| Abstract|| |
Infections including scrub typhus contribute to a significant proportion of community-acquired acute kidney injury (AKI) in the tropics. Scrub typhus infection now requires global attention since disease outbreaks are being reported across continents. We intended to study the clinical profile, renal involvement, and parameters predicting renal involvement in scrub typhus infection. This is a retrospective study. The medical records of all patients who were admitted and treated for scrub typhus infection for a study period of two years (from September 2015 to August 2017) were analyzed, and salient clinical features and laboratory results were collected from the hospital data. Statistical analysis was done from the collected data. Our study had 272 patients including 81 children. Adults constituted 70.96% (n = 193) and the remaining 29.04% (n = 81) were pediatric population. Among adults, females constituted 62.7% (n = 121) and males 37.3% (n = 72). The mean age of the adult population was 45.7 ± 15 years and that of pediatric patients was 8.56 ±5.1 years. 18.7% of adult cases and 3.70% of pediatric cases had AKI. Renal replacement therapy was required in 3.67% of adult cases. Mortality was 4.14% in adults and 1.23% in children. Hypotension, pulmonary involvement, central nervous system involvement, multiorgan dysfunction syndrome, increased total counts, elevated aspartate transaminase levels, and hypoalbuminemia predicted AKI in our adult population. Scrub typhus should be considered as a differential in cases presenting with fever and AKI. Outcomes of scrub typhus infection in terms of mortality seem to be improving in this region.
|How to cite this article:|
Jayaprakash V, Vamsikrishna M, Indhumathi E, Jayakumar M. Scrub typhus-associated acute kidney injury: A study from a South Indian Tertiary Care Hospital. Saudi J Kidney Dis Transpl 2019;30:883-90
|How to cite this URL:|
Jayaprakash V, Vamsikrishna M, Indhumathi E, Jayakumar M. Scrub typhus-associated acute kidney injury: A study from a South Indian Tertiary Care Hospital. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2020 Feb 17];30:883-90. Available from: http://www.sjkdt.org/text.asp?2019/30/4/883/265464
| Introduction|| |
The etiology of acute kidney injury (AKI) in developing countries and developed countries are different. Infections such as malaria, leptospirosis, acute gastroenteritis, typhoid, and dengue are predominant causes of community-acquired AKI in the tropics., Recent reports suggest that scrub typhus is one of the important differentials to be considered in patients presenting with fever and AKI.,,,
Scrub typhus is a challenging public health problem in the “tsutsugamushi triangle” region, which includes the Asia-Pacific countries and the Indian subcontinent. A neglected tropical disease now requires global attention, as cases and disease outbreaks are also reported in several other regions such as the middle-east, Africa, and South America, and also in travelers to the endemic region for this infec-tion.,,, In the past two decades, outbreaks of scrub typhus have been reported from south, north, north-east, and western regions of the Indian subcontinent.,,,,,,,,,,,
Patients usually present with fever, myalgia, headache, gastrointestinal symptoms, breath-lessness, jaundice, and eschar. Acute lung injury (ALI), meningitis, myocarditis, and multiorgan dysfunction syndrome (MODS) occur in severe cases. Scrub typhus infection can cause varying degrees of renal involvement ranging from asymptomatic urinary abnormalities to dialysis-dependent renal failure. The clinical profile, renal involvement, incidence of multiorgan dysfunction, and mortality had been highly variable across several centers in this region over the past two decades.,,,,,, We intended to study the clinical profile, renal involvement, parameters predicting renal involvement’ and outcomes of scrub typhus infection in our study population.
| Materials and Methods|| |
This is a retrospective study. The medical records of all patients who were admitted and treated for scrub typhus infection for a study period of two years (from September 2015 to August 2017) were analyzed. The study group included both adult and pediatric population.
The pediatric age group was defined as ≤18 years of age. Significant clinical findings such as fever, jaundice, gastrointestinal symptoms, and eschar were recorded. Laboratory results of hemoglobin, total counts, platelet count, blood urea, serum creatinine, serum electrolytes, serum bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), and serum albumin levels were obtained. Complications such as hypotension, ALI, acute respiratory distress syndrome (ARDS), myocarditis, ence-phalopathy and meningoencephalitis, and disseminated intravascular coagulation (DIC) were recorded. Scrub typhus infection was diagnosed by enzyme-linked immunosorbent assay (ELISA) technique (InBios Scrub Typhus Detect IgM ELISA kit), and the test was performed according to the manufacturer’s instructions.
