Clinical Profile of Scrub Typhus Meningoencephalitis among South Indian Children

Clinical Profile of Scrub Typhus Meningoencephalitis among South Indian Children Abstract Re-emerging scrub typhus is gaining recognition as an important cause of paediatric meningoencephalitis in tropics. We studied the clinical profile of scrub typhus meningoencephalitis (STME) in children <12 years. Of 270 serology-confirmed cases of scrub typhus, 14 (5%) had features consistent with STME and 9 (64%) of these children were between 5 and 12 years of age; 12 (85%) children presented to the hospital during the second week of illness. Fever, headache and altered sensorium were observed in all children, while meningeal signs, papilledema and seizures were observed in 8 (57%), 7 (50%) and 6 (43%) children, respectively. The mean CSF protein level, glucose level, cell count and percentage of lymphocytes were 75 mg/dl, 46 mg/dl, 41 cells and 86%, respectively. STME should be considered in febrile children from endemic area with neurological features, such as headache or altered sensorium. Lumbar puncture is mandatory to confirm STME and rule out close differential diagnosis, such as pyogenic and tubercular meningitis. scrub typhus, meningoencephalitis, neurological, children INTRODUCTION Scrub typhus is an acute febrile illness caused by obligate intracellular Gram-negative bacterium Orientia tsutsugamushi. The causative organism is transmitted by the bite of six-legged larval form (chigger) of trombiculid mite (Leptotrombidium). The rodents on which these mites (larval forms) normally feed act as a primary host, while human beings are accidental host [1]. Scrub typhus, once thought to be endemic in rural areas of Asia, is now re-emerging as an important cause of undifferentiated febrile illness in children from the urban and suburban parts of India, especially South India [2–4]. The wide spectrum of presentation seen in childhood scrub typhus, even among those from same geographical area, can be attributed to the genotypic diversity of the pathogen, host differences and other numerous unrecognized factors [4, 5]. Paediatric scrub typhus can range from mild, non-specific febrile illness to severe life-threatening condition with complications, such as myocarditis, meningoencephalitis, septic shock and acute respiratory distress syndrome [5, 6]. The vascular leak, oedema and ischaemic injury secondary to either hypotension or vasculitis by this vasculotropic organism are the main pathogenic mechanisms responsible for complications. Scrub typhus meningoencephalitis (STME) is the commonest presentation of central nervous system (CNS) involvement, and it is associated with higher morbidity and mortality [7]. Though there are many studies from adult population, data from paediatric population are limited. Most of our understanding about this condition is extrapolated from adult studies. This study was done with the objective of documenting the clinical presentation and outcome of STME in children. MATERIAL AND METHODS This prospective observational study was conducted in the paediatric department of a teaching hospital in South India after obtaining formal institutional ethical committee approval. All scrub typhus serology-positive children <12 years with CNS symptoms and cerebrospinal fluid (CSF) findings suggestive of meningoencephalitis were included in the study after obtaining a formal written informed consent from parents. The diagnosis of scrub typhus was made with IgM ELISA (InBios International, Inc., USA; optical density >0.5 was considered positive). Meningoencephalitis was defined by presence of both clinical and CSF features as per guidelines [8]. (A) Clinical features: (presence of any one or more of the following) Altered sensorium, headache, vomiting, seizures, nuchal rigidity, signs of raised intracranial pressure (ICP) AND (B) CSF findings: (presence of any one of the following) Elevated protein >45 mg/dl, CSF cells >5/mm3). • Children with either CNS symptoms or abnormal CSF findings alone were excluded. All children with undifferentiated fever for >7 days underwent scrub typhus serological testing by IgM ELISA. Children who developed neurological symptoms or signs during the course underwent lumbar puncture. Children fulfilling both clinical and CSF criteria were included in study. The demographic details, history and physical examination findings (including fundal examination), course in hospital and outcomes were documented. These children underwent complete blood count, liver function test, renal function test with serum electrolytes, urine albumin, prothrombin time (PT) and computed tomography (CT) brain if not done early, and results were documented. Statistical analysis was performed using the SPSS software, version 23.0 (SPSS Inc., Chicago, Ill., USA).The association between the clinical and laboratory parameters was determined using the chi-square test and univariate logistic regression analysis. Significant independent variables from the univariate analysis were used as the input variables for the multivariate analysis to determine the features associated with the occurrence of STME. The odds ratio (OR) with 95% confidence interval (CI) and p-values were obtained to examine the statistical significance of the study. p value of < 0.05 was taken as significant. RESULTS During the study period, 270 children tested positive for scrub typhus, of which 20 (7%) children had clinical features of meningitis. Six children were excluded from the study, as CSF analysis was not performed in three critically ill children, inconclusive CSF findings in two children, and one child had co-infection with malaria. Only 14 (5%) children who had both clinical features and CSF findings suggestive of STME were analysed. The demographic details are summarized in Table 1. All cases were seen between months of September and February. Table 1 Demographic data of children with STME Serial number Demographic data (n = 14) 1. Age distribution (years)  Infant <1 2  1–5 3  5–12 9  Mean age of presentation 6.9±2.7 years 2. Sex distribution  Male 7  Female 7 Serial number Demographic data (n = 14) 1. Age distribution (years)  Infant <1 2  1–5 3  5–12 9  Mean age of presentation 6.9±2.7 years 2. Sex distribution  Male 7  Female 7 Table 1 Demographic data of children with STME Serial number Demographic data (n = 14) 1. Age distribution (years)  Infant <1 2  1–5 3  5–12 9  Mean age of presentation 6.9±2.7 years 2. Sex distribution  Male 7  Female 7 Serial number Demographic data (n = 14) 1. Age distribution (years)  Infant <1 2  1–5 3  5–12 9  Mean age of presentation 6.9±2.7 years 2. Sex distribution  Male 7  Female 7 The children presented to our hospital during the second week of illness, with mean duration of fever of 11 ± 3 days (range: 