Abstract
Acute Kidney Injury (AKI) associated with Scrub typhus is an emerging health problem which is more common in the tropics including India. This study intended to find out the occurrence of Scrub typhus among the Community Acquired Acute Kidney Injury patients in a tertiary care hospital in Assam, North East India. AKI patients with acute febrile illness admitted to Gauhati Medical College and Hospital, Guwahati, Assam were included in the study and demographic characteristics along with clinical features were recorded. The detection of Scrub typhus was done by IgM Enzyme Linked Immunosorbent Assay (ELISA) test (Optical Density > 0.5) and polymerase chain reaction (PCR) analysis. Routine haematological and biochemical tests were performed. Molecular characterization of Orientia tsutsugamushi was done followed by phylogenetic analysis. The Graph Pad Prism software 9 was used for statistical analysis. Out of 221 AKI patients admitted to hospital, 45 patients (20.4%) were confirmed to be Scrub typhus positive and among them, 4 cases were co-infected with leptospirosis. Majority of Scrub typhus positive AKI patients were in Stage I (82.2%) under KDIGO guideline. “Karp” was the predominant circulating serotype. The study showed cases of Scrub typhus associated Acute Kidney Injury was high and mortality was 11.1%. Hence, in this region, further studies need to be done with large number of population and more emphasis need to be given on differential diagnosis.
Supplementary Information
The online version contains supplementary material available at 10.1007/s12088-023-01137-x.
Keywords: Acute Kidney Injury, IgM ELISA, Orientia tsutsugamushi, Scrub typhus
Introduction
Acute Kidney Injury (AKI) is a major health problem and is associated with long term risk of chronic kidney injury and subsequent progression to end-stage kidney disease. AKI has been estimated to affect over 13 billion people worldwide every year; 85% of whom living in developing tropical countries [1]. It can occur both in hospital and community settings. In hospital settings it occurs as part of multi-organ involvement primarily in Intensive Care Unit (ICU) set up [2]. The aetiology of community acquired acute kidney injury (CA-AKI) in tropical countries can usually be attributed to a single cause, mostly infective and AKI related toxins and is markedly determined by epidemiology of disease spectrum encountered in their environment [3].
Scrub typhus (ST) is an important cause of tropical acute febrile illness prevalent in Northeast India as well as in rest of the country. The disease is caused by the Gram-negative bacterium Orientia tsutsugamushi (formerly Rickettsia tsutsugamushi) and is transmitted to humans by infected Leptotrombidium mite larva (chiggers) [4]. ST infection is known to be prevalent in a high number of Indian populations. Due to the potential overlapping of the common signs and symptoms of ST disease with other acute febrile infections, the clinical manifestations of ST infections are often confused and difficult to identify. Both molecular and serological tests can be used to diagnose ST infection [5].
Incidence of CA-AKI associated with tropical infectious pathogens is always underestimated due to lack of practical implications of the existing AKI definition (KDIGO) [6] as most of the patients usually present to hospital with already reduced urinary output and/or glomerular filtration rate (GFR), thus lacking information on baseline data of kidney functions.
Several published studies describing association of Scrub typhus with AKI predicted kidney to be the most common organ affected by Scrub typhus [7–9]. A prospective case record-based study of Scrub typhus done in southern India showed that out of 259 Scrub typhus patients, 23.2% had AKI [10]. A retrospective cross-sectional north Indian study showed an AKI incidence rate of 35.3% in Scrub typhus patients [11]. A western Himalayan study showed that 35% patients had AKI associated with Scrub typhus [12].
Although there are very few reports of acute febrile illness with or without acute encephalitis syndrome (AES) [13, 14], there are no published data of CA-AKI associated with this pathogen from North-east India. However, a number of reports on high prevalence rate of Scrub typhus in North east India and Assam has been documented in various studies [13, 15] Therefore, considering the wide prevalence of Scrub typhus cases in Assam as well as other North eastern states of India, the aim of the present study was to assess the occurrence of Scrub typhus among the CA-AKI patients from a tertiary care hospital of Assam, North-east India.