Hypotension was defined as arterial systolic blood pressure below 90 mm Hg and/or the requirement of inotropes. Pulmonary involvement was defined as the presence of infiltrates in chest radiograph or computed tomography imaging, presence of moderate to severe hypoxia (SaO2 <90%), presence of ALI, and/or the need for ventilator support during inpatient (IP) stay. Central nervous system (CNS) involvement was defined as the presence of Glasgow Coma Scale <8/15 or <5T/10 during IP stay. Kidney disease improving global outcomes (KDIGO) staging was used to define AKI.
The clinical profile, renal involvement, factors predicting renal involvement, and outcomes were analyzed for adults. The study population was divided into AKI and “no AKI” groups, and parameters including serum creatinine, hemoglobin, total counts, platelet counts, serum bilirubin, AST, ALT, serum albumin, and total days of hospitalization of each group were compared for statistical significance. Similarly, parameters such as hypotension, lung involvement, CNS involvement, MODS, and mortality were compared between AKI and “no AKI” groups for statistical significance. Descriptive statistical analysis was done for children.
Institutional ethics committee approval was obtained (IEC-NI/18/JAN/63/15). Results were analyzed using Statistical Package for the Social Sciences (SPSS) version 16.0 software (SPSS Inc., Chicago, IL, USA)
| Results|| |
Our study included 272 patients including children. Adults constituted 70.96% (n = 193) and the remaining 29.04% (n = 81) were pediatric patients.
Among adults, females constituted 62.7% (n = 121) and males 37.3% (n = 72). The mean age of the adult population was 45.7 ± 15 years [Table 1]. Fever was present in all the cases. Gastrointestinal symptoms such as anorexia, nausea, and vomiting were present in 21.24% (n = 41) of cases, jaundice in 6.22% (n = 12) of cases, and eschar was present in 28.49% (n = 55) of cases. The most common location of the eschar was thighs, followed by neck and chest, abdomen, perineum, axillae, and the back. Hypotension was present in 11.9% (n = 23) of cases, lung involvement in 11.9% (n = 23), and CNS involvement was present in 3.1% (n = 6) of cases.
|Table 1: Baseline clinical characteristics of adult study patients (n = 193).|
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The mean presenting and peak serum creatinine of the study population were 0.98 ± 0.87 mg/dL and 1.22 ± 1.28 mg/dL, respectively. The mean hemoglobin was 11.2 ± 1.79 g/dL, total count was 9969 ± 4963 cells/mm3, and platelet count was 1.63 ± 0.79 lakh/mm3. The mean AST and ALT levels were 142 ± 257 IU/L and 132 ± 330 IU/L, respectively. The mean serum albumin was 3.37 ± 0.56 g/dL. MODS was present in 9.8% (n = 19) of the cases. The mean duration of hospital stay (DOHS) was 6.96 ± 4.79 days. Renal replacement therapy (RRT) was required in 3.67% (n = 7) of cases. Mortality was 4.14% (n = 8).
Thirty-six adults (18.7%) had AKI in our study population. Among them, 21 (10.88%) were in Stage I, 7 (3.67%) in Stage II, and 8 (4.14%) were in Stage III AKI. The remaining 81.3% (n = 157) constituted the “no AKI” group. We compared hemoglobin, total count, platelet count, serum creatinine, AST, ALT, serum albumin, and mean DOHS between AKI and “no AKI” groups and found a significant statistical difference for total counts, AST, serum albumin, and mean DOHS [Table 2]. To evaluate the predictors of AKI, we also compared the presence of hypotension, lung involvement, CNS involvement, and MODS between AKI and “no AKI” groups, and it was found that all these parameters were significantly present in the AKI group (Pearson Chi-square test) and were predictors of AKI in scrub typhus infection in our population. Mortality was significantly higher in the AKI group when compared to the “no AKI” group (P <0.001; Fisher’s exact test) [Table 3].
