RICKETTSIAL INFECTION: DIVERSITIES, DILEMMA AND CHALLENGES Dr. Moniruzzaman Ahmed Associate Professor, Dept of Medicine MAG Osmani Medical College, Sylhet

RICKETTSIAL INFECTION: DIVERSITIES, DILEMMA AND

CHALLENGES

Dr. Moniruzzaman AhmedAssociate Professor, Dept of MedicineMAG Osmani Medical College, Sylhet

Rickettsial diseases - 4 distinct genera:

•Rickettsia, Orientia, Ehrlichia (Ehrlichia chaffeensis, the agent of human monocytic ecrlichiosis) and Anaplasma (Anaplasma phagocytophilium, the agent of human granulocytic anaplasmosis)•Diseases caused by Rickettsia and Orientia species often reffered to as rickettsioses •Coxiella burnetii, the agent of Q fever and Bartonella spp. were recently removed from the order Rickettsiales Parola P, Paddock CD, Raoult D. Tick-borne rickettsioses around the world: emerging diseases challenging old concepts. Clin Microbiol Rev. 2005;18:719–56

RICKETTSIAL SPECIES-BIOVARS

SPOTTED FEVER GROUP RICKETTSIOSES (SFGR) / TICK BORN RICKETTSIAL DISEASE (TBRD)

TYPHUS GROUP (TG)

SCRUB TYPHUS GROUP

RICKETTSIA- BIOLOGY

• Small obligate intracellular parasites

• Gram-negative bacteria• Stain poorly with Gram stain

(Giemsa)• “Energy parasites” but not obligate,

have capacity to make ATP• Parasite of arthropods – fleas, lice,

ticks and mites• Reservoirs - animals, insects and

humans

From 1906 to 1910, Howard T Ricketts isolated the pathogen and showed that it circulated among ticks and mammals in the wild. Tragically, this talented rickettsiologist was affected by epidemic typhus and died in 1910, at the age of 39 years.

The genus Rickettsia is named after Howard Taylor Ricketts (1871–1910), who studied Rocky Mountain spotted fever in the Bitterroot Valley

TRANSMISSION, PATHOGENESIS & PATHOPHYSIOLOGY

SPOTTED FEVER GROUP RICKETTSIOSES (SFGR)/ TICK BORN RICKETTSIAL

DISEASE(TBRD)

PROTYPICAL DISEASES

ORGANISM DISEASE DISTRIBUTION

R.Rickettsii Rocky Mountain spotted fever

Western hemisphere

R. akari Rickettsialpox USA, former Soviet Union

R. conorii Boutonneuse fever, Kenya tick typhus, Israeli tick typhus, Mediterranean spotted fever(MSF), Indian tick typhus, Astrakhan tick typhus, Marseilles fever

Mediterranean countries, Africa, India, Southwest Asia

R. sibirica Siberian tick typhus Siberia, Mongolia, northern China

R. australia Australian tick typhus Australia

R. japonica Oriental spotted fever Japan

(SFGR)/(TBRD)

GEOGRAPHICAL DISTRIBUTION

Update on Tick-Borne Rickettsioses around the World: a GeographicApproachPhilippe Parola,a Christopher D. Paddock,b Cristina Socolovschi,a Marcelo B. Labruna,c Oleg Mediannikov,a Tahar Kernif,dMohammad Yazid Abdad,e* John Stenos,e Idir Bitam,f Pierre-Edouard Fournier,a Didier RaoultaOctober 2013 Volume 26 Number 4 Clinical Microbiology Reviews p. 657–702

GEOGRAPHICAL DISTRIBUTION (South America)



GEOGRAPHICAL DISTRIBUTION (EUROPE)





GEOGRAPHIC DISTRIBUTION

Geographic and temporal distribution of rickettsioses is largely determined by their vectors

“One continent, one pathogenic tick-born rickettsia” an anachronism

Prevalent throughout the world except Antarctica

Summary of prevalent Rickettsiae in Southeast Asia,their reservoirs and vectors for disease

transmissionRickettsiae Main reservoirs Main vectors

Typhus groupMurine typhus (R.typhi)

Rats(Rattus rattus, Rattus norvegicus, other Rattus sp.)

