Some epidemiological features of the Mediterranean spotted fever re-emerging in Bulgaria.

INTRODUCTION: The Mediterranean spotted fever (MSF), caused by Rickettsia conorii conorii strain Malish, is transmitted by the brown dog tick Rhipicephalus sanguineus. In Bulgaria, cases of MSF occurred in two epidemic waves, the first in 1948-1970, (after there were no report of new cases more than for 20 years) and the second started in 1993 and is still going on. The AIM of the study was to investigate the epidemiological characteristics of the re-emerging MSF in Plovdiv city and its suburbs, which is the largest endemic region in the country. MATERIALS AND METHODS: The MSF patients treated between 1993 and 2011 were 1254. MSF was confirmed by immunofluorescent assay (IFA) in the Reference Rickettsioses Laboratory. Descriptive and analytic epidemiological methods were used to determine the routes and ways of infection, the epidemiological locus, seasonality, patients' age, gender and social structure, and the clinical severity of the cases. RESULTS: We established that MSF spread in the region in two distinct phases: from 1993 to 2003 during which the disease was increasingly spreading and the second phase taking place from 2004 till 2011 during which the disease was gradually decreasing. The incidence is between 0.13 and 25.62, mean 10.91 per 100 000 populations (11.88 and 9.56 per 100 000 populations for phases I and II, respectively); between 1.14% and 6.25% of the infected people died (mean 2.07%, 3.46% and 1.25% for phases I and II, respectively). The age distribution of patients shows predominance of 40-59-year-olds (31.66%), reaching a peak in patients older than 60 years (37.5%). Children and adolescents under 19 years are less affected (18.12%), while the least affected are the young adults between 20-39 (12.7%). Urban population is almost twice as affected as rural population regardless of the gender. The disease has summer seasonality, peaking in August. Eschar (tache noire) was found in 77.91% of the patients. Despite the decline and predominance of mild forms (43.12%), the re-emerging MSF still presents with lots of severe forms (11.45%) and malignant forms (8.54%), which makes almost one fifth of all patients to be at serious risk of getting ill with a severe disease with complications and possible fatal outcome. CONCLUSION: Almost two decades after it re-emerged in Bulgaria, MSF is still potentially active despite the decreasing incidence and mortality rate. During the phase of decline, the re-emerging MSF kept the basic epidemiologic characteristics it had in the first phase of rapid increase. The epidemiologic characteristics of MSF in the region are in support of its prevention and control.

Analysis of risk factors for malignant Mediterranean spotted fever indicates that fluoroquinolone treatment has a deleterious effect.

OBJECTIVES: To identify risk factors for malignant Mediterranean spotted fever (MSF) caused by Rickettsia conorii conorii. PATIENTS AND METHODS: Epidemiological, clinical and biological characteristics as well as risk factors (including treatment regimens) for severe MSF cases were analysed retrospectively. A patient with two or more organ dysfunctions or patient death was defined as a severe case. RESULTS: During the study period (January 1999 to December 2009), 161 MSF cases were referred to our centre for rickettsioses. Twenty-six cases (16.1%) were considered severe, which is 3-fold higher than in our previous studies. The clinical and laboratory findings were comparable to those reported elsewhere except that the type of antibiotic treatment was associated with disease severity. Doxycycline administration prior to deterioration of disease (in 31 patients) protected patients from development of severe MSF [relative risk (RR) 0.248, 95% confidence interval (CI) 0.08-0.76] and induced earlier defervescence compared with the other treatment regimens (3.02 ± 2.2 days versus 7.1 ± 6.57 days, P = 0.021). In contrast, fluoroquinolone treatment (in 21 patients) was significantly and independently associated with MSF severity (RR 2.53, 95% CI 1.40-4.55) and was associated with a significantly longer hospital stay. CONCLUSIONS: In this retrospective study fluoroquinolone treatment was associated with increased MSF disease severity. Fluoroquinolones have been previously associated with treatment failure in typhus and scrub typhus cases. Thus, we do not recommend the use of fluoroquinolones to treat rickettsial diseases.