|Table 2: Comparison of laboratory parameters between AKI and “no AKI” group in adults.|
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|Table 3: Comparison of clinical findings between AKI and “no AKI” group in adults.|
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Our study included 81 children [Table 4]. The mean age of pediatric patients was 8.56 ± 5.1 years. The mean presenting and peak serum creatinine in this group were 0.45 ± 0.18 mg/dL and 0.48 ± 0.22 mg/dL, respectively. The mean hemoglobin was 10.73 ± 1.64 g/dL, total counts were 8667 ± 3712 cells/ mm3, and platelet counts were 1.69 ± 0.59 lakhs/mm3. The mean AST and ALT levels were 70 ± 39 IU/L and 64 ± 43 IU/L, respectively. The mean serum albumin was 3.54 ± 0.44 g/dL. The mean DOHS was 5.3 ± 2.6 days. AKI was present in three patients (3.70%). Eschar was seen in 16 (19.7%), hypotension in 14 (17.28%), lung involvement in four (4.93%), CNS involvement in one (1.23%), and MODS in two cases (2.46%). Mortality was 1.23% (n = 1). None of the pediatric AKI cases required RRT. The child who died had nondialysis requiring AKI and MODS. The other two children recovered.
|Table 4: Baseline clinical characteristics of the study children (n = 81).|
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The peak incidence of scrub typhus in our study population was in the months of December, January, and February, and 46.32% (n = 126) of cases got admitted in this period (winter in our region). The incidence was lowest in months of April, May, and June (summer), when only 0.03% (n = 9) of cases got admitted [Figure 1].
| Discussion|| |
Scrub typhus is a vector-borne disease caused by the Gram-negative intracellular bacillus Orientia tsutsugamushi. It is transmitted through the bite of the larval forms of trombiculid mites, which inhabit the semi-arid tropical regions with high temperature and high humidity. An eschar, which is a classical feature of scrub typhus infection, occurs at the site of infected vector bite. It presents as a papule, later ulcerates and ultimately forms a black crust. Other clinical features such as fever, myalgia, and gastrointestinal symptoms usually occur in the 2nd week after the vector bite. Severe complications including multi-organ failure occur in some cases., The severe multiorgan manifestations include jaundice, AKI, pulmonary complications including ARDS, myocarditis, pericarditis, CNS complications including meningitis and/or encephalitis, septic shock, and DIC.,,
AKI and renal involvement in scrub typhus are believed to be multifactorial in origin. The possible mechanisms of renal failure include prerenal failure, septic shock, rhabdomyolysis, vasculitis, acute interstitial nephritis, and direct renal invasion of O. tsutsugamushi.,, Weil Felix test, which was previously used to diagnose scrub typhus infection, is outdated because of low sensitivity and the availability of better diagnostic tests today. Immunofluo-rescence antibody assay (IFA), and similar tests such as indirect immunoperoxidase and immunochromatographic tests, and molecular methods like polymerase chain reaction (PCR), which usually target genes of the outer membrane proteins like 56 kDa, have high sensitivity but are seldom used in endemic regions because they are complicated, expensive, and not readily available., The commonly used test for diagnosis is ELISA. IgM ELISA using the 56 kDa antigen is easy to perform and has good sensitivity and specificity. Antibiotics used for treatment of scrub typhus infection include doxycycline, chlo-ramphenicol, and azithromycin.
Scrub typhus outbreak and the associated renal involvement have been previously reported from South India.,,,,, However, no recent data on renal involvement and outcomes are available.
