Accomando, S.

Cardella, F.

Cascio, A.

Costa, A.

Giordano, S.

Iaria, C.

Maggio, M.

Mansueto, P.

Zangara, V.

CASCIO, ANTONIO

Cardella F

Zangara V

Costa A

Iaria C

Giordano S.

MAGGIO, Maria Cristina

ACCOMANDO, Salvatore

MANSUETO, Pasquale

Archivio istituzionale della ricerca - Università di Palermo

NEW MICROBIOLOGICA, 34, 421-424, 2011Coronary involvement in Mediterranean spotted feverAntonio Cascio1, Maria Cristina Maggio2, Francesca Cardella2, Valeria Zangara2, Salvatore Accomando2, Alessandro Costa3, Chiara Iaria4, Pasquale Mansueto5, Salvatore Giordano61Dipartimento di Patologia Umana, Università di Messina, Messina, Italy;2Dipartimento Universitario Materno Infantile, Università di Palermo, Palermo, Italy;3Dipartimento di Patologia e Microbiologia Sperimentale, Università di Messina, Messina, Italy;4AILMI (Associazione Italiana per la Lotta contro le Malattie Infettive; Italian Association for the Control of Infectious Diseases),University of Messina, Messina, Italy;5Unità Operativa Complessa di Medicina Interna, Dipartimento di Medicina Clinica e delle Patologie Emergenti, Università di Palermo, Palermo, Italy;6Unità Operativa Complessa di Malattie Infettive, ARNAS “Civico, Di Cristina, Benfratelli”, Palermo, ItalyINTRODUCTIONMediterranean spotted fever (MSF) is caused byRickettsia conorii, which is transmitted by thedog tick Rhipicephalus sanguineus. It is an acuteinfectious disease typically characterized byfever, skin rash, and a black eschar at the site oftick bite (Raoult and Roux, 1997). Every year,about 300 cases are notified (mainly from Junethrough September) on the Italian island ofSicily (Cascio et al., 2001, Cascio et al., 1998).Sporadic cases have been diagnosed in travelersCorresponding authorProf. Antonio CascioProgramma interdipartimentale di Infettivologia Speciale,Medicina Tropicale e delle Migrazioni e Parassitologia Policlinico “G. Martino”Via Consolare Valeria, 1 - 98125 MessinaE-mail: acascio@unime.itin other countries as well (Laurent et al., 2009).We describe the case of a 3-year-old boy withMSF who developed a transient right coronaryartery ectasia.CASE REPORTIn July 2010 a 3-year-old Italian boy who had pre-viously been healthy was admitted to the pedi-atric emergency clinic of the “G. Di CristinaChildren Hospital” with persistent high fever of 4days duration. In addition, to occasional chillsaccompanying the fever and mild myalgia of thelegs, there were no other complaints, specifical-ly, no nausea, vomiting, or diarrhea, no coughingor dyspnea, and no headaches. Physical exami-nation revealed a temperature of 40°C, a pulse of104 beats per minute, and a blood pressure ofMediterranean spotted fever (MSF) is a tick-borne acute febrile disease caused by Rickettsia conorii and characterizedby 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 boywith MSF who developed a transient right coronary artery ectasia. The patient was brought to the hospital after fourdays of fever and mild myalgia of the legs. The suspicion of MSF arose due to the presence of a maculo-papular skinrash and treatment with oral clarithromycin was started. After four days fever persisted and the differential diagno-sis of Kawasaki syndrome was considered. Echocardiography showed a dilated right coronary artery with hyper-reflective walls. Treatment with intravenous immunoglobulin was initiated while clarithromycin was continued. Afterone day the fever disappeared. An immunofluorescent antibody test performed after four weeks confirmed a R. conoriiinfection. A follow-up echocardiography was normal six weeks and six months later. We suggest that ectasia of the coro-nary arteries may be a manifestation of rickettsial vasculitis. Prospective studies are needed to understand the frequencyand the possible consequences of this phenomenon in the course of MSF.KEY WORDS: Rickettsia, Ehrlichia, Anaplasma, Spotted fever, Boutonneuse fever, Coronary, Kawasaki syndromeSUMMARYReceived March 03, 2011 Accepted July 13, 201192/50 mmHg. The boy appeared quite sick. Hepresented a generalized maculo-papular rash con-sisting of sparse papules that affected also thepalms and soles. Conjunctives and pharynx werehyperemic. The liver and spleen were palpable 2cm under the costal margins. Rhonchi were heardon thoracic auscultation. He had a palpable lym-phadenopathy in the neck. The rest of the physi-cal examination was unremarkable. Complete blood count and formula revealed a to-tal leukocyte count of 14,780 cells per L with 71%neutrophils, 