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CASE REPORT
Year : 2022 | Volume
: 59
| Issue : 4 | Page : 380-385
Unusual clinical presentations of scrub typhus, a neglected tropical disease: A case series from north India
Shiva Verma1, Suruchi Shukla2, D Himanshu3, KK Sawlani3, Shantanu Prakash2, Amita Jain2
1 Department of Microbiology, Vardhman Mahavir Medical College & Safdarjung Hospital, New Delhi, India
2 Postgraduate Department of Microbiology, King George’s Medical University, Lucknow, Uttar Pradesh, India
3 Department of Medicine, King George’s Medical University, Lucknow, Uttar Pradesh, India
Correspondence Address:
Dr. Shiva Verma
Department of Microbiology, Vardhman Mahavir Medical College (VMMC) & Safdarjung Hospital, New Delhi
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/0972-9062.355960
Background & objectives: Scrub typhus is a neglected tropical disease common in Asia and Africa. It usually presents with non-specific symptoms like fever, rashes, and lymphadenopathy. It has a varying range of clinical picture that often leads to misdiagnosis and initiation of non-specific treatment. This disease is thus associated with high morbidity and mortality. We aim to highlight the uncommon presentations of this common disease to create awareness regarding the unusual presentations of scrub typhus.
Methods: This prospective study was performed over a period of two months enrolling eleven adult patients with serological evidence of anti-scrub typhus IgM antibodies.
Results: All enrolled 11 cases [5 males (45.5%) and 6 females (54.5%)] were positive for anti-ST IgM antibodies and negative for other tested microbial agents. 7/11 (63.6%) patients were admitted with a clinical diagnosis of acute encephalitis syndrome (AES as per standard WHO definition), 3/11 (27.3%) patients presented with jaundice and 1/11 (9.1%) patients presented with rashes. Two out of 7 (28.6%) AES cases had developed peripheral gangrene of extremities.
Interpretation & conclusion: Scrub typhus is a common tropical disease that can have various unusual clinical presentations like meningoencephalitis, vasculitis, acute kidney injury, jaundice, MODS. It closely mimics other infective etiologies making its diagnosis difficult. A high index of suspicion and clinical awareness is required in clinical practice to identify the different presentations of this disease so that early treatment can be initiated to reduce morbidity and mortality associated with this disease.
Keywords: Gangrene; AES; MODS; Jaundice
Scrub typhus, caused by bacteria Orientia tsutsugamushi is a serious public health problem in the Asia-Pacific area. It threatens one billion people globally, and causes illness in one million people each year[1]. It is a re-emerging and neglected tropical disease in India, accounting for almost 50% of the undifferentiated fever in southern regions of the country and about 20-31% of acute encephalitis cases in north and north-eastern parts of the country[2],[3],[4].
The disease usually presents with symptoms like fever, diffuse lymphadenopathy, myalgia, rash, and eschar. Sometimes it can have unusual presentations, ranging from mild flu-like illness to organ failure with fatal complications like pneumonia, Acute respiratory distress syndrome (ARDS), Multi Organ Dysfunction (MODS), encephalitis, hepatitis, acute kidney injury etc[5],[6]. Lack of suspicion of scrub typhus (ST), mainly due to variable and unusual clinical presentations, causes institution of non-specific treatment that often leads to adverse outcomes. Case fatality rates can go up to 30-70% if no appropriate treatment is received. However, if diagnosed early and a specific treatment with doxycycline or azithromycin is initiated, the cure rate is high with the median case fatality rate falling from 6% to 1.4% with appropriate treatment[5]. Despite the increasing awareness of this disease and continuous efforts of the World Health Organization (WHO), the incidence of ST is increasing globally[5]. The complexity of the disease coupled with myriad nonspecific presentations that mimic other tropical diseases, and limited diagnostic facilities in resource-limited regions is a major factor in its resurgence.
In this study, we present a case series of 11 patients with diverse clinical presentations of ST admitted within two months in a tertiary care centre of north India. Our aim is to increase the awareness regarding uncommon presentations of this treatable disease thereby facilitating early diagnosis and treatment to save patients from life threatening complications and death.
