Renal Involvement in Mediterranean Spotted Fever: Clinical and Histopathological Data.

OBJECTIVE: Mediterranean spotted fever (MSF) is a tick-borne rickettsial infection endemic to the Mediterranean coastline countries. As a result of growing tourism, imported cases have been registered in many nonendemic countries and regions. We present clinical laboratory parameters and histopathological data on renal impairment in patients with MSF. The study meets our goal of identifying kidney involvement and detecting renal damage in people with MSF. SUBJECTS AND METHODS: Three hundred fifty patients with MSF with a diagnosis confirmed by immunofluorescence analysis were tested for serum urea, creatinine, and albumin. Fifty-five patients with malignant form of MSF were divided into 2 groups: 19 fatalities and 36 survivors. The percentage of patients with acute renal failure (ARF) was compared in both groups. RESULTS: Subjects with elevated urea and creatinine levels increased from 5.21 to 3.47% in mild to 48.78 and 29.26% in severe MSF, respectively. Loss of serum albumin also increased from mild to severe MSF. Renal impairment comprised 60% of the cohort of 55 patients with malignant MSF: 89.4% in the group of deaths and almost twice less in the survivors. ARF developed in 84.2% of fatal cases and was >2 times less in survivors. Postmortem light microscopy of renal samples of 9 fatal cases revealed perivascular mononuclear inflammatory infiltrates, vasculitis with fibrinoid necrosis, acute tubular necrosis, interstitial edema, hemorrhage, and thrombosis. CONCLUSION: Renal pathology associated with MSF rickettsial infection consists of systemic small vessel vasculitis and vascular injury, leading to ARF in the most severe cases.

Molecular confirmation & characterization of Rickettsia conorii in north India: A report of three cases.

Background & objectives: In India, spotted fever group rickettsiae (SFGR) are an underdiagnosed cause of acute febrile illness (AFI). The non-specific Weil-Felix test is the first diagnostic modality for the diagnosis of SFGR in many laboratories due to the lack of advanced diagnostic facilities in developing countries. The aim of this study was to detect SFGR using molecular methods in the patients, presenting with AFI in a tertiary care centre in north India. Methods: Consecutive patients (>14 yr of age) with AFI were enrolled over a six month period. Standard investigations for common pathogens causing AFI in India (malaria, dengue, scrub typhus, leptospirosis and enteric fever) were carried out. In patients who were negative for all of the above investigations, blood was subjected to polymerase chain reaction (PCR) targeting outer membrane protein A (ompA) gene of Rickettsia. Results: Of the 51 patients with an undiagnosed aetiology, three were positive by ompA PCR. Two of the PCR products produced good sequences and BLAST identification confirmed them as Rickettsia conorii. The sequences of R. conorii reported from south India clustered with two previously reported novel rickettsial genotypes. The study sequences clustered in a group different from that of Rickettsia spp. of the south Indian sequences reported earlier. Interpretation & conclusions: This study showed the existence of R. conorii in north India. Testing for SFGR may be included in the diagnostic workup of AFI for better disease management.

Spotted fever rickettsioses causing myocarditis and ARDS: a case from Sri Lanka.

BACKGROUND: Spotted fever group of rickettsial infections are emerging in Sri Lanka. We describe a patient with rapidly progressing ARDS and myocarditis secondary to spotted fever caused by Rickettsia conorii. ARDS and myocarditis are rare complications of Rickettsia conorii infections and only a few cases are reported to date. CASE PRESENTATION: A 53 years old manual worker presented with fever for 5 days and a skin rash. He was in circulatory failure on admission and developed severe hypoxaemia with gross changes in chest radiograph by next day requiring assisted ventilation. He had myocarditis causing left ventricular failure and acute respiratory distress syndrome. He was confirmed to have spotted fever rickettsial infection with rising titre of indirect immunofluorescence antibodies to Ricketssia conorii and made a complete recovery with appropriate antibiotic therapy and supportive care. CONCLUSION: Rickettsial infections can present with diverse manifestations. Even the patients with severe organ involvements such as myocarditis and ARDS can be completely cured if timely identified and treated.

[Haemophagocytic syndrome secondary to Mediterranean spotted fever]. / Syndrome d'activation macrophagique secondaire à une fièvre boutonneuse méditerranéenne.

