The Balkans, often referred to as the Balkan Peninsula, although the two are not coterminous, is a geopolitical and cultural region of southeastern Europe. The Balkans are highly mountainous; Mount Musala (2,925 metres (9,596 ft)) in the Rila mountain in Bulgaria is the highest. Many linguistic families meet in the region, including the Slavic, Romance, Hellenic, Albanian, and Turkic language families, while the main religions are Orthodox Christianity, Roman Catholicism and Sunni Islam.The BalkansTerritories that constitute the Balkan region regardless geographic borders of the peninsula (in dark orange are marked the territories located mostly inside the peninsula and in light orange mostly outside the peninsula)The term "The Balkans" covers not only those countries which lie within the boundaries of the Balkan Peninsula, but may also includeSlovenia and Romania. Prior to 1991 the whole of Yugoslavia was considered to be part of the Balkans. The term "The Balkans" is sometimes used to describe only the areas in the Balkan peninsula: Moesia, Macedonia, Thrace, Kosovo, Šumadija, Bosnia,Herzegovina, Dalmatia, Thessaly, Epirus, Peloponnese and others, but more often it includes the rest of former Yugoslavia (Serbia, Croatia and Slovenia) and Romania, namely the provinces of: Vojvodina, Slavonia, Banat, Wallachia, Moldavia, Transylvania, and others. Italy as a totality, is generally accepted as part of Western Europe and the Apennines. The term "the Balkans" was coined by August Zeune in 1808.The Balkans comprise the following territories: Albania (28,748 km2) Bosnia and Herzegovina (51,197 km2) Bulgaria (110,993 km2) Croatia (56,594 km2) Greece (131,990 km2) Kosovo[a] (10,908 km2) Macedonia (25,713 km2) Montenegro (13,812 km2) Romania (238,391 km2) Serbia (88,361 km2 including Kosovo; 77,474 km2 excluding Kosovo[a]) Slovenia (20,273 km2) – mostly not includedAll territories (745,799 km2 excluding Slovenia; 766,072 km2 including Slovenia)
The classification of rickettsia has seen a significant reorganization in the recent past particularly due to technological advances in molecular genetics.
They appear blue with Giemsa’s stain and their growth is enhanced in the presence of sulphonamides.
Travellers, wood cutters, farmers and armed forces personnel as their occupational or recreational activities bring them in contact with habitats that support the vectors or animal reservoir species associated with these pathogens
The Weil–Felix test is an agglutination test for the diagnosis of rickettsial infections. It was first described in 1916. By virtue of its long history and of its simplicity, it has been one of the most widely employed tests for rickettsia on a global scale, despite being superseded in many settings by more sensitive and specific diagnostic tests.The basis of the test is the presence of antigenic cross-reactivity between Rickettsia spp. and certain serotypes of non-motile Proteus spp., a phenomenon first published by Edmund Weil andArthur Felix in 1916. The serum of patients diagnosed with epidemic typhus was found to agglutinate in the presence of bacteria now known as Proteus vulgaris. Ensuing work elucidated that it was in fact the somatic (O) antigen that cross-reacted with anti-rickettsial antibodies, and furthermore, that different Proteus O antigens would cross-react with different species of Rickettsia.Typhus group rickettsiae (Rickettsiaprowazekii, R. typhi) react with P. vulgaris OX19, and scrub typhus (Orientiatsutsugamushi) reacts with P. mirabilis OXK. The spotted fever group rickettsiae (R. rickettsii, R. africae, R. japonica, etc.) react with P. vulgaris OX2 and OX19, to varying degrees, depending on the species.The Weil–Felix test suffers from poor sensitivity and specificity, with a recent study showing an overall sensitivity as low as 33% and specificity of 46%. Other studies have had similar findings. As a result, it has largely been supplanted by other methods of serology, including indirect immunofluorescence antibody (IFA) testing, which is the gold standard. However, in resource-limited settings, it still remains an important tool in the diagnosis and identification of public health concerns, such as outbreaks of epidemic typhus.
