Asian Pacific Journal of Tropical Medicine (2011)261-264 261 Contents lists available at ScienceDirect Asian Pacific Journal of Tropical Medicine journal homepage:www.elsevier.com/locate/apjtm Document heading Scrub typhus: pathophysiology, clinical manifestations and prognosis doi: Senaka Rajapakse1*, Chaturaka Rodrigo1, Deepika Fernando2 Department of Clinical Medicine, Faculty of Medicine, 25 Kynsey Road, Colombo 8, Sri Lanka Department of Parasitology, Faculty of Medicine, 25 Kynsey Road, Colombo 8, Sri Lanka 1 2 ARTICLE INFO ABSTRACT Article history: Received 7 November 2011 Received in revised form 27 January 2012 Accepted 15 March 2012 Available online 20 April 2012 Scrub typhus is a zoonosis caused by the pathogen Orientia tsutsugamushi (O. tsutsugamushi). The disease has significant prevalence in eastern and Southeast Asia. Usually presenting as an acute febrile illness, the diagnosis is often missed because of similarities with other tropical febrile infections. Many unusual manifestations are present, and these are described in this review, together with an outline of current knowledge of pathophysiology. Awareness of these unusual clinical manifestations will help the clinician to arrive at an early diagnosis, resulting in early administration of appropriate antibiotics. Prognostic indicators for severe disease have not yet been clearly established. Keywords: Scrub typhus Orientia tsutsugamushi Clinical manifestations 1. Introduction Scrub typhus is a vector borne zoonosis caused by the organism Oricntia tsutsugamushi (O. tsutsugamushi). This acute febrile illness is endemic in many countries in eastern and south-east Asia and northern Australia[1]. Trombiculid mites (Leptotrombidium deliense, L. palladium etc) are the natural hosts of the pathogen. The infected larval stages of mites (chiggers) inoculate humans (accidental hosts) while feeding. The pathogens multiply at the site of entry which later develops in to an eschar[2] and this is followed by a febrile illness, with many clinical manifestations. It is estimated that 1 million new cases appear annually and 1 billion people are at risk of infection[3]. The incidence of cases of scrub typhus has been increasing since the early eighties[4]. While some attribute this to the appearance of new strains of pathogens, it is also possible that cases were misdiagnosed or under-diagnosed in the past, thus underestimating the mortality and morbidity due to the disease. It is difficult to conclude whether this is an already existent yet unappreciated prevalence or a true rise in incidence[5-7]. For example, assessment of patients with prolonged undiagnosed fever in Southern India and Sri Lanka by serological examination have shown that *Corresponding author: Professor Senaka Rajapakse MD, FRCP Edin, FACP, Consultant Physician, Department of Clinical Medicine, Faculty of Medicine, University of Colombo 25, Kynsey Road, Colombo 8, Sri Lanka. Tel: +94 777 579776 Fax: +94 112 689188 E-mail: senaka.ucfm@gmail.com a significant proportion (9.2%-37.5%) had evidence of current and past infection with scrub typhus[8,9]. While in many instances a simple febrile illness, scrub typhus has potentially fatal outcome with multiple organ dysfunction in severe cases[10]. Estimates of mortality rates from scrub typhus lie between 0%-30% in untreated patients[11]. Clinical manifestations can be diverse, and this brief review summarizes the pathophysiology of the disease, the different clinical manifestations, and their relationship to prognosis. 2. Methods We searched PUBMED using the keywords ‘scrub typhus’ or ‘O. tsutsugamushi’ in any field. The search was restricted to articles published in English within the last 15 years (1994-2009) as they would contain more recent data. We screened all abstracts for relevance, i.e., data on clinical manifestations and presentations, pathophysiology, and prognosis (independent coding by three reviewers). Suitable data was available in 112 sources. Data sources included; reviews published in core clinical journals, cohort studies, interventional studies, clinical trials and cross sectional analyses. Hundred and one papers were reviewed from a selected 112 (90.2%). 3. Pathophysiology O. tsutsugamushi survives in the wild in a cycle involving trombiculid mites (principal vectors) and other vertebrates 262 Senaka Rajapakse et al./Asian Pacific Journal of Tropical Medicine (2011)261-264 (small mammals and birds). Humans are accidental hosts for the pathogen. O. tsutsugamushi is different from rickettsia in its genetic makeup, cell wall structure and many authors now agree that it is an obligate intracellular gram negative bacterium [12]. The larval stage of the mites (chiggers) harbouring the bacterium, bite exposed individuals in vulnerable niches such as forests and mite infested undergrowth during occupational and recreational activities. Following the bite, the pathogen multiplies at the site of inoculation and subsequently induces local and systemic manifestations of infection[13]. The severity of