Syndromic classification of rickettsioses: an approach for clinical practice

International Journal of Infectious Diseases 28 (2014) 126–139

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Review

Syndromic classification of rickettsioses: an approach for clinical practice A´lvaro A. Faccini-Martı´nez a, Lara Garcı´a-A´lvarez b, Marylin Hidalgo a, Jose´ A. Oteo b,* a b

Microbiology Department, Faculty of Sciences, Pontificia Universidad Javeriana, Bogota´, Colombia Infectious Diseases Department, Center of Rickettsioses and Vector-borne Diseases, Hospital San Pedro-CIBIR, Logron˜o, Spain

A R T I C L E I N F O

Article history: Received 28 February 2014 Received in revised form 23 April 2014 Accepted 24 May 2014 Corresponding Editor: Eskild Petersen, Aarhus, Denmark Keywords: Rickettsioses Syndrome Arthropod-borne diseases Rickettsia spp. Rash Eschar

S U M M A R Y

Rickettsioses share common clinical manifestations, such as fever, malaise, exanthema, the presence or absence of an inoculation eschar, and lymphadenopathy. Some of these manifestations can be suggestive of certain species of Rickettsia infection. Nevertheless none of these manifestations are pathognomonic, and direct diagnostic methods to confirm the involved species are always required. A syndrome is a set of signs and symptoms that characterizes a disease with many etiologies or causes. This situation is applicable to rickettsioses, where different species can cause similar clinical presentations. We propose a syndromic classification for these diseases: exanthematic rickettsiosis syndrome with a low probability of inoculation eschar and rickettsiosis syndrome with a probability of inoculation eschar and their variants. In doing so, we take into account the clinical manifestations, the geographic origin, and the possible vector involved, in order to provide a guide for physicians of the most probable etiological agent. ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/3.0/).

1. Introduction Rickettsioses are zoonotic infections caused by obligate intracellular bacteria of the genera Rickettsia and Orientia, belonging to the family Rickettsiaceae.1–3 The lifecycle of these microorganisms is determined by their survival in small mammals (which can act as reservoirs or as amplifiers) and in arthropods, such as ticks, fleas, lice, and mites, which can also act as vectors. In this regard, and with the exception of Rickettsia prowazekii, the human is usually an accidental host.4 From the first description of R. prowazekii as an etiological agent of epidemic typhus in 1916 up to the late 1980s, eight further species were described as causes of rickettsioses around the world: Rickettsia rickettsii, Rickettsia typhi, Rickettsia conorii subsp. conorii, Rickettsia akari, Rickettsia sibirica, Rickettsia australis, Rickettsia conorii subsp. israelensis, and Orientia tsutsugamushi.5 However, with the development and implementation of molecular biology in the 1990s, this list has since grown and more than 30 species and subspecies are recognized. Most of them have been implicated as human pathogens.6

* Corresponding author. Tel.: +34 699607264. E-mail address: [email protected] (J.A. Oteo).

Rickettsioses have no pathognomonic signs, although there are signs and symptoms that are highly suggestive, such as the presence of fever, rash, lymphadenopathy, and an eschar (tache noire). Unfortunately not always and not all rickettsioses present typical signs and symptoms. In most cases clinical suspicion together with a positive serology is sufficient to make the diagnosis of rickettsiosis, although in order to reach an accurate diagnosis and confirm the etiological agent, isolation or molecular biology assays are needed. By definition, a syndrome is a set of signs and symptoms that characterizes a disease with several causes or etiologies.7 This definition is applicable to rickettsioses because different species can cause similar clinical presentations. Therefore, we propose a syndromic classification for these infections (exanthematic rickettsiosis syndrome with a low probability of inoculation eschar and rickettsiosis syndrome with a probability of inoculation eschar and their variants) in order to provide clinicians with a guide to the suspected etiological agent and thus direct the diagnosis taking the clinical manifestations, geographic area, and the possible vector involved into account. We provide only a brief description of the recommended treatment, since the antibiotic management of rickettsioses is simple (doxycycline, except where there are contraindications) and remains the same regardless of the species

http://dx.doi.org/10.1016/j.ijid.2014.05.025 1201-9712/ß 2014 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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127

Figure 1. Map showing the distribution of the main human tick-borne rickettsioses.

involved. Figure 1 is a map showing the distribution of the main human tick-borne rickettsioses. 2. Exanthematic rickettsioses syndrome with a low probability of inoculation eschar This is characterized by an acute febrile illness where a rash is the predominant clinical manifestation and the presence of an inoculation eschar cannot be seen or its presence is exceptional. Two variants are proposed taking into account the distribution of the rash (Figure 2).

trunk involvement. Maculopapular, petechial, or purpuric lesions can be observed (Figure 3).9 In 10% of cases we do not observe rash, generally in dark skin people and ederly people.10 In R. rickettsii infection, the presence of an inoculation eschar is an unusual finding (only five cases reported in the literature from 1981 to 2012).11–14 The geographical distribution of R. rickettsii, the most pathogenic species of the tick-borne rickettsiae, is limited to the Western Hemisphere where its primary vectors are ticks of the genera Dermacentor, Rhipicephalus, and Amblyomma (Table 1).15 2.2. With centrifugal rash distribution

2.1. With centripetal rash distribution This type of rash is characteristic of the rickettsioses caused by R. rickettsii. It occurs only in 3–5% in the first 3 days, increasing to 60–70% between days 7 and 10 of the disease.8 It usually starts on the wrists and ankles as small not itchy red macular lesions, with subsequent extension to the extremities and palmoplantar and

Syndrome

Exanthemac rickesioses with low probability of inoculaon eschar

Type of rash

Centripetal rash

Epidemiological background

Rickesia spp.