Xenopsylla cheopis

Scrub typhus (O. tsutsugamushi) Rats (Rattus sp. and Bandicota sp.)

Trombiculid mites (Larval stage )

Spotted fever groupR.Honei

Rats ( Rattus sp. And Bandicota indica.)

Ixodes granulatus, Ixodes sp., Rhipicephalus sp.

R. felis Rats(Rattus sp) and shrews (Suncus murinus)Domestic cats, dogs, cows and pigs.

Ctenocephalides orientis, C. felis felis, X. cheopis

R. Conorii subsp. indica Rats ( Rattus sp.) R. sanguineus

R. helvetica Unknown Ixodes spp

R. japonica Rats ( Rattus sp. And B. indica.) Various species of animal ticks.

Am. J. Trop. Med. Hyg., 91(3), 2014, pp. 451–460Review Article: Rickettsial Infections in Southeast Asia: Implications for Local Populaceand Febrile Returned TravelersAr Kar Aung,* Denis W. Spelman, Ronan J. Murray, and Stephen Graves

Short Report: Serosurveillance of Orientia tsutsugamushi and Rickettsia typhi in

Bangladesh

Short Report: Serosurveillance of Orientia tsutsugamushi and Rickettsia typhi in Bangladesh Rapeephan R. Maude,* Richard J. Maude, Aniruddha Ghose, M. Robed Amin, M. Belalul Islam, Mohammad Ali, M. Shafiqul Bari, M. Ishaque Majumder, Ampai Tanganuchitcharnchai, Arjen M. Dondorp, Daniel H. Paris, Robin L. Bailey, M. Abul Faiz, Stuart D. Blacksell, and Nicholas P. J. DayAm. J. Trop. Med. Hyg., 91(3), 2014, pp. 580–583

A total of 155 clinically suspected febrile patients were enrolled in the study. Out of them, 136 (88%), 31 (23%) and 61 (43%) were positive by Weil-Felix test, ELISA and PCR respectively.Out of the 61 PCR positive products, 16 were sequenced in Sapporo Medical University, Japan where 13 were found to be 99.9% consistent with Rickettsia felis.

An ongoing study in Mymensingh Medical

College

A case series of 40 rickettsial infection in MMCH found 60% positive for scrub typhus by using Weil-Felix test (Miah MT, Rahman S, Sarker CN, Khan GK, Barman TK, 2007. Study on 40 cases of Rickettsia. Mymensingh Med J 16: 85–88)

Association of tick genera and rickettsial species

CLINICAL MANIFESTATIONS•Clinical symptoms of tick-borne SFG rickettsioses begin 4 to 10 days after a bite and typically include fever, headache, muscle pain, rash, local lymphadenopathy, and, for most of these diseases, a characteristic inoculation eschar at the bite site

•Life-threatening manifestations : prolonged fever, renal failure, myocarditis, meningoencephalitis, hypotension, ARDS, multiple organ failure

A crusty necrotic lesion with or without a surrounding erythematous halo which suggests the location of the vector bite

ESCHAR (TACHE NOIRE)

LARLymphangitis may be present in several rickettsiosesHalf of the cases of R. sibirica subsp. mongolitimonae infection present this sign (rope-like lymphangitis between the inoculation eschar and lymphadenitis) the infection being termed lymphangitis-associated rick-ettsiosis (LAR) also present in infections caused by R. heilongjiangensis and R. africae

DEBONEL / TIBOLA /SENLATTwo dominant signs characterize this syndrome: an inoculation eschar and regional lymphadenopathy The occurrence of fever and rash is rare. DEBONEL/TIBOLA (Dermacentor-borne necrosis erythema lymphadenopathy/tick-borne lymphadenopathy), also called SENLAT (scalp eschar and neck lymphadenopathy after tick bite) when the tick bite affects only the scalpProduced by different species of Rickettsia. The main etiological agent is Rickettsia slovaca