7–19 days). The mean duration of hospital stay was 9 and 11 days for cases with and without eschar, respectively. The neurological features and CSF findings of the individual cases are summarized in Table 2. The clinical and laboratory features of 23 children with isolated neurological features, such as altered sensorium and headache (without CSF finding of meningoencephalitis), were compared with 14 children (included in our study). In univariate analysis, the following factors were statistically significant in STME group, viz children presenting in post-monsoon months (OR = 0.2, p < 0.001, CI = 0.04–1.7), dyspnoea (OR = 5.6, p = 0.018, CI = 0.08–6.32), vomiting (OR = 10, p = 0.04, CI = 1.11–89.7), hepatomegaly (OR = 0.08, p = 0.002, CI = 0.017–0.41), elevated hepatic transaminase (OR = 4, p = .04, CI = 1–21.7) and shock requiring inotrope (OR = 4.3, p = 0.03, CI = 1.2–15). However, none of these factors were found to be significant in multivariate logistic regression analysis. The clinical features, laboratory findings and complications are tabulated in Table 3. Table 2 Neurological features, neuroimaging, complications, CSF findings and outcome of children with STME (n = 14) Cases Clinical features Neurological finding Fever subsided post- therapy Complication CSF findings Out come General Eschar Fundus Imaging CT Protein Glucose Cells DC 1 Headache, vomiting, ALOC seizures, meningeal signs − Papilledema CT suggest ICP 3 Nil 62 40 22 P10 L 90 Recovered 2 Headache, vomiting, ALOC seizures, meningeal signs − Papilledema bilateral more on right side CT suggest ICP 5 Shock requiring inotrope+AKI 88 56 12 L100 ADA— Normal Persistent right sixth Nr palsy 3 Headache, vomiting, ALOC seizures − Papilledema Not done 3 Nil 77 34 30 P30L 70 Recovered 4 Headache, vomiting, ALOC seizures + Normal CT suggest ICP 4 Shock requiring inotrope 60 44 32 P28 L72 Recovered 5 Headache, ALOC, meningeal signs − Normal Not done 3 Nil 92 70 97 P10 L90 Recovered 6 Headache, ALOC, vomiting, meningeal signs + Papilledema Normal 2 Nil 77 45 97 P11 L89 Recovered 7 Headache, ALOC + Normal Normal 2 Nil 70 34 110 P25 L75 Recovered 8 Headache, ALOC, vomiting + Normal Normal 3 Nil 59 30 17 L100 Recovered 9 Headache, ALOC, meningeal signs − Papilledema Not done 3 Nil 64 45 14 L100 Recovered 10 Headache, ALOC, vomiting meningeal signs − Retinal haemorrhage + Papilledema CT suggest ICP 4 Severe thrombocytopenia 60 61 20 P25 L75 Recovered 11 Headache, ALOC, seizures + Normal Not done 2 Nil 69 40 30 P33 L67 Recovered 12 Headache, ALOC, meningeal signs − Normal Normal 4 Bleeding tendency+ prolonged PT 104 43 48 L100 Recovered 13 Headache, ALOC, seizures − Papilledema CT suggest ICP 3 Nil 89 32 33 P33 L67 Recovered 14 Headache, ALOC, meningeal signs + normal Not done 2 Nil 77 60 12 L100 Recovered Cases Clinical features Neurological finding Fever subsided post- therapy Complication CSF findings Out come General Eschar Fundus Imaging CT Protein Glucose Cells DC 1 Headache, vomiting, ALOC seizures, meningeal signs − Papilledema CT suggest ICP 3 Nil 62 40 22 P10 L 90 Recovered 2 Headache, vomiting, ALOC seizures, meningeal signs − Papilledema bilateral more on right side CT suggest ICP 5 Shock requiring inotrope+AKI 88 56 12 L100 ADA— Normal Persistent right sixth Nr palsy 3 Headache, vomiting, ALOC seizures − Papilledema Not done 3 Nil 77 34 30 P30L 70 Recovered 4 Headache, vomiting, ALOC seizures + Normal CT suggest ICP 4 Shock requiring inotrope 60 44 32 P28 L72 Recovered 5 Headache, ALOC, meningeal signs − Normal Not done 3 Nil 92 70 97 P10 L90 Recovered 6 Headache, ALOC, vomiting, meningeal signs + Papilledema Normal 2 Nil 77 45 97 P11 L89 Recovered 7 Headache, ALOC + Normal Normal 2 Nil 70 34 110 P25 L75 Recovered 8 Headache, ALOC, vomiting + Normal Normal 3 Nil 59 30 17 L100 Recovered 9 Headache, ALOC, meningeal signs − Papilledema Not done 3 Nil 64 45 14 L100 Recovered 10 Headache, ALOC, vomiting meningeal signs − Retinal haemorrhage + Papilledema CT suggest ICP 4 Severe thrombocytopenia 60 61 20 P25 L75 Recovered 11 Headache, ALOC, seizures + Normal Not done 2 Nil 69 40 30 P33 L67 Recovered 12 Headache, ALOC, meningeal signs − Normal Normal 4 Bleeding tendency+ prolonged PT 104 43 48 L100 Recovered 13 Headache, ALOC, seizures − Papilledema CT suggest ICP 3 Nil 89 32 33 P33 L67 Recovered 14 Headache, ALOC, meningeal signs + normal Not done 2 Nil 77 60 12 L100 Recovered Note: ALOC, altered level of consciousness; DC, differential count; P, polymorphonuclear cells; L, lymphocytes. Table 2 Neurological features, neuroimaging, complications, CSF findings and outcome of children with STME (n = 14) Cases Clinical features Neurological finding Fever subsided post- therapy Complication CSF findings Out come General Eschar Fundus Imaging CT Protein Glucose Cells DC 1 Headache, vomiting, ALOC seizures, meningeal signs − Papilledema CT suggest ICP 3 Nil 62 40 22 P10 L 90 Recovered 2 Headache, vomiting, ALOC seizures, meningeal signs − Papilledema bilateral more on right side CT suggest ICP 5 Shock requiring inotrope+AKI 88 56 12 L100 ADA— Normal Persistent right sixth Nr palsy 3 Headache, vomiting, ALOC seizures − Papilledema Not done 3 Nil 77 34 30 P30L 70 Recovered 4 Headache, vomiting, ALOC seizures + Normal CT suggest ICP 4 Shock requiring inotrope 60 44 32 P28 L72 Recovered 5 Headache, ALOC, meningeal signs − Normal Not done 3 Nil 92 70 97 P10 L90 Recovered 6 Headache, ALOC, vomiting, meningeal signs + Papilledema Normal 2 Nil 77 45 97 P11 L89 Recovered 7 Headache, ALOC + Normal Normal 2 Nil 70 34 110 P25 L75 Recovered 8 Headache, ALOC, vomiting + Normal Normal 3 Nil 59 30 17 L100 Recovered 9 Headache, ALOC, meningeal signs − Papilledema Not done 3 Nil 64 45 14 L100 Recovered 10 Headache, ALOC, vomiting meningeal signs − Retinal haemorrhage + Papilledema CT suggest ICP 4 Severe thrombocytopenia 60 61 20 P25 L75 Recovered 11 Headache, ALOC, seizures + Normal Not done 2 Nil 69 40 30 P33 L67 Recovered 12 Headache, ALOC, meningeal signs − Normal Normal 4 Bleeding tendency+ prolonged PT 104 43 48 L100 Recovered 13 Headache, ALOC, seizures − Papilledema CT suggest ICP 3 Nil 89 32 33 P33 L67 Recovered 14 Headache, ALOC, meningeal signs + normal Not done 2 Nil 77 60 12 L100 Recovered Cases Clinical features Neurological finding Fever subsided post- therapy Complication CSF findings Out come General Eschar Fundus Imaging CT Protein Glucose Cells DC 1 Headache, vomiting, ALOC seizures, meningeal signs − Papilledema CT suggest ICP 3 Nil 62 40 22 P10 L 90 Recovered 2 Headache, vomiting, ALOC seizures, meningeal signs − Papilledema bilateral more on right side CT suggest ICP 5 Shock requiring inotrope+AKI 88 56 12 L100 ADA— Normal Persistent right sixth Nr palsy 3 Headache, vomiting, ALOC seizures − Papilledema Not done 3 Nil 77 34 30 P30L 70 Recovered 4 