DEET - N,N-Diethyl-meta-toluamide, abbreviated DEET, is a slightly yellow oil. It is the most common active ingredient in insect repellents. It is intended to be applied to the skin or to clothing, and provides protection against tick bites, mosquito bites, chiggers, and other insects that can transmit disease.
Orientiatsutsugamushi and transmitted by the bite of infected larvae of the mite Leptotrombidiumdeliense.The term scrub is used because of the type of vegetation (terrain between woods and clearings) that harbours the vector; however, the name is not entirely correct because certain endemic areas can also be sandy, semi-arid and mountain deserts.It was suspected to be the leading cause of pyrexia of unknown origin (PUOs) in forces of the United States (US) of America during the Viet Nam conflict, and caused two confirmed cases among the US troops during the Korean War.
Scrub typhus is endemic to a part of the world known as the tsutsugamushi triangle (after O. tsutsugamushi). This extends from northern Japan and far-eastern Russia in the north, to the territories around the Solomon Sea into northern Australia in the south, and to Pakistan and Afghanistan in the westAsia-Pacific or Asia Pacific (abbreviated as Asia-Pac, Asia Pac, AsPac, Aspac, Apac, APAC, APNIC, APJ, JAPA or JAPAC) is the part of the world in or near the Western Pacific Ocean. The region varies in size depending on context, but it typically includes at least much of East Asia, Southeast Asia, and Oceania.The term may also include Russia (on the North Pacific) and countries in the Americas which are on the coast of the Eastern Pacific Ocean; the Asia-Pacific Economic Cooperation, for example, includes Canada, Chile, Russia, Mexico, Peru, and the United States.Alternatively, the term sometimes comprises all of Asia and Australasia as well as small/medium/large Pacific island nations - for example when dividing the world into large regions for commercial purposes (e.g. into Americas, EMEA and Asia Pacific).Even though imprecise, the term has become popular since the late 1980s in commerce, finance and politics though the economies within the region are heterogeneous, they are mostly emerging markets experiencing rapid growth.
Rather than biting or piercing the skin,mite larvae prefer to insert their mouthparts down hair folliclesor pores. A large numbers of the Orientiatsutsugamushi arepresent in the salivary glands of the larvae and these areinjected into its host when it feeds (23). Human infection takesplace when man accidentally picks up an infective larval mitewhile walking, sitting, or lying on the infested ground.incubation period ranging from 6 to 21 days (usually 10 - 12days), patients usually present with fever and headache. Othersymptoms and signs include myalgia, chills, cough, adenopathy,and diarrhoea. The patient is often labeled as “fever of unknownorigin” because of the non specific symptoms. In about half thepatients, a skin ulcer may develop after the onset of fever atthe site of the mite bite. The ulcer is approximately 1 cm indiameter and fills with fluid, eventually rupturing and forminga black eschar. A macular rash may appear on the body on 5thto 7th day and last for a few hours to a few days. Complicationssuch as pneumonitis, myocarditis, encephalitis and peripheralcirculatory failure may occur. Deaths usually occur as a resultof late presentation or a delayed diagnosisLeptotrombidiumdeliense and Leptotrombidiumakamushi.
The mites feed on serum of warm blooded animals only once in their lifeSince the other life stages (nymph and adult) do not feed on vertebrate animals. Both the nymph and the adult are free-living in the soil.
Scrub typhus is generally seen in people whose occupational or recreational activities bring them into contact with ecotypes favourable with vector chiggers
The cheapest and most easily available test is the Weil-Felix test, but this is notoriously unreliable. Fifty per cent of patients have a positive test result during the second weekComplement-fixation test (a serological test to detect specific antibody or specific antigen in a patient’s serum).