This is typical of R. typhi and R. prowazekii infections. The rash usually starts on the trunk and spreads to the extremities without palmoplantar involvement. In both rickettsioses, the exanthema is characterized by macular, maculopapular, or petechial lesions.27 The latter lesions and compromise of the axillary area are more frequent in R. prowazekii infection.28 Characteristically, an

The Americas Ticks: Amblyomma, Dermacentor or Rhipicephalus genus

R. rickesii

Centrifugal rash

Tropical or subtropical areas and Mediterranean Area Fleas

Populaons at risk of parasism by body lice. Flying squirrels (USA)

R. typhi

Figure 2. Algorithm for exanthematic rickettsioses and a low probability of inoculation eschar.

R. prowazekii

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Table 2 Exanthematic rickettsioses with a centrifugal rash distribution and a low probability of inoculation eschar Rickettsia species

Geographical distribution

Known vector or possible vectors

References

R. typhi

Worldwide

29

R. prowazekii

America

Xenopsylla cheopis, Ctenocephalides felis Lice and fleas from flying squirrels (USA)

USA (wild cycle) Mexico, Guatemala, Ecuador, Bolivia, Chile, Argentina, Peru, Colombia Europe Figure 3. Purpuric rash on a patient with Rickettsia rickettsii rickettsiosis. Courtesy of Dr Rodrigo Angerami.

32–36

Pediculus humanus humanus

France, Russia Africa Algeria, Burundi

Table 1 Exanthematic rickettsioses with a centripetal rash distribution and a low probability of inoculation eschar Rickettsia species

Geographical distribution

R. rickettsii

America Canada USA

Mexico Costa Rica Panama Colombia Brazil Argentina

Known vector or possible vectors

References

Dermacentor andersoni Dermacentor variabilis, D. andersoni, Rhipicephalus sanguineus, Amblyomma americanum R. sanguineus, Amblyomma cajennense sensu lato (s.l.) Haemaphysalis leporispalustris A. cajennense s.l. A. cajennense s.l. A. cajennense s.l., Amblyomma aureolatum, R. sanguineus A. cajennense s.l.

16 12,17,18

16,19

20 21 22 23–25

26

Figure 4. Eschar (tache noire) on a patient with Rickettsia conorii rickettsiosis.

inoculation eschar does not occur. As observed for R. rickettsii rickettsioses, the rash is commonly missed on dark skin. In these cases it is very important to look for scratches secondary to lice parasitization or antecedents of bites in the case of fleas. Also, in R. prowazekii infection, the patient presents with confusion, purpura, and gangrene may be observed.28 R. typhi has a worldwide distribution predominantly in tropical and subtropical areas, where its main vector is the rat flea Xenopsylla cheopis, followed by Ctenocephalides felis.29 R. prowazekii infection is related to outbreaks in populations at risk of parasitism by body lice (Pediculus humanus humanus), where poor hygiene and overcrowding are common (homeless, displaced, refugees, and imprisoned).28 However, in the USA the eco-epidemiology of this disease is often associated with the presence of and contact with flying squirrels (Glaucomys volans) and its ectoparasites, in which an enzootic or wild cycle is described.30 Significantly, R. prowazekii is the only species of Rickettsia able to produce a latent infection and subsequently manifests in a recrudescent way called ‘Brill– Zinsser’ disease, where the presence of rash is less common (Table 2).31 3. Rickettsioses syndrome with a probability of inoculation eschar This is characterized by an acute febrile illness with or without rash, where one of the most common signs is the inoculation eschar. An eschar is defined as a crusty necrotic lesion with or without a surrounding erythematous halo, which suggests the location of the vector bite (Figure 4).37 This is one of the most

common clinical manifestations in different rickettsioses associated with tick bites and in O. tsutsugamushi infections.38 We propose four syndrome variants taking into consideration other associated signs (Figure 5 and Tables 3–6). 3.1. Associated with a maculopapular/purpuric rash 3.1.1. Rickettsia felis infection Since the first reports, R. felis disease has been identified by clinical manifestations similar to those caused by R. typhi. It tends to manifest a generalized maculopapular rash on the trunk, with the difference that in some cases it also presents an inoculation eschar associated with regional lymphadenopathy.39 However, recent studies in Sub-Saharan Africa (Kenya and Senegal) show that R. felis can also cause an acute non-specific febrile illness without rash or inoculation eschar.40 In Senegal it has been proposed as the primary etiological agent of a new ulcerative-type disease termed ‘yaaf’ by the authors.41 Thus, R. felis is currently extremely common in some African countries (appearing as an eruptive febrile illness), with evidence in infecting mosquitoes (genera Anopheles and Aedes) and gorilla stools, suggesting that these mammals could be potential reservoirs.42,43 Human infection with this Rickettsia species has been described worldwide. The prevalence of infection in the main suspected vector (the cat flea, C. felis) is very high and it has been found all around the world.44 R. felis grows in vitro only at low temperatures.45

