Low serum total nitrite and nitrate levels in severe leptospirosis

Abstract

BackgroundThe relationship between inducible nitric oxide synthatase activity and disease severity in leptospirosis is unclear. Nitric oxide is converted to nitrites and nitrates, thus nitrite and nitrate levels (NOx) in serum are considered surrogate markers for nitric oxide. NOx are excreted through the kidneys, and elimination is diminished in renal impairment. We assessed the correlation of NOx with disease severity in patients with leptospirosis, compared with healthy controls and non-leptospirosis fever patients.MethodsAll patients admitted over a two-month period to the National Hospital, Colombo, Sri Lanka with a clinical picture suggestive of leptospirosis were included. Leptospirosis was confirmed by the microscopic agglutination test (titre≥400). Severe leptospirosis was defined by the presence of two or more of the following criteria: jaundice (bilirubin> 51.3 μmol/l), oliguria (urine output < 400 ml/day), serum creatinine> 133 μmol/l or blood urea > 25.5 mmol/l, or the presence of organ dysfunction. Non-leptospirosis fever patients and healthy volunteers were used as control groups. NOx levels were measured using a modified Griess reaction.ResultsForty patients were confirmed as having leptospirosis and 26 of them had severe disease. NOx levels were significantly higher in confirmed leptospirosis patients compared to healthy controls, MAT equivocal patients and non-leptospirosis fever patients (p<0.001). NOx concentrations were also significantly higher in patients with severe compared to mild leptospirosis (p<0.001). Once NOx levels were corrected for renal function, by using the ratio NOx/creatinine, NOx levels were actually significantly lower in patients with severe disease compared to other patients, and values were similar to those of healthy controls.ConclusionsWe postulate that high NOx levels may be protective against severe leptospirosis, and that finding low NOx levels (when corrected for renal function) in patients with leptospirosis may predict the development of severe disease and organ dysfunction.

Leptospirosis: challenges in diagnosis, and predictors of severity

“…23 There has been much debate as to whether uncorrected levels of nitrate/nitrite (NOx) are a reliable index of NO activity. In malaria, high NOx levels have been shown to be associated with worse prognosis.…”

“…There has been much research into this subject over the past decade, and several potential biomarkers have already been earmarked for further investigation. 22 These include biochemical molecules such as nitric oxide and its metabolites, 23 cytokines such as IL-1, 6, TNF-, 24 polymorphisms of human leukocyte antigen (HLA) and cytokine genes, 25 human serum mannose binding lectin (which identifies pathogens activating the immune system), soluble ST2 receptors, long pentraxin PTX3 and copeptin. 26 …”

Current immunological and molecular tools for leptospirosis: diagnostics, vaccine design, and biomarkers for predicting severity

“…In severe leptospirosis, since there is renal impairment, it is possible that the raised NO level may not reflect increased synthetic activity but reduced clearance of NO via the kidneys. In fact a recently published paper by Kalugalage et al [ 40 ] demonstrated that, as in malaria, the corrected NO concentration (corrected for renal impairment) in patients with severe leptospirosis is actually lower than in non-leptospirosis fever patients and patients with mild leptospirosis. The pathophysiological basis for this phenomenon remains elusive.…”

Diagnosing and predicting outcome in leptospirosis: the need for clinically relevant basic sciences research

“…In severe leptospirosis, since there is often renal impairment, it is possible that the raised NO levels reflect reduced renal clearance of NO rather than increased synthesis. Kalugalage et al demonstrated that, similar to what was seen in malaria, the corrected total NOx (nitrite+nitrate) concentration (i.e., corrected for renal impairment) in patients with severe leptospirosis was actually lower than in patients with mild leptospirosis and non-leptospirosis fever [16]. The pathophysiological basis for this pheno-menon remains elusive.…”