Background The pathophysiologic mechanisms of severity of Mediterranean spotted fever (MSF) and the host and microbial risk factors for a fatal outcome are incompletely determined. Methods In a prospective study of 140 patients with documented identification of the causative rickettsial strain admitted to 13 Portuguese hospitals during 1994−2006, univariate and multivariate analyses determined the risk factors for a fatal outcome. Findings Seventy one (51%) patients were infected with Rickettsia conorii Malish strain and 69 (49%) with Israeli spotted fever (ISF) strain. Patients were admitted to ICU (29%), hospitalized as routine inpatients (67%), or managed as outpatients (4%). Deaths occurred in 29 (21%) adults. Fatal outcome was significantly more likely for patients with ISF strain infection, and alcoholism was a risk factor. The pathophysiology of a fatal outcome involved significantly greater incidence of petechial rash, gastrointestinal symptoms, confusion/obtundation, dehydration, tachypnea, hepatomegaly, leukocytosis, coagulopathy, azotemia, hyperbilirubinemia, and elevated hepatic enzymes and creatine kinase. Some but not all these were observed more often in ISF strain-infected patients. Conclusions Although fatalities and similar clinical manifestations occurred with both strains, ISF strain was more virulent than Malish strain. Multivariate analysis revealed that acute renal failure and hyperbilirubinemia were most strongly associated with a fatal outcome.

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.

Mild/moderate MSF is associated with a strong and balanced intralesional proinflammatory and anti-inflammatory response, with a dominant type 1 immunity, whereas severe MSF is associated with increased expression of chemokine mRNA. Whether these factors are simply correlates of mild and severe MSF or contribute to antirickettsial immunity and pathogenesis remains to be determined.

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