Rickettsia: Spotted fever group- RMSF, R. conori, R. africae, R. akari

OVERVIEW: What every clinician needs to know

Pathogen name and classification

Rickettsiae are obligate intracellular gram-negative bacteria that are associated with arthropod vectors. Currently, the Rickettsia genus contains 25 officially validated species, of which 16 are human pathogens and 2 are suspected to cause Rickettsioses. The members of the Rickettsia genus are divided into 2 groups according to their pathogenicity and their phenotypic properties:

The spotted fever group (SFG)
Typhus group (TG)
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R. bellii and R. canadensis belong to different groups
5 Rickettsial genes (16S rDNA, gltA, ompA, ompB, and sca4 genes) are proposed to determine new genus and species of Rickettsiae
These zoonoses are among the oldest known vector-borne diseases, but new species continue to be describing in vectors and in human samples. Among them, some have a role in human pathology.
Rickettsia is mainly associated with ticks, but also lice, fleas and mites, and causes spotted fevers or typhus in humans
Rickettsiae are strictly intracellular bacteria whose size range from 0.3 x 0.8 µm to 0.5 x 2 µm, and have cell wall and lipopolysaccharide similar to other gram negative bacteria.
Not visible by gram staining but is visible by Gimenez or Giemsa staining
These bacteria live free in the cytoplasm and divide by binary fission in the cytoplasm
Traditional methods used in bacteriology cannot be routinely applied to Rickettsiae because of their intracellularity
Diagnostic identification of Rickettsiosis remains in serology, cell culture, immunohistochemistry and molecular biology

What is the best treatment?

Susceptibility to antibiotics is tested in vitro with cells culture methods as plaque assay or microplaque colorimetric assay which allow to determine minimal inhibitory concentration (MIC).
Rickettsiae are susceptible to doxycycline, thiamphenicol and fluoroquinolone. Beta-lactams, aminoglycosides and cotrimoxazole are not active.
R. massiliae, R. aeschlimanii and R. raoultii are resistant to rifampicin
All SFG Rickettsiae are resistant to erythromycin
Susceptibility in vitro of Rickettsiae to other macrolides is variable

Josamycin seems to be the most active compared to clarithromycin and pristinamycin
Treatment must be instituted without waiting for laboratory confirmation when Rickettsiosis is strongly suspected
No routinely given antibiotics for asymptomatic tick bites
Recommendation for SFG treatment is:

Doxycycline at 200mg/day for adults and 5mg/kg/day for children

Contraindicated in children under 8 years old because of the risk of tooth discoloration

Contraindicated in pregnant women because of toxicity for fetus

But when a single or short therapy (5-10 days) with doxycycline is administrated in children, the risk of dental staining is negligible.

For severe Mediterranean spotted fever (MSF) or rocky mountain spotted fever (RMSF), a 200mg dose of intravenous doxycycline can be used, followed by doxycycline per os during 10 days

Alternatives exist for pregnant women and children:

Josamycin: 3g/day during 7 days for pregnant woman and 100mg/kg/day for 5 days in children.

Duration of treatment is variable depending on clinical outcome. Treatment must be prolonged 3 days after apyrexia.

Fluoroquinolone are also used for treatment of spotted fever group Rickettsiosis:

Fluoroquinolone are significantly associated with more severe spotted fever infection, particularly for patients presenting MSF.

Using fluoroquinolone for Rickettsioses treatment is not recommended.

How do patients contract this infection, and how do I prevent spread to other patients?

Epidemiology: see individual infections under “what are the clinical manifestations of infection with this organism?” section.
Avoid being bitten by ticks, after being in the woods body inspection is advised. Use DEET.

What host factors protect against this infection?

Patients in contact with arthropod in endemic areas are at risk for contracting Rickettsioses.
Among tick-borne SFG, some species cause more severe disease than others. Rickettsia conoriiand R. rickettsiicause more severe disease and cause greater fatal cases than R. africae, R. felisand R. mongolitimonae.
Several host factors such as age (>60 years), comorbidities (chronic alcoholism, diabetes), immunosuppression, and deficiency in G6PD are associated with more severe disease and more fatalities.

