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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 9  |  Issue : 3  |  Page : 84-89

Severe scrub typhus infection in infancy with multiple organ dysfunction: A retrospective observational study from Eastern India


1 Department of Pediatric Medicine, Institute of Child Health, Medical College Kolkata, Kolkata, West Bengal, India
2 Department of Pediatric Medicine, Medical College Kolkata, Kolkata, West Bengal, India

Date of Submission20-Jan-2022
Date of Decision06-Mar-2022
Date of Acceptance08-Mar-2022
Date of Web Publication12-May-2022

Correspondence Address:
Dr. Sanchari Ghosh
Department of Pediatric Medicine, Institute of Child Health, Kolkata - 700 017, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpcc.jpcc_10_22

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  Abstract 


Background: Scrub typhus is relatively less common among infants but found to have a mentionable association with multiple organ dysfunction and turbulent course. The aim of this study was to delineate the clinicolaboratory profile of infantile scrub typhus, complication, course of illness, and responsiveness to therapy.
Subjects and Methods: This retrospective observational study was undertaken in two tertiary care pediatric teaching centers in eastern India among infants with diagnosis of scrub typhus. Clinical features, especially pattern of organ dysfunction, laboratory findings with emphasis on hyperferritinemia, and treatment schedules with responsiveness to therapy, were analyzed retrospectively.
Results: A total of 272 cases of scrub typhus had been admitted during the study period. Among them, 17 kids (6.25%) were infants. All of them presented with lethargy and poor feeding as a common complaint along with seizures and respiratory distress. Seven out of 17 (41%) were identified early. Fifteen (88%) were critically ill and required pediatric intensive care unit admission, out of which 13 (76.4%) patients were put on ventilator support. Thirteen (76.4%) of them developed hyperferritinemia with multi-organ dysfunction syndrome (MODS) and required additional immunotherapy. Sixteen of them recovered completely without any sequelae. Severe complications such as acute respiratory distress syndrome and MODS were significantly high (P = 0.001 and 0.004, respectively) and hospital stay was longer (P-0.04) in infants in comparison to older children.
Conclusion: We conclude that infantile scrub typhus, though not very common, should be considered an important differential in infants presenting with an acute febrile illness with hyperferritinemia and MODS. Infants with scrub typhus can have a more stormy disease course compared to their older counterparts.

Keywords: Multiple organ dysfunction, scrub typhus, sepsis


How to cite this article:
Ghosh S, Roychowdhoury S, Giri PP, Basu A, Sarkar M. Severe scrub typhus infection in infancy with multiple organ dysfunction: A retrospective observational study from Eastern India. J Pediatr Crit Care 2022;9:84-9

How to cite this URL:
Ghosh S, Roychowdhoury S, Giri PP, Basu A, Sarkar M. Severe scrub typhus infection in infancy with multiple organ dysfunction: A retrospective observational study from Eastern India. J Pediatr Crit Care [serial online] 2022 [cited 2022 Dec 6];9:84-9. Available from: http://www.jpcc.org.in/text.asp?2022/9/3/84/345088




  Introduction Top


Rickettsial diseases, in general, are a group of rapidly re-emerging vector-borne infections across the world with usually an acute, short course that can range from mild undifferentiated fever to severe incapacitating illness and fatalities, if not suspected, diagnosed, and treated early in time. Scrub typhus, transmitted by the bite of larval stage of the trombiculid mite or chigger, is the most common rickettsial disease in India.[1],[2] It begins as an acute febrile illness caused by Orientia tsutsugamushi. The initial nonspecific symptoms of fever, headache, pain abdomen, and myalgia might progress into a more debilitating illness with development of palpable purpuric/vasculitic rashes usually involving the extremities with or without an eschar with subsequent vital organ dysfunction.[2],[3],[4] Although scrub typhus is now increasingly being diagnosed in pediatric population, it is extremely rare in infants as they are mostly kept indoors in protected environment, hence less chances of exposure to the bite of chiggers. Infantile scrub typhus seldom presents with this well-defined course of illness due to rapid progression of the disease process, thus making early suspicion and diagnosis very difficult. Infants are very rarely affected by scrub typhus. They might still contract the disease after being bitten at home by chiggers hidden in the layers of clothing or creeks of wooden furniture.[4],[5] Here, we have included 17 cases of infantile scrub typhus encountered during the study period, in two tertiary care pediatric teaching institutes of Kolkata, India.

