Clinical manifestations of scrub typhus

Clinical manifestations of scrub typhus Senaka Rajapaksea,*, Praveen Weeratungab, Sriharan Sivayoganathana and Sumadhya Deepika Fernandoc a

Tropical Medicine Research Unit, Department of Clinical Medicine, Faculty of Medicine, University of Colombo, 25, Kynsey Road, Colombo 08, Sri Lanka; bUniversity Medical Unit, National Hospital, Regent Street, Colombo 08, Sri Lanka; cDepartment of Parasitology, Faculty of Medicine, University of Colombo, 25, Kynsey Road, Colombo 08, Sri Lanka *Corresponding author: Tel: +94 112695300; Fax: +94 112689188; E-mail: [email protected]

Received 18 November 2016; revised 25 February 2017; editorial decision 14 March 2017; accepted 11 April 2017 The mite-borne rickettsial zoonosis scrub typhus is widely prevalent in parts of Southeast and Far East Asia, and northern Australia. The disease is an acute febrile illness, associated with rash and often an eschar, which responds dramatically to treatment with antibiotics. In some cases it results in a serious illness leading to multiple organ involvement and death. The disease manifestations are thought to result from a systemic vasculitis, caused by both direct effects of the organisms as well as an exaggerated immune response, although little is understood about its pathogenesis. A wide spectrum of clinical manifestations, affecting nearly every organ system, have been described with scrub typhus. Some of these manifestations are serious and life threatening. In this systematic review, we summarise the typical and atypical manifestations of scrub typhus reported in the literature. Awareness of these unusual manifestations will hopefully guide clinicians towards diagnosing the condition early, and initiating early appropriate antibiotics and other supportive measures. Keywords: Atypical manifestations, Clinical features, Orientia tsutsugamushi, Scrub Typhus

Introduction Scrub typhus is a vector borne rickettsial zoonosis caused by the organism Orientia tsutsugamushi. It is an emerging infectious disease in many parts of the world, and is endemic to South Eastern and Far Eastern countries of Asia (India, Sri Lanka, Pakistan, Japan, Thailand and Korea), also extending from Afghanistan down to northern Australia, the so-called Tsutsugamushi triangle.1 Trombiculid mites (such as Leptotrombidium delicense and L. palladium) are the natural host of the organism, and the disease is transmitted to humans through infected larval stages (chiggers) of the mites during feeding. In some cases, the pathogens multiply at the site of entry, forming an inflammatory lesion known as an eschar, which is characteristic of the disease.2 The term scrub typhus is based on the typical habitat endemic to the vector, although the disease is prevalent in a wide range of habitats. An estimated one million new cases appear annually, and one billion people are at risk of infection.3 Scrub typhus is characteristically a simple acute febrile illness, associated with rash and often an eschar, which responds dramatically to treatment with antibiotics.4 Laboratory confirmation of scrub typhus is generally by serological methods, with the indirect fluorescent assay being the most commonly used test; paired titres are usually required to make a confirmatory diagnosis.5 ELISA and passive haemagglutination assay are also available. The Weil-Felix test is now

considered less useful, as it has low sensitivity and specificity. Culture of the organism and PCR are only available in few specialised centres. The pathophysiology of scrub typhus is not fully understood, though in general it is thought to be due to focal or disseminated vasculitis. The principal target site of the organism is the vascular endothelium. Both host and pathogen factors contribute to the development of vasculitis, with both humoral and cellular immunity playing a role.4 In some individuals, scrub typhus results in a severe illness with multi-organ dysfunction; left untreated, mortality rates can be as high as 30%.4 Like many other tropical diseases, a wide range of clinical manifestations have been reported with scrub typhus. In this paper, we describe both common, as well as atypical and unusual manifestations of scrub typhus, based on a systematic review of the published literature.