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129

Rickesioses with probability of inoculaon eschar

Type of rash

Maculopapular/purpuric rash

Flinders Islands, Eastern Australia, Thailand and Nepal

Epidemiological background

Europe, Africa and the Americas Worldwide Fleas

Ticks: R. sanguineus complex

Europe, Africa and Asia The Americas Ticks: R. sanguineus complex

Ticks: Amblyomma genus

Europe and Africa; mainly in Mediterranean and Black Sea countries

Asia

Asia

Asia or Southern Russia Ticks: Dermacentor genus

Ticks: R. sanguineus complex

Ticks: Dermacentor or Haemaphysalis genus

Ticks: Dermacentor, Haemaphysalis or Ixodes genus

Ticks: Bothriocroton, Haemaphysalis, Ixodes or Rhipicephalus genus

Africa and Europe Ticks: Hyalomma or Rhipicephalus genus

Asian Pacific, Chile and Dubai Trombiculid or chiggers

R. sibirica mongolimonae Rickesia spp.

R. parkeri

R. felis R. massiliae

R. sibirica subsp. sibirica R. conorii complex

R. japonica R. heilongjiangensis

R. aeschlimannii R. honei

O. tsutsugamushi

Figure 5. Algorithm for exanthematic rickettsioses with the probability of an inoculation eschar.

3.1.2. Rickettsia massiliae infection To date, only four confirmed human cases of infection with this species have been published; in all cases an inoculation eschar was observed. Two of them had a maculopapular rash (Italy and France),46,47 one was purpuric (Argentina),48 and the remaining case had no evidence of a rash (Italy); it is likely that warmer weather has an impact on the epidemiology of this rickettsiosis.47,49 R. massiliae usually infects ticks of the Rhipicephalus sanguineus complex, predominantly in Europe50 and in the USA,51 and it has been identified recently in the hard tick Dermacentor marginatus in southern Hungary.52 R. massiliae has been involved in double infections with R. conorii in R. sanguineus ticks (southern France).53 3.1.3. Rickettsia parkeri infection The presence of this Rickettsia, as with R. rickettsii, is geographically limited to the Western Hemisphere.15 The clinical manifestations are characterized by a maculopapular rash, in some cases vesiculopapular, with palmoplantar involvement and, in more than 90% of cases, associated with single or multiple inoculation eschars and the possibility of regional lymphadenopathy. Hence, this is one of the few rickettsioses to produce an eschar in America.54–56 The recognized vectors are Amblyomma maculatum and Amblyomma triste.15 However, Amblyomma ovale has recently been proposed as an alternative vector of a variation of R. parkeri known as Rickettsia sp. Atlantic rainforest strain, given the findings in Colombia57 and Brazil,58 and this is now recognized as a human pathogen.58 R. parkeri has also been detected in Amblyomma tigrinum ticks in Cochabamba (Bolivia)59 and in Ixodes scapularis from Louisiana (USA).60 3.1.4. Rickettsia conorii infection Since its first description as a human pathogen in 1910 until the end of the last century, this was recognized as the only causative agent of tick-borne rickettsioses in Europe.50 In 2005, R. conorii was proposed as a complex with four subspecies based on epidemiological and clinical differences.61 The following subspecies were recognized: R. conorii subsp. conorii, R. conorii subsp. israelensis, R. conorii subsp. caspia, and R. conorii subsp. indica, all geographically restricted to the Eastern Hemisphere. R. conorii subsp. conorii is

widely distributed and is the main cause of exanthematic rickettsioses associated with inoculation eschar in Mediterranean countries (European and African) and in the Black Sea.38 Clinically, patients present with a maculopapular or purpuric rash with involvement of the palms and soles (Figure 6) and the presence of a single or multiple inoculation eschars (mainly in children).50 For the other subspecies, the finding of an inoculation eschar is less frequent and their geographical distribution is more restricted. Patients infected with R. conorii subsp. conorii usually have a single eschar and a generalized maculopapular rash (97%), and the mortality rate is close to 2.5%. For R. conorii subsp. caspia, the symptoms include eschar (23%), a macular rash (94%), and conjunctivitis; no fatal cases have been reported. R. conorii subsp. indica frequently presents a purpuric rash, however an eschar is rarely found and no fatal forms have been reported. Finally, R. conorii subsp. israelensis rickettsiosis has a lesser presence of eschar than R. conorii subsp. conorii and results in a mild to severe illness.38,62 Although the main vector is the brown dog tick R. sanguineus, other species belonging to the same complex could also act as vectors.50 3.1.5. Rickettsia sibirica subsp. sibirica infection This is characterized by a benign evolution with a low probability of complications.16 Clinically, it presents a maculopapular or petechial rash associated with an inoculation eschar (more than 95% of cases) and regional lymphadenopathy.63 The geographical distribution is limited to the Asiatic Russia (Siberia) region and the countries located in the south of Russia (Kazakhstan, China, and Mongolia), where the main vectors are ticks of the genus Dermacentor, especially Dermacentor nuttalli.38,64 In contrast to the rickettsioses caused by Rickettsia heilongjiangensis, in Siberia, cases of infection by R. sibirica subsp. sibirica tend to be more frequent in the months of April and May.64 3.1.6. Rickettsia heilongjiangensis infection Although this species was originally isolated from Dermacentor silvarum ticks in 1982 in Heilongjiang Province (China), it was not recognized as a human pathogen until the late 1990s/early 2000.16,65 Cases often occur in patients 50 years old and during

130

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Table 3 Rickettsioses with a probability of inoculation eschar and a maculopapular/purpuric rash Rickettsia species

Geographical distribution

Known vector or possible vectors

References

R. felis R. massiliae

Worldwide Confirmed cases in Italy, France, and Argentina

Ctenocephalides felis Species belonging to the Rhipicephalus sanguineus complex

44

R. parkeri

America USA, Peru Brazil

Amblyomma maculatum, Ixodes scapularis (USA) (?) Amblyomma triste, Amblyomma ovale (Rickettsia sp. genotype Atlantic rainforest) A. ovale (Rickettsia sp. genotype Atlantic rainforest) (?) A. triste Amblyomma tigrinum R. sanguineus