[Rickettsia conorii infection in Romania, 2000-2008]. / Evolutia febrei butonoase în România 2000-2008.

OBJECTIVES: presenting the epidemiological aspects of Rickettsia conorii infection in Romania between 2000-2008. METHODS: A descriptive epidemiology study of Rickettsia conorii infection cases noticed in Romania between 2000-2008, which provide data regarding: time, place a4d person. The study also presents some risk factors. RESULTS: All cases were sporadic and were noticed in southern Romania. The highest incidence was registered in 2001 in Constanta district (44.2% per ten thousand inhabitants). The majority of cases were registred between April-November with a maximum of cases in August (38%) The patients were mainly from urban areas (80%); The more affected age group was 45-54 year (25%). The most predominant clinical expression was the medium one (58% of cases). In 99% of the cases, the release status from the hospital was cured and the evolution of the illness was favorable. In this period were just 2 deceased In 96% of the confirmed cases the tick exposure has appeared within the contact with parasited animals and took place in 60% of cases at home. 4% of the cases recognaised a professional contact with parasitated animals. In 93% of the cases the reservoir was represented by the parasitated dog. CONCLUSION: The sporadic evolution of the cases demonstrated that the natural focality of the disease in Romania persists, the distribution of cases matches with that of Rickettsia conorii and its tick vectors and also with the period of greatest activity of the vector (Rhipicephalus sanguineous, specific for dogs). The disease clearly represents a public health problem whose magnitude is not known.

Host- and microbe-related risk factors for and pathophysiology of fatal Rickettsia conorii infection in Portuguese patients.

BACKGROUND: The pathophysiologic mechanisms that determine the severity of Mediterranean spotted fever (MSF) and the host-related and microbe-related risk factors for a fatal outcome are incompletely understood. METHODS: This prospective study used univariate and multivariate analyses to determine the risk factors for a fatal outcome for 140 patients with Rickettsia conorii infection admitted to 13 Portuguese hospitals during 1994-2006 with documented identification of the rickettsial strain causing their infection. RESULTS: A total of 71 patients (51%) were infected with the Malish strain of Rickettsia conorii, and 69 (49%) were infected with the Israeli spotted fever (ISF) strain. Patients were admitted to the intensive care unit (40 [29%]), hospitalized as routine inpatients (95[67%]), or managed as outpatients (5[4%]). Death occurred in 29 adults (21%). A fatal outcome was significantly more likely for patients infected with the ISF strain, and alcoholism was a risk factor. The pathophysiology of a fatal outcome involved significantly greater incidence of petechial rash, gastrointestinal symptoms, obtundation and/or confusion, dehydration, tachypnea, hepatomegaly, leukocytosis, coagulopathy, azotemia, hyperbilirubinemia, and elevated levels of hepatic enzymes and creatine kinase. Some, but not all, of these findings were observed more often in ISF strain-infected patients. CONCLUSIONS: Although fatalities and similar clinical manifestations occurred among both groups of patients, the ISF strain was more virulent than the Malish strain. Multivariate analysis revealed that acute renal failure and hyperbilirubinemia were most strongly associated with a fatal outcome.

The presence of eschars, but not greater severity, in Portuguese patients infected with Israeli spotted fever.

In Portugal, Mediterranean spotted fever (MSF) is caused by R. conorii Malish and Israeli spotted fever (ISF) strains. It has been suggested that the ISF strain isolated from patients with MSF causes different clinical manifestations compared to those caused by Malish strain, namely the absence of eschar and greater severity. The aim of this study was to analyze the presence or absence of eschar and of fatality in Portuguese patients infected with either Malish or ISF strain. Of 94 patients with a clinical diagnosis of MSF between 1994 to 2004, 47 were infected with Malish strain and 47 with ISF strain. Eschars were reported in 20 patients (49%) infected with Malish strain, and in 17 (39%) with ISF strain. The presence of eschar is not statistically associated to a greater extent with either R. conorii strain (P=0.346). A total of 22 patients died, 9 infected with Malish strain and 13 infected with ISF strain, and no statistically significant difference was found (P=0.330). This study showed that the concepts of absence of the eschar and greater severity in Israeli spotted fever infection should be revised.