Methods We performed a PUBMED search for all papers published with no date or language restrictions, using the keywords ‘scrub typhus’ or ‘Orientia’ or ‘tsutsugamushi’ or ‘chigger-borne rickettsiosis’ in any field. There were 1643 abstracts in the original search with duplicates removed. The software Thomson-Reuters Endnote X7® was used to filter articles. Bibliographies of cited literature

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were also searched for additional references. All abstracts were read through independently by three of the authors (SS, PW and SR). Observational studies, clinical trials, case series, and case reports of patients with a confirmed diagnosis of scrub typhus were screened for inclusion. We included papers which provided data regarding clinical manifestations of scrub typhus. In all cases included, a laboratory diagnosis of scrub typhus was considered essential, by any of the established diagnostic tests, such as indirect immunofluorescence, IgM ELISA, Weil-Felix test, or genomic diagnosis. Reports where co-infection with other diseases was considered possible were not included—this decision was taken by consensus between the three reviewing authors. Data extraction was done by SS, PW and SDF. Data from 157 papers were included in the final review (Figure 1). We categorised clinical manifestations based on the systems affected; i.e., cardiovascular, respiratory, neurological, gastrointestinal, haematological, renal, endocrine and ocular (Table 1). A separate section discusses pregnancy-related complications of the infection.

Clinical features of classical scrub typhus The incubation period of scrub typhus in humans is around 10–12 days, and can vary between 6 and 21 days.4 It usually presents as an acute febrile illness, with high fever, malaise, headache and cough. Generalised lymphadenopathy maybe

Figure 1. PRISMA diagram of papers selected.

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present. The most characteristic clinical feature of scrub typhus is the presence of an eschar at the site of the bite of the mite (Figure 2). If present, it is almost diagnostic. The prevalence of an eschar is highly variable, from 7 to 80% in various studies, and this variation maybe due to difficulties in identifying the eschar in dark skinned individuals, differences in the eschar inducing capacity of different strains of the organism, and the atypical appearance of eschars in skin folds and moist skin. The eschar starts as a small papule, which enlarges and undergoes central necrosis to turn black. The groin, axilla, waist, neck and other exposed parts of the body are common sites. Towards the end of the first week, a maculopapular rash starting on the trunk and spreading to the limbs maybe seen. Most of the systemic manifestations of the disease start towards the beginning of the second week. These are described below.

Cardiovascular manifestations There is evidence that the heart can be involved in scrub typhus, although the exact pathogenesis of cardiac involvement and its impact on outcome are yet unclear. Reversible cardiomegaly (detected by chest radiography) was documented in just over a quarter of patients, in a case series of 130 patients with scrub typhus.6 Histopathological evidence of cardiac lesions (vasculitis and perivasculitis in the myocardium, with cellular infiltration in the endocardium and pericardium) have been demonstrated on

Transactions of the Royal Society of Tropical Medicine and Hygiene

Table 1. Atypical clinical manifestations of scrub typhus, with related citations Clinical manifestations

Prevalence

Data sources

Cardiovascular manifestations Electrocardiographic changes Sinus tachycardia Relative bradycardia ST-T changes Atrial flutter or fibrillation Atrial standstill PR-interval prolongation Prominent U-waves Ventricular premature beats Q-T prolongation Myocarditis

73% 46% 53% 10–29% NA Single report NA 7% 4% NA NA

Observational studies: Hollander,8 Fang et al.,9 Aronoff et al.,11 Kim et al.,12 Thipmontree et al.10

Pericarditis Myocardial infarction Respiratory manifestations Radiographic changes: Bilateral reticular opacities Air space nodules Ground-glass opacities Consolidation Hilar lymph node enlargement Pneumonitis/pneumonia

Single report NA 65% 40–48% 13% 10–25% 25% 25% 51%

Pleural effusion

15–20%

Acute respiratory distress syndrome

5–15%

Neurologic manifestations Meningitis/meningo-encephalitis/ Encephalitis

Acute disseminated encephalomyelitis Cranial nerve palsies Cerebrovascular events Parkinsonism/other movement disorders Cerebellitis Trigeminal neuralgia Demyelinating polyneuropathy Neuropathy/radiculopathy/ mononeuritis Transverse myelitis Gastrointestinal manifestations Acute abdomen Diarrhoea Pancreatitis

7–26%

NA

Case series: Watt et al.15 Case reports: Jeong et al.,13 Tzeng et al.14

Case reports: Jeong et al.,13 Tzeng et al.,14 Yotsukara et al.19 Case series: Sittiwangkul,16 Levine7 Case report: Chang et al.18 Case reports: Kim et al.,20 Dhiman et al.21 Observational studies: Chareonsak et al.,6 Abhilash et al.,24 Choi et al.,25 Jeong et al.88