Headache, vomiting, ALOC seizures + Normal CT suggest ICP 4 Shock requiring inotrope 60 44 32 P28 L72 Recovered 5 Headache, ALOC, meningeal signs − Normal Not done 3 Nil 92 70 97 P10 L90 Recovered 6 Headache, ALOC, vomiting, meningeal signs + Papilledema Normal 2 Nil 77 45 97 P11 L89 Recovered 7 Headache, ALOC + Normal Normal 2 Nil 70 34 110 P25 L75 Recovered 8 Headache, ALOC, vomiting + Normal Normal 3 Nil 59 30 17 L100 Recovered 9 Headache, ALOC, meningeal signs − Papilledema Not done 3 Nil 64 45 14 L100 Recovered 10 Headache, ALOC, vomiting meningeal signs − Retinal haemorrhage + Papilledema CT suggest ICP 4 Severe thrombocytopenia 60 61 20 P25 L75 Recovered 11 Headache, ALOC, seizures + Normal Not done 2 Nil 69 40 30 P33 L67 Recovered 12 Headache, ALOC, meningeal signs − Normal Normal 4 Bleeding tendency+ prolonged PT 104 43 48 L100 Recovered 13 Headache, ALOC, seizures − Papilledema CT suggest ICP 3 Nil 89 32 33 P33 L67 Recovered 14 Headache, ALOC, meningeal signs + normal Not done 2 Nil 77 60 12 L100 Recovered Note: ALOC, altered level of consciousness; DC, differential count; P, polymorphonuclear cells; L, lymphocytes. Table 3 Clinical and laboratory profile of children with STME Clinical profile Number of cases (n = 14) % Symptoms  Fever 14 100   7–14 days 12 85.7   >14 days 2 14.3  Cough 12 85.7  Vomiting 7 50  Headache 14 100  Myalgia 10 71.4  Abdomen pain/distension 5 35.7  Seizures 6 42.9 Signs  Altered level of consciousness 14 100  Pallor 11 78.6  Facial puffiness/oedema 9 64.3  Generalised lymphadenopathy 6 42.9  Eschar 6 42.9  Hepatomegaly 4 28.6  Splenomegaly 9 64.3  Papilledema 7 50  Nuchal rigidity 8 57 Laboratory profile  Total leukocyte count   Normal 3 21.4   Decreased 1 7.1   Increased 10 71.4  Neutrophilic leucocytosis 10 71.4  Thrombocytopenia (<150 000/mm3) 11 78.6  SGOT increased (>2 ULN IU/L) 12 85.7  SGPT increased (>2 ULN IU/L) 10 71.4  Hypoalbuminemia (<3 g/dl) 6 42.9  Bilirubin increased (>2 mg/dl) 3 21.4  Prolonged PT 1 7  Increased BUN/serum creatinine 1 7  Hyponatremia (<130 meq/l) 9 64.3  Albuminuria 8 57.1 Complications  Shock requiring inotrope + AKI 2 14  Severe thrombocytopenia (<20 000/mm3) 1 7  Bleeding tendency—upper gastrointestinal bleed 1 7 Clinical profile Number of cases (n = 14) % Symptoms  Fever 14 100   7–14 days 12 85.7   >14 days 2 14.3  Cough 12 85.7  Vomiting 7 50  Headache 14 100  Myalgia 10 71.4  Abdomen pain/distension 5 35.7  Seizures 6 42.9 Signs  Altered level of consciousness 14 100  Pallor 11 78.6  Facial puffiness/oedema 9 64.3  Generalised lymphadenopathy 6 42.9  Eschar 6 42.9  Hepatomegaly 4 28.6  Splenomegaly 9 64.3  Papilledema 7 50  Nuchal rigidity 8 57 Laboratory profile  Total leukocyte count   Normal 3 21.4   Decreased 1 7.1   Increased 10 71.4  Neutrophilic leucocytosis 10 71.4  Thrombocytopenia (<150 000/mm3) 11 78.6  SGOT increased (>2 ULN IU/L) 12 85.7  SGPT increased (>2 ULN IU/L) 10 71.4  Hypoalbuminemia (<3 g/dl) 6 42.9  Bilirubin increased (>2 mg/dl) 3 21.4  Prolonged PT 1 7  Increased BUN/serum creatinine 1 7  Hyponatremia (<130 meq/l) 9 64.3  Albuminuria 8 57.1 Complications  Shock requiring inotrope + AKI 2 14  Severe thrombocytopenia (<20 000/mm3) 1 7  Bleeding tendency—upper gastrointestinal bleed 1 7 Note: BUN, blood urea nitrogen; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic pyruvic transaminase; ULN, upper limit of normal. Table 3 Clinical and laboratory profile of children with STME Clinical profile Number of cases (n = 14) % Symptoms  Fever 14 100   7–14 days 12 85.7   >14 days 2 14.3  Cough 12 85.7  Vomiting 7 50  Headache 14 100  Myalgia 10 71.4  Abdomen pain/distension 5 35.7  Seizures 6 42.9 Signs  Altered level of consciousness 14 100  Pallor 11 78.6  Facial puffiness/oedema 9 64.3  Generalised lymphadenopathy 6 42.9  Eschar 6 42.9  Hepatomegaly 4 28.6  Splenomegaly 9 64.3  Papilledema 7 50  Nuchal rigidity 8 57 Laboratory profile  Total leukocyte count   Normal 3 21.4   Decreased 1 7.1   Increased 10 71.4  Neutrophilic leucocytosis 10 71.4  Thrombocytopenia (<150 000/mm3) 11 78.6  SGOT increased (>2 ULN IU/L) 12 85.7  SGPT increased (>2 ULN IU/L) 10 71.4  Hypoalbuminemia (<3 g/dl) 6 42.9  Bilirubin increased (>2 mg/dl) 3 21.4  Prolonged PT 1 7  Increased BUN/serum creatinine 1 7  Hyponatremia (<130 meq/l) 9 64.3  Albuminuria 8 57.1 Complications  Shock requiring inotrope + AKI 2 14  Severe thrombocytopenia (<20 000/mm3) 1 7  Bleeding tendency—upper gastrointestinal bleed 1 7 Clinical profile Number of cases (n = 14) % Symptoms  Fever 14 100   7–14 days 12 85.7   >14 days 2 14.3  Cough 12 85.7  Vomiting 7 50  Headache 14 100  Myalgia 10 71.4  Abdomen pain/distension 5 35.7  Seizures 6 42.9 Signs  Altered level of consciousness 14 100  Pallor 11 78.6  Facial puffiness/oedema 9 64.3  Generalised lymphadenopathy 6 42.9  Eschar 6 42.9  Hepatomegaly 4 28.6  Splenomegaly 9 64.3  Papilledema 7 50  Nuchal rigidity 8 57 Laboratory profile  Total leukocyte count   Normal 3 21.4   Decreased 1 7.1   Increased 10 71.4  Neutrophilic leucocytosis 10 71.4  Thrombocytopenia (<150 000/mm3) 11 78.6  SGOT increased (>2 ULN IU/L) 12 85.7  SGPT increased (>2 ULN IU/L) 10 71.4  Hypoalbuminemia (<3 g/dl) 6 42.9  Bilirubin increased (>2 mg/dl) 3 21.4  Prolonged PT 1 7  Increased BUN/serum creatinine 1 7  Hyponatremia (<130 meq/l) 9 64.3  Albuminuria 8 57.1 Complications  Shock requiring inotrope + AKI 2 14  Severe thrombocytopenia (<20 000/mm3) 1 7  Bleeding tendency—upper gastrointestinal bleed 1 7 Note: BUN, blood urea nitrogen; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic pyruvic transaminase; ULN, upper limit of normal. DISCUSSION Neurological involvement in rickettsiosis is known ever since typhus is recognized, as the term ‘typhus’ itself means ‘smoky or hazy mentation’. Focal exudates of mononuclear cells in the leptomeninges and haemorrhage in the brain parenchyma seen in the autopsy specimens of fatal scrub typhus cases reveal neurotropic nature of this organism [9]. Common clinical spectrum of CNS scrub typhus cases includes aseptic meningitis, meningoencephalitis, isolated cranial nerve palsies and Guillain–Barre syndrome [10]. In our study, all children with STME presented during post-monsoon and winter months of the year, i.e. between September and February. The growth of new vegetation following rainy season that harbours the vector and subsequent human exposure can explain the surge in scrub typhus during this period [11]. Similarly, the natural host, rodents (Suncus murinus and Rattus rattus) were heavily infested with vector species (Leptotrombidium deliense) during the same period in South India, explaining this seasonal trend [12]. The incidence of STME was more in older children (64%), between 5 and 12 years of age with mean age of presentation of 6.9 ± 2.7 years, similar to other studies [13]. Though most studies showed male preponderance, we found the distribution to be equal in both sexes [13, 14]. The commonest neurological feature was altered sensorium, and 85% of those children presented during the early second week of illness. The mean duration of fever was 11 ± 3 days (median: 10.5 days), which was higher than other similar studies (7–8 days) [13, 14]. This may be because of majority of cases referred from peripheral hospitals late in the course of illness. There was a relative delay in definitive diagnosis and treatment, as serology was performed only after 7 days of fever. Other common features were headache (100%) and nuchal rigidity (57%). Single episode of generalized tonic clonic seizure (GTCS) was the commonest type of seizure seen in 35% cases in our study, while one child presented with status epilepticus. Though GTCS is commonly seen, rare cases of focal seizures have been reported [15, 16]. Clinical features of raised ICP along with bilateral optic disc oedema were seen in 35% cases and all of them promptly responded to anti-oedema measures. The presence of raised ICP in STME varies widely from 7 to 33% in other similar studies, and delayed presentation could be a plausible explanation for such high rates of raised ICP in our study [13, 14]. However, 14% of cases had isolated optic disc oedema without clinical features of raised ICP raising the possibility of direct retinal involvement in scrub typhus [17]. Retinal involvement includes cotton wool spots, haemorrhage and optic disc swelling as a result of local vascular inflammation. Most cases of optic disc swelling are caused by local vascular changes rather than increased intracranial pressure [17]. In general, retinal involvement in systemic rickettsial infection had good visual prognosis [18]. Mean CSF protein (75 mg/dl) and glucose (46 mg/dl) were less when compared with other studies [13, 14, 19], while mean CSF cell count (41 cells) and percentage of lymphocytes (86%) were similar to most other published studies [13, 14]. So CSF picture in scrub typhus closely mimics that of partially treated pyogenic meningitis, early phase of tubercular meningitis and aseptic meningitis. However, presence of >50% lymphocytes and modestly elevated protein levels will point more towards STME [19]. There is conflicting data regarding the usefulness of CSF adenosine deaminase (ADA) levels in differentiating STME from tuberculous meningitis in adults [20, 21]. Diffuse brain oedema was the commonest finding in children with STME, which was seen in 55% of cases in our study. Few specific MRI brain findings reported in adult studies includes subcortical, periventricular involvement and cerebral microhaemorrhages [22]. However, because paediatric MRI was not conducted owing to non-affordability, data were lacking or were unavailable . The aspartate transaminase was the commonly elevated liver transaminase (85%), which was in contrast from an adult study where the elevation of alanine transaminase >60 U/l predicted STME [19]. Doxycycline was started on an average of Day 9 of illness for 43% cases with eschar, and the fever touched the baseline on an average of 60 h post-therapy. In the absence of eschar (57% cases), doxycycline was started on an average of Day 12 of illness, and it took 79 h for the fever to touch the baseline, which was higher when compared with other studies [13, 14]. However, presence of eschar did not correlate with development of STME or response to treatment [23]. The presence of eschar was significantly associated (p = 0.05) with lesser duration of hospital stay. Incidence of complications were higher in children without eschar (75%) than the ones with eschar (25%), and this can possibly explain the difference in duration of hospital stay. Though doxycycline is poorly distributed in brain, all but one case in our study responded promptly to doxycycline [24]. One child however developed shock and acute kidney injury (AKI) despite doxycycline administration, thus necessitating intravenous azithromycin administration. Thus, doxycycline was effective in 93% of cases. There is no difference noted between doxycycline and azithromycin in terms of fever defervescence, length of hospital stay or survival rates [24]. However, use of azithromycin in cases with poor response to doxycycline, especially in meningoencephalitis, has shown favourable outcome [25]. Shock requiring inotrope was the commonest complication seen (14%). The outcome was uniformly good with treatment in all children except one child who had persistent retinal oedema, which eventually resolved after 2 months. Small sample size, non-affordability to perform CSF DNA polymerase chain reaction, single serology sample for diagnosis and sampling after 7 days of fever were some of the limitations of our study. CONCLUSION The incidence of meningoencephalitis was 5% in children with scrub typhus and was seen commonly in 5–12 years, presenting late in the second week of illness during the post-monsoon months. Absence of seizures or meningeal signs did not rule out STME in these children. Presence of eschar was associated with lesser duration of hospital stay. CSF findings in STME closely mimic aseptic meningitis, early tubercular and partially treated pyogenic meningitis. Most of the children responded well to doxycycline. Shock was the commonest complication associated with STME. Optic disc oedema can be present even in the absence of raised ICP. STME should be considered as one of the differentials in all children hailing from the endemic area with fever for >7 days along with neurological features, such as headache or altered sensorium. Lumbar puncture is mandatory to confirm STME and rule out other important differential diagnosis. What is already known? Meningoencephalitis is a rare presentation of scrub typhus in Indian children. Altered sensorium commonly present in the first week of illness. What this study adds? STME was seen in 5% cases of serology-positive scrub typhus. Most STME cases presented during second week of illness. All STME cases occurred during post-monsoon months. Absence of seizures or meningeal signs does not rule out STME. Lumbar puncture is mandatory to confirm STME and rule out other close differentials, such as partially treated bacterial meningitis. Optic disc oedema can be present in the absence of raised intracranial pressure. 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Outcome of intravenous azithromycin therapy in patients with complicated scrub typhus compared with that of doxycycline therapy using propensity-matched analysis . Antimicrob Agents Chemother 2013 ; 58 : 1488 – 93 . Google Scholar CrossRef Search ADS PubMed 25 Dhanapriya J , Dineshkumar T , Sakthirajan R , et al. Scrub typhus meningitis in a renal transplant recipient . Indian J Nephrol 2017 ; 27 : 151 – 153 . http://dx.doi.org/10.4103/0971-4065.181883 Google Scholar CrossRef Search ADS PubMed © The Author [2017]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Tropical Pediatrics Oxford University Press