INTRODUCTION: Haemophagocytic syndrome (HS) is a rare disease with a severe prognosis that is defined by clinical, laboratory and histopathological criteria. Infections represent the classical cause of HS. HS secondary to Mediterranean spotted fever (MSF) is rare with only a few cases being reported in the literature. OBSERVATIONS: We report two cases of HS secondary to MSF in 2 men aged 77 and 63 years presenting a febrile maculo-purpuric eruption with inoculation ulcer associated with laboratory abnormalities (cytopenia, elevated ferritin, hypertriglyceridaemia). Haemophagocytosis was present in 2 cases. Serology and PCR for Rickettsia conorii were positive and militated in favour of recent infection responsible for the diagnosis of MSF. DISCUSSION: The first case of HS was described in 1979. Sixteen cases of HS secondary to MSF are described in the literature. Cytopenia associated with hyperferritinaemia and hypertriglyceridaemia strongly suggests MSF complicated by HS. The prognosis depends on the time elapsed since diagnosis and host-specific factors. Immunosuppressants and antibiotics may be necessary to ensure healing. CONCLUSION: Rickettsioses can induce HS, and this potential complication with a severe prognosis must be known.

Widespread subcutaneous necrosis in spotted fever group Rickettsioses from the coastal belt of Sri Lanka- a case report.

BACKGROUND: Spotted fever group rickettsioses (SFGR) transmitted mostly by ticks are increasingly discovered around the World and some of them are either re-emerging or emerging in Sri Lanka. Accidental human infections caused by these vector borne zoonotic diseases generally give rise to nonspecific acute febrile illnesses which can be complicated by multi organ involvement carrying high morbidity and mortality. Nonspecific clinical features and non-availability of early diagnostic facilities are known to result in delay in the diagnosis of rickettsial infections. Therefore, awareness of their prevalence and more importantly their clinical features would be help in the early diagnosis and institution of appropriate therapy. CASE PRESENTATION: A 39-year-old otherwise healthy female presented with an acute febrile illness complicated by severe small joint and large joint arthritis, jaundice, acute kidney injury and disseminated intravascular coagulation (DIC) mimicking palindromic rheumatism or severe sepsis. She later developed a widespread fern-leaf pattern necrotic skin rash with evidence of vasculitis on the palms and soles, aiding the clinical diagnosis of SFGR. She had very high antibody titres against R. conorii antigen confirming the diagnosis and recovered completely with anti-rickettsial therapy. CONCLUSION: We feel that clinicians should be aware of the unusual clinical presentations such as purpura fulminans and 'fern-leaf' pattern necrotic skin rash of SFGR infection. Such knowledge would not only benefit those who practice in tropics with limited diagnostic facilities but also would improve the management of acute febrile illness in returning travelers who visit endemic areas.

First detection of Rickettsia conorii ssp. caspia in Rhipicephalus sanguineus in Zambia.

Ticks are important vectors for Rickettsia spp. of the spotted fever group all around the world. Rickettsia conorii is the etiological agent of boutonneuse fever in the Mediterranean region and Africa. Tick identification was based on morphological features and further characterized using the 16S rRNA gene. The ticks were individually tested using pan-Rickettsia real-time-PCR for screening, and 23S-5S intergenic spacer region, 16S rDNA, gltA, sca4, ompB, and ompA genes were used to analyze the Rickettsia positive samples. Rickettsia conorii ssp. caspia was detected in tick collected in Zambia for the first time, thus demonstrating the possibility of the occurrence of human disease, namely Astrakhan fever, due to this Rickettsia ssp. in this region of Africa. The prevalence of R. conorii ssp. caspia was 0.06% (one positive tick out of 1465 tested ticks) and 0.07% (one positive tick out of 1254 tested Rh. sanguineus).

Parinaud's oculoglandular syndrome revealing subclinical Rickettsia conorii infection.

The purpose of this study was to report a case of Parinaud's oculoglandular syndrome associated with subclinical Rickettsia conorii infection. We report a case of a 66-year-old male patient presented with unilateral persistent granulomatous conjunctivitis in the left eye and an ipsilateral preauricular lymphadenopathy without associated systemic features. Laboratory evaluation showed a positive indirect immunofluorescence antibody test for R. conorii. The patient received a 2-week course of oral doxycycline, with subsequent complete resolution of all his symptoms. Rickettsial disease should be considered in the differential diagnosis of oculoglandular syndrome with or without associated systemic symptoms in any patient living in or returning from a specific endemic area.

Skin lesions and inoculation eschars at the tick bite site in spotted fever group rickettsioses: experience from a patient series in eastern crete, Greece.