Observational studies: Song et al.29 Case reports: Premarathna et al.,26 Hung et al.,27 Chen et al.,28 Munigangaiah et al.,30 Manickam et al.32 Observational studies: Charoensak et al.,6 Abilash et al.,24 Kim et al.30 Case series review: Winwanitkit et al.31 Observational studies: Charoensak et al.,6 Wang et al.,37 Venkategowda et al.38 Case series: Tsay et al.40 Case reports: Tseng et al.,39 Saxena et al.41 Observational studies: Silpapojakul et al.,46 Viswanathan et al.,47 Abhilash et al.,45 Misra et al.,43 Sood et al.50 Case series: Pai et al.,48 Kar et al.,53 Jamil et al.44 Case reports: Fang et al.,49 Saifudheen et al.,51 Kim et al.,52 Yum et al.54 Case reports: Chen et al.,55 Kim et al.56

NA NA

Case reports: Kim et al.,56 Lee et al.,58 Lin et al.,59 Premaratna et al.,62 Kang et al.,63 Mahajan et al.64 Case reports: Remalayalam et al.,65 Yang et al.,66 Kim et al.67 Case reports: Chiou et al.,69 Koti et al.,70,71 Premaratna et al.68

NA NA NA NA

Case reports: Karanth et al.,77 Bhat et al.,74 Bhoil et al.,75 Mahajan et al.76 Case report: Arai et al.72 Case reports: Lee et al.,79 Lee et al.,78 Kim et al.80 Case reports: Ting et al.,81 Muranjan et al.,83 Hayakawa et al.,84 Banda et al.82

NA

Case reports: Lee et al.,85 Mahajan et al.86

NA Single report NA

Case reports: Kundavaram et al.,91 Mahajan et al.92 Case report: Premaratna et al.97 Case reports: Dhakal et al.,101 Bhatt et al.,99 Yi et al.,103 Ahamed et al.,98 Sv et al.102

NA

Continued

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Table 1. Continued Clinical manifestations

Prevalence

Data sources

Cholecystitis Gastro-intestinal haemorrhage

NA 25%

Splenic infarction Peritonitis/haemoperitoneum Liver dysfunction

NA NA 89%

Case reports: Hayakawa et al.,84 Lee et al.,104 Wang et al.,105 Lee et al.,106 Lee et al.104 Observational studies: Aung et al.,96 Kim et al.107 Case reports: Mahajan et al.,108 Bae et al.109 Case reports: Raj et al.,134 Park et al.111 Case reports: Lee et al.,93 Lin et al.,94 Thipmontree et al.95 Observational study: Hu et al.110 Case reports: Goswami et al.,112 Shioi et al.113

Haematological manifestations Disseminated intravascular coagulopathy Haemophagocytic lymphohistiocytosis Monoclonal gammopathy Persistent thrombocytopaenia Thrombosis Splenomegaly Renal manifestations Acute kidney injury Nephrotic syndrome Endocrine manifestations Adrenal insufficiency Thyroiditis

NA

Case reports: Ognibene et al.,115 Ben et al.,116 Izumo et al.,117 Ono et al.118

NA

Case reports: Basheer et al.,122 Lin et al.,123 Chen et al.,124 Iwasaki et al.,125 Kobayashi et al.,126 Kwon et al.,127 Takami et al.,128 Valsalan et al.,129 Sankhyan et al.,130 Pazhaniyandi et al.,119 Pragna et al.,120 Zhou et al.121 Case reports: Cho et al.131 Case reports: Kumar et al.132 Case reports: Jena et al.,133 Nagaki et al.152 Observational study: Park et al.111

NA Single report NA 47%

Single report

Observational studies: Subhalaxmi et al.,136 Kumar et al.,135 Varghese et al.,137 Case reports: Lee et al.,138 Hsu et al.,141 Kim et al.143 Case reports: Lee et al.146

Single report Single report

Case reports: Mookkappan et al.147 Case reports: Kim et al.148

18–53%

NA: not available. Prevalence figures are only estimates, based on available observational studies.