Serological methods are most reliable when a four-fold rise in antibody titre is looked for. Although many techniques have been used successfully for sero diagnosis, relatively few are used regularly by most laboratories. ELISA provides more sensitivity and equal specificity when compared to commercial test kits
O. tsutsugamushi can be demonstrated by standard and by nested PCR.
Rapid defervescence after antibiotic treatment is so characteristic that it is used as a diagnostic test for O. tsutsugamushi infectionThese antibiotics are bacteriostatic and merely slow the multiplication of the organism while the patient develops a protective immune response. Both animals and humans develop nonsterile immunity and viable rickettsiae have been recovered from lymph tissue long after infection
1. Rickettsial DiseasesAmita Kashyap
2. Rickettsial Diseases Emerging or re – emerging pathogens in many places of the world Definitive diagnosis is difficult hence occurrence often goes unrecognized New genetic tools – lead to discovery of many new rickettsial diseases over the past 20 years. Of the 14 currently recognized rickettsioses, six have been described within the last15 years
3. Rickettsial Diseases Require living cells for growth, yet are true bacteria as they have metabolic enzymes and cell walls, and are susceptible to antibiotics. Mammalian reservoirs and invertebrate vactors (ticks, mites, fleas, and lice). Some invertebrate vectors can also serve as reservoirs. Humans are usually accidental hosts and play little role in natural disease transmission. Four Groups: ◦ 1) Spotted fever group; 2) Typhus group; 3) Scrub
4. Global : The geographic as well as temporal distribution is largely determined by their vectors. Louse borne rickettsial diseases are reported from across the world. Common flea species like the dog, cat, and rat flea are also global in distribution. Ticks are more restricted in their distribution. Tick borne diseases are, therefore, more localized in their
5. India : Large number of documented outbreaks of rickettsial diseases, particularly Scrub typhus among Indian Armed Forces personnel from different parts of the country Occurrence of Rickettsioses, including scrub typhus as well as spotted fevers have been reported from H. P., Maharashtra, Assam, West Bengal, Kerala and Tamil Nadu
6. Epidemiologic Features of RickettsialDis. Diseases Dis. Agent Vector Animal GeographicalGroup Reservoir DistributionTyphu Epide Rickett Human Humans Mountainouss mic sia body louse regions of Africa,Group typhu prowaz Asia, and Central s ekii and South America. India - J&K, Himachal, Uttarakhand, W Bengal, Arunachal Pradesh. Murin Rickett Rat flea Rats, Worldwide e sia (Xenopsylla mice typhu typhi cheopis) s Indian Rickett Tick (Ixodes Dogs, Africa, India, Tick sia sp Boophilus rodents Europe, East, Typhu conorii sp Mediterranean, India s Haemophysal - Uttaranchal
7. Epidemiologic Features of RickettsialDis. Diseases Agent Dis. Vector Animal GeographicalGroup Reserv Distribution oirSpotted Rickettsia Rickettsi Mite House Russia, SouthFever l a mite Africa, Korea,Group pox akari Turkey, Balkan countries Rocky Rickettsia Tick Rodent Mexico, Central and Mountain rickettsii s South America S. FeverOrientia Scrub Orientia Mite (L Asia and Australia typhus tsutsugam deliense) India - J&K, ushi Himachal, Uttarakhand, W Bengal, Arunachal PradeshOthers Q fever Coxiella Inhalation Goats, Worldwide burnetii of infectious sheep, aerosols; cattle, tick cats
8. Agent Rickettsiae are a diverse collection of organisms with several differences. The common threads that hold the rickettsiae into a group are their epidemiology and being obligate intracellular Rickettsia are small (0.3 X 2 μm) aerobic, obligate intracellular
9. Agent continued… Theorder Rickettsiales has two families ◦ Rickettsiacese – has two genera : Rickettsia and Orientia. ◦ Anaplasmataceae - has five genera. At least 26 agents from the order Rickettsiales have been recognized as human pathogens. Host : Travellers, wood cutters,
10. Transmission Transmission: by the ◦ bite of infected ticks and mites and ◦ contamination of the bite or other skin wounds with the faeces of infected lice and fleas. ◦ The rickettsiae present in the dried excreta of insects may also enter through the conjunctivae or even through inhalation. In ticks and mites transovarial and trans - stadial transmission of rickettsia frequently occurs. Spread through the bloodstream to infect vascular endothelium in the skin, brain, lungs, heart, kidneys, liver, gastrointestinal tract and other organs.
