Liver injury in patients with dengue infection is common. Most patients have mild and transient hepatitis. Acute liver failure (ALF) in dengue infection is rare but results in an extremely poor prognosis.

To identify prognostic predictors of ALF and death in patients with dengue-induced severe hepatitis (DISH).

We retrospectively reviewed 2311 serologically confirmed adolescent and adult dengue patients who were hospitalized during a 12-year study period (between 2007 and 2019) at the university hospital of King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Patients with DISH [n = 134 (5.80%)], defined as a baseline transaminase > 10 times the normal reference cut-off level, and DISH with subsequent ALF as defined by the American Association for the Study of the Liver Diseases 2011 criteria [n = 17 (0.74%)], were included. Predictors of ALF and in-hospital death were identified using logistic regression analysis.

Of the 151 dengue-infected patients with severe liver injury or ALF, 51% were female, with a mean age of 27.9 ± 14.5 years. Capillary leakage syndrome (CLS) occurred in 68.2% (n = 103) of DISH and 100% of ALF patients. The mortality rate was low in DISH patients (0.8%) but was remarkably high if ALF developed (58.8%). In univariate analysis, age, sex, hematocrit, white blood count, atypical lymphocyte count, platelet count, international normalized ratio (INR), bilirubin, serum glutamate-oxaloacetate transaminase, serum glutamate-pyruvate transaminase, alkaline phosphatase, albumin, creatinine, Model for End-Stage Liver Disease (MELD) score, presence of liver comorbidity and presence of CLS were identified as potential prognostic parameters for ALF or death. In multivariate analysis, the MELD score remained the only predictor of ALF with an adjusted odds ratio (aOR) of 1.3 [95% confidence interval (CI): 1.1-1.5; P = < 0.001]. An initial MELD score ≥ 15 was associated with ALF from DISH with an area under the receiver operating characteristic (AUROC) of 0.91, 88.2% sensitivity and 87.3% specificity. Regarding mortality prediction, the deterioration of liver function to ALF was the most significant factor related to death in DISH patients (aOR 108.5, 95%CI: 5.5-2145.4, P = 0.002). Other independent factors associated with death included baseline INR (aOR 10.4, 95%CI: 2.6-40.5, P = 0.001). An INR ≥ 1.5 predicted death from DISH with an AUROC of 0.83 (81.8% sensitivity and 86.8% specificity).

The MELD score is the best predictor of ALF in DISH patients, a complication from dengue that is associated with high mortality. The presence of ALF and the baseline INR level are independent markers of death in DISH patients.

Dengue is a common cause of acute liver failure in tropical countries. Paracetamol is the recommended antipyretic for dengue. Related observational studies in dengue have suggested that excessive paracetamol intake is related to hepatic injury. We aimed to evaluate whether standard dose paracetamol as an antipyretic in dengue infection caused transaminase elevation, and to evaluate the efficacy of paracetamol.

In this randomised, double-blind, placebo-controlled trial, adult participants (aged ≥18 years) with dengue, as confirmed by either positive NS1 antigen, positive dengue IgM antigen with thrombocytopenia, or positive PCR test, were enrolled at three Royal Thai Army hospitals in Thailand. Key exclusion criteria were baseline AST or ALT concentrations of more than 3 times the upper limit of normal, cirrhosis, indication of paracetamol other than dengue infection, concurrent diagnosis of other causes of fever, or pregnancy. Patients were randomly assigned (1:1), by a computer-generated block randomisation procedure (block size of six), to receive either paracetamol (500 mg) or placebo (500 mg) every 4 h when body temperature exceeded 38°C during hospitalisation. Participants and investigators were masked to treatment assignment. The primary outcome was the proportion of participants with transaminase elevation, defined as serum aspartate transaminase (AST) and alanine transaminase (ALT) concentrations of more than 3 times the upper limit of normal on recovery day, in the intention-to-treat population. Prespecified interim analyses for safety and efficacy were performed with group sequential stopping boundaries. This trial is registered with ClinicalTrials.gov, number NCT02833584.

Between Sept 1, 2016, and Dec 12, 2017, 125 participants were randomly assigned to receive either paracetamol (n=63) or placebo (n=62). 123 participants were included in the intention-to-treat population. The median daily dose of study medication was 1·5 g (IQR 0·8-2·0). The study was terminated early owing to a higher rate of transaminase elevation in the paracetamol group than in the placebo group (22% vs 10%; incidence rate ratio 3·77, 95% CI 1·36-10·46, p=0·011). The change of AST and ALT concentrations in the paracetamol group was higher than in the placebo group (mean difference 12·43 U/L per day, 7·16-17·71, p<0·0001 for AST; 7·40 U/L per day, 95% CI 3·68-11·13, p=0·0001 for ALT). Three participants in the paracetamol group had severe dengue: two had upper gastric haemorrhage and one had acute kidney injury. No patients died or had liver failure.

Use of standard dose paracetamol in dengue infection increased the incidence of transaminase elevation, and also overall transaminase concentrations in the absence of a counterbalancing reduced fever or pain score.