The objective of this study was to describe the clinical, laboratory profile, treatment, and outcome of infants diagnosed with scrub typhus and to compare these variables with noninfant group of children in the same time period.


  Materials and Methods Top


This retrospective observational study was conducted in pediatric medicine ward and intensive care unit (ICU) of two tertiary care teaching institutes of eastern India over a period of 2 years (April 2019–May 2021). Ethical approval for this study was obtained (No. IEC/225/2020), which waived need of informed consent. Infants (age >28 days and <1 year) and older children (age >1 year) admitted with scrub typhus confirmed by IgM ELISA (optical density >0.5) and Weil–Felix test during the study period were reviewed from computerized patient database registry.

Study definitions

Multiple organ dysfunction syndrome (MODS) was defined as a clinical syndrome characterized by the development of progressive and potentially reversible physiologic dysfunction in 2 or more organs or organ systems. Hyperferritinemic sepsis with MODS was taken as evidence of hepatobiliary dysfunction with disseminated intravascular coagulation along with an associated serum ferritin level of >500 ng/ml.[6] The organ dysfunctions were classified according to Goldstein et al.[7]


  Data collection Top


Detailed history and physical findings were noted in all cases. Demographic profiles such as age and sex were recorded. Clinical features such as fever, rash, eschar, convulsion, respiratory distress, shock, and organomegaly were recorded. Laboratory investigations such as complete hemogram, C-reactive protein (CRP), electrolytes, ferritin, coagulation profile, and liver function tests were performed. Treatments received in the form of anti-rickettsial antibiotics, immunomodulatory drugs, different organ support modalities, and the various complications such as acute respiratory distress syndrome (ARDS), MODS, and disseminated intravascular coagulation (DIC) were noted. These variables were compared between the infant and noninfant groups of children

Treatment modalities

A baseline administration of intravenous (IV) doxycycline (5 mg/kg/day) was common to all the patients for a total of 7–10 days depending upon the clinical response and the severity of initial symptoms. The patients requiring immunosuppressant, in view of the cytokine storm, were divided into three clusters, of which one was treated with a combination of IV immunoglobulin (IVIG) and pulse methylprednisolone therapy, the other with single-drug therapy of IVIG, and another with IV dexamethasone. The time of resolution of symptoms with clinical recovery along with normalization of laboratory parameters was noted and analyzed with respect to the severity of the initial disease picture and the therapy administered.

A well-designed pro forma containing various parameters under study was used for data collection. The data were maintained in Microsoft Excel. IBM SPSS Statistics for Windows, version XX (IBM Corp., Armonk, N.Y., USA) was used for the statistical analysis of the data. Categorical data were analyzed in terms of numbers and percentages. Quantitative data were expressed as mean (standard deviation) or median (interquartile range). Quantitative continuous variables were compared between the groups using Mann–Whitney's nonparametric tests if the variable had a nonnormal distribution or unpaired Student's t-test if the variable had a normal distribution. Qualitative variables were compared by Chi-square test (χ2) and Fisher's exact test. P < 0.05 was considered statistically significant.


  Results Top


A total of 272 cases of scrub typhus had been admitted during the study period. Among them, 17 were infants (6.25%). The male and female ratio was 10:7. The mean age of presentation was 4 months 15 days months while the median was 2 months 17 days.

Clinical features

Among these 17 patients admitted in the two tertiary care pediatric teaching centers, 7 (47%) had a history of fever for ≤7 days whereas the other 10 (58%) had been having fever for a duration of 7–14 days. Lethargy and poor feeding were a common association in all the cases. Seizures were a predominant presentation, with 13 out of 17 cases (76.4%) suffering from convulsions, and 10 (58.8%) of them went into a state of altered sensorium. Ten out of 17 (58.8%) patients developed bleeding manifestations, suggestive of coagulopathy. However, a characteristic eschar was found in only three cases (17.6%). Splenomegaly was noted in all except one, whereas hepatomegaly was found in 13 (76.4%) patients [Table 1].
Table 1: Clinical manifestations of infants with scrub typhus