Clinical Profile of Scrub Typhus Meningoencephalitis among South Indian Children

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Abstract

Abstract Re-emerging scrub typhus is gaining recognition as an important cause of paediatric meningoencephalitis in tropics. We studied the clinical profile of scrub typhus meningoencephalitis (STME) in children <12 years. Of 270 serology-confirmed cases of scrub typhus, 14 (5%) had features consistent with STME and 9 (64%) of these children were between 5 and 12 years of age; 12 (85%) children presented to the hospital during the second week of illness. Fever, headache and altered sensorium were observed in all children, while meningeal signs, papilledema and seizures were observed in 8 (57%), 7 (50%) and 6 (43%) children, respectively. The mean CSF protein level, glucose level, cell count and percentage of lymphocytes were 75 mg/dl, 46 mg/dl, 41 cells and 86%, respectively. STME should be considered in febrile children from endemic area with neurological features, such as headache or altered sensorium. Lumbar puncture is mandatory to confirm STME and rule out close differential diagnosis, such as pyogenic and tubercular meningitis. scrub typhus, meningoencephalitis, neurological, children INTRODUCTION Scrub typhus is an acute febrile illness caused by obligate intracellular Gram-negative bacterium Orientia tsutsugamushi. The causative organism is transmitted by the bite of six-legged larval form (chigger) of trombiculid mite (Leptotrombidium). The rodents on which these mites (larval forms) normally feed act as a primary host, while human beings are accidental host [1]. Scrub typhus, once thought to be endemic in rural areas of Asia, is now re-emerging as an important cause of undifferentiated febrile illness in children from the urban and suburban parts of India, especially South India [2–4]. The wide spectrum of presentation seen in childhood scrub typhus, even among those from same geographical area, can be attributed to the genotypic diversity of the pathogen, host differences and other numerous unrecognized factors [4, 5]. Paediatric scrub typhus can range from mild, non-specific febrile illness to severe life-threatening condition with complications, such as myocarditis, meningoencephalitis, septic shock and acute respiratory distress syndrome [5, 6]. The vascular leak, oedema and ischaemic injury secondary to either hypotension or vasculitis by this vasculotropic organism are the main pathogenic mechanisms responsible for complications. Scrub typhus meningoencephalitis (STME) is the commonest presentation of central nervous system (CNS) involvement, and it is associated with higher morbidity and mortality [7]. Though there are many studies from adult population, data from paediatric population are limited. Most of our understanding about this condition is extrapolated from adult studies. This study was done with the objective of documenting the clinical presentation and outcome of STME in children. MATERIAL AND METHODS This prospective observational study was conducted in the paediatric department of a teaching hospital in South India after obtaining formal institutional ethical committee approval. All scrub typhus serology-positive children <12 years with CNS symptoms and cerebrospinal fluid (CSF) findings suggestive of meningoencephalitis were included in the study after obtaining a formal written informed consent from parents. The diagnosis of scrub typhus was made with IgM ELISA (InBios International, Inc., USA; optical density >0.5 was considered positive). Meningoencephalitis was defined by presence of both clinical and CSF features as per guidelines [8]. (A) Clinical features: (presence of any one or more of the following) Altered sensorium, headache, vomiting, seizures, nuchal rigidity, signs of raised intracranial pressure (ICP) AND (B) CSF findings: (presence of any one of the following) Elevated protein >45 mg/dl, CSF cells >5/mm3). • Children with either CNS symptoms or abnormal CSF findings alone were excluded. All children with undifferentiated fever for >7 days underwent scrub typhus serological testing by IgM ELISA. Children who developed neurological symptoms or signs during the course underwent lumbar puncture. Children fulfilling both clinical and CSF criteria were included in study. The demographic details, history and physical examination findings (including fundal examination), course in hospital and outcomes were documented. These children underwent complete blood count, liver function test, renal function test with serum electrolytes, urine albumin, prothrombin time (PT) and computed tomography (CT) brain if not done early, and results were documented. Statistical analysis was performed using the SPSS software, version 23.0 (SPSS Inc., Chicago, Ill., USA).The association between the clinical and laboratory parameters was determined using the chi-square test and univariate logistic regression analysis. Significant independent variables from the univariate analysis were used as the input variables for the multivariate analysis to determine the features associated with the occurrence of STME. The odds ratio (OR) with 95% confidence interval (CI) and p-values were obtained to examine the statistical significance of the study. p value of < 0.05 was taken as significant. RESULTS During the study period, 270 children tested positive for scrub typhus, of which 20 (7%) children had clinical features of meningitis. Six children were excluded from the study, as CSF analysis was not performed in three critically ill children, inconclusive CSF findings in two children, and one child had co-infection with malaria. Only 14 (5%) children who had both clinical features and CSF findings suggestive of STME were analysed. The demographic details are summarized in Table 1. All cases were seen between months of September and February. Table 1 Demographic data of children with STME Serial number Demographic data (n = 14) 1. Age distribution (years)  Infant <1 2  1–5 3  5–12 9  Mean age of presentation 6.9±2.7 years 2. Sex distribution  Male 7  Female 7 Serial number Demographic data (n = 14) 1. Age distribution (years)  Infant <1 2  1–5 3  5–12 9  Mean age of presentation 6.9±2.7 years 2. Sex distribution  Male 7  Female 7 Table 1 Demographic data of children with STME Serial number Demographic data (n = 14) 1. Age distribution (years)  Infant <1 2  1–5 3  5–12 9  Mean age of presentation 6.9±2.7 years 2. Sex distribution  Male 7  Female 7 Serial number Demographic data (n = 14) 1. Age distribution (years)  