Phramongkutklao College of Medicine.

The disease caused by each of the four serotypes of dengue virus (DENV) have plagued humans since last century. Symptoms of dengue virus (DENV) infection range from asymptomatic to dengue fever (DF) to severe dengue disease (SDD). One third of the world's population lives in regions with active urban DENV transmission, and thousands of serologically naïve travelers visit these areas annually, making a significant portion of the human population at risk of being infected. Even though lifelong immunity to the homotypic serotype is achieved after a primary DENV infection. Heterotypic DENV infections may be exacerbated by a pre-existing immune memory to the primary infection and can result in an increased probability of severe disease. Not only, age, comorbidities and presence of antibodies transferred passively from dengue-immune mother to infants are considered risk factors to dengue severe forms. Plasma leakage and multiple organ impairment are well documented in the literature, affecting liver, lung, brain, muscle, and kidney. However, unusual manifestation, severe or not, have been reported and may require medical attention. This review will summarize and discuss the increasing reports of unusual manifestations in the clinical course of dengue infection.

Dengue is one of the most important mosquito-borne infections. Severe cases are more frequently observed in adults. However, in 2008, the State of Rio de Janeiro, Brazil, experienced a severe dengue epidemic that primarily affected children and caused many cases of dengue hemorrhagic fever (DHF) and death.

A cross-sectional analytical study was conducted to examine laboratory diagnosis and clinical epidemiologic factors for confirmed dengue cases in patients aged less than 16 years, from January to June 2008, at a municipal hospital in the City of Rio de Janeiro, Brazil. Variables associated with severe outcomes and P values less than .05 were evaluated by means of a logistic regression model.

Of the 419 dengue cases studied, 296 were classified as DHF and 123 as classical dengue. Six patients who had DHF died. In multivariate analysis, some laboratory and clinical variables were independently associated with DHF: age 5 years or older (odds ratio [OR], 4.94; 95% confidence interval [CI], 1.30-18.71), abdominal pain (OR, 8.59; 95% CI, 3.17-23.27), hepatomegaly (OR, 15.87; 95% CI, 5.38-46.85), and positive tourniquet test (OR, 10.84; 95% CI, 3.96-29.71). Hypoalbuminemia occurred more frequently than hemoconcentration in DHF cases, and high aminotransferase levels were associated with severity.

Age greater than 5 years, abdominal pain, painful hepatomegaly, and positive tourniquet test were predictors of DHF. The high frequency of hepatic impairment suggests that acetaminophen should be avoided in severe cases of dengue.

In children, paracetamol overdose due to deliberate self-poisoning, accidental exposure or medication errors can lead to paediatric acute liver failure and death. In Australia and New Zealand, the nature of ingestion and outcomes of paracetamol-associated paediatric acute liver failure have not been described.

To describe the nature and outcomes of paracetamol-associated paediatric acute liver failure.

Retrospective analysis of paracetamol-associated paediatric acute liver failure cases presenting 2002-2012.

New Zealand and Queensland Paediatric Liver Transplant Services.

14 of 54 cases of paediatric acute liver failure were attributed to paracetamol, the majority were secondary to medication errors. 12 of the 14 children were under the age of 5 years. Seven children received doses in excess of 120 mg/kg/day. Many of the other children received either a double dose, too frequent administration, coadministration of other medicines containing paracetamol or regular paracetamol for up to 24 days. Three children underwent transplant. One of these and one other child died.

In Australia and New Zealand, paracetamol overdose secondary to medication errors is the leading cause of paediatric acute liver failure. A review of regional safety practices surrounding paracetamol use in children is indicated.

To analyze the liver dysfunction and evolution of signs and symptoms in adult dengue patients during a two-month follow-up period.

A prospective cohort study was conducted in Campos dos Goytacazes, Rio de Janeiro, Brazil, from January to July, 2008. The evolution of laboratory and clinical manifestations of 90 adult dengue patients was evaluated in five scheduled visits within a two-month follow-up period. Twenty controls were enrolled for the analysis of liver function. Patients with hepatitis B, hepatitis C, those known to be human immunodeficiency virus (HIV) seropositive and pregnant women were excluded from the study.

At the end of the second month following diagnosis, we observed that symptoms persisted in 33.3% (30/90) of dengue patients. We also observed that, 57.7% (15/26) of the symptoms persisted at the end of the second month. The most persistent symptoms were arthralgia, fatigue, weakness, adynamia, anorexia, taste alteration, and hair loss. Prior dengue virus (DENV) infection did not predispose patients to a longer duration of symptoms. Among hepatic functions, transaminases had the most remarkable elevation and in some cases remained elevated up to the second month after the disease onset. Alanine aminotransferase (ALT) levels overcame aspartate aminotransferase (AST) during the convalescent period. Male patients were more severely affected than females.

Dengue fever may present a wide number of symptoms and elevated liver transaminases at the end of the second month.

The current guidelines for treatment of malaria include paracetamol to children with fever. No convincing evidence for the beneficial effects of this practice exists. Studies show that time to parasite clearance is significantly longer in children treated with paracetamol, which questions the policy. Whether this is of clinical importance has not been investigated.