Effect of blocking the CXCL9/10-CXCR3 chemokine system in the outcome of endothelial-target rickettsial infections.

Rickettsiae cause systemic infections such as Rocky Mountain spotted fever and boutonneuse fever. The main cellular target of these obligately intracellular bacteria is the endothelium. T lymphocytes are the most important effectors of immunity, and the CXCR3 ligands CXCL9 and CXCL10 may play an important role in the T cell-mediated clearance of rickettsiae from the infected vasculature as suggested by recent expression studies. Here we showed that antibody-mediated neutralization of CXCL9 and CXCL10, and CXCR3 gene knockout, had no effect on survival or bacterial loads of mice infected with rickettsiae. We also demonstrated that rickettsiae triggered the endothelial expression of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 in vivo. These findings suggested that antigenic presentation by endothelial cells together with an endothelial inflammatory phenotype induced by the rickettsial infection may be sufficient to arrest T cells and trigger their anti-rickettsial effector mechanisms without the need for chemokines.

Fc-dependent polyclonal antibodies and antibodies to outer membrane proteins A and B, but not to lipopolysaccharide, protect SCID mice against fatal Rickettsia conorii infection.

An emphasis on cellular immunity against Rickettsia has led to neglect of analysis of the role of antibody. The availability of an excellent mouse model of spotted fever rickettsiosis enabled investigation of a potential role of antibody in immunity to Rickettsia conorii. C3H severe combined immunodeficiency (SCID) mice were passively transfused with monoclonal antibodies against rickettsial outer membrane protein A (OmpA), OmpB, or lipopolysaccharide (LPS), polyclonal anti-R. conorii serum, Fab fragments of polyclonal antiserum, or no antibodies and then challenged 48 h later with 10 50% lethal doses (LD(50)) of R. conorii. All mice that received monoclonal antibodies against OmpA and two of four mice that received monoclonal antibodies against OmpB or polyclonal antisera were completely protected, but the recipients of anti-LPS antibodies or the Fab fragments were not protected. Polyclonal antibody treatment of C3H SCID mice that had been infected with 10 LD(50) of R. conorii 4 or 5 days earlier prolonged the life of the infected mice from 10.4 to 22.5 days and resulted in decreased levels of infectious rickettsiae in the spleen and liver 24 and 48 h later. Treatment with protective antibodies resulted in the development of large aggregates of R. conorii antigens in splenic macrophages and intraphagolysosomal rickettsial death and digestion. The kinetics of development of antibodies to R. conorii determined by immunoblotting revealed antibodies to LPS on day 6 and antibodies to OmpA and OmpB on day 12, when recovery from the infection had already occurred. Antibodies to particular epitopes of OmpA and OmpB may protect against reinfection, but they may not play a key role in immunity against primary infection. Antibodies might be useful for treating infections with antibiotic-resistant organisms, and some B-cell epitopes should be included in a subunit vaccine.

Mediterranean spotted fever in Portugal: risk factors for fatal outcome in 105 hospitalized patients.