The main clinical signs and symptoms caused by a rickettsial infection typically begin 6-10 days after the bite and are accompanied by nonspecific findings such as fever, headache and muscle pain. The diagnosis is mainly based on serological tests, however antibody presentation may be delayed, at least at the early stages of the disease, while seroconversion is usually detected 10-15 days after disease onset. Culture is difficult, requires optimized facilities and often proves negative. Under this scope, the presence of a characteristic inoculation eschar at the bite site may prove a useful clinical tool towards the early suspicion and diagnosis/differential diagnosis of tick-borne rickettsioses, even before the onset of rash and fever or serological confirmation. We describe herein the presence of skin lesions and/or an inoculation eschar at the tick bite site in 17 patients diagnosed, by molecular means, as suffering from spotted fever group rickettsioses. The detection of the pathogen's DNA in biopsy samples proved to be a useful means for early rickettsiae detection and identification. Moreover, the presence of an infiltrated erythema always seemed to precede the appearance of an eschar by 2-5 days and the initiation of fever by 1-10 days; these two signs might also prove useful in the context of the final diagnosis.

[South African tick bite fever in a group of Russian tourists].

The paper describes a clinical case of South African tick bite fever in a group of Russian tourists. The group of 5 people who had been ill with this disease after a tourist trip to the South African Republic (the Kruger National Park in the north-eastern province of Mpumalanga) were followed up. During their trip, all of them were bitten by different insects many times. The disease exhibited different clinical presentations; however, all the patients were noted to have a fever with slight intoxication and a maculopapular rash at different sites of the body; 3 had lymphadenopathy and one had a primary effect at the site of tick sticking. The diagnosis was verified by indirect immunofluorescence for the detection of high titers to Rickettsia conorii. The course of the disease was favorable in all the patients treated with antibiotics (doxycycline or ceftriaxone).

The case of Mediterranean spotted fever of the traveler returned from Zambia.

We report the case of a traveler who returned from Zambia and was diagnosed with Mediterranean spotted fever (MSF), an infectious disease caused by Rickettsia conorii conorii. The patient presented to Sapporo City General Hospital with symptoms of fever, malaise, headache, and rash. The pathogen was identified by Polymerase Chain Reaction assays and subsequent analyses. The patient improved with 10-day treatment of oral doxycycline. Although some cases of MSF have been reported in sub-Saharan Africa, none have been reported in Zambia. Rhipicephalus sanguineus sensu lato, the vector of the Rickettsia conorii conorii, has been found in various areas of Zambia. Our case report highlights the potential threat of Mediterranean spotted fever in urban areas of Zambia.

Rhipicephalus sanguineus from Hungarian dogs: Tick identification and detection of tick-borne pathogens.

The brown dog tick, Rhipicephalus sanguineus is a complex of tick species with an unsettled species concept. In Europe, R. sanguineus is considered mainly a Mediterranean tick with sporadic findings in central and northern Europe. R. sanguineus is known as a vector of a range of pathogens of medical and veterinary importance, most of which not yet reported as autochthonous in Hungary. A total of 1839 ticks collected by veterinarians from dogs and cats were obtained in Hungary. The study aims at precise determination of ticks identified as R. sanguineus and detection of pathogens in collected ticks. All ticks were morphologically determined and 169 individuals were identified as R. sanguineus. A subset of 15 ticks was selected for molecular analysis (16S rDNA, 12S rDNA, COI). Phylogenetic analyses invariably placed sequences of all three markers into a single haplotype identified as R. sanguineus sensu stricto. All 169 brown dog ticks were tested for the presence of A. platys, E. canis, R. conorii, B. vogeli and H. canis. None of the investigated ticks was positive for the screened pathogens, though A. phagocytophilum sequence was detected in a single tick.

Cervids as Sentinels for Rickettsia spp. in Portugal.

Cervids are highly exposed to ticks, however, their role in the life cycle of these rickettsiae has not been fully elucidated. Given the expanding distribution and growing population of deer species in Portugal, coupled with their direct and indirect interactions with humans during hunting, it becomes crucial to explore their role as sentinels and potential reservoirs of Rickettsia. The present investigation aimed to detect and evaluate exposure to Rickettsia in free-living deer from Portugal. Blood samples (n = 77) were collected from hunted game animals (red deer and fallow deer) from different areas throughout Portugal (Idanha-a-Nova, Monte Fidalgo, Montalvão and Arraiolos) and sera were tested by immunofluorescence assay, to detect antibodies. Additionally, blood DNA samples were screened for SFGR by nested-polymerase chain reaction targeting a fragment of the outer membrane protein B (ompB) gene, as well as for Anaplasma and Ehrlichia spp. targeting the 16S rRNA gene. Thirty-five per cent (25 deer and two fallow deer) tested positive (sera with a titer ≥1:64) for IgG antibodies against Rickettsia conorii. No rickettsial DNA was detected by PCR for the ompB gene, and all DNA samples tested negative for Anaplasma and Ehrlichia. As far as we know, this study is the first screening of cervid species in Portugal for Rickettsia antibodies. The findings suggest that these animals serve as useful sentinel indicators for the circulation of rickettsiae, offering a complementary perspective to studies focused on ticks. The increasing numbers of hunted deer in Portugal and the potential zoonotic features of Rickettsia spp. highlight the importance of continued surveillance directed at tick-borne diseases, especially those involving wild animals.