Material and Methods
A hospital based cross-sectional study was conducted for a period of one year from April 2021 to March 2022. A total of 221 consecutive samples of adult AKI Patients who presented with fever (temperature ≥ 38.3 °C), admitted at Gauhati Medical College and Hospital (GMCH), Guwahati, during the study period were included in the study after taking informed consent. On the basis of age, patients were grouped into four age groups: 18–20 years, 21–40 years, 41–60 years and > 60 years. The socio-demographic, clinical and laboratory data of the patients were collected in a pre-designed proforma. The present work was carried out at Department of Microbiology, Gauhati Medical College and Hospital, Assam, India and was approved by our Institute Ethics Committee (IEC), vide letter no. MC/190/2007/Pt-II/April 2021/TH-23.
Case Definition
As per Kidney Disease Improving Global Outcome (KDIGO) guidelines, AKI was defined as: Increase in serum creatinine by ≥ 0.3 mg/dl (≥ 26.5 µmol/l) within 48 h [6].
Sample Collection and Processing
Under aseptic conditions, 5 ml venous blood samples were collected: 2 ml in clot activated vials & 3 ml in Ethylenediamine tetra acetic acid (EDTA) vials. The separated serum from clot activated vials was stored at − 20 °C until further tested for IgM Enzyme Linked Immunosorbent Assay (ELISA).
IgM ELISA Scrub Typhus
Scrub Typhus Detect™ IgM ELISA System (InBios International Inc. Seattle, USA) was used for detection of single point IgM antibody. Test were considered positive when optical density (OD) found to be > 0.5. All patients were also tested for Malaria by Peripheral Blood Smear test, Dengue by IgM ELISA or IgG ELISA depending on the duration of fever, Typhoid by Typhidot test and Leptospira by IgM ELISA. All kit tests were done as per manufacturer’s instructions.
DNA Extraction and Polymerase Chain Reaction (PCR)
DNA was extracted from buffy coat of 5 ml blood collected in EDTA vials using a QIA amp DNA Blood mini kit (Qiagen, Hilden, Germany) and final eluted volume was stored at − 80 °C until PCR. Molecular diagnosis was made by performing Semi Nested PCR targeting 56-KDa type specific antigen (tsa56) gene using an in-house primer. Primers used for PCR were designed using online Primer3Web version 4.1.0. Outer set of primers, Outer forward (5′-AAACCTAGCGCTTCTCCTGT-3′) and outer reverse (5′-GATGCTCCTTGTTGCTGCTT-3′) and an inner reverse primer (5′-GCGGCATGACAAAATTCAACT-3′) was used to amplify 250 bp region of tsa56 gene.
PCR Amplification
PCR amplification was carried out in a 25 µl of final reaction volume containing 12.5 µl Go Taq® Green Mastermix, 0.8 µl each of Outer Forward Primer and Outer Reverse Primer, 2 µl template and 8.9 µl Nuclease free Water. The PCR conditions consisted of denaturation at 95 °C for 3 min followed by 35 cycles of denaturation at 95 °C for 30 s, annealing at 51.5 °C for 32 s, extension at 72 °C for 34 s and a final extension 72 °C for 5 min for first round of PCR.
Second round PCR was performed with the same components as in first round PCR except outer reverse primer was substituted by an inner reverse primer. A 1:25 dilution was made from the first amplified PCR product and 2 µl of this dilution was added to the second round of PCR mixture making the final volume of 25 µl. PCR cycling conditions of 2nd round PCR was same as in 1st round PCR. The result was interpreted by running PCR products in 1.2% agarose gel along with 100 bp ladder (Fig. 1).
Fig. 1.
PCR amplification of 250 bp region of tsa56 gene of Orientia tsutsugamushi. Lane 1—100 bp DNA Ladder, Lane 2–7—Clinical isolates
Sequencing Analysis
The amplified tsa56 gene amplicons were purified and sent for sequencing. Raw sequence data were edited using Bioedit version 7.0 (Hall 1999). Further, Basic Local Alignment Search Tool (BLAST) analysis was done to find the best possible homology of our samples.
GenBank Sequence Accession Numbers
The sequencing data of 14 sequence isolates obtained from our study were submitted to NCBI GenBank with the following accession numbers in consecutive order: OQ784602 to OQ784615.
