Scrub Typhus Is an Under-recognized Cause of Acute Febrile Illness with Acute Kidney Injury in India

Citation: Kumar V, Kumar V, Yadav AK, Iyengar S, Bhalla A, et al. (2014) Scrub Typhus Is an Under-recognized Cause of Acute Febrile Illness with Acute Kidney Injury in India. PLoS Negl Trop Dis 8(1): e2605. doi:10.1371/journal.pntd.0002605
Published: January 30, 2014

Abstract
Background: Infection-related acute kidney injury (AKI) is an important preventable cause of morbidity and mortality in the tropical region. The prevalence and outcome of kidney involvement, especially AKI, in scrub typhus is not known. We investigated all patients with undiagnosed fever and multisystem involvement for scrub typhus and present the pattern of renal involvement seen.
Orientia tsutsugamushiMethods: From September 2011 to November 2012, blood samples of all the patients with unexplained acute febrile illness and/or varying organ involvement were evaluated for evidence of scrub typhus. A confirmed case of scrub typhus was defined as one with detectable Orientia tsutsugamushi deoxyribonucleic acid (DNA) in patient's blood sample by nested polymerase chain reaction (PCR) targeting the gene encoding 56-kDa antigen and without any alternative etiological diagnosis. Renal involvement was defined by demonstration of abnormal urinalysis and/or reduced glomerular filtration rate. AKI was defined as per Kidney Disease: Improving Global Outcomes (KDIGO) definition.
Results: Out of 201 patients tested during this period, 49 were positive by nested PCR for scrub typhus. Mean age of study population was 34.1±14.4 (range 11–65) years. Majority were males and a seasonal trend was evident with most cases following the rainy season. Overall, renal abnormalities were seen in 82% patients, 53% of patients had AKI (stage 1, 2 and 3 in 10%, 8% and 35%, respectively). The urinalysis was abnormal in 61%, with dipstick positive albuminuria (55%) and microscopic hematuria (16%) being most common. Acute respiratory distress syndrome (ARDS) and shock were seen in 57% and 16% of patients, respectively. Hyperbilirubinemia was associated with AKI (p = 0.013). A total of 8 patients (including three with dialysis dependent AKI) expired whereas rest all made uneventful recovery. Jaundice, oliguria, ARDS and AKI were associated with mortality. However, after multivariate analysis, only oliguric AKI remained a significant predictor of mortality (p = 0.002).
Conclusions: Scrub typhus was diagnosed in 24% of patients presenting with unexplained febrile illness according to a strict case definition not previously used in this region. Renal abnormalities were seen in almost 82% of all patients with evidence of AKI in 53%. Our finding is contrary to current perception that scrub typhus rarely causes renal dysfunction. We suggest that all patients with unexplained febrile illness be investigated for scrub typhus and AKI looked for in scrub typhus patients.

Author Summary
A large number of patients present to Indian hospitals with acute febrile illness and multisystem involvement. Acute kidney injury is an important component. Clinical manifestations do not allow distinction between infectious etiologies with overlapping presentations. Many of the cases remain undiagnosed and therefore are not treated, resulting in high mortality. Despite having all the elements of endemicity, scrub tuphus, caused by the rickettsia and transmitted to humans by the bites of trombiculid mite, is not regognized in Indian hospitals due to non-availability of locally validated diagnostic tests. Previous reports have been limited to serologyic testing, with high false positives due to past exposure rather than acute infection. Moreover, kidney involvement in this condition is not well known. We looked for scrub typhus DNA in 201 patients with an acute febrile illness. About 25% tested positive; kidney involvement was seen in over 80%, and acute kidney injury in 53%. Acute kidney injury was a predictor of mortality. All these are new findings of public health importance and suggest the need to include testing for this condition in the diagnostic armanetarium and development of local serological cutoffs.
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