured in patients with severe dengue progressively declined in longitudinal samples. Conclusion Our data indicate that the identified 20 gene signature predicts the development of severe dengue in patients prior to its onset and suggest that dengue infection itself triggers this host response. These findings may provide new insight into the pathogenesis of severe dengue and have implications for the development of a prognostic molecular assay to identify patients at risk to develop severe dengue. Disclosures T. E. Sweeney, Inflammatix, Inc.: Employee and Shareholder, Salary. P. Khatri, Inflammatix, Inc: Scientific Advisor and Shareholder, Licensing agreement or royalty.

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Immunophenotyping and transcriptional profiling of human plasmablasts in dengue.

10.1101/2021.04.09.439257 ◽

2021 ◽

Author(s):

Charu Aggarwal ◽

Keshav Saini ◽

Elluri Seetharami Reddy ◽

Mohit Singla ◽

Kaustuv Nayak ◽

...

Keyword(s):

Chemokine Receptors ◽

Influenza Infection ◽

Transcriptional Profiling ◽

Dengue Infection ◽

Warning Signs ◽

Severe Dengue ◽

Dengue Disease ◽

Mucosal Tissues ◽

Dengue With Warning Signs

Previous studies have shown that plasmablasts expand massively in dengue patients as compared to many other situations such as influenza infection or vaccination. However, a detailed understanding of the phenotypes and transcriptional features of these cells is lacking. Moreover, despite India having nearly a third of global dengue disease burden, there is virtually no information on plasmablasts responses in dengue patients from India. Here, we provide a detailed characterization of plasmablast responses from dengue confirmed febrile children in India. Immunophenotyping and RNA seq analysis showed that in addition to secreting dengue specific antibodies, these massively expanding cells expressed several adhesion molecules, chemokines and chemokine receptors that are involved in endothelial interactions, homing to skin or mucosal tissues including intestine. Surprisingly, we found that these cells also upregulated expression of several cytokine genes that are involved in angiogenesis, leukocyte extravasation and vascular permeability. These transcriptional features were qualitatively similar to plasmablasts from influenza vaccinees. Interestingly, the expansion of the plasmablasts in dengue patients was significantly lower in patients with primary dengue infection compared to those with secondary dengue. Moreover, within the primary dengue patients, their expansion was significantly lower in patients with mild dengue infection (DI) compared to patients with dengue with warning signs (DW) or severe dengue (SD). These results significantly improve our understanding of human plasmablast responses in dengue.

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Management of Dengue in Children: An Update

Dhaka Shishu (Children) Hospital Journal ◽

10.3329/dshj.v35i2.49702 ◽

2020 ◽

Vol 35 (2) ◽

pp. 162-178

Author(s):

Mirza Md Ziaul Islam

Keyword(s):

Fluid Resuscitation ◽

Dengue Infection ◽

Clinical Manifestations ◽

Therapeutic Index ◽

Severe Dengue ◽

Management Problem ◽

Aggressive Fluid Resuscitation ◽

Critical Phase ◽

Plasma Leakage ◽

Severity Of The Disease

Dengue viruses cause symptomatic infections or asymptomatic seroconversion. Symptomatic dengue infection is a systemic and dynamic disease. It has a wide clinical spectrum that includes both severe and non-severe clinical manifestations. Due to its dynamic nature, the severity of the disease will usually only be apparent around defervescence which often coincides with the onset of the critical phase. For a disease that is complex in its manifestations, management is relatively simple, inexpensive and very effective in saving lives, so long as correct and timely interventions are instituted. The main hemodynamic elements of dengue shock is hypovolemia with decreased vascular capacitance resulting from plasma leakage. Thus, the strategy of aggressive fluid resuscitation of septic shock is not applicable to severe dengue with plasma leakage. Volume replacement in children with dengue shock is a challenging management problem. Aggressive fluid resuscitation may indeed be harmful and should be limited to dengue shock with hypotension. There is a “narrow therapeutic index”; therefore, fluids have to be given timely, at the appropriate volume, rate, of the appropriate type (crystalloids, colloid and/or blood) and for the appropriate duration. Therein lies the challenge to physicians who are not familiar with the important practice of fluid titration through frequent and meticulous assessment. Progression of the disease through the critical phase should be tracked in hours of plasma leakage. Recognizing the cues to discontinue intravenous fluid therapy is just as important as knowing when to start it. Given time and hemodynamic stability, other issues such as thrombocytopenia, coagulopathy and raised liver enzymes will recover spontaneously or with supportive care. DS (Child) H J 2019; 35(2) : 162-178

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