Infant <1 2  1–5 3  5–12 9  Mean age of presentation 6.9±2.7 years 2. Sex distribution  Male 7  Female 7 The children presented to our hospital during the second week of illness, with mean duration of fever of 11 ± 3 days (range: 7–19 days). The mean duration of hospital stay was 9 and 11 days for cases with and without eschar, respectively. The neurological features and CSF findings of the individual cases are summarized in Table 2. The clinical and laboratory features of 23 children with isolated neurological features, such as altered sensorium and headache (without CSF finding of meningoencephalitis), were compared with 14 children (included in our study). In univariate analysis, the following factors were statistically significant in STME group, viz children presenting in post-monsoon months (OR = 0.2, p < 0.001, CI = 0.04–1.7), dyspnoea (OR = 5.6, p = 0.018, CI = 0.08–6.32), vomiting (OR = 10, p = 0.04, CI = 1.11–89.7), hepatomegaly (OR = 0.08, p = 0.002, CI = 0.017–0.41), elevated hepatic transaminase (OR = 4, p = .04, CI = 1–21.7) and shock requiring inotrope (OR = 4.3, p = 0.03, CI = 1.2–15). However, none of these factors were found to be significant in multivariate logistic regression analysis. The clinical features, laboratory findings and complications are tabulated in Table 3. Table 2 Neurological features, neuroimaging, complications, CSF findings and outcome of children with STME (n = 14) Cases Clinical features Neurological finding Fever subsided post- therapy Complication CSF findings Out come General Eschar Fundus Imaging CT Protein Glucose Cells DC 1 Headache, vomiting, ALOC seizures, meningeal signs − Papilledema CT suggest ICP 3 Nil 62 40 22 P10 L 90 Recovered 2 Headache, vomiting, ALOC seizures, meningeal signs − Papilledema bilateral more on right side CT suggest ICP 5 Shock requiring inotrope+AKI 88 56 12 L100 ADA— Normal Persistent right sixth Nr palsy 3 Headache, vomiting, ALOC seizures − Papilledema Not done 3 Nil 77 34 30 P30L 70 Recovered 4 Headache, vomiting, ALOC seizures + Normal CT suggest ICP 4 Shock requiring inotrope 60 44 32 P28 L72 Recovered 5 Headache, ALOC, meningeal signs − Normal Not done 3 Nil 92 70 97 P10 L90 Recovered 6 Headache, ALOC, vomiting, meningeal signs + Papilledema Normal 2 Nil 77 45 97 P11 L89 Recovered 7 Headache, ALOC + Normal Normal 2 Nil 70 34 110 P25 L75 Recovered 8 Headache, ALOC, vomiting + Normal Normal 3 Nil 59 30 17 L100 Recovered 9 Headache, ALOC, meningeal signs − Papilledema Not done 3 Nil 64 45 14 L100 Recovered 10 Headache, ALOC, vomiting meningeal signs − Retinal haemorrhage + Papilledema CT suggest ICP 4 Severe thrombocytopenia 60 61 20 P25 L75 Recovered 11 Headache, ALOC, seizures + Normal Not done 2 Nil 69 40 30 P33 L67 Recovered 12 Headache, ALOC, meningeal signs − Normal Normal 4 Bleeding tendency+ prolonged PT 104 43 48 L100 Recovered 13 Headache, ALOC, seizures − Papilledema CT suggest ICP 3 Nil 89 32 33 P33 L67 Recovered 14 Headache, ALOC, meningeal signs + normal Not done 2 Nil 77 60 12 L100 Recovered Cases Clinical features Neurological finding Fever subsided post- therapy Complication CSF findings Out come General Eschar Fundus Imaging CT Protein Glucose Cells DC 1 Headache, vomiting, ALOC seizures, meningeal signs − Papilledema CT suggest ICP 3 Nil 62 40 22 P10 L 90 Recovered 2 Headache, vomiting, ALOC seizures, meningeal signs − Papilledema bilateral more on right side CT suggest ICP 5 Shock requiring inotrope+AKI 88 56 12 L100 ADA— Normal Persistent right sixth Nr palsy 3 Headache, vomiting, ALOC seizures − Papilledema Not done 3 Nil 77 34 30 P30L 70 Recovered 4 Headache, vomiting, ALOC seizures + Normal CT suggest ICP 4 Shock requiring inotrope 60 44 32 P28 L72 Recovered 5 Headache, ALOC, meningeal signs − Normal Not done 3 Nil 92 70 97 P10 L90 Recovered 6 Headache, ALOC, vomiting, meningeal signs + Papilledema Normal 2 Nil 77 45 97 P11 L89 Recovered 7 Headache, ALOC + Normal Normal 2 Nil 70 34 110 P25 L75 Recovered 8 Headache, ALOC, vomiting + Normal Normal 3 Nil 59 30 17 L100 Recovered 9 Headache, ALOC, meningeal signs − Papilledema Not done 3 Nil 64 45 14 L100 Recovered 10 Headache, ALOC, vomiting meningeal signs − Retinal haemorrhage + Papilledema CT suggest ICP 4 Severe thrombocytopenia 60 61 20 P25 L75 Recovered 11 Headache, ALOC, seizures + Normal Not done 2 Nil 69 40 30 P33 L67 Recovered 12 Headache, ALOC, meningeal signs − Normal Normal 4 Bleeding tendency+ prolonged PT 104 43 48 L100 Recovered 13 Headache, ALOC, seizures − Papilledema CT suggest ICP 3 Nil 89 32 33 P33 L67 Recovered 14 Headache, ALOC, meningeal signs + normal Not done 2 Nil 77 60 12 L100 Recovered Note: ALOC, altered level of consciousness; DC, differential count; P, polymorphonuclear cells; L, lymphocytes. Table 2 Neurological features, neuroimaging, complications, CSF findings and outcome of children with STME (n = 14) Cases Clinical features Neurological finding Fever subsided post- therapy Complication CSF findings Out come General Eschar Fundus Imaging CT Protein Glucose Cells DC 1 Headache, vomiting, ALOC seizures, meningeal signs − Papilledema CT suggest ICP 3 Nil 62 40 22 P10 L 90 Recovered 2 Headache, vomiting, ALOC seizures, meningeal signs − Papilledema bilateral more on right side CT suggest ICP 5 Shock requiring inotrope+AKI 88 56 12 L100 ADA— Normal Persistent right sixth Nr palsy 3 Headache, vomiting, ALOC seizures − Papilledema Not done 3 Nil 77 34 30 P30L 70 Recovered 4 Headache, vomiting, ALOC seizures + Normal CT suggest ICP 4 Shock requiring inotrope 60 44 32 P28 L72 Recovered 5 Headache, ALOC, meningeal signs − Normal Not done 3 Nil 92 70 97 P10 L90 Recovered 6 Headache, ALOC, vomiting, meningeal signs + Papilledema Normal 2 Nil 77 45 97 P11 L89 Recovered 7 Headache, ALOC + Normal Normal 2 Nil 70 34 110 P25 L75 Recovered 8 Headache, ALOC, vomiting + Normal Normal 3 Nil 59 30 17 L100 Recovered 9 Headache, ALOC, meningeal signs − Papilledema Not done 3 Nil 64 45 14 L100 Recovered 10 Headache, ALOC, vomiting meningeal signs − Retinal haemorrhage + Papilledema CT suggest ICP 4 Severe thrombocytopenia 60 61 20 P25 L75 Recovered 11 Headache, ALOC, seizures + Normal Not done 2 Nil 69 40 30 P33 L67 Recovered 12 Headache, ALOC, meningeal signs − Normal Normal 4 Bleeding tendency+ prolonged PT 104 43 48 L100 Recovered 13 Headache, ALOC, seizures − Papilledema CT suggest ICP 3 Nil 89 32 33 P33 L67 Recovered 14 Headache, ALOC, meningeal signs + normal Not done 2 Nil 77 60 12 L100 Recovered Cases Clinical features Neurological finding Fever subsided post- therapy Complication CSF findings Out come General Eschar Fundus Imaging CT Protein Glucose Cells DC 1 Headache, vomiting, ALOC seizures, meningeal signs − Papilledema CT suggest ICP 3 Nil 62 40 22 P10 L 90 Recovered 2 Headache, vomiting, ALOC seizures, meningeal signs − Papilledema