20.5% lymphocytes, and 3% mono-cytes, hemoglobin 11 g% and a platelet count of303,000 per L. Blood biochemical tests showedthe following abnormal results: C-reactive pro-tein, 29.2 mg/l (normal value, <5 mg/l); fibrino-gen, 444 mg/dl (normal value, 200-400 mg/dl);lactic dehydrogenase, 478 U/l (normal value, 100-240 U/l). Other biochemical studies including glu-cose, aspartate aminotransferase, alanine amino-transferase, glutamyl transpeptidase, total pro-tein, albumin, cholesterol, blood urea nitrogen,creatine phosphokinase, creatinine, alkaline phos-phatase and total bilirubin and coagulation pro-files were all within normal limits. The diagnosis of MSF was considered very likelyand oral clarithromycin at 15 mg/kg/day wasstarted. As fever persisted after 4 days, the pres-ence of an infection other than MSF, as well asatypical Kawasaki syndrome (KS) were taken inconsideration. For this reason blood cultures,serology for a number of viral and bacterialpathogens, chest X-ray, abdominal echographyand echocardiography were performed.Chest X-ray showed a honeycomb appearance ofthe right perihilar region and diffuse interstitialseptal thickening. An abdomen ultrasound ex-amination showed an enlarged homogeneous liv-er and an slightly enlarged spleen (longitudinaldiameter, 86 mm [normal value for 2-4-year-oldchildren, 64-85 mm]. Cardiac ultrasound showeda functionally and structurally normal heart. Theright coronary artery had a diameter of 2.8 mmwith hyper-reflective walls (Figure 1). The widthof the left coronary artery was normal (diameter,1.7 mm). The electrocardiogram showed nochanges.Considering the diagnosis of KS, treatment with2 g/kg intravenous immunoglobulin and aspirinwas initiated while clarithromycin was contin-ued to cover for atypical and intracellular bacte-ria. Moreover, an infection with R. conorii con-tinued to be regarded as a likely possibility. Inthe meantime, serological studies for HIV-1, HIV-2, HSV1 and HSV2, cytomegalovirus, parvovirus,Mycoplasma pneumoniae, Chlamydia pneumoni-ae and Brucella, were negative. Tests for EBVcapsid IgG and IgM antibodies were negative.IgM and IgG antibodies against R. conorii wereboth moderately positive (1:80 and 1:40, respec-tively) by indirect immunofluorescent antibodytest (IFAT). Multiple blood cultures, a urine cul-ture and a pharyngeal swab were negative forbacteria and fungi. After one day the fever haddisappeared and the patient was alert and play-ful. Blood cultures were still negative. WBC, C-reactive protein (CRP) and fibrinogen values nor-malized. The patient was then discharged fromthe hospital in good clinical condition. Continuedaspirin treatment was advised. Four weeks later,the patient was in excellent condition and IgMand IgG titers against R. conorii had risen to1:320 and 1:640, respectively. The diagnosis ofMSF was then considered proven. Cardiac ul-trasonography six weeks after presentation wasnormal (left and right coronary artery diameter<2.0 mm) and aspirin was discontinued. At six-month follow-up no echocardiographic abnor-malities were found.DISCUSSIONTypical clinical features of MSF include fever,myalgia, headache, generalized maculo-papular422 A. Cascio, M.C. Maggio, F. Cardella, V. Zangara, S. Accomando, A. Costa, C. Iaria, P. Mansueto, S. GiordanoFIGURE 1 - Echocardiogram showing dilated right coro-nary artery with hyperreflective walls.rash and an inoculation eschar (‘tache noire’) atthe site of the tick bite (Raoult and Roux, 1997).The black eschar is found in about 70% of cases;cervical adenopathy is often present when the“tache noire” is present on the scalp or in theneck. The rash may be only represented by sparsemaculo-papular elements in about 7% of casesand sometimes by petechiae. Conjunctival hy-peremia is present in about 6% of cases (Cascioet al., 1998).The major target of pathogenic Rickettsiae is theendothelium lining the small and medium-sizedblood vessels. Accordingly, invasion and injury toendothelial cells, altered vascular permeability,platelet and hemostatic/fibrinolytic systemchanges, production of acute phase response pro-teins, activation of innate and acquired immunesystem, all leading to vascular inflammation/dys-function, collectively termed ‘rickettsial vasculitis’,is reflected in the clinical features of all rickettsialdiseases, especially in severe and complicated cas-es (Amaro et al., 2003, Paddock et al., 1999, Sahniand Rydkina, 2009). Furthermore, rickettsialspecies have been isolated from myocardial tissueor from the endothelium of coronary