TYPHUS GROUP

HISTORY AND HISTORICAL IMPACT OF TYPHUS

Europian history has been affected by Typhus epidemics from the the 15th through the 20th centuries, Pediculus humanus corporis as having a more profound effect on human history than any other animalRickettsia prowazeki is isolated and identified by Da Rocha-Lima in 1916. Named in honor of H. T. Ricketts and L. von Prowazek, both of whom contracted typhus in the course of their investigations and diedIn 1829, the French clinician Louis clearly differentiated Typhus Fever from Typhoid Fever (Wolback et al., 1922)Transmission of Epidemic Typhus by the body louse was first demonstrated experimentally by Nicolle and others (1909)Early History. The first pestilence attributed to louse-borne typhus was the Athenian Plague of 430 B.C.The Fifteen Century. An epidemic of louse-borne typhus struck the besieging army of Spanish and within a month had killed 17,000 of the original 25,000 soldiers. The Sixteen Century. Western civilizations at that time regarded their God as a somewhat capricious tyrant, who either gave life or took it. Having no recourse to medicine as a means of explaining their devastations, medieval man turned to spiritual and metaphysical sources. A number of so-called "Assize Epidemics" occurred in England at this time, most notably at Oxford in 1577 and Exeter in 1589. The Oxford epidemic was of such import that the University there was closed for 30 years afterward.The Seventeenth Century. In the Thirty Years War of 1618-1648 along with Plague and starvation, typhus was responsible for the loss of 10,000,000 people in which only 350,000 men died in combat . The Eighteenth Century. The 18th century was marred by many small epidemics of typhusThe Nineteenth Century. Napoleon Bonaparte's campaign against the Russians in 1812 Napoleon had organized his "Grande Armee", numbering 600,000 well-seasoned troops -Only 90,000 French soldiers reached Moscow out of the original army of 600,000. The great majority, possibly as high as 300,000, had died of Epidemic Typhus and dysentery. Epidemic Typhus had helped defeat Napoleon and end his dreams of a French-ruled world. Typhus was endemic in Russia with some 82,000 cases a year recorded before 1914‘Either socialism will defeat the louse’, ‘or the louse will defeat socialism’; ‘All attention to this problem comrades!’ Lenin observedThe Twentieth Century. Nicolle's proof of the transmission of typhus by body lice in 1910 Insurance Company as saying that as many as twenty-five million cases of typhus occurred during the years 1918-1922 with upwards of three million deaths. To dehumanise the Jews the Nazi Propaganda Minister Joseph Goebbels declared: ‘These are no longer people…The task is not humanitarian but surgical. Steps have to be taken here, and really radical ones tool. Otherwise Europe will perish from the Jewish disease.’


Rickettsia prowazeki is isolated and identified by Da Rocha-Lima in 1916. Named in honor of H. T. Ricketts and L. von Prowazek, both of whom contracted typhus in the course of their investigations and died

In 1829, the French clinician Louis clearly differentiated Typhus Fever from Typhoid Fever (Wolback et al., 1922)

Transmission of Epidemic Typhus by the body louse was first demonstrated experimentally by Nicolle and others (1909). Nicolle received the Nobel Prize for his work on typhus in 1928.

Henrique da Rocha Lima and Stanislas von Prowazeck

Charles Jules Henri Nicolle


15th-19th century Epidemics in Europe as a result of war, disaster, or in prisoners

The Sixteen Century The Oxford was closed for 30 years

The Seventeenth Century. In the Thirty Years War of 1618-1648 along with Plague and starvation, typhus was responsible for the loss of 10,000,000 people in which only 350,000 men died in combat

The Nineteenth Century. Only 90,000 French soldiers reached Moscow out of the original army of 600,000. Epidemic Typhus had helped defeat Napoleon and end his dreams of a French-ruled world


‘Either socialism will defeat the louse’, ‘or the louse will defeat socialism’; ‘All attention to this problem comrades!’ Lenin observed

To dehumanise the Jews the Nazi Propaganda Minister Joseph Goebbels declared: ‘These are no longer Steps have to be taken here, and really radical ones tool. Otherwise Europe will perish from the Jewish disease.’