11. Clinical Features and Treatment of RickettsialDisease Diseases Clinical Features IP Weil Felix Treatment ReactionEpidemic 6-15 Headache, chills, fever, OX - 19 Doxycyclinetyphus Days prostration, 100mg BD for confusion, photophobia, 7 – 10 days or vomiting, till person is rash (generally starting afebrile. on trunk) Pregnant women- Chlorampheni col 60 - 75mg/ kg/day in 4 divided dosesMurine 8-16 As above, generally less OX - 19 As abovetyphus Days severeIndian Tick 5 - 10 Fever, eschar, regional OX - 19 Same asTyphus days adenopathy, Or OX - 2 above maculopapular rash on Alternative - extremities Ciprofloxacin
12. Clinical Features and Treatment of RickettsialDisease Diseases Clinical Features IP Weil Felix Treatment ReactionRocky 2-14 Headache, fever, OX – 19 Same asMountain Days abdominal pain, macular Or OX - 2 abovespotted rash progressing intofever opular or petechial (starting on extremities)Scrub 6-21 Fever, headache, OX - K Doxycyclinetyphus Days sweating, 100mg BD. conjunctival injection, Rifampicin 600 - adenopathy, 900mg/day, eschar, rash, respiratory Azithromycin and distress Ciprofloxacin are other alternativesQ fever 3 - 30 Fever, headache, chills, None Doxycycline. days sweating, Rifampicin, pneumonia, hepatitis, Ciprofloxacin endocarditis as other
13. Diagnosis Serology Titres of specific antibodies rise to diagnostic levels usually by the second week of illness. Indirect Fluorescent Antibody (IFA) and ELISA tests are available for serology. The Weil – Felix test, which uses the OX and K strains of Proteus vulgaris and P. mirabilis, respectively is still the most widely used diagnostic test in India. (not very sensitive/ specific ) PCR is also being increasingly used to confirm the diagnosis
14. Prevention and Control The essential method of prevention is avoidance of potentially vector infected areas and Use of personal protective measures. Use of insect repellents such as DEET (N,N-Diethyl-meta-toluamide) in combination with appropriate clothing such as long sleeves and anklets may be useful in avoiding contact with vectors.
15. Scrub Typhus: A dreaded disease of pre-antibiotic era An acute, febrile, infectious illness, caused by Orientia tsutsugamushi (zoonotic disease) First described from Japan in 1899. Humans are accidental hosts Disease of Military importance- 36,000 soldiers were either incapacitated or died during World War II The first known vaccine actually used to inoculate human subjects was dispatched to India by the Allied Land Forces, South-East Asia Command, in June 1945 Scrub typhus is essentially an occupational disease among rural residents in the Asia- Pacific region.
16. World/ Asia Endemic to a part of the world known as the “tsutsugamushi triangle”, which extends from northern Japan and far-eastern Russia in the north, to northern Australia in the south, and to Pakistan in the west An estimated one billion people are at risk for scrub typhus and An estimated one million cases occur annually. Mortality rates in untreated patients range from 0-30%.
17. Epidemiology • North: northern Japan and far- eastern Russia • South: to northern Australia • West: to Pakistan and Afghanistan Infected vector live in jungle, scrub & grassland
18. The vector is present in most countries of the SEAEndemic in certain geographical regions of India,Indonesia, Maldives, Myanmar, Nepal, Sri Lanka and Thai Scrub typhus-affected countries of Asia
19. India Scrub typhus is a reemerging infectious disease in India Prevalent in many parts of India but lack specific data Outbreaks reported from areas located in the sub-Himalayan belt, from Jammu to Nagaland. Himachal Pradesh, Sikkim and Darjeeling (West Bengal) during 2003-2004 and 2007. From southern India during the cooler
20. India S/S are often non-specific (Fever, Eschar, Regional lyphadenopathy, Maculopapule rash, leukopenia). The non-specific presentation and lack of the characteristic eschar in 40% patients makes the misdiagnosis and underreporting Non availability of diagnostic facilities leads to lack of precise incidence of the disease An estimated one billion people are at risk for scrub typhus and An estimated one million cases occur annually.
