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1 Recent trends in emerging and re-emerging microbial infections: an update 2 on Scrub Typhus 3 Abstract 4 In the era of emerging and re-emerging infectious diseases which has seen many endemics, 5 epidemics and pandemics throughout the world attributed to viral, parasitic and bacterial 6 microbes, preparedness assumes significance. Changing microbial behaviour due to genetic 7 variations as seen in Influenza virus is responsible for emergence of newer strains which are 8 antigenically different from the existing ones is responsible for infections that cause severe 9 morbidity and mortality. Other microbial species including the Dengue virus, Chikungunya 10 virus, Crimean Congo haemorrhagic fever virus transmitted to human through vectors, 11 Listeria monocytogenes, Leptospira spp, Legionella pneumophila cause frequent endemics 12 and epidemics worldwide. Emergence of multi-drug resistant species of Mycobacterium 13 tuberculosis has already thrown a challenge for the control and eradication programmes 14 against tuberculosis. Other bacterial species resistant to many antimicrobials currently being 15 used owing to the genetic variations cause infections in human that are very difficult to treat. 16 Scrub typhus is a unique disease caused by Orientia tsutsugamushi, an intracellular bacterium 17 transmitted by the bite of chiggers (larval forms of mites) and is usually present endemically 18 whose clinical features are very similar to other prevalent infectious diseases in the same 19 geographical areas. The need of the hour is to have a good knowledge of microbial infections 20 in respective geographic regions and predicting emerging and re-emerging infectious diseases 21 which could contribute to better patient management. 22 Key Words: Emerging infections, re-emerging infections, Scrub Typhus, Orientia 23 tsutsugamushi 24 Introduction 25 Emerging infectious diseases (EIDs) are diseases of infectious origin whose incidence in 26 humans has increased within the recent past or threatens to increase in the near future. 27 Emerging infections are those which are either new or previously undefined diseases as well 28 as old diseases with new features. Infectious diseases which are newly introduced to a 29 particular geographic location or a new population (e.g. it may present in young adults where 30 previously it was only seen in the elderly), those showing newer clinical features and 31 resistance patterns to available antimicrobial agents should be considered as emerging and re1 32 emerging diseases. Other characteristics of an emergent infectious disease include rapid 33 increase in the incidence and spread of the disease, reappearance of a disease which was once 34 endemic but had since been eradicated or controlled new recognition of an infectious agent in 35 the population or realization that an established clinical condition has an infectious origin. 36 Over 30 new infectious agents have been detected worldwide in the last three decades and 60 37 per cent of these are of zoonotic origin with more than two-thirds of these have initially 38 originated in the wildlife [1, 2]. 39 Emerging infectious diseases account for 26 per cent of annual deaths worldwide. Nearly 30 40 per cent of 1.49 billion disability-adjusted life years (DALYs) are lost every year to diseases 41 of infectious origin [3]. The burden of morbidity and mortality associated with infectious 42 diseases falls most heavily on people in developing countries, and particularly on infants and 43 children (about three million children die each year from malaria and diarrhoeal diseases 44 alone) [4]. 45 Patho-physiology of Scrub typhus 46 Among the many emerging bacterial infections, the causative of scrub typhus/bush typhus, 47 Orientia tsutsugamushi is responsible for re-emerging zoonotic disease. Previously called as 48 Rickettsia tsutsugamushi, O tsutsugamushi is a gram-negative bacillus. It is an intracellular 49 parasite belonging to the family Rickettsiaceae and was first isolated and identified in 1930 in 50 Japan. Scrub typhus is transmitted by some species of trombiculid mites /Chiggers 51 (Leptotrombidium deliense) and produces a characteristic skin lesion identified as black 52 eschar. Adult mite does not feed on man and only feeds on the serum of warm blooded 53 animals. The Larval form/ Chiggers which are very small and seen only with the help of a 54 magnifying glass actually bite. 55 Humans are accidental hosts and symptoms appear after an incubation period is six to twenty- 56 one days after the bite of chiggers which is usually painless and not noticed by the patients. 57 Clinical presentation of patients suspected to be suffering from scrub typhus may include 58 fever with chills, headache, muscle pain, cough, and gastrointestinal symptom. Other clinical 59 signs that may appear in patients are centrifugal macular rash on the trunk, ocular pain, 60 conjunctival inflammation, delirium, eschar, splenomegaly and lymphadenopathies [5]. 61 Complications of scrub typhus include haemorrhage, disseminated intravascular coagulation 62 (DIC), multiple organ dysfunction syndrome (MODS), shock, central nervous system (CNS) 2 63 involvement, renal impairment and acute respiratory distress syndrome (ARDS). 64 Leucopoenia and abnormal liver function tests (>90%) are commonly seen in the early phase 65 of the illness. Pneumonitis, encephalitis, and myocarditis may occur in the late phase of 66 illness [5]. 