autopsy in patients with serologically confirmed scrub typhus,7 although studies so far show that cardiac involvement is transient, and rarely fatal by itself. Electrocardiographic (ECG) changes in scrub typhus have been described in many studies, as far back as 1946. Various ECG changes have been reported; e.g., sinus tachycardia,8–10 sinus bradycardia,9,11 atrial flutter or fibrillation,12 atrial standstill,13,14 heart block,10 PR-interval prolongation,8,9 ST-T change,8,9,12,15 prominent U-waves,9,15 ventricular premature beats15 and Q-T prolongation.9 Relative bradycardia is a common feature in scrub typhus, and may be seen in over 50% of patients.11 It is not necessarily a sign of severity, and many patients with mild disease show relative bradycardia during the illness or during recovery. In fact, there is no conclusive evidence to suggest that any of the ECG abnormalities seen in scrub typhus correlate with severity, or indicate worse outcome. In patients with more severe illness, ECG changes could simply be a result of deranged homeostasis (electrolyte imbalance, acidosis) rather than a primary effect of infection. There have been several case reports of patients with scrub typhus and myocardial involvement resulting in clinically evident heart failure. Myocarditis associated with conduction abnormalities such transient atrioventricular dissociation and junctional escape rhythm with atrial standstill, resulting in clinical heart failure has been reported; these patients had echocardiographic

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evidence of depressed cardiac function.10,13,14 Myocarditis has been described in the paediatric population as well, with fatal outcome. In a case series of four children presenting with myocarditis resulting in severe hypotension, two of the children died despite intensive vasoactive support and mechanical ventilation support.16 Acute right heart failure due to scrub typhus has also been reported.17 Pericarditis has been reported to occur following scrub typhus,18 with pericardial fluid positive for scrub typhus on indirect immunofluorescence. In one report, a 34year-old man recently treated for scrub typhus was readmitted with dyspnoea on effort and orthopnea.19 His chest radiograph demonstrated cardiac enlargement and lung congestion, and ECG showed first degree heart block. The patient made an uneventful recovery with antibiotics and heart failure treatment, and subsequent cardiac investigations, including echocardiogram and myocardial perfusion scan, were normal. Interestingly, an endomyocardial biopsy performed revealed densely staining rickettsial organisms in the cytoplasm of the cardiac endothelial cells, in addition to infiltrative changes. It is purported that the pathological mechanism of inflammatory changes seen in the heart is secondary to vasculitis and perivasculitis caused by scrub typhus,7 although evidence is only from very early studies. Scrub typhus has been reported to result in acute myocardial infarction as well. A 58-year-old man who had been treated for


Figure 2. Eschar on anterior chest wall of a patient with scrub typhus.

scrub typhus was readmitted with ST segment elevation myocardial infarction.20 He was successfully treated with primary coronary intervention. A similar case of acute myocardial infarction resulting from scrub typhus was reported from India.21 There is evidence from a nationwide study in Taiwan that scrub typhus increases the subsequent risk of developing acute coronary syndrome,22 and this may be related to the purported increased risk of coronary events following acute infection in general.23

Respiratory manifestations Scrub typhus is frequently associated with the development of respiratory complications. Radiological abnormalities are relatively common in scrub typhus.6,24 A case series of 130 Thai patients demonstrated pulmonary involvement in 61.5%.6 Initial radiography showed abnormalities in as much as 64.6% of the patients. Common radiographic abnormalities included bilateral reticular opacities (48.5%), air space nodules (13.1%) and pleural effusion (10.8%), in addition to cardiac abnormalities such as cardiomegaly and congestive heart failure. In another series of 75 consecutive patients with scrub typhus, radiographic abnormalities were seen in 72%.25 Other radiographic findings noted included ground-glass opacities, consolidation, septal lines and hilar lymph node enlargement. Scrub typhus pneumonitis has been documented in several case reports,26–28 and it has been suggested that the presence of pneumonitis may be a marker of severe disease.29 Other manifestations described include pneumonia, pulmonary edema, pulmonary haemorrhage and pleural effusion.30–34 Definite pneumonia with evidence of consolidation attributed to scrub typhus has been reported, which cleared with antibiotic therapy.35 In this series of three cases, one had features of atypical pneumonia with diffuse bilateral reticular infiltrations, and the other two had focal consolidation. Pleural effusions seen in scrub typhus could be either transudative or exudative, and are