21. The characteristic feature of an outbreak of scrub typhus:(i) the obvious association with certain types of terrain;(ii) the large percentage of susceptible people, who may be infected simultaneously following exposure over relatively short periods;(iii) the absence of a history of bites or attack by arthropods
22. Agent It is an obligate intracellular gram-ve bacterium that has a large number of serotypes. Does not have a vacuolar membrane; thus, it growsOrientia - freely in the cytoplasm oftsutsugamushi undermicroscope infected cells.[Courtesy: Departmentof Entomology, Armed O. tsutsugamushi has aForces Research different cellwall structureInstitute of MedicalSciences (AFRIMS)] and genetic composition than that of the rickettsiae.
23. Agent The mite is very small (0.2 – 0.4mm) and can only be seen through a microscope or magnifying glass. O. tsutsugamushi includes heterogeneous strains classified in five major serotypes: Boryon, Gilliam, Karp, Kato and Kawazaki. Differentiation of serotypes is important for laboratory diagnosis. Orientia tsutsugamushi can be cultivated on L929
24. Disease transmission Transmitted to humans and rodents by the bite of infected larvae of the trombiculid mite Leptotrombidium deliense (“chiggers”), which feeds on lymph and tissue fluid rather than blood. The bite of the mite leaves a characteristic black eschar that is useful to the doctor for making the diagnosis.
25. Mode of Transmission Rats & Mice Mite Mite Humans (Accidental hostNo direct person to person transmissionMite Islands
26. Transmission The adult mites have a four-stage: ◦ egg, larva, nymph and adult. The larva is the only stage (chigger) that can transmit the disease to humans and other vertebrates Chigger mites act as the primary reservoirs for O.tsutsugamushi They get infected by feeding on the body fluid of small mammals, including the rodents (rattus),
27. Transmission They maintain the infection throughout their life stages and has transovarial transmission. The infection passes from the egg to the larva or adult - transtadial transmission. Thus, chigger mite populations can autonomously maintain their infectivity over long periods of time.
28. Earlier it was thought that rodents were the natural reservoir of infection, but it is now believed that mites are both the vector and the reservoirChigger mites fed on theinner’s ear lobe of wild-caught rat This mite is fastidious in matters of temperature, humidity and food,
29. Clinical Presentation The I.P.- 5 to 20 days (mean, 10-12 days) The chigger bite is painless or as a transient localized itch. Bites are often found on the groin, axillae, genetalia or neck. The illness begins rather suddenly with shaking chills, fever, severe headache, infection of the mucous membrane lining the eyes (the conjunctiva), and swelling of the lymph nodes. A spotted rash on the trunk may be
30. Clinical Presentation Eschars are rare in patients in countries of South-East Asia Indigenous persons of typhus-endemic areas commonly have less severe illness, often without rash or eschar Whether this is due to past exposure to the organism, or to other factors, is unknown. Symptoms may include muscle and gastrointestinal pains. More virulent strains of O. tsutsugamushi can cause haemorrhaging and intravascular
31. Clinical Presentation Complications may include atypical pneumonia, overwhelming pneumonia with adult respiratory distress syndrome (ARDS)–like presentation, myocarditis, and disseminated intravascular coagulation (DIC). Often exhibit leucopenia. Acute scrub typhus appears to improve viral loads in patients with HIV. (This interaction is currently unexplained).
32. Specifc features Maculopapular rashes Onset: Appear at the end of the 1st week, lasts 3~7days. Location: Chest, abdomen, whole trunk, or upper and lower limbs. rarely involves the face, palms and soles. .
33. Specifc featuresRegional lymphadenopathy: occur at the end of the 1st week. localize: the draining lymph node around the primary eschar characterized by tenderness and enlargementGeneralized lymphadenopathy: appears 2-3 days later.