Phylogenetic Analysis
Raw sequence data were manually edited and consensus sequences were constructed using Bioedit version 7.0. A total of 22 reference sequences belonging to most widely distributed serotypes of O. tsutsugamushi were retrieved from GenBank. To elucidate the serotypes of the sequenced isolates, molecular phylogenetic tree was generated using molecular evolutionary genetic analysis software (MEGA-X). Multiple sequence alignment of all the studied samples along with the reference sequences was performed using the built-in ClustalW integrated in MEGA-X software. The tree was generated using Neighbour joining method based on the T92 + G model. Reliability of the phylogenetic tree was tested using 1000 bootstrap value.
Statistical Analysis
The data was summarized and analysed using GraphPad Prism 9 Software. The data was denoted as number and percentage as appropriate. For categorical data, comparison was done using Chi Square test and continuous data are expressed as mean ± SD and means of two study groups were compared using an unpaired t test. The difference between two groups of unpaired data was analysed by Mann Whitney U test. A p value < 0.05 implies statistical significance in this study.
Results
In the study period, out of 221 AKI Patients with acute febrile illness, 45 (20.4%) cases were found to be Scrub typhus positive and among them 4 cases were co-infected with leptospirosis. Other infections present in non-scrub group of AKI were Leptospirosis in 35 (15.8%), lower respiratory tract infection (LRTI) in 18 (8.1%), urinary tract infection in 20 (9.04%), Typhoid in 1 (0.5%) and unknown infections in 106 (47.9%) cases.
The mean age of Scrub typhus AKI (SAKI) patients was 44.58 ± 15.66 whereas Other AKI (OAKI) was 46.20 ± 12.93. Maximum number of cases (118/221; 53.4%) was found in the age group of 41–60 years, out of which 20 (44.4%) were SAKI. Male preponderance was seen in both groups, SAKI (71.1%) and OAKI (67.0%).
Sociodemographic profile shows most of the SAKI group to be farmers and labourers (46.7%) followed by shopkeepers (35.5%) and others (Teacher-8.9%, Homemaker-6.7% and Student-2.2%) and highest number was found among people living in rural areas (86.4%, p < 0.05).
Clinical Features and Co-morbidities of SAKI and OAKI Group
The predominant clinical symptoms among SAKI were headache (33.3%), gastrointestinal symptoms like vomiting, diarrhea and jaundice (26.6%), swelling of face, legs, abdomen (17.8%), cough and altered sensorium (11.1%), rash (8.9%) and lymphadenopathy (4.4%). Mean duration of fever was 7.15 ± 1.10 (p < 0.05) as compared to OAKI (8.03 ± 1.88). Eschar was not detected in any case of SAKI. Oliguria (urine volume < 400 ml/day) was observed in 13.33% in Scrub typhus. Most of the clinical signs and symptoms were similar in both group of patients, but headache (33.3% vs 33.0%, p = 0.02) was statistically more prevalent among SAKI group than OAKI group of patients while jaundice (14.8% vs 4.4%, p = 0.003) was more prevalent among OAKI than SAKI group of patients. This may be due to inclusion of Leptospira patients in OAKI (Table 1—Supporting File).
According to KDIGO criteria, majority of Scrub typhus group were found in Stage 1 (82.2%) followed by Stage 2 (11.1%) and Stage 3 (6.7%).
Laboratory Parameters of SAKI, LAKI and OAKI Group
The mean blood leucocytes count was slightly higher in SAKI than OAKI group (9841.29 ± 5541.38 vs 7390 ± 3187). C-reactive protein was comparatively higher in SAKI than OAKI group (54 mg/dl vs 43 mg/dl). Significantly lower platelet count was observed in SAKI than OAKI group (137 ± 25.12 vs 154.05 ± 56.22, p = 0.04). The mean level of urea and creatinine among SAKI group were 82.57 ± 53.24 and 3.02 ± 1.33 respectively. Liver enzymes were almost in normal limits (AST 54 U/L and ALT 54 U/L) in SAKI group. Serum bilirubin was higher in SAKI than OAKI group (1.5 mg/dl vs 1.1 mg/dl). While no statistical significance observed in total leucocyte count, urea, AST, ALT between SAKI and OAKI group, a significantly increased level of urea (106.04 ± 69.55 vs 82.57 ± 53.24, p = 0.04), creatinine (4.45 ± 2.96 vs 3.02 ± 1.33; p = 0.003), AST (96 vs 54 U/L, p = 0.004) and ALT (86 vs 54 U/L, p = 0.0013) were observed in LAKI (Leptospira associated AKI) group than the SAKI group (Table 1).
Table 1.