Contribution of NK cells to the innate phase of host protection against an intracellular bacterium targeting systemic endothelium.

We investigated the mechanisms by which natural killer (NK) cells mediate innate host defense against infection with an endothelium-targeting intracellular bacterium, Rickettsia. We found that a robust Rickettsia-induced innate response in resistant mice cleared the bacteria early in the infection and was associated with significantly higher frequencies of splenic interferon (IFN)-γ (+) CD8(+) T cells and cytotoxic NK cells compared with susceptible mice. More importantly, NK cell-deficient Rag(-/-)γc(-/-) animals displayed significantly increased susceptibility to Rickettsia infection compared with NK cell-sufficient Rag(-/-) mice, as evidenced by impaired bacterial clearance, early development of severe thrombosis in the liver, and a decreased serum level of IFN-γ. Furthermore, the lack of NK cells also impaired host resistance of CB-17 scid mice to Rickettsia, similar to what was observed in Rag(-/-)γc(-/-) mice. Interestingly, perforin deficiency in Rag(-/-)Prf1(-/-) mice resulted in greater thrombosis and insignificantly different systemic levels of IFN-γ compared with Rag(-/-) mice, suggesting that perforin, which is mainly produced by NK cells, is involved in the prevention of vascular damage. Together, these findings reveal that NK cells mediate the innate phase of host protection against infection with rickettsiae, most likely via IFN-γ production. Furthermore, NK cells are involved in preventing rickettsial infection-induced endothelial cell damage, possibly via perforin production.

Genome sequence of Rickettsia conorii subsp. indica, the agent of Indian tick typhus.

Rickettsia conorii subsp. indica is the agent of Indian tick typhus. The present study reports the draft genome of Rickettsia conorii subsp. indica strain ITTR (ATCC VR-597).

Genome sequence of Rickettsia conorii subsp. israelensis, the agent of Israeli spotted fever.

Rickettsia conorii subsp. israelensis is the agent of Israeli spotted fever. The present study reports the draft genome of Rickettsia conorii subsp. israelensis strain ISTT CDC1, isolated from a Rhipicephalus sanguineus tick collected in Israel.

Deleterious effect of ciprofloxacin on Rickettsia conorii-infected cells is linked to toxin-antitoxin module up-regulation.

OBJECTIVES: To confirm and better understand the deleterious effect of fluoroquinolones reported during Rickettsia conorii infection in humans. METHODS: We used a new plaque assay to test the effect of ciprofloxacin on cells infected by R. conorii. Controls were mock-treated infected cells and infected cells treated with doxycycline. We used real-time quantitative RT-PCR to quantify vapC and vapB transcripts in cells infected by R. conorii treated with ciprofloxacin or mock treated. RESULTS: By plaque assay, at baseline (0 h) there is no difference in lytic area between cells treated with ciprofloxacin (whatever concentration used) and controls. Ciprofloxacin at 0.5 and 50 mg/L induced a significant increase in lytic areas compared with the control at 2 h, 4 h, 6 h (P<0.0001) and 24 h (P<0.0001 and P=0.035, respectively) when not induced with doxycycline. By real-time quantitative RT-PCR, ciprofloxacin was found to cause an up-regulation of toxin-antitoxin (TA) module transcription. Indeed, the mRNA levels of vapC and vapB were significantly increased at 2 h and 4 h in cells treated with 50 mg/L ciprofloxacin (not with 0.5 mg/L ciprofloxacin) compared with control levels (fold change >2.9). CONCLUSIONS: These in vitro findings correlated with our previous clinical findings: fluoroquinolones have a deleterious effect during R. conorii infection, not found with doxycycline. We speculate that the toxic effect of fluoroquinolones on R. conorii-infected cells is mediated by the overexpression of TA, possibly followed by their release into the host cytoplasm as described in Rickettsia felis.

Q fever, spotted fever group, and typhus group rickettsioses among hospitalized febrile patients in northern Tanzania.