34. Differential Diagnosis Serology - ◦ Weil-Felix test,- Cheapest and most easily available, 50% of patients have a +ve test result during the second week. ◦ Complement-fixation test Each patient’s serum is systematically tested against five O. tsutsugamushi serotypes. ( An IgM titer > 1:32 and/or a four-fold increase of titers between two sera confirm a recent infection). However, due to cross-reactions among serotypes, it is difficult to identify accurately a
35. Differential Diagnosis The gold standard is indirect immunofluorescence antibody (IFA). Indirect immunoperoxidase (IIP) is a modification of the standard IFA method that can be used with a light microscope, results are comparable to IFA. Commercial rapid diagnostic kits provide reliable and well-accepted preliminary results within one hour, but the availability of these tests is severely limited by their cost. ELISA provides more sensitivity and equal specificity when compared to commercial test
36. Differential Diagnosis The organism can be grown in tissue culture or mice from the blood of patients but results are not available in time to guide clinical management. Molecular detection using polymerase chain reaction (PCR) is possible from ◦ Skin rash biopsies, L. N. biopsies or Ethylene Diamine Tetra Acetic acid (EDTA) blood. Realtime PCR assays are as sensitive as standard PCR but are more rapid
37. Specimen for laboratory andDispatch Depends on diagnostic method to be used. And are preserved and shipped as follows: ◦ Skin or lymph node biopsy If frozen at - 80°C after sampling, ship in dry ice for culture. At room temperature for PCR. If formalin-treated or paraffin- embedded, ship at room temperature for immunohistochemistry.
38. Continued…Heparinized blood• Conserve at -80°C and then ship in dry ice for culture.EDTA blood• Conserve at +4°C and then ship at room temperature for PCR.Serum• Conserve at +4°C, then ship at room temperature. Collect two serum specimens 10 days apart.
39. Treatment Antibiotic therapy brings Rapid defervescence- doxycycline,/ chloramphenicol Doxycycline and rifampicin combination- where there is poor response to doxycycline Azithromycin or chloramphenicol -In children or pregnant women Relapses if the antibiotic treatment is discontinued too quickly, especially in patients treated within the first few days No significant morbidity or mortality occurs in patients who receive appropriate
40. Prophylactic treatment Single oral dose of chloramphenicol or tetracycline given every five days for a total of 35 days, with 5-day non- treatment intervals, actually produces active immunity to scrub typhus. This procedure is recommended under special circumstances in certain areas where the disease is endemic.
41. Vaccine against scrub typhus? There is enormous antigenic variation in Orientia tsutsugamushi strains, and immunity to one strain does not confer immunity to another A vaccine developed for one locality may not be protective in another locality, because of antigenic variation. This complexity continues to hamper efforts to produce a viable vaccine
42. Precautions to protect you from scrub typhus? Protective clothing. Insect repellents containing dibutyl phthalate, benzyl benzoate, diethyl toluamide,etc applied to the skin and clothing to prevent chigger bites. Do not sit or lie on bare ground or grass Clearing of vegetation and chemical treatment of the soil may help to break up the cycle of transmission from chiggers to humans to other chiggers.
43. Control strategy Case identification - early diagnosis of acute scrub typhus can greatly reduce the chance of life-threatening complications Public education -Advocacy, awareness and education activities should be targeted at schoolchildren, teachers and women groups in endemic areas involving community-based organizations
44. Institution for research and training onscrub typhus in the SEA Region The Armed Forces Research Institute of Medical Sciences (AFRIMS) Bangkok, Thailand is the WHO Collaborating Centre (CC) for Emerging Diseases that is providing technical support for outbreak investigation and capacity building for diagnosis and control of scrub typhus. The Department of Entomology, AFRIMS is the only laboratory in the world that has the ability to rear and colonize scrub typhus-infected Leptotrombidium mites, the vector of
45. MCQs1. Limited area of intensive transmission of rickettsiae called as (a) Typhus Island (b) Mite islands (c) Rickettsiae Island (d) None of the above2. Agent for Indian Tick Typhus is (a) Rickettsia typhi(b) Rickettsia conorii (c) Rickettsia akari (d) Rickettsia prowazekii3. Most commonly reported rickettsial infection in India is (a) Scrub typhus (b) Indian Tick Typhus (c) Epidemic typhus (d) Rickettsial pox4. Epidemic Typhus is transmitted by (a) Tick (b) Mite (c) Human louse (d) Rat flea5. The infection is transmitted to man through the bite of which form of infective mite (a) Larvae (b) Pupa (c) Male adult (d) Female adult