Our study included both adult and pediatric population. Females constituted 62.7% (n = 121) of adults in our study. In similar studies, females constituted 41% to 75.9% of study population.,,,, The mean age of our adult population is 45.7 ± 15 years. In similar studies, the mean age varied from 30.37 ± 18.81 years to 57.94 ± 18.85 years.,,,,,
Fever was present in all the cases, gastrointestinal symptoms in 41 (21.24%), and jaundice in 12 cases (6.22%) in our adult population. In published studies from the Indian subcontinent, fever was present in 98%—100% of cases, gastrointestinal symptoms in 19.5%—55.18% of cases, and jaundice in 5.2%—42.9% of cases.,,,, Eschar was present in 55 adults (28.49%). The incidence varied from 6.57% to 43.5% in other similar studies.,,,,,
Hypotension was reported in 1.8%—16.3% of cases in the literature.,, In our adult population, it was present in 23 cases (11.9%). Lung involvement was seen in 23 adults (11.9%). In published studies, the incidence of ARDS was 11.5%–57.14%.,, CNS involvement was present in six adult patients (3.1%). In similar studies, the incidence varied from 6.37% to 28.57%.,,,, MODS was present in 9.8% (n = 19) of adult cases. Vikrant et al reported MODS in 10.3% of cases and Varghese et al in 34% of cases.
The KDIGO classification was used to define AKI in our adult population. AKI was present in 36 adults (18.7%) in our study. Kumar et al and Sedhain et al also used KDIGO classification for AKI and reported incidence at 53.06% and 40.4%, respectively. Hwang et al used RIFLE classification to define AKI and reported incidence of 35.88%. Vikrant et al included patients with serum creatinine >1.5% as AKI and reported an incidence of 35%. Similarly, Varghese et al reported AKI in 18% of cases by including patients with serum creatinine >2.5 mg/dL. RRT was required in 3.67% (n = 7) of adult cases, and hemodialysis was offered as RRT in all of them. In other studies from the Indian subcontinent, RRT requirement in the study population was reported as 2.8%–6.12%.,,, Hwang et al reported CRRT requirement in 0.6% of cases in their study population from South Korea.
There was statistically significant difference in total counts, AST levels, serum albumin, and mean DOHS in AKI patients, when compared to the “no AKI” group. It can be inferred that leukocytosis, transaminitis, and hypoalbu-minemia could be predictors of renal involvement in scrub typhus infection. Similarly, clinical findings such as hypotension, pulmonary involvement, CNS involvement, and MODS predicted AKI in our adult population.
Sedhain et al reported that pneumonia, shock, and ARDS predicted AKI in their study population. Kumar et al reported oliguria and jaundice as risk factors for the development of AKI. In South Korean population, Hwang has found that increasing age, preexisting renal impairment, hypoalbuminemia, and delayed presentation to the hospital after symptom onset are significant risk factors for AKI.
Mortality was 4.14% (n = 8) in our adult cases. In patients who expired, ARDS was present in seven cases and RRT was required in two cases. Sedhain et al, who investigated scrub typhus outbreak in the Nepalese population, have reported mortality of 1.79%. Other studies from this region reported mortality in the range of 9%–16.3%.,[l5],,, Our study suggests that there is significant reduction in mortality in scrub typhus infection from our region. Vikrant et al have reported that age >46 years, leukocytosis, thrombocytopenia, hypoalbuminemia, and reduced DOHS predicted mortality. Varghese et al have found that the presence of CNS dysfunction, renal failure, shock, ventilator requirement and elevated bilirubin and alkaline phosphatase levels are factors predicting mortality.
In our pediatric population, AKI was present in three patients (3.70%), eschar in 16 (19.7%), hypotension in 14 (17.28%), lung involvement in four (4.93%), CNS involvement in one (1.23%), and MODS in two cases (2.46%). Mortality was 1.23% (n = 1). The incidence of AKI and other complications were less in our pediatric population when compared to the published pediatric studies from this region.,,
The seasonal trend in the incidence of scrub typhus has been previously reported in studies. Similar to our study findings, Mathai et al had reported scrub typhus cases in South India during the cooler months. In studies done by Vikrant et al and Subbalaxmi et al, majority of the cases were admitted in the months from August to October. Environmental factors such as rainfall and temperature, which vary from region to region, influence the growth of scrub vegetation, the habitat for trombiculid mites.,
Our study population is the largest when compared to the other recent studies from South India, and it includes both the adult and pediatric populations. Improving mortality trend was reported by Varghese et al from this region, but the study period was a decade earlier. Our study suggests even better outcomes in terms of renal involvement and mortality and includes a recent study cohort. Better physician awareness about this tropical infectious disease, empiric antibiotic usage including doxycycline and azithromycin at the primary health-care level, early referral of patients, and better intensive care could have contributed to the improved mortality trend.