End of WWII, DDT for control

Discovery of Tetracycline and Chloramphenicol in late 1940

Delousing and Disinfection

In German soilders had to show delousing certificates when on

leave

Neither the queens nor the kings, the lice shaped the history of Europe

TYPHUS

DiseaseGroup

Disease Agent Vector AnimalReservoir

Geographical Distribution

Typhus Group

EpidemicTyphus

Sylvatic typhus

R.prowazekii

Humanbody louse

Flea

Humans,

Fleas, flying squirells

Mountainous regions of Africa, Asia, and Central, north and South America.

Murinetyphus

R. typhi Rat flea(Xenopsyllacheopis)

Rats, cat, mice

Tropical and subtropical areasWorldwide

EPIDEMIC TYPHUS

• Incubation period approximately 1 week

• Sudden onset of fever, chills, headache and myalgia

• Rash after one week– Maculopapular progressing to

petechial or hemorrhagic– First on trunk and spreads to

extremities (centrifugal spread)• Complications

– Myocarditis, stupor, delirium (Greek “typhos” = smoke)

• Recovery may take months, debilitating

• Mortality rate can be high (60-70%) but this may be because of the situation, such as famine

Brill-Zinsser Disease

• The rickettsia can remain latent and reactivate months or years later, with symptoms similar to or even identical to the original attack of typhus, including a maculopapular rash

• Mild illness and low mortality rate.

• Rash is rare

Rickettsia typhi - Murine or endemic typhus

• Occurs worldwide• Vector - rat flea

– Bacteria in feces• Reservoir - rats

– No transovarian transmission

– Normal cycle - rat to flea to rat

• Humans accidentally infected

• Incubation period 1 - 2 weeks

• Sudden onset of fever, chills, headache and myalgia

• Rash in most cases begins on trunk and spreads to extremities (centrifugal spread)

• Mild disease - resolves even if untreated

SCRUB TYPHUS

SCRUB TYPHUS GROUP

Antigenic group

Disease Species Vector Animal reservoir

Geographic distribution

Scrub typhus

Scrub typhus

Orientiatsutsugamushi

Larval mite(chigger)

Rodents Asia-Pacific region from maritime Russia and China to Indonesia and North Australia to Afghanistan

Scrub typhus

Scrub Typhus

Orientia chuta

Unknown Unknown Dubai

Isolation of a Novel Orientia Species (O. chuto sp. nov.)from a Patient Infected in DubaiLeonard Izzard,1,2 Andrew Fuller,3 Stuart D. Blacksell,4,5 Daniel H. Paris,4,5 Allen L. Richards,4,6,7Nuntipa Aukkanit,4,5 Chelsea Nguyen,1 Ju Jiang,6 Stan Fenwick,2 Nicholas P. J. Day,4Stephen Graves,1 and John Stenos1,2*JOURNAL OF CLINICAL MICROBIOLOGY, Dec. 2010, p. 4404–4409 Vol. 48, No. 12

Scrub typhus

Orientia tsutsugamushi is the causative agent & transmitted to humans through the bite of thrombiculid mites.

The chigger (larval) phase is the only stage that is parasitic on animals or humans.

First described in china 318 AD, isolated in Japan in 1930 Disease of rural villages and suburban areas. Term scrub is used because of the vegetation (terrain

between woods and clearing) that harbours the vector. Scrub typhus is endemic in tsutsugamushi triangle which

extends from northern Japan, far eastern Russia in the north to the Northern Australia in the south and pakistan in the west.

Estimated 1 billion people are at risk of scrub typhus and estimated 1 million cases occur annually.