bilateral more on right side CT suggest ICP 5 Shock requiring inotrope+AKI 88 56 12 L100 ADA— Normal Persistent right sixth Nr palsy 3 Headache, vomiting, ALOC seizures − Papilledema Not done 3 Nil 77 34 30 P30L 70 Recovered 4 Headache, vomiting, ALOC seizures + Normal CT suggest ICP 4 Shock requiring inotrope 60 44 32 P28 L72 Recovered 5 Headache, ALOC, meningeal signs − Normal Not done 3 Nil 92 70 97 P10 L90 Recovered 6 Headache, ALOC, vomiting, meningeal signs + Papilledema Normal 2 Nil 77 45 97 P11 L89 Recovered 7 Headache, ALOC + Normal Normal 2 Nil 70 34 110 P25 L75 Recovered 8 Headache, ALOC, vomiting + Normal Normal 3 Nil 59 30 17 L100 Recovered 9 Headache, ALOC, meningeal signs − Papilledema Not done 3 Nil 64 45 14 L100 Recovered 10 Headache, ALOC, vomiting meningeal signs − Retinal haemorrhage + Papilledema CT suggest ICP 4 Severe thrombocytopenia 60 61 20 P25 L75 Recovered 11 Headache, ALOC, seizures + Normal Not done 2 Nil 69 40 30 P33 L67 Recovered 12 Headache, ALOC, meningeal signs − Normal Normal 4 Bleeding tendency+ prolonged PT 104 43 48 L100 Recovered 13 Headache, ALOC, seizures − Papilledema CT suggest ICP 3 Nil 89 32 33 P33 L67 Recovered 14 Headache, ALOC, meningeal signs + normal Not done 2 Nil 77 60 12 L100 Recovered Note: ALOC, altered level of consciousness; DC, differential count; P, polymorphonuclear cells; L, lymphocytes. Table 3 Clinical and laboratory profile of children with STME Clinical profile Number of cases (n = 14) % Symptoms  Fever 14 100   7–14 days 12 85.7   >14 days 2 14.3  Cough 12 85.7  Vomiting 7 50  Headache 14 100  Myalgia 10 71.4  Abdomen pain/distension 5 35.7  Seizures 6 42.9 Signs  Altered level of consciousness 14 100  Pallor 11 78.6  Facial puffiness/oedema 9 64.3  Generalised lymphadenopathy 6 42.9  Eschar 6 42.9  Hepatomegaly 4 28.6  Splenomegaly 9 64.3  Papilledema 7 50  Nuchal rigidity 8 57 Laboratory profile  Total leukocyte count   Normal 3 21.4   Decreased 1 7.1   Increased 10 71.4  Neutrophilic leucocytosis 10 71.4  Thrombocytopenia (<150 000/mm3) 11 78.6  SGOT increased (>2 ULN IU/L) 12 85.7  SGPT increased (>2 ULN IU/L) 10 71.4  Hypoalbuminemia (<3 g/dl) 6 42.9  Bilirubin increased (>2 mg/dl) 3 21.4  Prolonged PT 1 7  Increased BUN/serum creatinine 1 7  Hyponatremia (<130 meq/l) 9 64.3  Albuminuria 8 57.1 Complications  Shock requiring inotrope + AKI 2 14  Severe thrombocytopenia (<20 000/mm3) 1 7  Bleeding tendency—upper gastrointestinal bleed 1 7 Clinical profile Number of cases (n = 14) % Symptoms  Fever 14 100   7–14 days 12 85.7   >14 days 2 14.3  Cough 12 85.7  Vomiting 7 50  Headache 14 100  Myalgia 10 71.4  Abdomen pain/distension 5 35.7  Seizures 6 42.9 Signs  Altered level of consciousness 14 100  Pallor 11 78.6  Facial puffiness/oedema 9 64.3  Generalised lymphadenopathy 6 42.9  Eschar 6 42.9  Hepatomegaly 4 28.6  Splenomegaly 9 64.3  Papilledema 7 50  Nuchal rigidity 8 57 Laboratory profile  Total leukocyte count   Normal 3 21.4   Decreased 1 7.1   Increased 10 71.4  Neutrophilic leucocytosis 10 71.4  Thrombocytopenia (<150 000/mm3) 11 78.6  SGOT increased (>2 ULN IU/L) 12 85.7  SGPT increased (>2 ULN IU/L) 10 71.4  Hypoalbuminemia (<3 g/dl) 6 42.9  Bilirubin increased (>2 mg/dl) 3 21.4  Prolonged PT 1 7  Increased BUN/serum creatinine 1 7  Hyponatremia (<130 meq/l) 9 64.3  Albuminuria 8 57.1 Complications  Shock requiring inotrope + AKI 2 14  Severe thrombocytopenia (<20 000/mm3) 1 7  Bleeding tendency—upper gastrointestinal bleed 1 7 Note: BUN, blood urea nitrogen; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic pyruvic transaminase; ULN, upper limit of normal. Table 3 Clinical and laboratory profile of children with STME Clinical profile Number of cases (n = 14) % Symptoms  Fever 14 100   7–14 days 12 85.7   >14 days 2 14.3  Cough 12 85.7  Vomiting 7 50  Headache 14 100  Myalgia 10 71.4  Abdomen pain/distension 5 35.7  Seizures 6 42.9 Signs  Altered level of consciousness 14 100  Pallor 11 78.6  Facial puffiness/oedema 9 64.3  Generalised lymphadenopathy 6 42.9  Eschar 6 42.9  Hepatomegaly 4 28.6  Splenomegaly 9 64.3  Papilledema 7 50  Nuchal rigidity 8 57 Laboratory profile  Total leukocyte count   Normal 3 21.4   Decreased 1 7.1   Increased 10 71.4  Neutrophilic leucocytosis 10 71.4  Thrombocytopenia (<150 000/mm3) 11 78.6  SGOT increased (>2 ULN IU/L) 12 85.7  SGPT increased (>2 ULN IU/L) 10 71.4  Hypoalbuminemia (<3 g/dl) 6 42.9  Bilirubin increased (>2 mg/dl) 3 21.4  Prolonged PT 1 7  Increased BUN/serum creatinine 1 7  Hyponatremia (<130 meq/l) 9 64.3  Albuminuria 8 57.1 Complications  Shock requiring inotrope + AKI 2 14  Severe thrombocytopenia (<20 000/mm3) 1 7  Bleeding tendency—upper gastrointestinal bleed 1 7 Clinical profile Number of cases (n = 14) % Symptoms  Fever 14 100   7–14 days 12 85.7   >14 days 2 14.3  Cough 12 85.7  Vomiting 7 50  Headache 14 100  Myalgia 10 71.4  Abdomen pain/distension 5 35.7  Seizures 6 42.9 Signs  Altered level of consciousness 14 100  Pallor 11 78.6  Facial puffiness/oedema 9 64.3  Generalised lymphadenopathy 6 42.9  Eschar 6 42.9  Hepatomegaly 4 28.6  Splenomegaly 9 64.3  Papilledema 7 50  Nuchal rigidity 8 57 Laboratory profile  Total leukocyte count   Normal 3 21.4   Decreased 1 7.1   Increased 10 71.4  Neutrophilic leucocytosis 10 71.4  Thrombocytopenia (<150 000/mm3) 11 78.6  SGOT increased (>2 ULN IU/L) 12 85.7  SGPT increased (>2 ULN IU/L) 10 71.4  Hypoalbuminemia (<3 g/dl) 6 42.9  Bilirubin increased (>2 mg/dl) 3 21.4  Prolonged PT 1 7  Increased BUN/serum creatinine 1 7  Hyponatremia (<130 meq/l) 9 64.3  Albuminuria 8 57.1 Complications  Shock requiring inotrope + AKI 2 14  Severe thrombocytopenia (<20 000/mm3) 1 7  Bleeding tendency—upper gastrointestinal bleed 1 7 Note: BUN, blood urea nitrogen; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic pyruvic transaminase; ULN, upper limit of normal. DISCUSSION Neurological involvement in rickettsiosis is known ever since typhus is recognized, as the term ‘typhus’ itself means ‘smoky or hazy mentation’. Focal exudates of mononuclear cells in the leptomeninges and haemorrhage in the brain parenchyma seen in the autopsy specimens of fatal scrub typhus cases reveal neurotropic nature of this organism [9]. Common clinical spectrum of CNS scrub typhus cases includes aseptic meningitis, meningoencephalitis, isolated cranial nerve palsies and Guillain–Barre syndrome [10]. In our study, all children with STME presented during post-monsoon and winter months of the year, i.e. between September and February. The growth of new vegetation following rainy season that harbours the vector and subsequent human exposure can explain the surge in scrub typhus during this period [11]. Similarly, the natural host, rodents (Suncus murinus and Rattus rattus) were heavily infested with vector species (Leptotrombidium deliense) during the