Material & MethodsThis study included 11 patients with serological evidence of anti-scrub typhus IgM antibodies admitted in Medicine department from 1st December 2019 to 31st January 2020 in a tertiary care hospital attached to a medical college in Uttar Pradesh, India. All patients had diverse, unusual clinical presentations like peripheral gangrene, jaundice and encephalitis. Demographic data and complete clinical profile of each patient was collected. A complete physical examination, vital signs and relevant investigations were also recorded.
Laboratory parameters tested
Anti-ST IgM antibodies were demonstrated in serum against the 56 kDa antigen of O. tsutsugamushi (OT) using a commercial IgM ELISA (Scrub Detect™, InBios International Inc., Seattle, Washington, USA). The cut-off value used in the study was an optical density of >0.5 as per manufacturer’s instructions.
A real time Polymerase chain reaction (PCR) for OT-DNA was also done on whole blood and/or tissue biopsy samples of these patients. Real time PCR was carried out as per protocol described by Ju Jiang et al.,[7]. DNA was extracted using the QIAamp extraction kit (Qiagen, Hilden, Germany) following the manufacturer’s protocol. Amplification was done on real time PCR machine (ABI 1500, Applied Biosystems, California, USA).
All patients presenting with AES were also tested for IgM antibodies against Japanese encephalitis (JEV), dengue and chikungunya using ELISA tests. Herpes encephalitis virus-1 (HSV-1) and Mycobacterium tuberculosis were also ruled out in these patients by performing real time PCR on CSF samples. Patients presenting with jaundice were also tested for Hepatitis B surface antigen, IgM antibodies against Hepatitis A, C and E viruses, Leptospira, and Salmonella Typhi. Patients with rashes were tested for IgM antibodies against dengue, chikungunya and Leptospirosis. Blood culture was done for these patients which was negative.
Ethical statement
Ethical clearance was obtained from the institutional Ethical Committee prior to the study.
ResultsAll enrolled 11 cases were positive for anti-ST IgM antibodies and negative for other tested microbial agents as mentioned previously. PCR was performed on whole blood of all patients and on tissue biopsy samples of patients with rash and was negative in all cases.
Demographic profile of ST cases
A total of 11 adult patients with age range 22-16 years (mean 41.6 ± 15.92 years) with serological evidence of anti-ST IgM antibodies were enrolled in the study. Seven (63.6%) of these patients were from eastern parts of Uttar Pradesh, two (18.2%) each were from central Uttar Pradesh and from districts adjoining the Nepal border. Ten (90.9%) patients were from rural backgrounds while one (9.1%) patient was from urban area [Table 1].
Table 1: Demographic, clinical and laboratory profile of scrub typhus cases on the day of admission and their clinical outcomeClinical details
Fever was the most common presenting feature seen in 10/11 (90.9%) patients followed by altered sensorium in 7 (63.6 %) patients. Duration of fever ranged from 5 to 20 days. Neither lymphadenopathy nor eschar was found in any of the patients. Duration of hospital stay ranged from 6 to 25 days.
7/11 (63.6%) patients were admitted with a clinical diagnosis of acute encephalitis syndrome (AES as per standard WHO definition)[8], 3/11 (21.3%) patients presented with jaundice and 1/11 (9.1%) patients presented with rashes. Two out of 7 (28.6%) AES cases had developed peripheral gangrene of extremities. 7/11 (63.6%) patients had deranged kidney function tests (KFTs) at the time of admission [Table 1].
Six atypical cases are being discussed here (2 cases of peripheral gangrene, 2 cases of jaundice, 1 case of acute kidney injury and 1 case of Haemophagocytic lymphohistiocytosis ((HLH) secondary to scrub typhus).