more likely to occur with older age, in men and in patients with cardiac involvement or low albumin.36 Acute respiratory distress syndrome (ARDS) is a relatively uncommon but serious complication associated with scrub typhus. In one retrospective review of 72 patients with scrub typhus in Taiwan, 8 patients developed ARDS; 2 died.37 All of them required ventilation. In a prospective observational study of 58 patients with scrub typhus, 24 developed ARDS, and 2 patients died.38 Although it is difficult to draw firm conclusions on contributory factors or factors associated with poor outcome, it has been suggested that delay in initiation of antibiotics may be associated with the development of ARDS.37 Dramatic recovery and rapid weaning of a patient on ventilator in ARDS within 48 hours after initiation of antibiotics has been reported, emphasising the importance of starting appropriate antibiotics where the suspicion of scrub typhus is high.39 In a series of 5 cases of ARDS among 33 hospitalised patients with scrub typhus, those with ARDS were more likely to be older; also, thrombocytopenia and early pneumonitis were more frequently observed in those with ARDS.40 In most studies, ARDS in scrub typhus has been often observed in the setting of multiorgan dysfunction syndrome, and is thus associated with higher mortality.37,41 Although the most common pathological finding in scrub typhus is vasculitis of the microvasculature of the involved organ, a different mechanism, without direct invasion of O. tsutsugamushi, has been proposed to be responsible for ARDS. Open lung biopsy in a patient rapidly deteriorating due to ARDS demonstrated diffuse alveolar damage in the organising stage without any evidence of vasculitis.42 Immunoflourescent antibody staining and PCR for O. tsutsugamushi failed to demonstrate any organisms in the biopsy sample. It is possible that an immunologic mechanism in the lung related to previous infection by O. tsutsugamushi, without direct invasion, may play a role in the pathogenesis of ARDS, as well as in other lung manifestations in scrub typhus.

Neurological manifestations Meningitis and meningo-encephalitis are common nervous system manifestations of scrub typhus.43–49 Meningoencephalitis is the more severe form, seen in a subset of patients, and characterised by altered sensorium and seizures.50–54 A retrospective study of 65 patients with scrub typhus revealed that 26% had scrub typhus meningitis, defined as the presence of headache or nuchal rigidity with either altered sensorium or focal neurological deficits on history or examination, with cerebrospinal fluid (CSF) pleocytosis.47 Despite having altered sensorium and cranial nerve deficits, these patients’ CT scans of the brain were normal. The only cranial nerve defect observed was unilateral or bilateral sixth cranial nerve palsy. All made complete clinical recovery. In another retrospective study of 189 patients with meningitis/meningoencephalitis due to scrub typhus, altered sensorium was seen in 53.7% and seizures occurred in 22%.45 The CSF findings in scrub typhus mimic those of TB meningitis (CSF lymphocytic pleocytosis with increased proteins),45,47 an important differential in countries where both diseases are prevalent. In a series of six patients with encephalitis due to

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scrub typhus, all exhibited altered sensorium, and three had generalised tonic-clonic seizures.53 None of them exhibited any focal neurological signs. Brain imaging demonstrated diffuse cerebral edema. CSF studies showed raised protein with lymphocytosis mimicking viral meningitis. All patients had multi-organ dysfunction syndrome and needed intensive care. The differentiation between meningitis, meningo-encephalitis and encephalitis, based on clinical features and radiologic findings, appears somewhat arbitrary; however, a significant proportion of scrub typhus patients with central nervous system involvement appear to have simple meningitis, with clinical and CSF findings similar to viral meningitis. In general, the outcome from central nervous system involvement is good with treatment, although fatalities have been reported. Two patients with acute demyelinating encephalomyelitis have also been reported in scrub typhus.55,56 A rapidly deteriorating 77-year-old man with scrub typhus underwent brain magnetic resonance imaging (MRI) which revealed white matter lesions involving both cerebral hemispheres.55 Despite clinical improvement after intensive care, the patient had persistent quadriplegia and showed little improvement. The second patient, a 22-year-old woman, developed bilateral sixth and seventh nerve palsies, bilateral gaze evoked nystagmus, anarthria, dysphagia, quadriparesis and sensory level at T1, with MRI showing lesions in the lower brainstem, cerebellar peduncles and spinal cord.56 Her CSF was positive for tsutsugamushi antibodies. She improved with treatment, but was left with residual neurological disability. Cranial nerve palsies are not uncommon in scrub typhus with central nervous system involvement. Isolated abducens nerve palsy57,58 and bilateral asymmetrical facial nerve palsy59 have been reported. Involvement of the optic nerve with unilateral60 or bilateral optic neuritis61 has also been described. Hearing loss is a well-known complication, and has been shown to improve gradually with antibiotic treatment.62–64 Severe persistent otalgia has also been reported.63 Vascular events in the central nervous system related to scrub typhus have been reported occasionally. Subdural haematoma has been observed in a patient presenting with scrub typhus and altered sensorium,65 suggesting that brain imaging may be important in patients with reduced consciousness. Another patient presenting with fever and altered sensorium was found to have a thalamic haemorrhage.66 Haemorrhagic transformation of scrub typhus encephalitis has also been reported.67 Other neurological complications such as transient parkinsonism,68,69 myoclonus,69,70 opsoclonus,70,71 trigeminal neuralgia72 and visual hallucinations73 have been reported, although rare. Isolated cerebellitis has also been described in scrub typhus,74–77 presenting with nystagmus, slurred speech and ataxia. Peripheral nervous system involvement has been reported in scrub typhus. Guillian-Barré syndrome is a known association of scrub typhus.78,79 In two patients presenting with ascending paralysis and intact sensation, nerve conduction studies showed slow conduction velocities and prolonged F-responses.79 Both patients improved clinically after being treated with intravenous immunoglobulin therapy in addition to standard antibiotics therapy. Miller Fisher syndrome, a variant of Guillian-Barré syndrome, has also been reported with scrub typhus.80 Brachial plexus neuropathy81,82 and lumbosacral radiculopathy resulting