15,60

R. conorii subsp. conorii

R. conorii subsp. israelensis

R. conorii subsp. indica R. conorii subsp. caspia

R. sibirica subsp. sibirica

Colombia Uruguay, Argentina Bolivia Europe Mediterranean countries (Portugal, Spain, France, Italy, Malta, Slovenia, Croatia, Albania, Greece, Cyprus) Countries around the Black Sea (Ukraine, Bulgaria, Turkey, Georgia) Africa Algeria, Morocco, Tunisia, Kenya, Somalia, Chad, Zimbabwe, South Africa Europe Portugal, Italy Africa Tunisia Asia Israel Asia India Europe Astrakhan, Kosovo, France Africa Chad Asia Siberia Kazakhstan China, Mongolia

R. heilongjiangensis

R. japonica

R. honei

R. aeschlimannii

O. tsutsugamushi

Asia China and Eastern Siberia Japan Asia Japan Thailand Korea Oceania Flinders Islands and Eastern Australia (R. honei strain marmionii) Asia Thailand Nepal Africa Morocco Algeria South Africa Tunisia Europe Greece Asia Kazakhstan, Uzbekistan, Afghanistan, Pakistan, India, Nepal, Bangladesh, Myanmar, Vietnam, Cambodia, Sri Lanka, Singapore, Brunei, Taiwan New Guinea, Philippines China Malaysia Indonesia Thailand Japan Korea

46–51

58

57 15 59

38,50

38

50

94

38

Rhipicephalus pumilio, R. sanguineus

38,53

Dermacentor nuttalli, Dermacentor marginatus, Dermacentor silvarum, Dermacentor pictus, Haemaphysalis concinna D. marginatus D. nuttalli, Dermacentor sinicus, Dermacentor auratus, D. silvarum, H. concinna

38

Haemaphysalis japonica douglasi, H. concinna, D. silvarum H. concinna

38,67

Haemaphysalis flava, Haemaphysalis longicornis, Dermacentor taiwanensis, Ixodes ovatus Haemaphysalis hystricis (R. japonica-like) H. longicornis

16,38

16 63

66

70 95 38,74,96

Bothriocroton hydrosauri, Ixodes tasmani, Haemaphysalis novaeguineae Ixodes granulatus Rhipicephalus haemaphysaloides (?), I. granulatus (?)

73

Hyalomma marginatum marginatum Hyalomma marginatum marginatum, Hyalomma aegyptium, Hyalomma dromedarii (?), Hyalomma marginatum rufipes (?) Rhipicephalus appendiculatus Hyalomma dromedarii (?)

94

Rhipicephalus turanicus (?)

78

72

94,97

98 77

84

Leptotrombidium deliense

L. deliense, Leptotrombidium fletcheri L. deliense, Leptotrombidium scutellare, Leptotrombidium gaohuensis L. deliense, L. scutellare, Leptotrombidium arenicola, L. fletcheri L. deliense, L. arenicola, L. fletcheri L. deliense, Leptotrombidium chiangraiensis, L. scutellare, Leptotrombidium imphalum Leptotrombidium akamushi, L. scutellare, Leptotrombidium pallidum L. pallidum, L. scutellare, Neotrombicula japonica (?), Eushoengastia koreaensis (?)

84,88

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131

Table 3 (Continued ) Rickettsia species

Geographical distribution

Known vector or possible vectors

References

Southeastern Russia Arab Emirates (Dubai) Oceania Northern Australia America Chile

L. pallidum, Leptotrombidium pavlovskyi Not determined

84 92 84

L. deliense 93

Not determined

Table 4 Rickettsioses with a probability of inoculation eschar and a vesicular rash Rickettsia species

Geographical distribution

R. africae

Africa East, West and Central region South

R. akari

R. australis

America Caribbean Islands Worldwide Confirmed cases in the USA, Mexico, Ukraine, Croatia, Holland, Turkey, South Africa and Korea Oceania Eastern Australia, Queensland (between the months of June and November)

Known vector or possible vectors

References

Amblyomma variegatum Amblyomma hebraeum, Rhipicephalus (Boophilus) decoloratus (?)

16 16,104

15

A. variegatum Liponyssoides sanguineus

113,115–121,124

16

Ixodes holocyclus, Ixodes tasmani, Ixodes cornuatus

Table 5 Rickettsioses with a probability of inoculation eschar and regional lymphadenopathy as a main sign Rickettsia species

Geographical distribution

Known vector or possible vectors

References

R. slovaca

Europe Confirmed cases in Portugal, Spain, France, Italy, Hungary, Bulgaria, Slovakia, Germany Europe Confirmed cases in Spain Europe Confirmed case in Slovakia and suspected cases in Spain, France, Poland America

Dermacentor marginatus, Dermacentor reticulatus

50,139

Candidatus R. rioja R. raoultii

Rickettsia sp. strain 364D (R. philipii)

USA (California)

130,131

D. marginatus 105,132,143–147

D. marginatus, D. reticulatus, Dermacentor nuttalli (Mongolia), Dermacentor silvarum (China) 140–142

Dermacentor occidentalis

Table 6 Rickettsioses with a probability of inoculation eschar and lymphangitis Rickettsia species

Geographical distribution

R. sibirica subsp. mongolitimonae

Europe France and Portugal Greece Spain Africa Egypt and Algeria South Africa

the months of June and July.16 Regarding the clinical manifestations, the rash is maculopapular and has a mild appearance, and this is accompanied by other signs including an inoculation eschar, lymphadenopathy, and, in a small proportion, lymphangitis and conjunctival injection.65 In 2010, the first case of R. heilongjiangensis infection confirmed by molecular tools was reported in Japan in a 35-year-old man with rash, fever, and two lesions compatible with inoculation eschars.66 Although Haemaphysalis japonica douglasi and D. silvarum are endemic in Eastern Siberia and China, epidemiological studies have determined Haemaphysalis concinna to be a possible vector.38,67

Known vector or possible vectors

References

Rhipicephalus pusillus Hyalomma anatolicum excavatum R. pusillus, Hyalomma marginatum (?)

