Indian J Pediatr DOI 10.1007/s12098-015-2001-2

ORIGINAL ARTICLE

CNS Manifestations in Orientia tsutsugamushi Disease (Scrub Typhus) in North India Ashwani Kumar Sood 1 & Lokesh Chauhan 1 & Hemant Gupta 1

Received: 25 June 2015 / Accepted: 16 December 2015 # Dr. K C Chaudhuri Foundation 2016

Abstract Objective To present the clinical, lab profile and outcome of a series of six children who had features of meningoencephalitis (median age of 10.5 y) diagnosed as confirmed scrub typhus (ST) by using a lgM ELISA commercial kit (InBiOS International Inc. USA). Methods This was a prospective observational study conducted at a tertiary care hospital, over a period of 7 mo through April 2014. All the patients with undifferentiated febrile illness (aged 1–18 y) with fever of 5–21 d duration were evaluated. After thorough physical examination they were subjected to blood investigations such as complete blood count (CBC), blood culture, hepatic and kidney function tests, serum electrolytes, cerebrospinal fluid (CSF) analysis and IgM ELISA for scrub typhus, coagulogram and chest radiograph, wherever indicated. Results During this period, of the total 81 confirmed cases based on a positive scrub IgM ELISA and/or eschar, 6 (7.4 %), had neurological involvement in the form of presence of neck stiffness, altered sensorium and/or seizures and the CSF findings were suggestive of meningoencephalitis and all had evidence of multiple organ dysfunction syndrome (MODS) needing intensive care. The CECT could be performed in four patients only showing evidence of effacement of sulci and evidence of brain edema. Conclusions This communication highlights that variable central nervous system (CNS) involvement is not uncommon in patients with scrub typhus with high mortality. CSF and

* Ashwani Kumar Sood [email protected] 1

Department of Pediatric & Adolescent Medicine, Indira Gandhi Medical College, Shimla, Himachal Pradesh 171001, India

neuro-radiology findings are nonspecific as these are also observed in patients with aseptic meningitis or encephalitis. Early suspection and institution of appropriate therapy without delay will lead to substantial reduction in the morbidity and mortality. Keywords Rickettsia . Children . Meningoencephalitis

Introduction Tsutsugamushi disease or scrub typhus (ST), a life threatening rickettsial zoonotic disease is highly endemic in the “tsutsugamushi triangle” extending from Afghanistan to China, Korea, the islands of the western Pacific and Indian Oceans and northern Australia [1, 2]. The word ‘typhus’ is Greek in origin and denotes ‘hazy’ or ‘smoky’, referring to the altered mental status of patients with rickettsial infections. The etiologic agent, Orientia tsutsugamushi is an obligate intracellular Gram-negative bacterium with eight major serotypes and is transmitted to humans through the bite of infected trombiculid mite larvae of the genus Leptotrombidium [3]. Scrub typhus is endemic in the tropical and subtropical regions of the Asian continent. It is a re-emerging infectious disease in India as well as in other parts of the world as per the recent reports from India, South Korea, northern China and Taiwan [4, 5]. More than one billion persons are at risk for scrub typhus, and approximately one million new cases occur every year [6]. It is also an important cause of acute undifferentiated febrile illnesses in India. Scrub typhus has diverse clinical manifestations ranging from a non-specific febrile illness to severe multi-organ dysfunction (MODS) with a wide spectrum of clinical manifestations such as fever, generalized lymphadenopathy, myalgia, headache, rashes, eschar, anorexia, gastrointestinal, pulmonary, renal, hematological and central nervous system (CNS)

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manifestations. Aseptic meningitis, encephalitis, seizures, isolated cranial nerve palsy, Landry-Guillain-Barré Syndrome (LGBS), stroke and deafness are some of reported CNS manifestations in adults [7–9]. However, there is limited published data on CNS manifestations of ST in pediatric population [10]. Most patients with ST recover without specific complications with an early diagnosis and management but clinical presentations of ST could be fatal if the diagnosis is delayed, at the extremes of age with greater bacterial load, in these circumstances the untreated case-fatality rate can vary from 7 to 30 % [11, 12]. CNS is the most crucial target in other rickettsial diseases, however, there have been several reports of encephalitis or meningitis without direct evidence of rickettsial invasion of the CNS in cases of ST. A recent retrospective study from Pondicherry reported meningitis in 17 patients with scrub typhus [10] but there is growing evidence in literature that O. tsutsugamushi does invade the CSF and CNS invasion may be seen in 2–5 % cases of tsutsugamushi disease [12] and in newer emerging areas, ST should be considered as one of the causes of aseptic meningitis during the seasonal outbreaks of ST [13–15]. Cranial nerve involvement such as unilateral or bilateral abducens palsies may occur with or without meningitis and facial palsy may ensue singly or in association with Guillain-Barré syndrome (GBS) [9]. This communication briefly describes the clinical and lab profile, course in the hospital and outcome of the ST patients with neurological manifestations admitted to a tertiary care teaching hospital in northern India (Table 1).