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in paraparesis83 have been noted to occur in scrub typhus. Mononeuritis multiplex has been described in one patient,84 involving right median, right ulnar, right sural and left saphenous nerves. There are two reports of transverse myelitis as a possible complication of scrub typhus, which improved with corticosteroids.85,86 An unusual case of polyneuropathy, cerebral infarction and white matter demyelination in a 64-year-old man with scrub typhus has been reported.87 The patient had developed reduced power in all four limbs associated with reduced sensation and ataxia, and developed multi-organ failure needing ventilatory support. Nerve conduction studies confirmed the presence of demyelinating sensorimotor polyneuropathy. Brain MRI showed features of cerebral infarction involving the right parietooccipital lobe and right corona radiata, and subsequent MRI showed features of progressive white matter lesions, similar to those seen in acute disseminated encephalomyelitis. The patient recovered and his neurological deficit improved over time. The pathogenesis of nervous system involvement may be multifactorial, although the main mechanism of involvement appears to be vasculitis and peri-vasculitis due to proliferation of O. tsutsugamushi in the endothelial cells. The demonstration of O. tsutsugamushi using nested PCR techniques, and typhus nodules, in patients suffering from scrub typhus meningitis/ meningo-encephalitis shows that direct invasion of the nervous system takes place.7,88,89 Nonetheless, secondary immunemediated mechanisms may be responsible for some of the manifestations.63,90 Other manifestations such as haemorrhage and infarction may have multiple contributory causes, especially when associated with multi-organ failure, such as prolonged hypotension, disseminated intravascular coagulopathy, and thrombocytopenia, in addition to direct scrub typhus vasculitis.

Gastrointestinal manifestations Scrub typhus can present as acute abdomen, without an underlying surgical cause.91,92 While there are no reports of spontaneous peritonitis with scrub typhus, two patients are reported to have presented with features of peritonitis secondary to gastric perforation; both were treated successfully with surgery.93 Haemoperitoneum has been reported, spontaneously,94 and following splenic rupture.95 Diarrhoea is not unusual, and in one series was reported to occur in 45% of patients with scrub typhus.96 There has also been a report of scrub typhus manifesting as fever and late onset diarrhoea, mimicking enteric fever, responding to doxycycline treatment.97 Pancreatitis is a well-known, though less commonly recognised, association of scrub typhus.98–102 Pseudocyst or pancreatic abscess formation has also been described.99,103 Pancreatitis is commonly associated with multi-organ involvement; in a series of seven scrub typhus patients complicated by pancreatitis, all patients had features of multi-organ dysfunction syndrome except one.98 The mortality associated with pancreatitis in scrub typhus was high (43%). As with most other disease processes in scrub typhus, the pathogenesis of pancreatitis is thought to involve an inflammatory process via vasculitis. Acalculous cholecystitis, a classical clinical and radiologic feature of dengue, has also been reported in scrub typhus.84,104,105