same period in South India, explaining this seasonal trend [12]. The incidence of STME was more in older children (64%), between 5 and 12 years of age with mean age of presentation of 6.9 ± 2.7 years, similar to other studies [13]. Though most studies showed male preponderance, we found the distribution to be equal in both sexes [13, 14]. The commonest neurological feature was altered sensorium, and 85% of those children presented during the early second week of illness. The mean duration of fever was 11 ± 3 days (median: 10.5 days), which was higher than other similar studies (7–8 days) [13, 14]. This may be because of majority of cases referred from peripheral hospitals late in the course of illness. There was a relative delay in definitive diagnosis and treatment, as serology was performed only after 7 days of fever. Other common features were headache (100%) and nuchal rigidity (57%). Single episode of generalized tonic clonic seizure (GTCS) was the commonest type of seizure seen in 35% cases in our study, while one child presented with status epilepticus. Though GTCS is commonly seen, rare cases of focal seizures have been reported [15, 16]. Clinical features of raised ICP along with bilateral optic disc oedema were seen in 35% cases and all of them promptly responded to anti-oedema measures. The presence of raised ICP in STME varies widely from 7 to 33% in other similar studies, and delayed presentation could be a plausible explanation for such high rates of raised ICP in our study [13, 14]. However, 14% of cases had isolated optic disc oedema without clinical features of raised ICP raising the possibility of direct retinal involvement in scrub typhus [17]. Retinal involvement includes cotton wool spots, haemorrhage and optic disc swelling as a result of local vascular inflammation. Most cases of optic disc swelling are caused by local vascular changes rather than increased intracranial pressure [17]. In general, retinal involvement in systemic rickettsial infection had good visual prognosis [18]. Mean CSF protein (75 mg/dl) and glucose (46 mg/dl) were less when compared with other studies [13, 14, 19], while mean CSF cell count (41 cells) and percentage of lymphocytes (86%) were similar to most other published studies [13, 14]. So CSF picture in scrub typhus closely mimics that of partially treated pyogenic meningitis, early phase of tubercular meningitis and aseptic meningitis. However, presence of >50% lymphocytes and modestly elevated protein levels will point more towards STME [19]. There is conflicting data regarding the usefulness of CSF adenosine deaminase (ADA) levels in differentiating STME from tuberculous meningitis in adults [20, 21]. Diffuse brain oedema was the commonest finding in children with STME, which was seen in 55% of cases in our study. Few specific MRI brain findings reported in adult studies includes subcortical, periventricular involvement and cerebral microhaemorrhages [22]. However, because paediatric MRI was not conducted owing to non-affordability, data were lacking or were unavailable . The aspartate transaminase was the commonly elevated liver transaminase (85%), which was in contrast from an adult study where the elevation of alanine transaminase >60 U/l predicted STME [19]. Doxycycline was started on an average of Day 9 of illness for 43% cases with eschar, and the fever touched the baseline on an average of 60 h post-therapy. In the absence of eschar (57% cases), doxycycline was started on an average of Day 12 of illness, and it took 79 h for the fever to touch the baseline, which was higher when compared with other studies [13, 14]. However, presence of eschar did not correlate with development of STME or response to treatment [23]. The presence of eschar was significantly associated (p = 0.05) with lesser duration of hospital stay. Incidence of complications were higher in children without eschar (75%) than the ones with eschar (25%), and this can possibly explain the difference in duration of hospital stay. Though doxycycline is poorly distributed in brain, all but one case in our study responded promptly to doxycycline [24]. One child however developed shock and acute kidney injury (AKI) despite doxycycline administration, thus necessitating intravenous azithromycin administration. Thus, doxycycline was effective in 93% of cases. There is no difference noted between doxycycline and azithromycin in terms of fever defervescence, length of hospital stay or survival rates [24]. However, use of azithromycin in cases with poor response to doxycycline, especially in meningoencephalitis, has shown favourable outcome [25]. Shock requiring inotrope was the commonest complication seen (14%). The outcome was uniformly good with treatment in all children except one child who had persistent retinal oedema, which eventually resolved after 2 months. Small sample size, non-affordability to perform CSF DNA polymerase chain reaction, single serology sample for diagnosis and sampling after 7 days of fever were some of the limitations of our study. CONCLUSION The incidence of meningoencephalitis was 5% in children with scrub typhus and was seen commonly in 5–12 years, presenting late in the second week of illness during the post-monsoon months. Absence of seizures or meningeal signs did not rule out STME in these children. Presence of eschar was associated with lesser duration of hospital stay. CSF findings in STME closely mimic aseptic meningitis, early tubercular and partially treated pyogenic meningitis. Most of the children responded well to doxycycline. Shock was the commonest complication associated with STME. Optic disc oedema can be present even in the absence of raised ICP. STME should be considered as one of the differentials in all children hailing from the endemic area with fever for >7 days along with neurological features, such as headache or altered sensorium. Lumbar puncture is mandatory to confirm STME and rule out other important differential diagnosis. What is already known? Meningoencephalitis is a rare presentation of scrub typhus in Indian children. Altered sensorium commonly present in the first week of illness. What this study adds? STME was seen in 5% cases of serology-positive scrub typhus. Most STME cases presented during second week of illness. All STME cases occurred during post-monsoon months. Absence of seizures or meningeal signs does not rule out STME. Lumbar puncture is mandatory to confirm STME and rule out other close differentials, such as partially treated bacterial meningitis. Optic disc oedema can be present in the absence of raised intracranial pressure. 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Journal of Tropical PediatricsOxford University Press

Published: Dec 18, 2017

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