Material and Methods This was a prospective observational study conducted at a tertiary care hospital, over a period of 7 mo through April 2014 after obtaining informed consent from the parents or caregivers. All the patients with undifferentiated febrile illness (aged 1–18 y) with fever duration of 5–21 d were evaluated. After thorough physical examination these were subjected to blood investigations such as complete blood count (CBC), blood culture, hepatic and kidney function tests, serum electrolytes and IgM ELISA for scrub typhus, coagulogram and X- ray chest wherever indicated. Of 239 patients subjected for scrub serology, 81(33.4 %) were diagnosed as having scrub typhus based on immunoglobulin M (IgM) assay detecting IgM antibodies to Orientia tsutsugamushi derived recombinant antigens and/or presence of eschar. A confirmed diagnosis of scrub typhus was based on a positive scrub IgM ELISA (Scrub Typhus Detect™ IgM ELISA, InBios India), and an optical density (OD) > 0.5 was considered positive and the test was performed as per manufacturer’s instructions. Six of

the 81 patients (7.4 %) with altered sensorium, convulsions and/or focal neurological signs were also subjected to CSF analyses and only four could be subjected to computed tomography (CT) scan. Cerebrospinal fluid (CSF) was anlysed for cytology and biochemistry and the centrifuged deposit was subjected to the Gram and Ziehl Neilsen staining techniques to identify bacteria or acid fast bacilli and cultures were inoculated for bacterial or mycobacterial growth. Electroencephalogram (EEG) study could not be done due to logistic issues. The repeat CSF examination was not performed due to serological diagnosis and clinical improvement during the next 48–72 h after initiation of antimicrobials.

Results During the study period, of the total 81 confirmed cases based on a positive scrub IgM ELISA and/or eschar, 6 (7.4 %), in the age group of 1 to 17 y (median of 10.5), had neurological involvement in the form of presence of neck stiffness, altered sensorium and/or seizures. Majority of the patients were boys and all belonged to rural areas. All had presented late to the medical facility before being referred to authors’ institution with abrupt fever of 5–10 d duration (median: 7.5 d), with onset of impaired sensorium between day 3 to 5 of fever, with a median Pediatric Glasgow coma scale of 7.5. The characteristic inoculation eschar was seen only in 1(16.6 %) of the patients. Five patients also had hyperbilirubinemia at the time of presentation with raised aminotransferases in 4, four patients had abnormal kidney function test (KFT) as well as deranged coagulogram without bleeding manifestations, whereas three subjects had hypoalbuminemia at the time of admission as well. Generalized tonic clonic seizures (GTC) were present in three patients (50 %) and neck stiffness in one. One of the patients also had abducens nerve palsy. The CSF analysis was abnormal in 5/6 patients and showed raised protein with normal CSF glucose level with lymphocytosis varying between 150 and 400 cells/cumm. Neuroimaging (CT scan) could be done only in three of the patients in this study as remaining were critically ill. CECT study was normal in one subject whereas the other two had evidence of diffuse enhancement suggestive of brain edema. All the patients were administered ceftriaxone, doxycycline and/or azithromycin, of which only the doxycycline was continued pending serology and culture reports, which was modified later after the serological confirmation of diagnosis of ST, doxycycline 2.2 mg/kg per dose twice daily (maximum doses of 200 mg BID) was continued for a period of 7–10 d and two patients also received empirical acyclovir initially. Intravenous azithromycin was administered to the infant

Indian J Pediatr Table 1

Clinical features, laboratory manifestations and complications in confirmed scrub typhus patients with the involvement of CNS Patient 1

Patient 2

Patient 3

Patient 4

Patient 5

Patient 6

Age (years)/Sex

1/M

17/F

16/M

12/F

9/M

5/M

Duration of fever before admission Chills/Rigor Myalgia

8

7

5

10

8

6

− −

+ −

+ +

− +

+ −

− +

Lymphadenopathy Hepatomegaly

+ +/tender

+/tender +

+ −

− +/tender

+/tender



Splenomegaly Rash

+ −

+ −

+ −

+ Diffuse maculopapular

− −

+ −

Jaundice



+

+

+

+



GCS

12/15

8/15

9/15

7/15

6/15

7/15

Seizures Meningeal signs

+ −

− +

+ +

+ +

− +

− −

Eschar





+







BP (mm of Hg) Urea (mg/dl)

76/54 54

66/42 298

84/64 96

70/52 134

74/48 108

82/58 48

Creatinine (mg/dl) Total Protein/Albumin (g/dl) Bilirubin (mg/dl) (Total/ Conjugated) Aspartate aminotransferase (IU) Alanine aminotransferase (IU) Cranial nerve