154,161

Hyalomma sp. Hyalomma truncatum

94

153 163,164

152

3.1.7. Rickettsia japonica infection This rickettsiosis was initially mistaken for scrub typhus or O. tsutsugamushi infection.16 Both infections are characterized by an acute febrile illness associated with a maculopapular rash, inoculation eschar, and the possibility of a severe clinical picture related with pulmonary and neurological complications and multiorgan failure; both also share a similar geographical distribution where their vectors (ticks and mites, respectively) are prevalent.68 However, in the infection caused by R. japonica, the presence of an inoculation eschar is more common (>90%) than in scrub typhus. On the other hand, eschar is not associated with lymphadenopathy is usually observed, and the rash may progress

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demonstrated the absence of infection or disease by R. aeschlimannii in people bitten (even for more than 1 week) by H. marginatum ticks infected with this Rickettsia.81

Figure 6. Purpuric rash affecting the soles of the feet in a patient with Rickettsia conorii rickettsiosis.

to a purpuric appearance.16 Regarding the epidemiology, most cases occur in Japan from April to October. The tick vectors recognized are Haemaphysalis flava, Haemaphysalis longicornis, Dermacentor taiwanensis, and Ixodes ovatus.16,38 Similarly, this rickettsiosis has also been described in South Korea and Thailand.69,70 3.1.8. Rickettsia honei infection This species was first isolated in clinical samples from patients in the Flinders Islands and is now recognized as the most frequent species causing tick-borne rickettsioses in Australia after R. australis.71 Clinical manifestations caused by R. honei include a maculopapular or purpuric rash without the presence of vesicles and palmoplantar involvement. An inoculation eschar is seen in half of the cases. Other signs such as lymphadenopathy and cough may occur.16 This rickettsiosis is more common during the months of December and January.16 The recognized vectors in Australia are Bothriocroton hydrosauri, Haemaphysalis novaeguineae, and Ixodes tasmani.72 Cases of human infection with this species have also been reported in Thailand, where the vector is Ixodes granulatus.73 In Nepal, the same tick species has been suggested as a possible vector, together with Rhipicephalus haemaphysaloides, as seen in a case published in 2011.72 In Eastern Australia, during 2003, a genetically related species of R. honei (marmionii strain) was isolated in patients with fever and headache. Only a small proportion had rash onset and an inoculation eschar.74 These cases occurred between February and June, in contrast to R. honei and R. australis infections. 3.1.9. Rickettsia aeschlimannii infection This Rickettsia species was first isolated in 1997 from Hyalomma marginatum ticks in Morocco;75 5 years later, the first human case was published involving a patient in the same country.76 Up until 2010, six more cases were attributed to this rickettsiosis (South Africa, Tunisia, Algeria, and Greece) by molecular and serological methods.77,78 Most cases started as an acute febrile illness associated with a maculopapular rash. Only two patients presented an inoculation eschar. It is remarkable that in the Algerian cases, one patient had more than one eschar and the other an associated purpuric rash component.79 R. aeschlimannii has been isolated in different species of anthropophilic ticks of the genera Hyalomma and Rhipicephalus from many countries of Africa and Europe. It is considered that infection with this Rickettsia species may have been underdiagnosed.77,80 However, a study from the north of Spain