Case descriptions
Case 1
A 33-year-old male presented with high-grade fever associated with chills and rigor since 12 days, peripheral gangrene involving four limbs since 1 days and altered sensorium since one day. He was a chronic alcoholic and smoker and regular substance abuser (marijuana). On examination he was febrile (102.5°F), his peripheries were cold and cyanosed with gangrenous changes [Figure 1] & [Figure 2] and peripheral pulses were not palpable. His Glasgow coma scale (GCS) scoring was E3V2M5. CNS examination revealed exaggerated deep tendon reflexes, cranial nerves were intact and there were no signs of meningeal irritation. Laboratory examination revealed anemia with leucocytosis and thrombocytopenia. His liver transaminases and Kidney Function Test (KFTs) were deranged. Autoimmune antibodies workup for vasculitis such as MPO, PR-3 antibodies, Cardiolipin IgM and IgG, Beta 2-glycoproteins (IgG) were negative. Arterial doppler study of both upper and lower limbs revealed ischaemic changes.
Case 2
A 76-year-old male presented with low grade fever associated with chills and rigor since 15 days, altered behaviour since 10 days and gangrene of toes since 5 days. On examination he was febrile (101.9°F), peripheries were cold and cyanosed with gangrenous changes in toes of both feet [Figure 3] with bilateral dorsalis pedis pulses not palpable. His GCS score was E3V4M5. CNS examination revealed neck rigidity, exaggerated deep tendon reflexes, cranial nerves intact. Laboratory examination revealed leucocytosis with thrombocytopenia. His liver transaminases and KFTs were elevated. Arterial Doppler study of both lower limbs revealed ischaemic changes.
Case 3
A 22-year-old post-partum female presented with jaundice since 14 days. She had delivered a still-born baby one week back and was referred to our hospital for further management. Her antenatal period was uneventful. On examination, she was icteric and had abdominal tenderness. Laboratory examination revealed normal WBC and decreased platelet counts, serum bilirubin was 15.2 mg/dL and urea was 129.9 mg/dL.
Case 4
A 30-year-old pregnant female at eight months of gestation presented with complaints of jaundice, pruritis and low grade fever since 5 days. Her antenatal period was uneventful. On examination, she was febrile (100.3°F), icteric and fetal sounds were not appreciated. She delivered a dead baby on the same day. On examination, she was icteric and had abdominal tenderness. Laboratory examination revealed normal WBC and decreased platelet counts, serum bilirubin was 16 mg/dL and KFTs were mildly elevated.
Case 5
A 50-year-old male presented with high grade fever associated with chills and rigor since 10 days, rashes on hands and feet since 7 days and altered sensorium since 3 days. On examination, he was febrile (103.3°F) and had rashes on both hands and lower limbs (upto knees) [Figure 4] & [Figure 5]. His GCS was E4V2M5 with no signs of meningeal irritation and intact cranial nerves. His liver transaminases were normal but KFTs were persistently deranged (S. urea 185.4 mg/dL, S. creatinine 5.8 mg/dL at time of admission) and required dialysis.
Case 6
A 60-year-old female presented with low grade fever and breathlessness since 10 days, multiple episodes of vomiting since 5 days and altered sensorium since 1 day. On examination, she was febrile (100.2°F), had pallor and pedal edema. Her GCS was E3V2M4 with no signs of meningeal irritation and intact cranial nerves. USG abdomen revealed splenomegaly. Laboratory examination revealed anemia with decreased WBC counts with thrombocytopenia. Her liver transaminases were elevated with normal KFTs. Serum ferritin was 26692.2 ng/ml, serum triglyceride was 700.9 mg/dL, fibrinogen 107 mg/dL. She was diagnosed as Hemophagocytic lymphohistiocytosis (HLH) secondary to scrub typhus on the basis of clinical and laboratory results. Her general condition worsened and she required mechanical ventilation on day 5 of hospital admission. The patient died on day 15 of admission.
DiscussionScrub typhus (ST) is grossly under-diagnosed and underreported disease mainly due to diverse presentations[5],[6]. Eleven adult patients of scrub typhus were admitted in the Medicine wards of our tertiary care hospital during the study period with no gender preponderance. Uttar Pradesh (UP), India is an endemic state for ST. Similar to other studies, more than 90% of our patients were from rural areas and all had acute clinical presentations[2]. The average duration of hospital stay was 2 weeks. All patients were treated with standard doxycycline or azithromycin therapy and 10/11 (90.9%) patients recoveredand were discharged in stable condition. Mortality was reported in 1/11 (9.9%) (Case 6). Though ST is known to cause rashes and eschar, we found rashes only in 2/11 (18.2%) cases. While eschar, which is a characteristic feature of ST, was not found in any of our patients, making a clinical diagnosis more difficult.