1.3 6.2/4.2

5.7 3.8/2.0

1.6 4.0/1.9

2.3 3.6/1.6

1.9 3.4/1.2

1.8 5.8/3.6

1.2/0.68

2.8/1.81

5.00/2.91

4.80/2.69

3.8/2.34

1.4/.86

112 59 −

79 51 Abducens

163 91 −

198 482 −

204 87 −

57 103 −

Oliguria (2 organ involvement) and required multidisciplinary intensive care. Three patients required ventilatory support. One patient had significant acute kidney injury requiring dialysis and recovered completely from it over the next 10 d. All patients required intensive care for a minimum of 5.5 d before they could be shifted out to the high dependency unit (HDU). Two (33.3) out of the six succumbed due to multi organ dysfunction ND Not done; S/O Suggestive of

patient or added for the subjects who showed inadequate response to doxycycline, as intravenous doxycycline was not available in our country and concerns regarding the absorption of enteric administered doxycycline in critically ill patients. EEG study could not be carried out for logistic problems and three patients (50 %) presenting with GTC were also administered levetiracetam intravenously for 3 d followed by oral therapy. All the patients had evidence of multi-organ dysfunction syndrome (MODS) (>2 organ involvement) and required

multidisciplinary intensive care. Three patients required ventilatory support. One patient (16.6 %) had significant acute kidney injury requiring dialysis and recovered completely from it over the next 10 d. All patients required intensive care for a median of 6.5 d before they could be shifted out to the high dependency unit (HDU). Two (33 %) among the six succumbed to the illness due to MODS. Cerebrospinal fluid (CSF) findings in the index study were suggestive of meningoencephalitis with no feature exclusive to rickettsial infections.

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Discussion Orientia tsutsugamushi is an obligate intracellular pathogen of the family Rickettsiaceae, and is the causative organism of scrub typhus [1]. The natural vector and reservoir is trombiculid mite and the larval forms (chiggers) of trombiculid mite transmit the disease to humans and other vertebrates [16]. O. tsutsugamushi is a very common infection in Southeast Asia as well as in the western Pacific Rim countries and is being reported increasingly from various regions of the world for the last few years. Scrub typhus has protean clinical manifestations ranging from simple febrile illness to multi organ involvement, resulting in significant morbidity and mortality [17] and can present with a variety of CNS manifestations. CNS involvement, of the central and peripheral nervous system, is a known complication of ST ranging from aseptic meningitis to frank meningoencephalitis with or without involvement of cranial nerves [8–10]. The magnitude of this problem continues to be underestimated in many endemic areas, especially in India where scrub is fast becoming an important cause of CNS manifestations. Because infection with this organism often presents as febrile illness, number of studies have investigated mechanism of involvement of the CNS in Scrub [17, 18]. The probable mechanism of organisms to gain access to the CNS is following infection of circulating monocytes and invasion of endothelial cells [17]. Nuchal rigidity, seizures, delirium, and meningitis are reported CNS manifestations [16, 17]. Direct invasion of CNS [15] and invasion of CNS by the organism based on polymerase chain reaction (PCR) of cerebrospinal fluid (CSF) has been shown conclusively recently [15, 18] and the involvement is generally thought due to leptomeningeal infiltration. CNS involvement in scrub typhus has also been documented at autopsy [19]. The meninges are more commonly involved by O. tsutsugamushi than by other rickettsial infections, and the overall histological picture of CNS is best described as meningoencephalitis [20, 21]. Rickettsia invades and multiplies in the vascular endothelium and results in widespread vasculitis involving capillaries, arterioles and small arteries [22, 23]. Histiocytes, lymphocytes and plasma cell infiltration of the meninges and perivascular spaces have also been described. In the present series, diagnosis of ST was confirmed based on positive ELISA testing for IgM antibodies against O. tsutsugamushi. This test has shown good sensitivity and specificity and has been adequately validated [24–26]. In the index case series, 6 (7.4 %) had neurological involvement manifesting as meningoencephalitis. Systemic manifestations were more frequent in these patients with CNS involvement probably due to the relatively unique propensity of O. tsutsugamushi to cause multiple organ dysfunction by infecting vascular endothelial cells in ST [14].