3.1.10. Orientia tsutsugamushi infection Previously included in the genus Rickettsia, this species was reclassified in 1995 based on findings from its cell wall and on phylogenetic analyses as a single species belonging to the genus Orientia with different related strains.82–84 Today, rickettsiosis by O. tsutsugamushi is an important cause of acute febrile illness and is endemic in the Asian Pacific region, extending from Afghanistan to China, Korea, the South Pacific Islands, and Northern Australia.84 The eco-epidemiology of this disease is determined by humid tropical regions where mites of the genus Leptotrombidium, known as trombiculids or chiggers, are reservoirs of O. tsutsugamushi and their larval stages act as human vectors.85 Wild rodents are the main hosts of these mites.86 Endemic regions are characterized by rice fields, scrubland, and the presence of primary deforestation.85,86 In Japan, unlike infection caused by R. japonica, infection by O. tsutsugamushi is usually more frequent in November.87 Other genera of the Trombiculidae family, such as Neotrombicula (N. japonica) and Eushoengastia (E. koreaensis), have also been implicated as possible vectors.88 The clinical manifestations may vary from mild to severe. Heart failure, acute renal failure, and central nervous system and respiratory system compromise, with interstitial pneumonia and acute respiratory distress syndrome (ARDS) are the most frequent causes of complications and death.89–91 The incubation period is usually higher than for other rickettsioses (up to 18–21 days).68,89 The fever usually appears abruptly, associated with headache, myalgia, and malaise. A week after the onset of these symptoms, a maculopapular rash with centrifugal distribution may appear (uncommon) and an inoculation eschar, which can be single or multiple (presence varies between 7% and 80% of cases), commonly associated with regional lymphadenopathy. Manifestations such as non-suppurative conjunctival injection and hearing loss are highly suggestive of this rickettsiosis.89,91 Human cases of infection by bacteria of the genus Orientia involving patients with a rash and inoculation eschar in Dubai (2010) and Chile (2011) have been published.92,93 These geographical areas are unusual for the occurrence of this disease, suggesting the presence of ‘new species’ of the genus Orientia. 3.2. Associated with a vesicular rash 3.2.1. Rickettsia africae infection This rickettsiosis, initially confused with R. conorii infection, was described in the 1990s by Kelly et al., who determined that it was produced by a new species belonging to the spotted fever group (SFG).99,100 This disease begins with an abrupt onset fever, headache, myalgia (predominantly in the cervical region), and typically single or multiple inoculation eschars (predominantly in the extremities), associated with a vesicular rash and lymphadenopathy in half of the cases (Figure 7).16 Its epidemiology is associated with the presence of R. africae in Amblyomma variegatum (Eastern, Western, and Central Africa and the Caribbean Islands) and Amblyomma hebraeum (Southern Africa) as its recognized vectors.15 However, R. africae has also been detected in other tick species, such as Amblyomma lepidum and Hyalomma dromedarii in northwest Africa,93,101,102 Amblyomma loculosum in New Caledonia,103 Rhipicephalus decoloratus in the Republic of Botswana,104 and Hyalomma aegyptium in Turkey.105 It is currently recognized as the most common rickettsiosis in European and American travelers returning from endemic areas of Africa and the Caribbean Islands.16,106 Figure 8 shows an algorithm for the approach to patients with rickettsioses and a vesicular rash.

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3.2.3. Rickettsia australis infection Unlike infection by R. honei, with which it shares similar clinical features, in the rickettsioses caused by R. australis the presence of an inoculation eschar is more frequent (over 60% of cases), associated with lymphadenopathy. Characteristically the rash is mainly vesicular or maculopapular.16 It can present as a moderate to severe disease, with complications such as renal failure, fulminant purpura, myopericarditis, pneumonia, splenic infarct, and vasculitis associated with mortality.38,122 Its distribution is restricted to the Australian territory, specifically to the Eastern region, where most cases usually occur from June to November. Ixodes holocyclus is the main vector;69,123 however R. australis has also been isolated from I. tasmani (Southern and Western Australia) and from Ixodes cornuatus (South Australia).16 Figure 7. Vesicular rash and eschar on a patient with Rickettsia africae rickettsiosis.

3.3. Associated with regional lymphadenopathy

3.2.2. Rickettsia akari infection R. akari together with O. tsutsugamushi are the rickettsial agents transmitted by mites.107 The first clinical manifestation of this rickettsiosis is a primary papulovesicular lesion at the location of inoculation at 24–48 h after the bite. This primary lesion becomes an eschar, frequently associated with regional lymphadenopathy.108 Constitutional symptoms, such as fever, headache, chills, and myalgia usually occur after a week.109 Characteristically, a generalized papulovesicular rash appears between 2 and 3 days after the onset of these symptoms. It is usually distributed on the face, trunk, and extremities, without compromise of the palms or soles, and it can be associated with vesicular enanthema on the palate, tongue, mouth, tonsils, or pharynx.108 The classic triad of this disease is described as fever, papulovesicular rash, and inoculation eschar.110 The evolution of this disease is usually benign in the absence of antibiotic treatment, without associated mortality.111 In 2008, two cases of acute hepatitis were described in patients infected with R. akari.112 Liponyssoides sanguineus (Allodermanyssus sanguineus) is the only vector and reservoir, and the domestic mouse (Mus musculus) is the primary host of L. sanguineus,113 although this mite has been found infesting wild and synanthropic rodents.114 The presence of R. akari has been described in some American countries,115–117 Europe,118,119 Asia,120 and Africa.121 Thus, this disease could have a worldwide distribution, taking into account the cosmopolitan behavior of M. musculus and the vector mite.114 It is very likely that this rickettsiosis is under-diagnosed or confused with other exanthematic diseases.

Two dominant signs characterize this syndrome: an inoculation eschar and regional lymphadenopathy. In contrast, the occurrence of fever and rash is rare. Within this clinical spectrum, the main syndrome is termed DEBONEL/TIBOLA (Dermacentor-borne necrosis erythema lymphadenopathy/tick-borne lymphadenopathy), also called SENLAT (scalp eschar and neck lymphadenopathy after tick bite) by other authors when the tick bite affects only the scalp. DEBONEL/TIBOLA and SENLAT are produced by different species of Rickettsia. In the case of SENLAT, other bacteria such as Bartonella henselae have also been involved.125 The main etiological agent is Rickettsia slovaca.126,127 This Rickettsia was first identified in D. marginatus and Dermacentor reticulatus (recognized vectors) in different European countries (Slovakia, Switzerland, France, Portugal, Spain, Germany, etc.) and was subsequently isolated (1997) and implicated as a human pathogen (early 2000) in France.128,129 Meanwhile, ‘Candidatus Rickettsia rioja’ and Rickettsia raoultii have also been implicated as secondary etiological agents in Spain. The former was detected by molecular techniques in clinical samples (blood and serum of patients) and in D. marginatus ticks removed from patients with a diagnosis of DEBONEL/TIBOLA in Spain (half of the cases),130,131 and R. raoultii was detected in ticks of the genus Dermacentor (mainly D. marginatus) removed from patients who developed the disease in different regions of Europe.105,132–134 DEBONEL/TIBOLA is characterized by a benign evolution and a short incubation period (average 5 days), with a later onset of a honey-like exudation in the region of the tick bite (>95% in the scalp), which evolves, within a few days, into an inoculation eschar

Syndrome

Rickesioses with probability of inoculaon eschar

Vesicular rash

Type of rash

Epidemiological background

Rickesia spp.

