Assessment of Microalbuminuria for Early Diagnosis and Risk Prediction in Dengue Infections

<div><h3>Background</h3><p>Dengue is the most important arboviral infection of humans. Following an initial febrile period, a small proportion of infected patients develop a vasculopathy, with children at particular risk for severe vascular leakage and shock. Differentiation between dengue and other common childhood illnesses is difficult during the early febrile phase, and risk prediction for development of shock is poor. The presence of microalbuminuria is recognized as a useful early predictor for subsequent complications in a number of other disorders with vascular involvement. Significant proteinuria occurs in association with dengue shock syndrome and it is possible that early-phase microalbuminuria may be helpful both for diagnosis of dengue and for identification of patients likely to develop severe disease.</p> <h3>Methodology/Principal Findings</h3><p>We measured formal urine albumin to creatinine ratios (UACRs) in daily samples obtained from a large cohort of children with suspected dengue recruited at two outpatient clinics in Ho Chi Minh City, Vietnam. Although UACRs were increased in the 465 confirmed dengue patients, with a significant time trend showing peak values around the critical period for dengue-associated plasma leakage, urine albumin excretion was also increased in the comparison group of 391 patients with other febrile illnesses (OFI). The dengue patients generally had higher UACRs than the OFI patients, but microalbuminuria, using the conventional cutoff of 30 mg albumin/g creatinine discriminated poorly between the two diagnostic groups in the early febrile phase. Secondly UACRs did not prove useful in predicting either development of warning signs for severe dengue or need for hospitalization.</p> <h3>Conclusion/Significance</h3><p>Low-level albuminuria is common, even in relatively mild dengue infections, but is also present in many OFIs. Simple point-of-care UACR tests are unlikely to be useful for early diagnosis or risk prediction in dengue endemic areas.</p> </div

The value of daily platelet counts for predicting dengue shock syndrome: Results from a prospective observational study of 2301 Vietnamese children with dengue

<div><p>Background</p><p>Dengue is the most important mosquito-borne viral infection to affect humans. Although it usually manifests as a self-limited febrile illness, complications may occur as the fever subsides. A systemic vascular leak syndrome that sometimes progresses to life-threatening hypovolaemic shock is the most serious complication seen in children, typically accompanied by haemoconcentration and thrombocytopenia. Robust evidence on risk factors, especially features present early in the illness course, for progression to dengue shock syndrome (DSS) is lacking. Moreover, the potential value of incorporating serial haematocrit and platelet measurements in prediction models has never been assessed.</p><p>Methodology/Principal findings</p><p>We analyzed data from a prospective observational study of Vietnamese children aged 5–15 years admitted with clinically suspected dengue to the Hospital for Tropical Diseases in Ho Chi Minh City between 2001 and 2009. The analysis population comprised all children with laboratory-confirmed dengue enrolled between days 1–4 of illness. Logistic regression was the main statistical model for all univariate and multivariable analyses. The prognostic value of daily haematocrit levels and platelet counts were assessed using graphs and separate regression models fitted on each day of illness. Among the 2301 children included in the analysis, 143 (6%) progressed to DSS. Significant baseline risk factors for DSS included a history of vomiting, higher temperature, a palpable liver, and a lower platelet count. Prediction models that included serial daily platelet counts demonstrated better ability to discriminate patients who developed DSS from others, than models based on enrolment information only. However inclusion of daily haematocrit values did not improve prediction of DSS.</p><p>Conclusions/Significance</p><p>Daily monitoring of platelet counts is important to help identify patients at high risk of DSS. Development of dynamic prediction models that incorporate signs, symptoms, and daily laboratory measurements, could improve DSS prediction and thereby reduce the burden on health services in endemic areas.</p></div

Longitudinal dynamics of UACRs in the confirmed dengue and OFI patient groups.

<p>All patients from Clinic A, and the confirmed dengue patients from Clinic B, are included. A significant time trend was observed in the dengue patients (p<0.0001), peaking on day 5 of illness, but no trend was apparent in the OFI patients (p = 0.22). The grey lines represent the evolution of the UACRs over time for each patient. The blue lines correspond to loess scatter plot smoothers.</p

Clinical and laboratory characteristics for the confirmed dengue and OFI patients groups.

<p>Continuous variables are summarized as median (interquartile range); categorical variables are summarized as frequency (%).</p><p>Missing values for:^(a) up to 3, ^(b) 5, ^(c) 9, ^(d) 12, ^(e) 20, ^(f) 48 cases.</p><p>OFI: other febrile illness.</p>*<p>If present, the severity of clinical symptoms was evaluated each day by study physicians using a pre-defined three point scale. For this analysis participants were considered to have persistent vomiting or severe abdominal pain if they scored two or more on the relevant scale, on any day during the acute illness.</p

Urine albumin creatinine ratio (UACR) values.

<p>Continuous variables are summarized as median (interquartile range); categorical variables are summarized as frequency (%).</p><p>For Clinic A, both dengue and OFI patients had urine albumin quantification performed on all urine samples, while for Clinic B urine albumin quantification was performed on the serial urine samples from confirmed dengue patients only, plus the enrolment and discharge day urine samples from the OFI patient group.</p>a<p>Missing values for 3 patients in each group.</p>b<p>The maximum UACR value observed during the acute illness.</p>c<p>Peak UACR ≥30 mg/g creatinine at any time during the acute illness.</p

Number of patients enrolled to the study at the two community clinics, according to final diagnosis.

<p>Number of patients enrolled to the study at the two community clinics, according to final diagnosis.</p

Univariate and multivariable linear regression analysis examining relationships between clinical and laboratory features present at enrolment and the platelet nadir in 465 dengue patients.

<p>The linear regression models were adjusted for age, sex, day of illness at enrolment and study site. There was no evidence for an interaction between UACR and study site (p = 0.91 for univariate analysis and 0.59 for multivariable analysis).</p><p>All factors from the univariate analysis were included in the multivariable model apart from microalbuminuria, since this was already represented by the UACR value.</p><p>There were ^(a) 3, ^(b) 11 and ^(c) 32 cases with missing values for these parameters.</p>(d)<p>A total of 423 patients were included in the multivariable model.</p

Reduced baseline logistic regression model for development of DSS and its performance (N = 2301).

<p>Reduced baseline logistic regression model for development of DSS and its performance (N = 2301).</p

Unadjusted and adjusted effects of candidate predictors at enrolment on clinical outcome (N = 2301).

<p>Unadjusted and adjusted effects of candidate predictors at enrolment on clinical outcome (N = 2301).</p

Trajectories of longitudinal haematocrit (Panel A) and platelet (Panel B) values for patients enrolled on day 3 who developed DSS between days 4 and 7 of illness (black lines and dots, with data censored from the day DSS occurred) and a control group of 20 randomly chosen patients enrolled on day 3 who did not develop DSS (grey lines and dots).

<p>For the haematocrit levels the black and grey symbols appear randomly superimposed, while for the platelet counts, the black dots tend to be generally lower than their grey counterparts, especially on the day before development of shock—i.e. patients with DSS tend to have lower platelet counts than patients without DSS on a specific day of illness, with the largest difference apparent on the day before shock occurs.</p