The disadvantage of the study is the retrospective design from a single center, using only IgM ELISA for diagnosing scrub typhus infection, and not analyzing different strains of O. tsutsugamushi species in disease outcomes. However, none of the larger studies have used IFA or molecular diagnostic tools for the diagnosis of scrub typhus infection, and in endemic regions in developing countries with high disease burden and classical disease presentation, our personal opinion is that IgM ELISA test is sufficient for diagnosis and IFA and/or PCR tests are not mandatory. High index of clinical suspicion and early diagnosis and prompt management could yield better clinical outcomes.
| Conclusion|| |
Scrub typhus should be considered as a diffe rential in cases presenting with fever and AKI, in both adults and children, especially in endemic regions. Hypotension, pulmonary involvement, CNS involvement, and MODS predict renal involvement. Laboratory parameters including increased total counts, elevated AST levels, and hypoalbuminemia predict AKI in our population. Mortality is high when the cases developed AKI. Majority of the cases were reported in the winter season. Outcomes of scrub typhus infection in terms of mortality seem to be improving in this region.
| Acknowledgment|| |
We thank Ms. Gayathri Babu, Senior lecturer in statistics for the statistical analysis.
We, the authors submit that the manuscript represents honest work and has been read and approved by all of us; the requirements for authorship as stated in the journal have been met, and the manuscript has not been submitted elsewhere for publication.
| References|| |
Cerdá J, Bagga A, Kher V, Chakravarthi RM. The contrasting characteristics of acute kidney injury in developed and developing countries. Nat Clin Pract Nephrol 2008;4:138-53.
Jha V, Chugh KS. Community-acquired acute kidney injury in Asia. Semin Nephrol 2008; 28:330-47.
Naicker S, Aboud O, Gharbi MB. Epidemiology of acute kidney injury in Africa. Semin Nephrol 2008;28:348-53.
Kumar V, Kumar V, Yadav AK, et al. Scrub typhus is an under-recognized cause of acute febrile illness with acute kidney injury in India. PLoS Negl Trop Dis 2014;8:e2605.
Abhilash KP, Jeevan JA, Mitra S, et al. Acute undifferentiated febrile illness in patients presenting to a tertiary care hospital in South India: Clinical spectrum and outcome. J Glob Infect Dis 2016;8:147-54.
Singhi S, Rungta N, Nallasamy K, et al. Tropical fevers in Indian intensive care units: A prospective multicenter study. Indian J Crit Care Med 2017;21:811-8.
] [Full text]
Shelke YP, Deotale VS, Maraskolhe DL. Spectrum of infections in acute febrile illness in central India. Indian J Med Microbiol 2017; 35:480-4.
] [Full text]
Walker DH. Scrub typhus – Scientific neglect, ever-widening impact. N Engl J Med 2016;375:913-5.
Xu G, Walker DH, Jupiter D, Melby PC, Arcari CM. A review of the global epidemiology of scrub typhus. PLoS Negl Trop Dis 2017;11:e0006062.
Weitzel T, Dittrich S, López J, et al. Endemic scrub typhus in South America. N Engl J Med 2016;375:954-61.
Nachega JB, Bottieau E, Zech F, Van Gompel A. Travel-acquired scrub typhus: Emphasis on the differential diagnosis, treatment, and prevention strategies. J Travel Med 2007;14:352- 5.
Kumar M, Krishnamurthy S, Delhikumar CG, Narayanan P, Biswal N, Srinivasan S. Scrub typhus in children at a tertiary hospital in Southern India: Clinical profile and complications. J Infect Public Health 2012;5:82-8.
Basu G, Chrispal A, Boorugu H, et al. Acute kidney injury in tropical acute febrile illness in a tertiary care centre – RIFLE criteria validation. Nephrol Dial Transplant 2011;26:524- 31.
Mathai E, Rolain JM, Verghese GM, et al. Outbreak of scrub typhus in Southern India during the cooler months. Ann N Y Acad Sci 2003;990:359-64.