Africa or Caribbean Islands

Worldwide

Australia

Ticks: Amblyomma genus

Mouse mite

Ticks: Ixodes genus

R. akari

R. australis

R. africae

Figure 8. Algorithm for rickettsioses with the probability of an inoculation eschar and a vesicular rash.

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3.4. Associated with lymphangitis

Figure 9. Big eschar and surrounding erythema in a patient with DEBONEL/TIBOLA (Rickettsia slovaca, Candidatus Rickettsia rioja, and Rickettsia raoultii).

surrounded by erythema (Figure 9). The eschar is usually larger than in other rickettsioses (up to 2 cm) and is associated with painful regional lymphadenopathy.135 When the tick bite is out of the scalp, the erythema resembles the ‘erythema migrans’ of Lyme disease. Other symptoms, such as rash, facial edema, and fever, occur in less than 20% of cases.135 Notably, a third of patients develop persistent alopecia where the eschar was present.135 DEBONEL/TIBOLA/ SENLAT is currently the second most prevalent tick-borne rickettsiosis in Europe after that caused by R. conorii,50 with human cases reported in France, Spain, Hungary, Slovakia, Bulgaria, Italy, Germany, and Portugal,50,136–139 where it tends to affect mainly women and children.132,135 A case of this syndrome caused by R. massiliae reported in Italy has recently been published.49 Figure 10 shows an algorithm for diagnosing this syndrome. There is another Rickettsia spp. related with this syndrome in the USA –Rickettsia sp. genotype 364D (Rickettsia philipii). Rickettsia sp. genotype 364D (R. philipii) was first isolated in 1966 in Dermacentor occidentalis ticks from Ventura County, California (USA).140 For a long time it was considered non-pathogenic. However, a case of infection in an 80-year-old man in the state of California in 2008 and then three pediatric cases in 2011, also in California, were confirmed.141,142 All cases had a benign course. Single inoculation eschars associated with regional lymphadenopathy are the main clinical signs. A rash is uncommon and is usually accompanied by mild fever, headache, myalgia, arthralgia, and malaise.141,142 Currently, this new Rickettsia sp. should be considered in the differential diagnosis of the rickettsioses that present an eschar in the USA, as are those caused by R. parkeri and R. akari.55

Syndrome

Lymphangitis is a clinical sign that may be present in several rickettsioses. Half of the cases of R. sibirica subsp. mongolitimonae infection present this sign (rope-like lymphangitis between the inoculation eschar and lymphadenitis) (Figure 11). This finding has led to the infection being termed lymphangitis-associated rickettsiosis (LAR). Lymphangitis is also present in those infections caused by R. heilongjiangensis and R. africae,16 although in a lesser proportion than in R. sibirica mongolitimonae infection.50 This species was first isolated in 1991 in Hyalomma asiaticum ticks from inner Mongolia (China).148 Five years later, its role as human pathogen was confirmed in France and there are 26 more cases reported in the literature.149–162 A single eschar is present in 80% of cases (only two cases with two eschars),151 associated with regional lymphadenopathy and a maculopapular rash affecting the palms and soles (70% of cases).160,162 Although the course of disease is benign in most cases, severe cases with septic shock160 and acute renal failure have been reported.153 Ocular involvement (retinal vasculitis) has also been described.156 Regarding its epidemiology, most cases have occurred in France, Spain, and Portugal.50 It has also been reported from Algeria,151 South Africa,152 Greece,153 and Egypt.158 The tick species involved as vectors are related to ticks of the genus Hyalomma, such as H. truncatum152 and H. anatolicum excavatum153 and Rhipicephalus pusillus in France,161 Spain,163,164 and Portugal.154 4. Other rickettsioses without assigned classification Because of the few cases described or the not reliable clinical features, some rickettsioses have not been assigned to any proposed syndrome in this article. 4.1. Rickettsia helvetica infection This is also known as the non-eruptive rickettsiosis.1 It has been reported only in Switzerland, Sweden, France, and Italy, where most patients have presented with isolated fever (no rash or inoculation eschar).50 However, some cases in Sweden have presented rash,165 perimyocarditis,166 and meningitis.167 The main vector is Ixodes ricinus.50 4.2. Rickettsia monacensis infection Two cases have been reported from Spain (2007) and one from Italy (2012).168,169 The Spanish cases presented with a febrile

Rickesioses with inoculaon eschar (>95% in scalp)

Other clinical characteriscs

Epidemiological background

Rickesia spp.

Regional lymphadenopathy

Europe

California (USA)

Ticks: Dermacentor genus

Ticks: D. occidentalis

R. slovaca, Candidatus R. rioja, R. raouli

Rickesia sp genotype 364D (R. philipii)

Figure 10. Algorithm for rickettsioses with predominant signs of eschar and lymphadenopathy.