arteries andmyocardial vessels in severe cases of rickettsialdisease (DiNubile, 1996, Nilsson et al., 1999,Walker et al., 1989). A case similar to ours wasdescribed in 3-year-old girl with murine typhus(van Doorn et al., 2006). In that study, as in ourcase, the temporary widening of the coronary ar-tery was possibly considered a manifestation ofsystemic rickettsial vasculitis. Rickettsiae have been initially implicated andsubsequently dismissed as possible causes of KS(Burns and Glode, 2004, Kafetzis et al., 2001,Rathore et al., 1993, van Doorn et al., 2006).However, the aspecific and partially overlappingsymptomatology of rickettsioses and KS makesdifferential diagnosis difficult (Jenkins et al.,1997, van Doorn et al., 2006). We found only tworeports in the international literature of KS oc-curring concomitantly with a rickettsial disease.These cases involved a 4-year-old girl with RockyMountain spotted fever (Bal and Kairys, 2009)and a 22-month-old girl with an Anaplasma spinfection (Chochlakis et al., 2009). However, itcannot be excluded that the inflammatory re-sponse to rickettsial infections can occasionallytrigger the cascade of events that eventuallyleads to KS.KS is an acute, self-limited systemic vasculitisof unknown aetiology that occurs in children.The diagnosis is confirmed by the lack of an-other known disease process to explain the ill-ness and by the presence of fever for at least fivedays and by the presence of four of the follow-ing five criteria: 1) bilateral conjunctival injection; 2) changes of the mucous membranes of the up-per respiratory tract: injected pharynx; inject-ed, fissured lips; strawberry tongue; 3) polymorphous rash; 4) changes of the extremities: peripheral oede-ma, peripheral erythema, periungual desqua-mation; 5) cervical adenopathy (Burns and Glode, 2004). A threatening feature of KS is coronary arteryaneurysms that develop in 20-25% of cases, whichcan subsequently (years later) cause sudden deathor myocardial infarction (Burns et al., 1996, Katoet al., 1992).Our patient suffered (apart from persistent highfever), from bilateral conjunctival injection, rashand cervical adenopathy - three of the requiredfour criteria. However, it is known that the clini-cal symptoms of KS can develop sequentially dur-ing the course of the disease (Burns and Glode,2004). Because our patient’s dilated right coro-nary artery was attributed to KS, immunoglobu-lins were administered. However, it is more like-ly that coronary ectasia was the result of the rick-ettsial vasculitis. Echocardiographic screeningcould be offered to patients with MSF for researchpurposes until its clinical relevance is confirmed.This may lead to the detection of more cases ofcoronary ectasia than presently appreciated.Similarly, retinal vasculitis was found in a highproportion of MSF patients, even in the absenceof ocular symptoms (Khairallah et al., 2004).CONCLUSIONSMSF should be included in the differential diag-nosis of KS in countries where MSF is endemicand in other countries when the patient has re-cently returned from an endemic area. R. conoriiinfection can cause coronary arteries ectasia andthis fact, together with the aspecific and partial-ly overlapping symptomatology of KS and MSFmay complicate differential diagnosis. Coronary involvement in Mediterranean spotted fever 423Prospective studies are necessary to understandthe frequency and the possible consequences ofcoronary artery ectasia in the course of MSF.ACKNOWLEDGEMENTSWritten consent was obtained from the patient’sparents for publication of the studyREFERENCESAMARO M., BACELLAR F., FRANCA A. (2003). Report ofeight cases of fatal and severe Mediterranean spot-ted fever in Portugal. Ann. NY Acad. Sci. 990, 331-343.BAL A.K., KAIRYS S.W. (2009). Kawasaki disease fol-lowing Rocky Mountain spotted fever: a case re-port. J. Med. Case Reports. 3, 7320.BURNS J.C., GLODE M.P. (2004). Kawasaki syndrome.Lancet. 364, 533-544.BURNS J.C., SHIKE H., GORDON J.B., MALHOTRA A.,SCHOENWETTER M., KAWASAKI T. (1996). Sequelae ofKawasaki disease in adolescents and young adults.J. Am. Coll. Cardiol. 28, 253-257.CASCIO A., COLOMBA C., DI ROSA D., SALSA L., DI MARTINOL., TITONE L. (2001). 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Accomando, A. Costa, C. Iaria, P. Mansueto, S. Giordano

Coronary involvement in Mediterranean spotted fever

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Coronary involvement in Mediterranean spotted fever

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