Laboratory parameters of SAKI, LAKI and OAKI GROUP
| Laboratory Parameters | SAKI | OAKI | SAKI vs OAKI p value |
SAKI | LAKI (Leptospira associated AKI) | SAKI vs LAKI p value |
SAKI with CKD |
|---|---|---|---|---|---|---|---|
|
S. urea (19.5–42.8 mg/dl) |
82.57 ± 53.24 (95.5%) |
94.58 ± 60.10 (81.9%) |
0.13 |
82.57 ± 53.24 (95.5%) |
106.04 ± 69.55 (94.3%) |
0.04* |
199.3 ± 62.3 (100%) |
| S. creatinine (0.66–1.25 mg/dl) |
3.02 ± 1.33 (100%) |
3.82 ± 3.09 (100%) |
0.002* |
3.02 ± 1.33 (100%) |
4.45 ± 2.96 (100%) |
0.003* |
4.74 ± 1.94 (100%) |
| Total leucocyte count (4 to 11) × 106/L | 9841.29 ± 5541.38 | 7390 ± 3187 | 0.15 | 9841.29 ± 5541.38 | 10,064.87 ± 5224.63 | 0.38 | 6666.66 ± 5484.82 |
| AST# (17–59 U/L) |
54 (46.7%) |
55 (46.3%) |
0.44 |
54 (46.7%) |
96 (48.6%) | 0.004* | 45 |
| ALT# (4–50 U/L) |
54 (26.7%) |
58 (72.9%) |
0.11 |
54 (26.7%) |
86 (85.7%) | 0.0013* |
54 (66.7%) |
| Total bilirubin# (0.20–1.30 mg/dl) |
1.5 (26.7%) |
1.1 (27.7%) |
0.3 |
1.5 (26.7%) |
1.1 (82.8%) | 0.07 |
1.8 (66.7%) |
| CRP# (> 10 mg/dl) |
54 (35.5%) |
43 (32.2%) |
0.47 | 54 (35.5%) |
51.14 (60.0%) |
0.37 |
12 (66.7%) |
| Platelet count (150–400/uL) | 137 ± 25.12 | 154.05 ± 56.22 | 0.04* | 137 ± 25.12 | 164.05 ± 75.50 | 0.02* | 111 ± 42.50 |
*p value < 0.05 is considered statistically significant
#Median formula was used for AST, ALT, Total bilirubin, CRP and Mann Whitney U test was used to compare AST, ALT, Total bilirubin, CRP among SAKI and OAKI, and SAKI and LAKI group
Outcome of AKI Cases
All cases of SAKI were treated with doxycycline (intravenous or orally 200 mg/day for 7–10 days). Among the 80% recovered cases in SAKI, Stage I was 71.11%, Stage II was 6.6%, Stage III was 2.2% and among the 11.1% expired cases, Stage I was 40%, Stage II was 20% and Stage III was 40%. The average no. of dialysis sessions attended by the SAKI group was 1.67 ± 1.15 (Table 2).
Table 2.
Outcome of AKI cases
| Outcome | SAKI | OAKI | SAKI vs OAKI p value |
SAKI | LAKI | SAKI vs LAKI p value |
|---|---|---|---|---|---|---|
| Recovered | 36 (80.0%) | 152 (86.3%) | 0.28 | 36 (80%) | 25 (71.4%) | 0.37 |
| Discharged against medical advice | 4 (8.8%) | 15 (8.6%) | 0.93 | 4 (8.8%) | 12 (8.5%) | 0.63 |
| Expired | 5 (11.1%) | 9 (5.2%) | 0.14 | 5 (11.1%) | 7 (20.0%) | 0.06 |
| Dialysis | ||||||
| Total number of dialysis | 1.67 ± 1.15 | 2.26 ± 1.33 | 0.5 | 1.67 ± 1.15 | 2 ± 1.22 | 0.28 |
Molecular Typing of O. tsutsugamushi
Results from the phylogenetic analysis suggested that all the studied samples belong to the serotype KARP-strains and majority of the samples (43/45; 95.5%) form a monophyletic clad within the serotype (Fig. 2).
Fig. 2.