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illness associated only with a maculopapular rash. The Italian case presented with fever associated with an inoculation eschar and without rash. I. ricinus is the suspected vector of this rickettsial species.50 4.3. Candidatus Rickettsia kellyi infection The only case reported was confirmed by molecular, histopathological, and serological methods. It involved a child from India who had a febrile illness associated with a maculopapular rash that affected the face, back, and limbs, including the palms and soles.170 The vector is unknown. 4.4. Rickettsia tamurae infection Only one case of R. tamurae infection has been reported.171 This involved a Japanese patient who presented with an inflammatory reaction in the popliteal region of his leg, secondary to the bite of a tick identified as Amblyomma testudinarium. It was possible to obtain molecular evidence of R. tamurae in the patient’s blood and skin lesions, and in the tick. 5. Microbiological diagnosis

Figure 11. Lymphangitis and eschar on a patient with lymphangitis-associated rickettsiosis (LAR) (Rickettsia sibirica mongolitimonae infection). Courtesy of Dr Rita de Sousa.

There are several different approaches to the diagnosis of human rickettsioses. As for other bacterial infectious diseases, the gold standard is culture. This approach is difficult because it requires appropriate laboratories and trained people, so it is only performed in reference centers with P3 level biosafety laboratories. However, the shell vial technique has facilitated the inclusion of culture in clinical microbiology laboratories. The sample must be processed quickly (in a few hours) or must be stored correctly.172,173 In recent years, molecular tools have been incorporated into the routine methods of a great number of laboratories. Molecular tools such as PCR and quantitative PCR (qPCR) are increasingly used. The most common ones are those that use the amplification of different preserved genes of the genus Rickettsia (gltA, ompA, ompB, sca4, htrA, and 16S rDNA).174 This procedure allows a specific, sensitive,

Figure 12. Algorithm for microbiological diagnosis of rickettsioses.

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Table 7 Treatment of rickettsioses; based on Botelho-Nevers et al., 201262 Antibiotic

Indications

Dosage

Duration of treatment

Doxycycline (standard treatment for rickettsioses)

 Severe rickettsioses (including pregnant women and children), ideally intravenous  Adults or children >45 kg  Option for not severe rickettsioses in children and pregnant women

 Adults or children >45 kg: 100 mg twice a day  Pregnant women (late trimester): 100 mg twice a day  Children <45 kg: 2.2 mg/kg twice a day

Continued for 3 days after symptoms have resolved

 Josamycin: children 50 mg/kg twice a day, pregnant women 1 g/8 h  Clarithromycin for children: 15 mg/kg/day divided doses  Azithromycin for children: 10 mg/kg/day in 1 dose  Adults and pregnant women (first and second trimesters): 60–75 mg/kg/day in 4 divided doses  Children: 12.5–25 mg/kg every 6 h

Josamycin 5 days, clarithromycin 7 days, and azithromycin 3 days 5–10 days

Macrolides (josamycin, clarithromycin, and azithromycin) Chloramphenicol

 Alternative option in severe rickettsioses

and rapid diagnosis when samples (whole blood, serum, skin biopsy, eschar, removed tick, and others) are processed correctly.172,173 The use of a swab in cases where an eschar is present is very useful for the diagnosis by PCR.56,175 In most clinical microbiology laboratories, the diagnosis is made by the detection of antibodies measured using serological assays. Immunofluorescence (IFA) remains the reference method for this approach. However, it is not specific (cross-reactions among species) and is not sensitive in the first days of infection. To obtain the diagnosis it is necessary to study two samples (acute and convalescent sera), waiting at least 2 weeks between them. IgG and IgM can be studied, although the latter can frequently produce false-positive results. To obtain an accurate diagnosis it is necessary to observe seroconversion (4-fold increase in titer). In some reference laboratories, cross-absortion and Western blot are performed to increase the specificity.172,173 Figure 12 shows an algorithm useful for the diagnosis.

identification of the microorganism is impossible (for example, due to previous prescription of antimicrobials, or if a microbiology laboratory or other available techniques are missing). The aim of this review was to provide physicians with a diagnostic approach, taking into account the common signs and symptoms of these diseases. Nevertheless, to achieve a definitive diagnosis, microbiological assays are needed. Of note, the fact that one of these clinical syndromes is not compatible with the expected geographical distribution may suggest the emergence of a previously unknown species, new species, or even new clinical manifestations. Finally, despite being outside of the objective of this paper, we would like to emphasize that antibiotic treatment with doxycycline (including for children) must be started whenever a possible rickettsiosis is suspected, taking into consideration pregnant women and allergic patients. Acknowledgements

6. Treatment of rickettsioses Since rickettsioses are a threat to human life, empirical treatment must be started when they are suspected. Physicians should never wait for laboratory results. Doxycycline is the drug of choice for all of the known rickettsioses, even in children and pregnant women when the woman has a severe infection.176 For some rickettsioses such as Mediterranean spotted fever, a short course of doxycycline has been demonstrated to be effective and safe (doxycycline 200 mg twice daily for only 1 day).177 As an alternative to doxycycline (allergic patients, pregnant women), macrolides such as azithromycin or josamycin can be used. The use of quinolones is not recommended because it has been associated with an increased mortality.178 A review on the prevention of tick-borne diseases has recently been published, which provides useful information for the prevention and prophylaxis of tick-borne rickettsioses.179 Table 7 describes the duration, dosage, and other considerations of the most commonly used treatments for rickettsioses in adults, children, and pregnant women.62 7. Conclusions In the last two decades, with the development of new diagnostic methods, mainly based on molecular biology, the characterization and involvement of new species of Rickettsia as etiological agents of human diseases worldwide have increased considerably. Clinical manifestations combined with a thorough history (travel, epidemiological environment, and place of residence) and knowledge of the distribution of rickettsial agents and their vectors may help clinicians to correctly diagnose a rickettsiosis. This is especially relevant when microbiological

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