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Laboratory features

Scrub typhus IgM ELISA and Weil–Felix test (OXK >1:160) were done to confirm the diagnosis. In all 17 of the patients, both the tests came to be positive. CRP was found to be unanimously raised in all the cases. Hyponatremia, hypoalbuminemia, and thrombocytopenia were a common finding. Four of them (23.5%) showed leukopenia (TLC <4000/cmm) whereas seven (41.1%) of them presented with leukocytosis (TLC >11,000/cmm). Altered coagulation profile was a predominant finding, with 13 out of 17 patients developing the same (76%). Hyperferritinemia was, however, the most alarming finding, with all 17 patients showing a serum ferritin level of >500 ng/ml, going as high as >40,000 ng/ml in one of the cases. Combining clinical and laboratory parameters 10 (58.8%) had encephalopathy, and 9 (53%) patients developed ARDS. Almost three-fourth of the patients (76.4%) fulfilled criteria of hyperferritinemic MODS [Table 2].
Table 2: Laboratory profile of infants with scrub typhus

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Treatment and outcome

All 17 patients were initiated with IV doxycycline therapy at 5 mg/kg/day in two divided doses after diagnosis. Eight out of 17 patients became afebrile within 24 h of initiation of therapy (47%) and the rest became afebrile by 72 h. Fifteen (88%) of them required pediatric ICU (PICU) admission, out of which 13 patients were put on either invasive or noninvasive ventilator support at some point during the course of their illness. Ten (58.8%) patients required immunotherapy, in view of persistent hyperferritinemia and falling blood infective markers. Monotherapy with IVIG was given to two of them while IV dexamethasone monotherapy was given to one patient. Four cases received combination therapy with IVIG (2 g/kg) and IV dexamethasone whereas three of them were given combination therapy with IV pulse methylprednisolone (30 mg/kg/day for 3 days) and IVIG (2 g/kg). Thirteen out of 17 patients required blood product transfusion (76.4%). The average length of hospital stay was about 14 days. Six out of 17 developed nosocomial sepsis which led to a substantial rise in duration of hospital stay. All except one who succumbed after 8 h of admission to PICU survived. Fourteen out of 17 patients came for followed by regularly with a median duration of follow-up of 9 months. All of them were doing well without any sequelae [Table 3].
Table 3: Treatment and outcome of Infants with scrub typhus

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Severe clinical presentations such as convulsion, respiratory distress, shock, and bleeding were significantly higher in infancy in comparison to noninfant age group (P ≤ 0.01 for all variables). The mean duration of fever was significantly higher in infants (9.2 ± 3.2 vs. 5.6 ± 2.5, P = 0.04). One of the cardinal signs of scrub typhus, eschar, was noted to be present in significantly higher proportion of noninfant age group (48.4% vs. 17.6%, P = 0.04). Hemoglobin level and platelet count were significantly low in infants. Inflammatory markers such as CRP (90.5 [47.5–106.2] vs. 45.8 [21–67.5], P = 0.03) and serum ferritin (15750 [1947–24,000] vs. 750 [428–2550]), were elevated in infants. Severe complications such as ARDS (53% vs. 14.9%, P = 0.001) and MODS (76.4% vs. 8.2%) were markedly higher in children <1 year [Table 4].
Table 4: Comparison of clinical and laboratory parameters and severity of scrub typhus in infant and noninfant groups

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  Discussion Top


Scrub typhus usually presents as an acute febrile illness associated with a wide spectrum of features ranging from some nonspecific symptoms to severe illness causing multi-organ failure and eventual death.[8],[9] Due to its increased incidence in recent years, it has now been considered an important cause of acute undifferentiated fever in all ages.[10] Scrub typhus has been increasingly recognized all across India in pediatric age groups but is relatively rare in infancy. These mites and chiggers are mainly found in humid areas in fields, grasses, forests, and small bushes. As infants are rarely exposed to these habitats where the chiggers are found, they are less likely to be bitten by them, hence less incidence.[5],[11] In view of the increasing number of infantile scrub typhus cases across this study, we only found that 6.25% of children of scrub typhus had age below 1 year. We concluded that, though usually restricted to indoor environment, infants might be exposed to the bite of indoor chiggers that are carried home by some other members of the family from outside and reside in the crevices of wooden furniture, folds of clothing and in the beds.