67 Clinical symptoms of scrub typhus overlap with other endemic infectious diseases like 68 dengue fever, malaria, chikungunya, leptospirosis, Paratyphoid, other viral fevers and pyrexia 69 of unknown origin (P.U.O). Infections are usually confined to the areas where the insect 70 vector is prevalent and a strong clinical suspicion should be made among the people who give 71 a recent travel history to such regions. A recent report of patient suffering from acute 72 respiratory distress syndrome after being infected with Orientia tsutsugamushi reveals the 73 necessity to investigate further on the modes of transmission to human (inhalation/aerosols) 74 and the life-threatening nature of the disease in case of delay in suspicion and diagnosis [6]. 75 Epidemiology of Scrub Typhus 76 Endemic regions for scrub typhus include Asia, Australia, Korea, Japan, Thailand, Myanmar 77 China, India and Pakistan [7, 8 and 9]. Epidemic scrub typhus involving American soldiers 78 working in Vietnam during World War II has also been reported. In India scrub typhus has 79 been reported to be prevalent in Southern India (Rajasthan, AP, Pondicherry, Tamil Nadu, 80 Goa) and Northern India (Himalayan region of India) and north-western India [10, 11]. 81 Laboratory Diagnosis of Scrub Typhus 82 Laboratory diagnosis of scrub typhus can be performed using both conventional and 83 molecular methods. Traditional methods for diagnosis include Weil-Felix test, indirect 84 immunofluorescence, indirect immunoperoxidase (IIP), immunochromatography, enzyme 85 linked immunosorbant assay (ELISA) and culture. Interpretation of results of ELISA for the 86 detection of antibodies should be cautiously as even healthy individuals (18%) also react 87 positively [12]. A four-fold rise in titre should be considered as diagnostic in patients 88 showing clinical symptoms. Real-time quantitative polymerase chain reaction method (rt- 89 PCR) has been evaluated for the diagnosis of rickettsial infections [13]. Orientia 90 stutsugamushi does not grow in routine culture media used in clinical laboratories. Cell 91 culture technique is applied using monolayer of L929 cell lines for growing them in 92 laboratory [14]. 3 93 Discussion 94 Considering the fact that there is no vaccine available for protection against scrub typhus 95 disease, prevention of infection remains only the best alternative [15, 16]. People residing in 96 the endemic regions of the vector should be educated about protecting themselves form insect 97 bites by wearing protective clothes, using insect repellents, reducing visits to the forest areas 98 infested with trombiculid mites and chiggers. Previous studies have also evaluated the anti- 99 chigger effects of some oil extracts from plants [17].Screening international and national 100 travellers returning from potentially endemic places would contribute to early diagnosis of 101 scrub typhus thereby reducing the morbidity and mortality [18]. Resistance reports recently 102 of Orientia tsutsugamushi against quinolone group drugs should be considered as a cause of 103 serious concern [19]. 104 Management of scrub typhus includes initiation of antibiotics following strong clinical 105 suspicion supported with positive laboratory reports. Doxycycline is considered as the drug 106 of choice which can be given as single dose weekly for six weeks. I case of prophylactic 107 treatment while visiting the endemic areas the first dose should be taken before one week. 108 Other antimicrobial agents belonging to macrolide group (azithromycin, clarithromycin, 109 roxithromycin and telithromycin), rifampicin and chloramphenicol are also are effective 110 against Orientia tsutsugamushi [20]. 111 Conclusion 112 In conclusion it is very important both for the clinician and laboratory medicine personnel to 113 have a better understanding of the infections prevalent in a particular geographical region and 114 the characteristics of emerging and re-emerging infections. Timely clinical suspicion 115 supported by use of appropriate diagnostic techniques would be instrumental in better 116 management of patients. 117 References 118 1. Combating emerging infectious diseases in the South-East Asia Region. New Delhi: 119 World Health Organization, WHO SEARO; 2005. World Health Organization, 120 Regional Office for South East Asia Region 4 121 2. Dikid T, Jain SK, Sharma A, Kumar A, Narain JP. Emerging & re-emerging 122 infections in India: An overview. The Indian Journal of Medical Research. 123 2013;138(1):19-31. 124 125 126 127 3. Fauci AS. Infectious diseases: considerations for the 21st century. Clin Infect Dis. 2001;32:675–85 4. Taylor LH, Latham SM, Woolhouse ME. Risk factors for human disease emergence. Philos Trans R Soc Lond B Biol Sci. 2001;356:983–9 128 5. Scrub Typhus. http://emedicine.medscape.com/article/971797-overview#a0156 129 6. Angelakis E, Patrick G, Peloni JM, Wey PF, Perreal C, Raoult D. Orientia 130 tsutsugamushi in lung of patient with acute respiratory distress syndrome, France, 131 2013 132 http://dx.doi.org/10.3201/eid2102.140860 133 134 135 136 [letter]. Emerg Infect Dis. 2015 Feb [date cited]. 7. Suputtamongkol Y, Suttinont C, Niwatayakul K, et al. Epidemiology and clinical aspects of rickettsioses in Thailand. Ann N Y Acad Sci. May 2009;1166:172-9 8. Matsumura Y, Shimizu T. 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Tantibhedhyangkul W, Angelakis E, Tongyoo N, Newton PN, Moore CE, 163 Phetsouvanh R, et al. Intrinsic fluoroquinolone resistance in Orientia tsutsugamushi. 164 Int J Antimicrob Agents. 2010;35:338–41 165 20. Olson JG, Bourgeois AL, Fang RC, Coolbaugh JC, Dennis DT. Prevention of scrub 166 typhus. Prophylactic administration of doxycycline in a randomized double blind trial. 167 Am J Trop Med Hyg. Sep 1980;29(5):989-97 6