In one report, a 69-year-old woman presenting with right upper abdominal tenderness and fever was diagnosed and treated for acute calculous cholecystitis, since abdominal computerised tomography showed an oedematous gallbladder with calculi.106 She went on to developed a maculopapular rash and multiorgan failure, and a subsequent diagnosis of scrub typhus was made on serological testing. She recovered with standard antibiotic therapy. Whether the features of cholecystitis were due to scrub typhus, or whether the two conditions co-existed, is difficult to determine. Gastro-intestinal bleeding is yet another manifestation attributable to scrub typhus.96,107,108 In a case series of 20 patients from Thailand, a quarter of the patients were found to have haematemesis or malaena.96 In the largest endoscopic study of patients with scrub typhus to date, 58 patients with gastrointestinal symptoms were studied with upper gastrointestinal endoscopy.107 Superficial mucosal haemorrhage, multiple erosions and ulcers without any predilection of site were the common findings, and the severity of these manifestations correlated with the occurrence of cutaneous manifestations and overall disease severity. Histopathological examination showed characteristic features of acute vasculitis with infiltration of acute inflammatory cells and thrombus formation in blood vessels. Haematochezia associated with massive small bowel bleeding has also been described in scrub typhus.109 A 79-year-old man who was previously diagnosed as having scrub typhus presented with haematochezia. Colonoscopy revealed multiple ulcerations with bleeding in the terminal ileum. Gastro-eosphageal endoscopy was normal. He required surgical excision of affected bowel, and recovered. Histopathological examination of the resected part showed flask shaped ulcers and lymphocytic vasculitis of the ulcer bed. Liver dysfunction is a well-documented complication of scrub typhus.110,111 Abnormalities of liver function are common (elevated aspartate aminotransferase levels in 78–89%, elevated alanine aminotransferase levels in 64–92%, elevated alkaline phosphatase in 27–84% levels, elevated bilirubin levels in 16–38%). Notably, elevation of transaminases appears to be more common than raised bilirubin. Liver failure is rare, and of two reported cases of acute liver failure, one survived112 while the other died.113 Histopathological findings in this latter patient revealed submassive hepatocellular necrosis, inflammatory cell infiltration in Glisson’s capsules, and sporadic fibrin thrombi in the hepatic sinusoids.

Haematological manifestations Disseminated intravascular coagulopathy is a well-recognised complication of scrub typhus. Often associated with severe disease and multi-organ failure, disseminated intravascular coagulopathy is associated with a high mortality.114 It has been described in association with myocarditis,115,116 meningoencephalitis116 and ARDS.117 Autopsy findings in one fatal case revealed features of vasculitis and perivasculitis of the organs. The endothelial tissue of the white pulp of the spleen was markedly infiltrated by plasma cells.118 Haemophagocytic syndrome is a rare but serious complication of scrub typhus.119–129 Haemophagocytic syndrome, also

known as haemophagocytic lymphohistiocytosis (HLH), is thought to occur due to dysregulated activation and proliferation of lymphyocytes. It is often associated with macrophage hyperactivity, widespread haemophagocytosis and hypercytokinemia, leading to multi-organ dysfunction. The diagnosis is confirmed by bone marrow biopsy. Even though mortality in HLH can be as high as 60%,123 early diagnosis and initiation of antibiotics can dramatically improve clinical outcome, and there are several reports of patients with scrub typhus and HLH who survived with treatment; i.e., antibiotics, steroids and immunomodulatory therapy.122,124–130 In one child who died, the diagnosis of HLH was only made on autopsy.130 Monoclonal or bi-clonal gammapathies were demonstrated in 12 patients out of a series of 40 with scrub typhus (30%).131 Persistent thrombocytopaenia has been reported in a 5-year-old.132 Thrombotic complications are rare. In a 48-year-old man presenting with fever, focal seizures and focal neurological signs, MRI scan of the brain showed thrombosis of the anterior portion of the superior sagittal sinus with haemorrhagic venous infarct in the left frontal lobe, and a midline shift.133 Scrub typhus was subsequently confirmed by IgM ELISA. A thrombotic work-up for other causes was normal. Splenomegaly is a common feature in typhus, seen in up to 47% of patients, usually detected by imaging rather than clinically.111 Splenic infarction has also been documented,111,134 and there is one reported case of splenic rupture presenting as peritonitis.95