What are the clinical manifestations of infection with this organism?

Typically, the clinical symptoms of spotted fever Rickettsioses include fever, headache, myalgia, cutaneous rash, local lymphadenopathy and a characteristic inoculation eschar. But these clinical signs, and the severity and outcome of the disease, vary depending on the Rickettsial specie involved.

Tick-borne Rickettsioses

Mediterranean Spotted fever (MSF)

The causative agent is Rickettsia conorii subsp. conorii. Recently it has been proposed to modify the nomenclature of the R. conorii species through the creation of 4 subspecies (R. conorii subsp. conorii, R. conorii subsp. israelensis, R. conorii subsp. caspia, R. conorii subsp. indica) to accommodate both the genotypic homogeneity, geographic and pathogenic diversities of Rickettsia strains within this species.

The main vector is the worldwide dog tick, Rhipicephalus sanguineus.
MSF have seasonal distribution, it is a summer illness with most cases occurring between July and September. Recent study supports that warmer weather is linked to an increase in the aggressiveness of R. sanguineus.
MSF is endemic in the Mediterranean area, including Northern Africa and Southern Europe, and is also found in Central Europe and Central Africa.
The incubation period lasts around 6 days (1-16 days) and is asymptomatic.
MSF in the endemic zone is characterized by the association of:

fever, onset is abrupt with high (>39°C)

flu-like symptoms

maculopapular rash occurs 2 to 3 days after the fever, it is initially macular then maculopapular and generalized; palm and face is generally spared.

Black eschar at the bite site:

Indolent and usually present on the trunk and the limbs and are rarely multiple.

The duration of illness is between 12 to 20 days

Clinical improvement occurs within 48 hours of antibiotic treatment.

Severe forms include:

major neurological manifestations

multi-organ involvement which may occur in 5% of patients.

Recent MSF appears to be a more severe disease than it was in the past. The mortality rate is usually estimated at around 1%, but increased to 32.3% in Portugal in 1997.

Israeli spotted fever (ISF)

Rickettsia conorii subsp. israelensis
Also transmitted by R. sanguineus

Found in Israel

Also associated with human disease in Portugal and Sicily, suggesting that the geographical distribution is wider than previously thought.

Presence of eschar is less frequent than with MSF

ISF infections more severe and lethal than MSF

Astrakhan spotted fever

Transmitted by R. conorii subsp. caspia.

Endemic in Astrakhan and Russia around the Caspian Sea

Transmitted by Rhipicephalus pumilio

Clinically similar to MSF

Eschar

Lethal form is less frequent

Indian tick-bite typhus

R. conorii subsp.indica is the agent
Unlike MSF the rash may be purpuric and eschar is rarely found

Rocky mountain spotted fever (RMSF)

Rickettsia rickettsii is the aetiological agent
A prevalent Rickettsial disease in the USA
R. rickettsii is transmitted by infected hard ticks as Dermacentor variabilis, Dermacentor andersoni, R. sanguineus, A. cajennense and A.aureolatum.
The geographical distribution of RMSF is limited to western hemisphere countries such as USA, Canada, Mexico, Panama, Costa Rica, Argentina, Brazil and Colombia.
Seasonal, occurs from April to September
Most patients have moderate or severe illness
The incubation period is between 2 to 14 days
Clinical manifestations:

Sudden onset of fever and headache

Myalgia

Nausea, vomiting, intestinal disorders

Photophobia

A maculopapular then petechial rash appears on the third day:

Rash is located on the wrist and ankles with subsequent centrifugal progression to the palms and soles

Inoculation eschar is rarely found

Complications include:

Myocarditis

Renal failure

Neurological

Ocular

Pulmonary manifestations

Severe cases and fatal outcomes are associated with:

Old age

Inappropriate or postponed antibiotic treatment

Glucose-6-phosphate-dehydrogenase deficiency

African tick-bite fever (ATB)

Caused by Rickettsia africae
ATBF is the most common tick borne Rickettsial disease in the African continent; it is endemic particularly in Sub-Saharan Africa and in the French West indies.
Transmitted by Amblyommasp. ticks (A. variegatum and A. hebraeum) and Rhipicephalus boophilus.
Common in local African population but rarely diagnosed, the numbers of cases in European and American travelers increased these recent years.
Mean incubation period is 5-7 days but may be as long as 10 days.
An acute illness, typical symptoms include:

Fever

Headache

Myalgia

Nausea and asthenia

Inoculation eschar is predominant in lower limbs

In up to 54% of cases, patients present multiple eschars in relation to aggressiveness of the ticks.