CSF examination performed within 24 h of admission was abnormal in 5/6 patients in this series with raised protein, glucose values in normal range and lymphocytosis varying between 150 and 400 cells/cumm. In a retrospective analysis from South India, 17/65 (26 %) patients with ST had meningitis with presentation of comparatively low-grade fever and infrequent respiratory symptoms [10]. Twenty five cases of tsutsugamushi meningoencephalitis confirmed by rickettsial DNA tests from the CSF showed CSF WBC counts from 0 to 110/mm3 and CSF protein levels over 50 mg/dl [14]. In a Korean study, 89 patients with and 119 patients without severe complications due to ST were evaluated; 23 (11.3 %) patients with severe scrub also had meningoencephalitis [27] and all the patients with meningoencephalitis presented after 10 d of illness. A prospective study of Thai children revealed that scrub typhus was the second most common cause of aseptic meningitis next to Japanese encephalitis [15] whereas Varghese et al. [28] reported higher incidence of meningoencephalitis of 23.3 % in children compared to 9.5 % and 14 % in adults from India [28, 29]. A recent study from south India documented CNS involvement in 79 (41.8 %) of the study subjects with the confirmed scrub and abnormal CSF profile in 83 % of the patients [30]. Another study from rural western India also documented CSF abnormalities in majority of the pediatric patients in the age group of 1 mo–12 y; the limitations in this study being the use of Weil-Felix test for diagnosis [31]. A recent cross-sectional analysis of adult patients admitted with scrub typhus and bacterial meningitis to a tertiary care teaching institute in South India failed to demonstrate definite differentiating features in patients with bacterial or scrub meningitis/meningoencephalitis [14]. Multiple organ involvement in the form of acute respiratory distress syndrome (ARDS), azotemia, deranged liver enzymes and thrombocytopenia is common and is secondary to diffuse vasculitis [32]. The cases in present study had hyperbilirubinemia, raised

Fig. 1 Contrast Enhanced Computed Tomography (CECT) showing effacement of sulci and evidence of cerebral edema

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AST, evidence of AKI, abnormal coagulogram, hypoalbuminemia and generalised tonic clonic seizures (GTC), which is similar to as reported by earlier studies [28, 32, 33]. The index study contradicts the earlier perception that CNS involvement in scrub typhus is rare. There is some data describing radiological features in ST, but to best of authors’ knowledge no specific neuroradiological features pathognomic of ST have been described [34]. A Korean report documented neuroradiologic abnormalities on MRI mainly localised in periventricle and deep white matter in a patient of ST meningoencephalitis presenting with focal neurological signs [35] while Kar et al. reported abnormalities like diffuse cerebral edema along with T2-weighted and FLAIR hyper intensities in the putamen and thalamus, indicating primary involvement of the brain parenchyma on MR imaging in a case with ST meningoencephalitis whereas the index patients had only findings suggestive of diffuse brain edema on CT scan [36] (Fig. 1). As the rate of penetration of doxycycline into the brain or CSF is only 15–30 % of that into the bloodstream [37–39], whereas, the mean rifampin concentration of CSF is documented to be 0.73 mg/ml (range, 0.57–1.24 mg/ml), much higher than the minimum inhibitory concentration for O. tsutsugamushi [40], is concluding that rifampin appears to be more effective. The efficacy of azithromycin for CNS infection is controversial, because this drug penetrates the blood-brain barrier and lasts long in tissues, but has relatively low concentrations in CSF [41], whereas Jang et al. in their study observed that outcomes of azithromycin therapy are comparable to those of doxycycline therapy in patients with complicated scrub typhus [42]. Scrub typhus causes profound disturbances in T cell homeostasis [43], it suggests the possibility that mechanisms other than antibiotic resistance/failure are causes of CNS presentations. Rickettsial fever is known to respond dramatically to antimicrobial therapy within 48 h, and in the absence of such a response, the diagnosis of rickettsial fever needs to be reconsidered [44]. This communication highlights the observation that variable CNS involvement in children with ST is not uncommon. There is some data describing radiological features in scrub typhus [34, 36] but to best of authors’ knowledge no specific neuroradiological features pathognomic of scrub typhus have been described. This study is limited by its size; hence, it is difficult to say that the CSF abnormalities and imaging findings mentioned above are pathognomonic of scrub as these are also observed in aseptic meningitis or encephalitis too and hence, larger multi-centric studies on CSF characteristics and neuroradiology in ST infections with the involvement of CNS are warranted. Randomized controlled trials of doxycycline, azithromycin and rifampin in patients with ST meningitis and meningoencephalitis, and additional systematic studies

of the concentrations of doxycycline, azithromycin and rifampin achieved in brain tissue as well in CSF, are required to determine whether increasing the doxycycline dosage or using azithromycin or rifampin instead, will be more effective. Acknowledgments The authors acknowledge the support of the parents of the children and the residents and consultants and paramedics of the associated departments. Contributions AKS: Planning, conceptualization, editing, final analysis and submission of the manuscript; LC and HG: Enrollment, collection and analysis of data and follow-up. AKS will act as guarantor for the paper. Compliance with Ethical Standards Conflict of Interest None. Source of Funding None.

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CNS Manifestations in Orientia tsutsugamushi Disease (Scrub Typhus) in North India.

To present the clinical, lab profile and outcome of a series of six children who had features of meningoencephalitis (median age of 10.5 y) diagnosed ...
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