TSUTSUGAMUSHI TRIANGLE

TSUTSUGAMUSHI TRIANGLE

Clinical features-Scrub typhus

Incubation period - 1 to 3 weeks

Sudden onset of fever, chills, headache and myalgia Maculopapular rash (spots and bumps)

Begins on trunk and spreads to extremities (centrifugal spread)

Commonest symptom high grade fever ,headache muscle pain ,cough, and GI symptoms

Severe disease in 2ND week.Meningitis , meningo-encephalitis , deafness, pneumonia,

ARDS, MODS & myocarditis.Reinfection & Relapses are seen due to variable immunity to

different strains Mortality rates variable (1-15%)

ESCHAR

SYNDROMIC CLASSIFICATION OF RICKETTSIOSES

Syndromic classification of rickettsioses: an approach for clinicalPractice´lvaro A. Faccini-Martińez a, Lara Garciá-A´ lvarez b, Marylin Hidalgo a, Jose´ A. Oteo b,*International Journal of Infectious Diseases 28 (2014) e126–e139

SYNDROMIC CLASSIFICATION OF RICKETTSIOSES

Syndromic classification of rickettsioses: an approach for clinicalPractice´lvaro A. Faccini-Martińez a, Lara Garciá-A´ lvarez b, Marylin Hidalgo a, JoseInfectious Diseases 28 (2014) e126–e139

Laboratory Diagnosis

• Serologic assays (eg, indirect immunofluorescence, complement fixation, indirect hemagglutination, latex fixation, enzyme immunoassay, microagglutination) are preferable to the nonspecific and insensitive Weil-Felix test based on the cross-reactive antigens of Proteus vulgaris strains

• Immunofluorescence assay (IFA) is currently considered to be the reference serological method.

• Polymerase chain reaction (PCR) to detect rickettsiae in blood or tissue provides promise for early diagnosis. PCR testing and immunohistochemical staining of skin specimen obtained by performing a biopsy may help confirm the clinical diagnosis in patients with rash.

• The swabs of eschars may be used for molecular detection of rickettsial infections when biopsies are difficult to perform.

DILEMMA & CHALLENGES

A thorough history and knowledge of the distribution of rickettsial agents and their vectors

evidence of exposure to vector

clinical features like fever, rash, eschar, headache and myalgia

high index of suspicion are crucial factors

DIAGNOSIS

TREATMENT

Antibiotic Indication Dosage TreatmentDoxycycline (standard treatment of rickettsosis)

Severe rickettsioses (including pregnant women and children)Ideally intravenousAdults or children>45kg

Adults or children>45kg;100 mg twice a day pregnant women(last trimester):100 mg twice a day Children<45kg;22 mg twice a day

Continued for 3 days after symptoms has resolved

Macrolides(josamycin,clarythromycin and azithrothromycin

Option for not severe rickettsioses in children and pregnant women

Josamycin:children 50 mg/kg twice a day, pregnant women 1g/8hrlyClarithromycin for children :15mg/kg twice a day

Josamycin 5 daysClarithromycin 7 days and Azithromycin 3 days

Chloramphenicol Alternative option in severe rickettsioses

Azithromycin in children :10 mg /kg/day in 1 doseAdults and pregnant (first and second trimester); 60-75 mg/kg in4 divided dosesChildren12-25 mg/kg every 6 hourly

5-10 days

Syndromic classification of rickettsioses: an approach for clinicalPractice´lvaro A. Faccini-Martińez a, Lara Garciá-A´ lvarez b, Marylin Hidalgo a, JoseInfectious Diseases 28 (2014) e126–e139

But however secure and well-regulated civilized life may become; bacteria, protozoa, viruses, infected fleas, lice, ticks, mosquitoes, and bedbugs will always lurk in the shadows ready to pounce when neglect, poverty, famine, or war lets down the defenses.

Hans Zinsser

Rats, Lice and History (1934), 13-4.

Documents

RICKETTSIAL INFECTION: DIVERSITIES, DILEMMA AND CHALLENGES Dr. Moniruzzaman Ahmed Associate Professor, Dept of Medicine MAG Osmani Medical College, Sylhet