Rash is observed in 50% of cases and is vesicular in many cases

Regional lymphadenitis is found in some cases

Complications are rare and patients recover rapidly with doxycycline treatment

ATB testing should be suggested in febrile travelers returning from endemic area and travelers should be informed about risk of contracting ATB and prevention measures.

Scalp eschar and neck lymphadenopathy after tick bite (SENLAT)

Also called tick-borne lymphadenopathy (TIBOLA) and dermacentor-borne necrosis erythema and lymphadenopathy (DEBONEL).
Three defined as the association of a tick bite; an inoculation eschar on the scalp and cervical lymphadenopathies.
Rickettsial agents involved are Rickettsia slovaca and Rickettsia raoultii and candidatus Rickettsia rioja.
Transmitted by both ticks, Dermacentor marginatus and Dermacentor reticulatus.

R. raoultii seems to be more prevalent in ticks than R. slovaca, but R.slovaca is more pathogenic
SENLAT occurs in Europe and Central Asia, where these ticks are prevalent.
Ticks inhabit forests and pastures, and frequently bite women and children on the scalp during the colder months.
After few days of incubation, patients present an inoculation eschar on the scalp and neck lymphadenopathies.

Fever and rash are uncommon

Sequelae include localized alopecia at the bite site and chronic asthenia

Lymphangitis-associated rickettsiosis (LAR)

Caused by Rickettsia sibirica mongolitimonae
Vector is Hyalomma spp ticks: H. asiaticum in Asia, H. excavatum in Europe and H. truncatum in Africa.
Human cases are described in Greece, Portugal, South Africa and Southern France.
Incidence is higher in spring or summer.
Incubation period lasts 5 days.
Clinical characteristics of this mild disease are:

Fever

Headache

One or more frequently multiple eschars

Maculopapular rash

Enlarged lymph nodes and lymphangitis.

Case of retinal vasculitis is recently reported.

Aneruptive fever

Rickettsia helvetica has been isolated from Ixodes ricinus ticks in European and Asian countries.
.The pathogenic role of R. helvetica is unclear.
This bacterium seems to be associated with aneruptive fever in patients with serological evidence of R. helvetica infection.

Clinically present with:

Fever

Headache

Myalgia

No inoculation eschar or cutaneous rash in the warm season.

More severe infections are reported as septicaemia and meningitis.

Flea borne spotted fever

Caused by Rickettsia felis is the only SFG Rickettsia transmitted by fleas and is responsible to flea-borne spotted fever.

Only recognized vector is a cat flea, Ctenocephalides felis, an ectoparasite of domestic cats and dogs.

R. felis is distributed worldwide. Cases of R. felis infection are reported in the America, Asia, Tunisia and Europe.

Reports of confirmed human cases are uncommon but the bacterium is frequently isolated from fleas.

The disease is extremely prevalent in Africa. The bacterium has been found in mosquitos from Africa.
Patients infected with R. felis present with

Fever

Inoculation eschar

Maculopapular rash

Neurologic and digestive signs

Recently, R. felis is associated with many cases of uneruptive fever in Senegal.

Rickettsialpox

Caused by Rickettsia akari. It is transmitted to human by the house mouse mites, Liponyssoides sanguineus.
This disease is reported in United States, Ukraine, Croatia, South Africa, Bosnia, France, Italy, Costa Rica and Turkey.
The disease is characterized by:

Inoculation eschar at the site of bite

Regional lymphadenopathies

Followed by fever, headache and a papulovesicular rash one week later.

