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

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

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

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

Characteristics of index cases.

<p>Characteristics of index cases.</p

Summary of study design and enrollment.

<p>Summary of study design and enrollment.</p

Cluster composition and characteristics of cluster participants.

<p>*Denominator for percentages is the number of participants with an enrollment sample collected at Visit 1.</p><p>Cluster composition and characteristics of cluster participants.</p

Spatial and temporal distribution of cluster investigations.

<p>A: Map of Ho Chi Minh City, with inset showing the spatial distribution of dengue positive clusters (filled circles) and negative clusters (open diamonds) within 7 central districts (district numbers are shown). B: Number of dengue positive and negative cluster investigations, by month of enrollment.</p