BACKGROUND: The importance of Q fever, spotted fever group rickettsiosis (SFGR), and typhus group rickettsiosis (TGR) as causes of febrile illness in sub-Saharan Africa is unknown; the putative role of Q fever as a human immunodeficiency virus (HIV) coinfection is unclear. METHODS: We identified febrile inpatients in Moshi, Tanzania, from September 2007 through August 2008 and collected acute- and convalescent-phase serum samples. A ≥4-fold increase in immunoglobulin (Ig) G immunfluorescence assay (IFA) titer to Coxiella burnetii phase II antigen defined acute Q fever. A ≥4-fold increase in IgG IFA titer to Rickettsia conorii or Rickettsia typhi antigen defined SFGR and TGR, respectively. RESULTS: Among 870 patients, 483 (55.5%) were tested for acute Q fever, and 450 (51.7%) were tested for acute SFGR and TGR. Results suggested acute Q fever in 24 (5.0%) patients and SFGR and TGR in 36 (8.0%) and 2 (0.5%) patients, respectively. Acute Q fever was associated with hepato- or splenomegaly (odds ratio [OR], 3.1; P = .028), anemia (OR, 3.0; P = .009), leukopenia (OR, 3.9; P = .013), jaundice (OR, 7.1; P = .007), and onset during the dry season (OR, 2.7; P = .021). HIV infection was not associated with acute Q fever (OR, 1.7; P = .231). Acute SFGR was associated with leukopenia (OR, 4.1; P = .003) and with evidence of other zoonoses (OR, 2.2; P = .045). CONCLUSIONS: Despite being common causes of febrile illness in northern Tanzania, Q fever and SFGR are not diagnosed or managed with targeted antimicrobials. C. burnetii does not appear to be an HIV-associated co-infection.

Identification of rickettsial infections by using cutaneous swab specimens and PCR.

To determine the usefulness of noninvasive cutaneous swab specimens for detecting rickettsiae, we tested skin eschars from 6 guinea pigs and from 9 humans. Specimens from eschars in guinea pigs were positive for rickettsiae as long as lesions were present. Optimal storage temperature for specimens was 4 degrees C for 3 days.

Identification of potential hosts and vectors of scrub typhus and tick-borne spotted fever group rickettsiae in eastern Taiwan.

Scrub typhus and tick-borne spotted fever group (SFG) rickettsioses are transmitted by chiggers (larval trombiculid mites) and hard ticks, respectively. We assessed exposure to these disease vectors by extensively sampling both chiggers and ticks and their small mammal hosts in eastern Taiwan during 2007 and 2008. The striped field mouse Apodemus agrarius Pallas (Rodentia: Muridae) was the most common of the small mammals (36.1% of 1393 captures) and presented the highest rate of infestation with both chiggers (47.8% of 110 760) and ticks (78.1% of 1431). Leptotrombidium imphalum Vercammen-Grandjean & Langston (Trombidiformes: Trombiculidae) and immature Rhipicephalus haemaphysaloides Supino (Ixodida: Ixodidae) were the most abundant chiggers (84.5%) and ticks (>99%) identified, respectively. Immunofluorescent antibody assay revealed high seropositive rates of rodents against Orientia tsutsugamushi Hyashi (Rickettsiales: Rickettsiaceae), the aetiological agent of scrub typhus (70.0% of 437 rodents), and tick-borne SFG rickettsiae (91.9% of 418 rodents). The current study represents a first step towards elucidating the potential hosts and vectors in the enzootic transmission of O. tsutsugamushi and tick-borne SFG rickettsiae in Taiwan. Further studies should focus on characterizing pathogens in L. imphalum and R. haemaphysaloides, as well as the proclivity of both vectors to humans. Uncovering the main hosts of adult ticks is also critical for the prevention of SFG rickettsial infections.

Coronary involvement in Mediterranean spotted fever.

Mediterranean spotted fever (MSF) is a tick-borne acute febrile disease caused by Rickettsia conorii and characterized by fever, a maculo-papular rash and a black eschar at the site of the tick bite. We describe the case of a 3-year-old boy with MSF who developed a transient right coronary artery ectasia. The patient was brought to the hospital after four days of fever and mild myalgia of the legs. The suspicion of MSF arose due to the presence of a maculo-papular skin rash and treatment with oral clarithromycin was started. After four days fever persisted and the differential diagnosis of Kawasaki syndrome was considered. Echocardiography showed a dilated right coronary artery with hyperreflective walls. Treatment with intravenous immunoglobulin was initiated while clarithromycin was continued. After one day the fever disappeared. An immunofluorescent antibody test performed after four weeks confirmed a R. conorii infection. A follow-up echocardiography was normal six weeks and six months later. We suggest that ectasia of the coronary arteries may be a manifestation of rickettsial vasculitis. Prospective studies are needed to understand the frequency and the possible consequences of this phenomenon in the course of MSF.