Vivekanandan M, Mani A, Priya YS, Singh AP, Jayakumar S, Purty S. Outbreak of scrub typhus in Pondicherry. J Assoc Physicians India 2010;58:24-8.
Varghese GM, Abraham OC, Mathai D, et al. Scrub typhus among hospitalised patients with febrile illness in South India: Magnitude and clinical predictors. J Infect 2006;52:56-60.
Varghese GM, Trowbridge P, Janardhanan J, et al. Clinical profile and improving mortality trend of scrub typhus in South India. Int J Infect Dis 2014;23:39-43.
Attur RP, Kuppasamy S, Bairy M, et al. Acute kidney injury in scrub typhus. Clin Exp Nephrol 2013;17:725-9.
Subbalaxmi MV, Chandra N, Teja VD, et al. Scrub typhus-experience from a South Indian tertiary care hospital. BMC Infect Dis 2012; 12:77.
Dhanapriya J, Dineshkumar T, Sakthirajan R, et al. Scrub typhus meningitis in a renal transplant recipient. Indian J Nephrol 2017;27:151- 3.
] [Full text]
Vikrant S, Dheer SK, Parashar A, et al. Scrub typhus associated acute kidney injury – A study from a tertiary care hospital from Western Himalayan state of India. Ren Fail 2013;35:1338-43.
Sedhain A, Bhattarai GR. Renal manifestation in scrub typhus during a major outbreak in central Nepal. Indian J Nephrol 2017;27:440-5.
] [Full text]
Narvencar KP, Rodrigues S, Nevrekar RP, et al. Scrub typhus in patients reporting with acute febrile illness at a tertiary health care institution in Goa. Indian J Med Res 2012; 136:1020-4.
] [Full text]
Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2012;2:1-138.
Raoult D. Scrub typhus. In: Mandell GL, Douglas RG, Bennett JE, Dolin R, editors. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 6th
ed. Philadelphia, PA: Elsevier/Churchill Livingstone; 2005. p. 2309-10.
Mahajan SK. Scrub typhus. J Assoc Physicians India 2005;53:954-8.
Gupta V, Gautam V. Scrub typhus – A short review. J Commun Dis 2004;36:284-9.
Tsay RW, Chang FY. Serious complications in scrub typhus. J Microbiol Immunol Infect 1998;31:240-4.
Jeong YJ, Kim S, Wook YD, Lee JW, Kim KI, Lee SH. Scrub typhus: Clinical, pathologic, and imaging findings. Radiographics 2007;27: 161-72.
Lee S, Kang KP, Kim W, Kang SK, Lee HB, Park SK. A case of acute renal failure, rhabdo-myolysis and disseminated intravascular coagulation associated with scrub typhus. Clin Nephrol 2003;60:59-61.
Kim DM, Kang DW, Kim JO, et al. Acute renal failure due to acute tubular necrosis caused by direct invasion of Orientia tsutsugamushi
. J Clin Microbiol 2008;46: 1548-50.
Prakash JA, Abraham OC, Mathai E. Evaluation of tests for serological diagnosis of scrub typhus. Trop Doct 2006;36:212-3.
Blacksell SD, Tanganuchitcharnchai A, Nawtaisong P, et al. Diagnostic accuracy of the inBios scrub typhus detect enzyme-linked immunoassay for the detection of IgM antibodies in Northern Thailand. Clin Vaccine Immunol 2016;23:148-54.
Hwang K, Jang HN, Lee TW, et al. Incidence, risk factors and clinical outcomes of acute kidney injury associated with scrub typhus: A retrospective study of 510 consecutive patients in South Korea (2001-2013). BMJ Open 2017; 7:e013882.
Somashekar HR, Moses PD, Pavithran S, et al. Magnitude and features of scrub typhus and spotted fever in children in India. J Trop Pediatr 2006;52:228-9.
Digra SK, Saini GS, Singh V, Sharma SD, Kaul R. Scrub typhus in children: Jammu experience. JK Sci 2010;12:95-7.
Department of Nephrology, Sri Ramachandra Medical College, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai - 600 116, Tamil Nadu
[Table 1], [Table 2], [Table 3], [Table 4]