Infantile scrub typhus usually presents in an uncommon way in contrast to their elderly counterparts. There is no such comprehensive case series about infantile scrub typhus except few isolated case reports.[12] Jajoo et al. reported a case of a 19-day-old neonate with scrub typhus with MODS, who recovered completely with IV clarithromycin therapy.[13] Another reported case of infantile scrub typhus with MODS of a 27-day-old neonate also showed complete resolution with IV doxycycline.[14] A significant proportion of our patients had poor feeding, seizures, and altered sensorium, pointing toward predominant central nervous system (CNS) involvement. The presence of splenohepatomegaly was striking. Any febrile infant with organomegaly, not responsive to traditional broad-spectrum antibiotics with features of CNS involvement, should prompt the clinician to suspect scrub typhus, even in this unusual age group. Eschar which is a cardinal sign of scrub typhus was found in only 3 (17.6%) infants whereas it was noted in 98 (48.4%) out of 255 older children. This may contribute to the late identification of scrub typhus in infants, leading to severe complications. As compared to older children, our study revealed that infants can present with more severe clinical forms such as respiratory distress, shock, and bleeding manifestations. Early organ failure is common in infantile scrub typhus than its elder counterparts.[15]

Laboratory features of infantile scrub typhus also differ from other pediatric series with respect to higher incidence of anemia, cytopenias, hyperferritinemia, and coagulopathy. In our study, all the infants had serum ferritin of more than 500 ng/ml with median ferritin of 15,750 ng/ml. CRP was also markedly elevated in infants (111.2 ± 67.4 mg/dl), substantiating the theory on increased incidence of extreme hyperferritinemia and other inflammatory markers in most of the infantile scrub typhus patients. This is nothing but the reflection of the cytokine storm that leads toward MODS.

There is, however, a paucity of data available on the association between infantile scrub typhus and hyperferritinemic sepsis with MODS. In our study, all the patients presented with hyperferritinemia and 13 out of 17 fulfilled the diagnostic criteria of hyperferritinemic sepsis with MODS. Most of these babies presented with an acute febrile illness with features suggestive of severe sepsis (lethargy, seizures, shock, and ARDS) but did not respond well to conventional management of sepsis. The referral of patients was delayed in a few cases because of the perceived unlikelihood of scrub typhus in infants and that explains longer duration of fever among infants. Although the initial response to IV doxycycline therapy was appreciable in few of the cases, there was a secondary deterioration observed in many cases with new-onset fever spikes along with lowering of infective blood markers (CRP) associated with cytopenias but progressive rise in the pro-inflammatory markers (serum ferritin) suggestive of activation of the tissue macrophages. Secondary infection-associated HLH or hyperferritinemic sepsis with MODS is a well-recognized complication of scrub typhus in all age groups. Most of them can be treated only with appropriate antibiotics and supportive therapy without any immunotherapy. There are multiple publications on the profile of scrub typhus in the pediatric age group and its association with HLH.[16],[17],[18],[19] Most of these patients presented with life-threatening ARDS, AKI, and DIC at the time of hospitalization but recovered well on administration of doxycycline or azithromycin without any need for immunotherapy. However, in infants, the incidence as well as severity of hyperferritinemia tends to be higher. In our cohort, about 60% of them required some form of immunotherapy over IV antibiotic (doxycycline), to show or sustain recovery. There is no comprehensive case series on association of infantile scrub typhus with hyperferritinemic sepsis. Kwon et al. reported a case of infantile scrub typhus with hyperferritinemia and MODS which was treated with dexamethasone and etoposide alongside IV clarithromycin.[15]

Major limitation of our study is that it is a retrospective study and conducted in two centers. A prospective study in multiple centers could better delineate the exact nature and magnitude of the problem.


  Conclusions Top


Infantile scrub typhus, though not widely reported, should be kept in mind as one of the important differentials in a case of acute febrile illness with MODS. It is more often associated with features of hyperinflammation with hyperferritinemia and MODS due to severe cytokine storm, compared to older children who mostly have an uneventful course of illness.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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