Molecular Phylogenetic tree depicting the serotypes of sequence isolates
Discussion
Scrub typhus is a re-emerging zoonotic disease endemic in Asia–Pacific region including India known as ‘tsutsugamushi triangle” and one of the important causes of acute febrile illness with or without acute kidney injury [16, 17]. In the present study, we observed that 20.4% of AKI associated with acute febrile illness were infected with ST and all are Karp–like strains.
Sequencing of immune-dominant 56 kDa gene revealed more than 20 strains of ST circulating in “tsutsugamushi triangle”. However various studies indicated Karp and Gilliam as the predominant strains circulating in India and in Northeast India, Karp–like strains were found to be the predominant strain [18]. In our study, we did not find any other strain other than Karp-like strains which may be due to the limited number of cases. Also, all cases were of referral patients which were not representatives of whole population.
The incidence of AKI associated with ST reported to be 19–35.9% from various parts of India [16, 17, 19–24], which were found to be similar to our study. The high percentage of ST among AKI patients with acute febrile illness indicates that ST is still an under-recognized and under-reported cause of AKI with acute febrile illness. This may be due to the overlapping of symptoms with many other common infections along with lack of diagnostic facilities at all levels of healthcare facilities in India. Moreover, traditional diagnosis of ST is based on the presence of Eschar which differs among geographical locations and also depends on the type of serotypes. Our cohort study reported absence of eschar in the ST positive cases. An animal study done in mice showed that Karp-like strains were the most virulent serotype commonly associated with an absence of Eschar [25]. Previous studies done from the Himalayan region have also reported the absence of Eschar in adults predominantly in Karp-like strains [26]. In absence of eschar, diagnosis of ST is mostly done by serological tests based on Immunofluroescence technique and ELISA and by PCR targeting different genes [27]. Out of these, single-point IgM ELISA is the most commonly used diagnostic method for the detection of recent infections. The major limiting factor of ELISA is determining cut-off limit of OD in endemic areas including India. In the present study, we have considered OD > 0.5 as indicated in the ELISA kit (Inbios). The sensitivity and specificity of the kit were found to be 93.3% and 98.9% respectively when compared to PCR targeting the 56 kDa protein gene.
In present study, 3 patients out of 45 (6.7%) underwent dialysis, 2 patients with 1 and one patient with 3 numbers of dialysis. The mortality rate was 11.1% (5/45) which was comparatively lower than studies done in South India (13.3%), Cuttack (20%) and South Korea (14.8%).
Seasonal variation of Scrub typhus changes with climate. Most of the cases occur in post-monsoon season during cooler months of the year. Most of the cases in the present study were presented between September to March. During this period, people are usually involved in outdoor works in rice paddy fields, woody vegetation and jungles which is a common place for a large number of mites population. In concordance to our study, most of the studies, showed a preponderance of scrub typhus in rural adult males which may be due to the existence of a conductive environment for mites in rural areas and adult males are mostly involved in outdoor activities and exposure to infection for a longer time.
In the present study, a significant portion of patients (35/221, 15.8%) were positive for Leptospira IgM ELISA and among them, 4 (4/35, 11.4%) were co-infected with ST. A significantly high level of liver enzymes (p < 0.05) and high levels of creatinine and urea were associated with cases of leptospirosis than ST cases which indicated that hepato-renal involvement is more common and severe in leptospirosis than in ST. As both the tropical diseases are endemic in India, community-acquired AKI with acute febrile illness needs evaluation for both leptospirosis and ST in future. Both diseases are treatable; therefore early diagnosis and treatment will prevent the development of AKI and thereby reducing its burden.
Renal involvement in ST is considered to be multifactorial in origin and possible mechanisms are thought to be vasculitis of small blood vessels, acute interstitial nephritis, septic shock and direct renal invasion of the pathogen [28–30]. Although ST is endemic in India and considered to be a cause of acute febrile illness, life-threatening complications like AKI, AES and ARDS can develop if not treated promptly [14, 31]. As no vaccines are available against ST as of now, a high index of suspicion along with early treatment is warranted to prevent development of complications.
Limitations
As our ST-positive samples were fewer in number, so other ST strains circulating in this part of the country may be missed out. A study with a large number of samples will give a clearer picture regarding the circulating serotypes in this part of the country along with the type of strain most commonly associated with kidney involvement.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
The authors would like to thank the Department of Nephrology and Staff of Microbiology Department, Gauhati Medical College and Hospital, Guwahati, Assam, India for their help during the course of the study.
Declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Footnotes
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