Children with Plasmodium falciparum monoinfection and ≥20 parasites per 200 leucocytes at the Bandim Health Centre, Guinea-Bissau were randomized to receive paracetamol or placebo together with chloroquine for three days in a double blind randomized study. Temperature and symptoms were recorded twice daily during treatment and on day 3. The participants were interviewed and a malaria film taken once weekly until day 35. The data is in the form of grouped failure-times, the outcome of interest being time until parasitaemia during follow-up. Mantel-Haenszel weighted odds ratios are given. Other differences between and within the two groups have been tested using the Chi-square test and Mann-Whitney U test.

In the evening of the day of inclusion, the temperature was slightly, but statistically insignificant, higher in the placebo group and significantly more children complained of headache. At no other time was a significant difference in temperature or symptoms detected. However, 6 children from the placebo-group as compared to two children from the paracetamol-group were admitted to hospital with high fever and convulsions by day 3. No differences in the cumulative percentages of children with adequate clinical and parasitological response were found in the intention-to-treat analysis or in the per-protocol analysis.

Fewer children had early treatment failure and the mean temperature was slightly lower in the afternoon on day 0 in the paracetamol group. However, the cumulative adequate clinical and parasitological cure rates were not significantly different during the period of study. It is doubtful whether adding paracetamol to the treatment of uncomplicated malaria in children is beneficial.

NCT00137566.

Key symptoms observed during the febrile phase of dengue may identify patients who are likely to progress to severe disease.

To test this hypothesis, we examined the relationships between symptoms reported by patients at presentation and the development of severe outcomes.

Retrospective analysis of data recorded prospectively in 560 adult dengue patients admitted to an emergency department. A logistic regression analysis was used to quantify the association between symptoms reported at presentation and outcome.

Plasma leakage was observed in 95 patients (17%), severe thrombocytopenia (platelet counts <20 x 10(9)/L) in 93 patients (16.6%) and acute hepatitis in 42 patients (7.5%). Severe thrombocytopenia developed in 57% of patients with plasma leakage and 40.5% of patients with hepatitis. Patients who developed a plasma leakage syndrome were older, mainly male, and reported more often an abdominal pain and a cough. Diarrhea and taking paracetamol >60 mg/kg/day before admission were associated with the development of acute hepatitis. Seven patients died. The mortality rate was 6/95 (6.3%) in patients who developed plasma leakage, 3/42 (7.1%) in patients who developed hepatitis, 5/93 (5.4%) in patients with severe thrombocytopenia, and 3/12 (25%) in the patients who demonstrated together all these severe manifestations.

Plasma leakage, severe thrombocytopenia and acute hepatitis identified subgroups of adult dengue patients with increased mortality rates. Key symptoms reported by the patients at presentation such as abdominal pain, cough or diarrhea were significantly associated with the development of severe manifestations and should be considered as warning signs.

The main aim of this review was to compare the tolerability and safety between ibuprofen and paracetamol when used as anti-pyretic and analgesic agents in children up to 18 years of age.

MEDLINE (1950 to November 2008), EMBASE (1980 to November 2008), The Cochrane Library (2007, Issue 3), ACP Journal Club (1991 to November 2007) and Pascal (1987 to November 2007) were searched for randomised controlled trails (RCTs) (comparing ibuprofen and/or paracetamol with placebo), controlled observational studies and large case series comprised more than 1000 participants.

Adverse events (AEs) requiring discontinuation of medication; systemic reactions related to ibuprofen or paracetamol; serious AEs that are fatal, life-threatening or require hospitalisation; and serious AEs not requiring hospitalisation.

A total of 24 RCTs examined either ibuprofen and/or paracetamol versus placebo for AE data. Twelve other studies meeting our criteria were also included for AE data. Meta-analysis of systemic reactions demonstrated that tolerability and safety of ibuprofen was similar to placebo, as was paracetamol: ibuprofen versus placebo relative risk (RR) 1.39 (95% CI: 0.92, 2.10); paracetamol versus placebo RR 1.57 (95% CI 0.74, 3.33). A total of 2937 systemic AEs occurred in 21,305 patients taking ibuprofen compared with 1,466 systemic AEs in 11,164 patients taking paracetamol: RR 1.03 (95% CI 0.98, 1.10). There was no significant difference between the two groups. Narrative analysis of AE data identified conflicting evidence regarding hepatic injury with paracetamol and group A streptococcal infections with ibuprofen or paracetamol treatment.

Ibuprofen, paracetamol and placebo have similar tolerability and safety profiles in terms of gastrointestinal symptoms, asthma and renal adverse effects. While the study data investigated here may not reflect over-the-counter use, these results are still relevant in the context of any safety concerns relating to general ibuprofen or paracetamol treatment in children.

A 7-month-old infant developed acute fatal hepatic failure owing to inadvertent duplication of paracetamol prescriptions. Paracetamol toxicity should be considered in the differential diagnosis of infants presenting with acute hepatic failure.