Renal manifestations Acute kidney injury (AKI) is an under-recognised complication of scrub typhus135,136 and is a predictor of mortality.137 In one study of 49 patients with scrub typhus in India, the presence of renal abnormalities was as high as 82%, and AKI was present in 53%. Albuminuria was present in 55% and microscopic haematuria in 16%; overall abnormal urinalysis was found in 61%. Rhabdomyolysis could also play a contributory role.138–140 Antibiotics and supportive therapy generally results in resolution of AKI;141,142 however, there is a report of one patient with biopsy confirmed acute tubular necrosis who did not recover from AKI, and required long term haemodialysis.143 It must be noted that many cases of AKI in scrub typhus occur in the setting of multi-organ failure and, thus, numerous factors contribute to the development of AKI. However, renal tubular damage due to direct invasion of the tubules has been demonstrated in autopsy specimens.144,145 There is a single case report of nephrotic syndrome following scrub typhus in a 72-year-old woman, in whom biopsy showed membranous glomerulonephritis.146

Endocrine manifestations Adrenal insufficiency has been reported as a complication of scrub typhus, in a 45-year-old patient who developed postural hypotension not responding to intravenous fluids.147 The diagnosis was confirmed by adrenocorticotrophic hormone stimulation test. The patient improved with the administration of corticosteroids as well as standard antibiotic therapy. Sub-acute thyroiditis following scrub typhus has also been reported.148 There are two

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reports of scrub typhus associated with epidydimo-orchitis in children, which resolved with treatment.149,150

Ocular manifestations Ocular changes have been described in other rickettsioses, but are thought to be generally mild and self-limiting in scrub typhus. Scheie,151 in a very early study of 451 patients with scrub typhus, described papilloedema as the commonest manifestation, occurring during the second to third week, and persisting into convalescence. Various other ocular changes such as superficial retinal haemorrhages, soft exudates, engorgement of the retinal veins, uveitis and subconjunctival haemorrhages were noted. Visual acuity appeared to be unaffected. There are also reports of unilateral60 and bilateral optic neuritis.61 Branch retinal vein occlusion was reported in a 60-year-old woman with scrub typhus.152 She presented with headache and blurred vision following an insect bite to the right lower forehead. The occlusion of the branch retinal vein was believed to be due to vasculitis associated with scrub typhus.

Pregnancy related complications The clinical features of scrub typhus in pregnancy are, in general, no different to the usual manifestations, i.e., fever with chills, vomiting, myalgia, headache and abdominal pain. There is evidence of adverse pregnancy outcomes if scrub typhus is contracted during pregnancy. Pre-term delivery, miscarriages, small for gestational age babies, and neonatal death have been reported in women with scrub typhus infection during pregnancy.153–158 Pregnancy outcomes appear to be better in those who are treated early and appropriately, and there is some evidence to suggest that the choice of antibiotic matters, with azithromycin generally considered the favoured antibiotic in pregnancy.155–157 There are a few reports of vertical transmission of scrub typhus.159,160

Multi-organ dysfunction syndrome Multi-organ dysfunction syndrome is a commonly reported life threatening complication of scrub typhus.161,162 Among scrub typhus patients admitted to an intensive care unit in India, 85% of patients had dysfunction of three or more organ systems.162 Respiratory dysfunction is the commonest complication followed by haematological and cardiovascular complications. Dysfunction of all six organ systems was seen in 15%. Ventilatory support was required in 88%, and dialysis was required in 11%. The survival rate was 76% despite the complications.162 Patients usually respond to symptomatic treatment and antibiotic therapy.163

presence or absence of an eschar did not appear to relate to mortality.

Conclusions Classically a simple febrile illness with eschar and rash, scrub typhus has a myriad of atypical and unusual manifestations, affecting almost every organ system in the body. Some of these manifestations are serious and life threatening. While there is clear evidence that some of these manifestations are due to direct effects of the organism, it is also likely that some manifestations are immune-mediated. Scrub typhus should be an important differential diagnosis in patients presenting with acute febrile illness associated with organ involvement, in particular respiratory, neurological and cardiovascular dysfunction, especially in areas where scrub typhus is prevalent. We recommend routine screening of patients with such clinical features in areas of high endemicity. Also, awareness of the rarer manifestations is also important, and it is hoped that this review will guide clinicians towards suspecting the diagnosis of scrub typhus early when presented with unusual manifestations in the background of an acute febrile illness.

Authors’ contributions: SR conceived the review. SS and SR did the data searches. SS, SR and PW read through the abstracts and identified suitable papers, and extracted relevant data. PW and SDF checked the accuracy of the data extracted. SS wrote the first draft. SR and DF wrote the final draft, and all authors read and approved the final manuscript. SR is the guarantor of the paper. Funding: None. Competing interests: None declared. Ethical approval: Not required.

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