Mediterranean spotted fever (MSF) is the most important tick-borne disease in Portugal. It is a notifiable disease and during 1989-2000 the annual incidence rate in Portugal was 9.8/10(5) inhabitants. Although recognized as a benign acute disease and treated mainly with ambulatory procedures, some cases are severe and fatalities have increased in the last few years. In 1997, MSF mortality became more evident in Beja, a Portuguese southern district, with a case fatality rate of 32.3% in hospitalized patients. Analysis of 55 variables regarding epidemiologic, clinical, laboratory, and therapeutic data of fatal and nonfatal MSF cases were compared to identify risk factors in 105 patients hospitalized in Beja District Hospital, between 1994 and 1998. It was statistically significant that the patients dying in 1997 were younger than those in other years. The risk of dying is statistically significant in those who presented with diabetes, vomiting, dehydration, and uremia. The interval between the onset of symptoms to administration of anti-rickettsial therapy was the same for all patients. Therapy delay, reported by some authors to be associated with mortality of MSF, was not a risk factor in our study. The patients who died in 1997 died faster than those in other years. The variables studied could not explain the higher mortality rates observed in our study. Although one may speculate that the pathogenic strain of Israeli tick typhus, isolated in 1997, could be responsible for this increase of fatality rate, inherited patient factors might also be strongly associated with mortality.

Epidemiological characteristics of spotted fever in Israel over 26 years.

During the summer of 1997, 2 confirmed and several suspected fatal cases of spotted fever (SF) occurred in previously healthy young adults in Israel. This unusual cluster of events stimulated the current study. The incidence of SF in Israel from 1971-98 was analyzed. Incidence increased until 1980, declined until 1994, and increased slightly from 1994-97. Incidence was higher during the summer, among children aged 0-9 years, and in rural settlements in central Israel. From 1971-1997, 31 deaths were reported, mostly in the elderly. The deaths that occurred in 1997 are a reminder that, despite the fact that morbidity due to SF is described mainly in children, SF can have a rapidly fatal outcome in healthy young adults. Thus, even during periods of low incidence, careful monitoring and high awareness for prompt diagnosis and treatment are needed.

Fatal Israeli spotted fever in children.

We describe three Israeli children with fatal spotted fever. Clinical disease was characterized by irreversible shock, encephalopathy, renal failure, bleeding tendency, and death within 24 hours of admission. None of the patients had a history of tick bite, and no tache noire was noted. One child presented without rash, and the other two did not have antibodies to spotted-fever-group rickettsiae. The disease was confirmed by isolation of Rickettsia conorii from the patients' blood and tissues in cell cultures or from susceptible laboratory animals inoculated with human specimens. The present cases demonstrate the existence of a severe form of Israeli spotted fever in this population that resembles Rocky Mountain spotted fever. Because Israeli spotted fever may follow a quick, unpredictable, rapidly fatal clinical course, specific antimicrobial therapy should be promptly administered whenever the diagnosis is suspected.

The pathology of fatal Mediterranean spotted fever.

A 77-year-old woman from rural Spain had a febrile summertime disease develop with rash, eschar, and pulmonary, abdominal, and neurologic signs and symptoms. Mediterranean spotted fever (MSF) was diagnosed late in the course, and antirickettsial treatment was given only during the last 30 hours of life. Clinical manifestations of severe disseminated vascular injury included thrombocytopenia, hypoalbuminemia, edema of the lungs and legs, and severe prerenal azotemia. The diagnosis was documented by specific serology. Necropsy revealed vascular injury with perivascular lymphohistiocytic infiltrates suggestive of rickettsiosis in the central nervous system, lung, heart, kidneys, esophagus, stomach, colon, pancreas, spleen, and thyroid. Gastric hemorrhage and acute pneumonia contributed to the patient's death on day 18 of illness. Antimicrobial treatment and host defenses apparently reduced rickettsiae to an undetectable quantity. MSF has increased in incidence in the Mediterranean basin and has been reported in travelers returning to the United States.

Ixodid tick attacks on man in Israel: medical implications.

Various species of ixodid ticks that have been recorded to attack man were surveyed, and boutonneuse fever caused by Rickettsia conorii, which is transmitted in Israel by Rhipicephalus sanguineus s.l., is reviewed. Only in one case were a complement fixation test and exact determination of the species of the tick performed. Tick toxicosis and tick paralysis are discussed, and the possibility of human babesiosis and Lyme disease or erythema chronicum migrans appearing in Israel is considered.