illness depends on both host and pathogen related factors. Pathogen related factors may be attributed to the fact that different strains (Karp, Gilliam etc.) of O. tsutsugamushi may contribute differently to disease severity. Human hosts with G6PD deficiency are shown to have a worse prognosis than healthy individuals[14,15]. It is now established that the bacterium multiplies and disseminates within the human host and its principal target site is the endothelial cells. They have been located in endothelial cells of heart, lung, brain, liver, kidney, pancreas, skin and also isolated from macrophages of liver and spleen in post mortem samples[16]. Initially it was thought that the organism gains entry to the target organs through the lymphatic system. However in 2001, Walsh et al[17] have demonstrated the pathogen within mononuclear white blood cells in patients with acute infection, suggesting the possibility of a direct blood borne spread. The immune response induced by O. tsutsugamushi is a combination of humoral and cell mediated immunity. The rise of cytokines during an acute infection was demonstrated as far back as 1997 by Iwasaki et al[18]. In a small series of patients, they have shown a significant rise in macrophage colony stimulating factor (M-CSF), interferon gamma (IFN-毭) and granulocyte colony stimulating factor (G-CSF). Only a few patients showed a rise in tumour necrosis factor (TNF-毩) during the infection but it continued to rise during convalescence in those who had severe disease. These observations demonstrated that the macrophage and T lymphocyte response may be the driving factor in immunity against infection. More recently, de Fost et al[19] have demonstrated indirect evidence for cytotoxic lymphocyte (cytotoxic T cell and natural killer cell) activation during acute infection that may play a key role in destroying the infected host cells. The parasite has evolved to evade the immune mechanisms of the host. Given the high mortality rate of untreated disease, these mechanisms are of clinicopathological significance. Cho et al[20] showed that live O. tsutsugamushi down regulates the expression of the glycoprotein 96 (gp96) in infected macrophages and endothelial cells compared to non- infected cells in cell culture. This molecule is expressed in the endoplasmic reticulum of cells and plays a central role in major histocompatibility complex class I (MHC I) mediated antigen presentation, functioning of dendritic cells, antibody production and cross priming of immune cells[20]. Suppression of this glycoprotein may be one mechanism by which the pathogen neutralizes the host immune response. The relationship between O. tsutsugamushi infection and HIV is of interest in current context. Watt et al[21] for the first time demonstrated that HIV viral load fell during acute infection with scrub typhus in HIV positive individuals and serum samples from patients with acute typhus suppressed HIV-1 in vitro. A plausible hypothesis was that a humoral factor induced by acute infection suppressed HIV activity. However the authors failed to identify this molecule though there were several suggestions[22]. Several queries were raised regarding the methodology (small sample size, viral load measurements etc.) [23,24] of this initial observation. Another follow up study however, has shown further supportive evidence. Infusion of plasma from patients with mild acute scrub typhus, reduced viral loads in 7 out of 10 patients with HIV-1 infection. The beneficial effect was observed up to 8 weeks after a single transfusion. However, the in vivo impact of donor plasma was not seen in all HIV infected patients[25]. Several hypotheses have been developed to explain these observations including an inhibitory antibody mediated response, restriction of syncytia forming/maintenance of non syncytia inducing phenotypes of virus and specific activity against certain strains of the HIV virus[26]. However the actual mechanism for this observation remains an enigma. 4. Clinical manifestations The incubation period of O. tsutsugamushi in humans is around 10-12 d (can vary between 6-21 d)[13]. The clinical manifestations vary in severity from a mild febrile illness to a severe potentially fatal disease with multi organ dysfunction syndrome (MODS) . The typical systemic features of infection are well known and include fever, gastrointestinal disturbances, malaise, cough, myalgia and headache[13]. A maculopapular rash starting on the trunk and spreading in to the limbs is seen towards the end of the first week (since the onset of fever)[13]. Regional lymphadenopathy is commonly observed. Another significant finding is an eschar at the bite site which is almost diagnostic. The prevalence of eschars in patients diagnosed with scrub typhus have been reported as between 7%-80%[27-29]. Difficulty in detecting small eschars in dark skinned individuals, eschar inducing capacity of different strains of O. tsutsugamushi and atypical appearance of eschars in areas of damp and moist skin may be the reason for this