Siberian tick typhus

Caused by Rickettsia sibirica subsp. sibirica.
Several ticks are identified as vectors: Dermacentor nuttalli, D. marginatus,D. silvarum, D. pictus, D. sinicus, D. auratus, Hyalomma wellingtoni, H.yeni and Haemaphysalis concinna.
Described only in Siberia, northern China, Mongolia and Kazakhstan.
Occurs mainly in spring and summer.
The incubation period is 4-7 days.
Characterized:

Fever

Inoculation eschar

A rash which occurs 2-4 days after the symptoms and which may be purpuric

Regional lymphadenopathy

Headache

Myalgia

Digestive disorder

R. parkeri

Transmitted by Amblyomma maculatum in United States and A. triste in South America.
This bacterium is first identified in tick in 1939 but the first recognized case of human infection is reported only in 2004.
This disease was probably misidentified during several years as RMSF.
Both R. parkeri and RMSF are characterized by:

Fever

Headache

Myalgia

A maculopapular eruption in a delay of one week after tick bite

The presence of inoculation eschar and vesicular or pustular rash are more common compared to RMSF

Digestive disorder are generally absent

This disease is a milder illness than RMSF

Japanese spotted fever

Caused by Rickettsia japonica
Transmitted by ticks: H. longicornis, H. flava, D. taiwanensis andIxodes ovatus.
Predominant in Japan between April to October and is recently described in human in Thailand and in ticks in Korea.
Clinical manifestations include:

Fever

Headache

Chills

Eschar

A maculopapular rash occurs 2-3 days after onset of symptoms and may be petechial

Far eastern tick-borne rickettsiosis

Caused by Rickettsia heilongjiangensis
Transmitted by D. silvarum, H. concinna, and H. japonica douglasi
Few cases are reported in Russian Far East, China and Japan
Occurs mainly in summer months and seems to affects younger people
Clinical manifestations:

Fever

Headache

Eschar

Macular or maculopapular rash

Queensland tick typhus

Caused by Rickettsia australis
Transmitted from June to November in eastern Australia by Ixodes holocyclus, Ixodes tasmani andI. cornuatus.
Usually a mild illness including:

Fever

Headache

Myalgia

Eschar is present in up to half the cases

A maculopapular or vesicular rash appears in most patients

Lymphadenopathy in 70%

Complications include:

Renal failure

Purpura fulminans

Severe pneumonia, and may not be as benign as previously described

Flinders island spotted fever

Caused by Rickettsia honei.
Transmitted by reptiles’ ticks as Aponomma hydrosauriand Ixodes granulate.Ixodes tasmani, the main ticks that bites humans in Finders Island, is also described as vectors.
Described in Flinders island (a small island off the south of Australia), then in Australia, Thailand, and Sri Lanka.
Cases occurring spring and summer, particularly during December and January
Clinical characteristics:

Abrupt fever

Headache

Arthromyalgias

Slight cough

Inoculation eschar and regional adenopathies

An erythematous or purpuric rash occurs few days later

Infrequently reported tick-borne rickettsia

Rickettsia monacensis

Transmitted by I. ricinus

Found in Europe and northern Africa and from I. scapularis in the USA.

To date, two cases are described with:

Fever

Headache

Erythematous or maculopapular rash without inoculation eschar

The two patients recover without sequelae
R. amblyommii is present in America
Vectors include: A.americanum, A. coelebs and A. cajennense
Associated with:

Febrile disease with or without rash but the pathogenicity of this bacteria remains unknown.
R. aeschlimanii is transmitted byHyalomma marginatum marginatum and H. marginatum rufipes

Prevalent in Africa and southern Europe

Few cases are described, typical symptoms:

Inoculation eschar

Fever

Macular rash; purpuric lesions and multiple eschars are also possible
R. massiliae

Detected from ticks Rhipicephalus sp. in Europe, Africa, Argentina and USA

Only 2 cases are reported in Italy and in south of France

The first patient presented:

Fever

Maculopapular rash

Necrotic eschar

The second patient had:

Fever

Night sweats

Headache

Maculopapular rash

Two necrotic skin lesions associated with chorioretinitis

Rifampicin is contraindicated for treatment because R. massiliae is naturally resistant
R.asiatica is isolated from I. ovatus in Japan and could be a pathogen as well as R. tamurae isolated from Japan in 2006 in Amblyomma spp. ticks

What common complications are associated with infection with this pathogen?