Seven patients presented with features consistent with AES. All these patients presented with altered sensorium (GCS ranging between 6-12) with no focal neurological signs. Scrub typhus as an important cause of AES (acute encephalitis syndrome) has been reported mostly in paediatric patients from UP[9]. Though UP is an AES-JEV endemic belt, our state has seen a resurgence of adult AES cases due to ST in recent years[3]. CSF analysis of all our patients showed parameters mimicking viral meningoencephalitis which is documented in literature[10]. Other studies have also observed a similar pattern of CSF findings with some showing decreased glucose levels that are more consistent with a sub-acute tubercular meningitis like picture[11],[12].
Two of our patients presented with dry gangrene of lower extremity. Vasculitis is a rare complication of ST and has been reported in few case reports[13],[15]. It is important to differentiate between an infectious and non-infectious cause of gangrene because the treatment strategies are different.
As per worldwide literature, liver involvement is very rare in scrub typhus[16],[17]. But hepatic dysfunction has commonly been reported in ST from Indian studies with incidence varying from 48.5-80%[18],[20]. Consistent with these studies, elevated transaminases (more than threefold) were found in 7/11 (63.6%) of our cases. Thus scrub typhus can present with deranged LFTs and it should be ruled out in all cases of hepatitis with >3-fold elevation of transaminases.
Three patients presented with jaundice, two of them were pregnant and had poor fetal outcomes. Scrub typhus complicating pregnancy has been reported in past with majority of the cases observed in the third trimester[21]. Vertical transmission from transplacental and perinatal infection have been reported leading to neonatal scrub typhus. This may be associated with increased adverse pregnancy outcomes[21].
One patient presented with acute kidney injury (AKI). His KFTs were persistently deranged and required dialysis. Reports of incidence of acute kidney injury in scrub typhus are increasing and is associated with high rates of mortality[18],[19],[20],[21],[22]. Thus the possibility of scrub typhus should be borne in mind in patients presenting with AKI especially in endemic areas as these patients have worse haematological and biochemical parameters and are likely to suffer from various complications and high death rates. The incidence of MODS varies from 16.6-85.2% in scrub typhus[18]. Though a common complication of the disease, it is generally seen in the third week of illness. In our series, one patient presented with MODS within 10 days of illness.
Hemophagocytic lymphohistiocytosis (HLH) is a critical systemic inflammatory condition that results from cytokine overproduction. HLH is a potential severe complication of scrub typhus, with increasing number of cases being reported in the last 10 years[23],[24]. About 30 cases of HLH secondary to ST with mortality rate of 6.7% have been reported till date[23]. We had one patient (Case 8) of HLH secondary to scrub typhus. Her serum ferritin levels were markedly increased and she had hypofibrinogenemia. Though bone marrow biopsy did not show haemophagocytosis, the diagnosis was made on the basis ofthe HLH-2004 diagnostic criteria. Her general condition did not improve and required mechanical ventilation on day 5. Her ferritin levels decreased with doxycycline treatment but WBC counts did not improve and she died after 15 days.
LimitationSince the study was done in a short time duration, we cannot comment on year-round seasonality and frequency of cases of scrub typus in our region. Secondly, our diagnosis was based on raised IgM antibodies tested by ELISA. Though the gold standard test for scrub typus is Indirect immunofluroscence assay, a correlation of 97% between IgM ELISA and SD Bioline Tsutsugamushi rapid test is reported[25].
ConclusionScrub typhus can present with unusual presentations like ARDS, meningoencephalitis, vasculitis, acute kidney injury, jaundice and MODS. It is often misdiagnosed due to such non-specific presentations mimicking other tropical diseases. A high index of suspicion and clinical awareness can help in confirming the diagnosis and initiating early management to prevent fatality.
Conflict of interest: None
References
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