difference. The eschar starts as a small papule that enlarges and subsequently undergoes central necrosis to turn black. The common sites for finding an eschar are groin, axilla, waist and other exposed parts of the body. Kim et al[27] for the first time showed different patterns of eschar distribution in males and females. Authors attributed this to differences in skin folds, clothing and pressure points created by undergarments. The front of the chest and the area within 30 cm from the umbilicus were common sites for both sexes while lower limbs and back were also common areas for males and females respectively. However, the findings in other communities, where there are different gendered patterns in clothing and outdoor activities may reveal different results. From the second week onwards, a proportion of patients (especially those with untreated disease) will show evidence of systemic infection. This stage of illness can attack different organ systems such as the central nervous system (acute diffuse encephalomyelitis, encephalopathy, meningitis, deafness, cranial nerve palsies, eye manifestations)[30-35], cardiovascular system (rhythm abnormalities, myocardial involvement with congestive heart failure, vasculitis)[13,36,37], renal system (acute renal failure) [38-40], respiratory system (Interstitial pneumonia and acute respiratory distress syndrome)[41-44] and gastrointestinal system (alterations in liver functions, pancreatitis, diarrhoea) [45-48]. Sometimes MODS ensues [10,40,49]. Due to the wide variation in the clinical manifestations, the diagnosis of scrub typhus is often missed or made late. Senaka Rajapakse et al./Asian Pacific Journal of Tropical Medicine (2011)261-264 5. Scrub typhus in pregnancy The impact of scrub typhus in pregnancy is less explored. In a case series of eight patients treated for acute scrub typhus during pregnancy (confirmed by indirect immunofluorescence assay), Kim et al[50] describe a healthy outcome for both mothers and babies (without any congenital infections or malformations). All patients had an uncomplicated illness and gestational age at presentation varied between 10-29 weeks. However poor foetal outcome has been reported; Mathai et al[51] report of four women with scrub typhus in the second trimester, treated with ciprofloxacin, who all had miscarriages or still births. In another case report, an infected woman was treated with chloramphenicol successfully at 29 weeks of gestation. However the baby was born prematurely and died subsequently (no vertical transmission demonstrated) [52] . Neonatal scrub typhus has been reported in two instances with cord blood being positive for IgM[53,54]. Acute scrub typhus can be transmitted vertically but congenital malformation due to infection per se, has not been demonstrated. 6. Prognostic indicators Given the significant sequelae of infection, early identification of indicators for a worse prognosis will help in the management. However the literature on such indicators is limited and in studies where such factors are identified, the sample sizes are too small to come to solid conclusions. Lai et al [55] comparing 1 8 patients with delayed defervescence against 88 patients with fast recovery, cite absence of headache, relative bradycardia and jaundice as predictors of delayed defervescence. However, this study analyzed patients with scrub typhus, murine typhus and Q fever together and only 7 patients with scrub typhus had delayed defervescence. It is not clear whether these predictors differed for individual infections. In addition, delayed fever can be attributed to many other factors such as resistant strains and the choice of antibiotics (all these patients were treated with doxycycline). These findings have not been confirmed by other investigators. Sonthayanon et al[56] have demonstrated that higher DNA loads at admission are positively correlated with mortality and a longer duration of illness (P<0.001). While this is an interesting concept directly correlating bacterial burden with clinical outcome, its applicability in resource limited settings is doubtful because of the cost factor. In a retrospective epidemiological study, Lee et al[57] describes absence of an eschar, higher APACHE II scores and an event of ICU admission as independent risk factors associated with fatality (n=297, deaths=18). This shows a conflict in evidence with the previous study by Sonthayanon et al, who showed that the presence of an eschar was positively and significantly correlated with higher DNA loads at admission which in turn was associated with a fatal outcome. Due to such conflicts in evidence, gaps in data and small sizes of samples, it is difficult to establish clear prognostic indicators. This is an area for further research. 7. Conclusion Scrub typhus is an important infectious disease with 263 a potentially fatal outcome. Apart from the classical presentation as an acute febrile illness, many other unusual clinical manifestations are reported. 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