Most often complications include renal failure, neurological disorders, pulmonary manifestation, myocarditis and ocular disease.

How should I identify the organism?

Common non specific laboratory abnormalities include:

Elevated C-reactive protein, erythrocyte sedimentation rate
Abnormal liver enzyme
Thrombocytopenia
Abnormal white blood cells count

Diagnosis of the diseases can be achieved using serology, culture, polymerase chain reaction (PCR), and immunohistochemical analysis.

Serology is the easiest method for the diagnosis of SFG Rickettsioses.

Microimmunofluorescence (MIF) is the reference method

IFA detects IgG and IgM antibodies or both:

IgG titers greater than 128 and IgM titers greater than 64, or a 4-fold increase in antibodies titer or a seroconversion are consistent with a recent infection.

For SFG rickettsial infections, IgG and IgM are detected 7 to 15 days after the onset of disease and can be detectable for a long time.

Recommended to test an acute and a convalescent serum separated by one week.

Serological reaction is delayed for R. africae and R. slovaca compared to R. conorii infection.

Cross reactions between different SFG species is usual but not with typhus group, and in a few cases cross reaction are possible with others intracellular bacteria.

Western blotting is used to identify Rickettsia at the species levels and allows earlier detection of antibodies.

Cell cultures require biosafety level 3 laboratories and qualified personnel.

Samples of blood, skin biopsy and ticks can be inoculated into different cell lines such as HEL, L929, XTC, and others.

Shell vials procedure is the best for isolation of intracellular bacteria

Presence of Rickettsiae can be confirmed with Gimenez staining, indirect immunofluorescence assay with polyclonal specific antibodies or specific PCR assay.

The isolation of Rickettsia is very important and primordial to describe the bacteria and to discover new Rickettsial species.

Molecular tools are sensitive, specific and rapid for detection of Rickettsia in blood samples, ticks, paraffin-embedded tissues, skin biopsy or swabs of skin lesions.

Several recent studies show the efficacy and the reliability of swabs of eschars or vesicular lesions for molecular diagnosis of Rickettsioses.

Real-time PCR more recently developed is often used with primer and probes targeting various Rickettsial genes which can be used with suitable facilities in any laboratory.

Rickettsia can be detected directly in tissue specimen, particularly skin biopsy by histochemical stains as Giemsa or Gimenez, as well as immunohistochemical methods.

How does this organism cause disease?

Humans are infected by SFG Rickettsia directly by inoculation into the blood by an infected arthropod. In blood vessels, the bacteria penetrate in vascular endothelial cells by interaction between a host cell receptor (Ku70) and an adhesive (OmpB), an abundant surface protein of Rickettsia. This interaction triggered an enzymatic cascade inducing alteration of cytoskeletal actin at the entry site to phagocytose the Rickettsia. The bacterium is internalized in a phagosome and the Rickettsia lysed the cell membrane of the phagosome by secretion of phospholipase D and haemolysin C, and escape into the cytosol where they are divided by binary fission. The bacteria move into the cytosol by actin polymerization. The protein RickA stimulates activation of Arp2/3 which mediates polymerization of host actin at one of the poles of the bacterium and allow the Rickettsia to spread into the adjacent cells. The ability of the SFG Rickettsia to spread from cell to cell without passing through the intracellular space enable bacteria to evade the immune response and thus, contribute to the development of the infection to penetrate into others cells and sometimes enter the cell nucleus.

Most of the clinical characteristics of SFG Rickettsia are attributed to disseminated infection of the endothelium, where the bacteria grow and stimulate oxidative stress causing death of endothelial cells. The effect of Rickettsia in endothelial cells include an increase in microvascular permeability due to the disruption of junctions between infected endothelial cells, a generalized vascular inflammation, oedema, increased interaction between leukocytes-endothelium, and release of vasoactive mediator that promote coagulation and pro-inflammatory cytokines.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

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