Discussion

We describe the demographic, epidemiologic, clinical, and laboratory features of all 10 cases of CCHFV reported in Spain since 2013, when the causative agent was first discovered in this country^[11]. Our findings have updated the knowledge of CCHFV in Spain to show the pattern during the period 2013–2021 in southern Europe. Half (5/10) of the cases we described in this article were treated at Hospital Universitario de Salamanca ^(10–13]. CCHFV was found in western Spain in 2010 in ticks (Hyalomma lusitanicum) feeding on wild animals in the province of Caceres^[17].

Studies carried out in the same period and the same geographic areas in Spain in healthy donors^[18] showed a serologic prevalence of past infection of ≈1.16% and in patients who sought emergency care for febrile syndrome^[13] of ≈2.22%. Altogether, these results suggest that CCHF is underdiagnosed in this region. However, the high frequency of asymptomatic patients, which exceeds 88% in some studies, might also account for such differences^[3,4].

Spain’s geographic proximity to Africa is a risk factor for continuous entry of CCHFV. Its favorable climate, the wide presence of the vector involved in transmission, the variety of vertebrate animals that can act as amplifying hosts, and its location along the path of transit for migratory birds from CCHFV-endemic areas all increase the risk for spread of the virus.

Most infections in this study occurred in spring and summer in rural areas of central-western Spain. Of the cases that occurred in the southern part of the autonomous community of Castile and León, likely causes are specific climatic features (e.g., temperature, humidity), geographic conditions, flora and wildlife, the animal husbandry sector, and increased contact with animals and ticks. In this regard, field studies have confirmed that these areas are at risk for CCHF because of the abundance of H. lusitanicum ticks, the presence of CCHFV in the specimens collected, together with the high prevalence observed in wild and domestic animals in these and other areas of the country^[17,19–22].

The epidemiologic pattern we report for Spain resembles that of countries such as Greece and Kosovo^[23,24], with few and occasional cases, and clearly differs from the epidemiologic evolution of countries such as Turkey^[25], which has a marked and progressive increase in cases since its earliest recorded case in 2002. Those distinct epidemiologic evolution profiles might be related to differences in farming and sheepherding activities, as well as the specific climate conditions; in Turkey, a notable and specific risk factor is living at altitudes >836.5 m^[26]. We noted the possibility of secondary transmission of CCHF to healthcare workers, particularly during accidental contact such as resuscitation of severely ill patients, and the need for strict rules and protocol for handling potential secondary cases^[10].

Clinical findings in the patients we reviewed revealed that the most common symptoms were fever, exanthema, and myalgia. However, we also noted findings of bleeding (7/10 cases) at higher frequencies than those reported previously^[25]. Two patients with CCHFV experienced hemophagocytic syndrome with hemophagocytosis in the bone marrow. Hemophagocytic syndrome is a rare and severe disease characterized by fever; hepatosplenomegaly; cytopenia; elevated ferritin, lactate dehydrogenase and triglyceride levels; and hemophagocytosis in the bone marrow. Clinical and biologic symptoms of hemophagocytic syndrome are caused by cytokines secreted by T-lymphocytes and macrophages. A main challenge in patients with hemophagocytic syndrome is its diagnosis, which must meet well-established criteria^[27]. The relationship between CCHFV and hemophagocytic syndrome has been previously described^[28], but unlike in those studies, the patients in our review did not experience serious bleeding episodes. However, high levels of serum ferritin in patients who underwent analytical determination suggest a higher prevalence of hemophagocytic syndrome than previously described; further research is needed to elucidate the specific mechanisms involved.

All patients received doxycycline accompanied by other antimicrobial drugs, possibly because of initial suspicion of rickettsiosis. Five patients required intensive care treatment; 3 of them died. Ribavirin was prescribed to 3 patients, who all recovered and survived. Despite the potential benefit of ribavirin, the small number of patients makes it difficult to draw conclusions regarding its effectiveness for treating CCHF patients. Furthermore, a recent Cochrane meta-analysis was unable to confirm the potential benefit of ribavirin in CCHFV-infected patients^[29].

In Spain, where most CCHF patients have been diagnosed since 2018, the fatality rate of CCHF was as high as 30%. Of note, those 3/10 patients who died showed the highest Bakir-scale scores (>7) at admission. Previous studies have shown that in this viral infection transmitted by ticks, regional differences in mortality rates may be related to factors including the availability of advanced medical care facilities, faster diagnosis because of a better surveillance system that enables early detection of cases with mild to moderate clinical findings, the routes of acquisition of the infection, and the genotype of the virus. In Turkey, which has a CCHF mortality rate of ≈5%, the most common strain is homologous to the strain detected in Russia and Kosovo, whereas in Spain, the most common strain is the Africa III. Two of our cases infected with strain V have had good outcomes described; cases of genotypes III and V have been detected in the same area.

Previous studies indicated that birds are involved in the transmission of the Africa genotype III virus^[30]. Domestic animals such as pigs have been imported from countries in eastern Europe, indicating a possible relationship with the CCHF epidemiology of European strains, particularly those of genotype V. Of interest, a strain of CCHFV was detected in ticks in Spain^[21]. From a clinical point of view, genotypes III and IV have been associated with more deaths than genotype V in our cases, although the number of patients still remains very limited.

In Spain, circulation in wild animals of 3 different genotypes (III, IV, and V) of CCHFV has been demonstrated, even in the same geographic area; genotype III was the most prevalent. Those data suggest that the expansion pathways of the different CCHFV genotypes in Spain are complex and coincide over time; further studies are needed to clarify the dissemination of CCHFV in southern Europe. In addition, our results revealed a complex epidemiologic pattern in Spain in which uncommon CCHF cases were associated with high mortality rates. Thus, although the risk is considered low, hospital doctors and general practitioners should be alert to the possibility of new CCHF cases, given the high pathogenicity of CCHFV. A detailed medical history of the patient, including travel history and possible risk factors, is critical for fast diagnosis and appropriate adoption of therapeutic measures for timely control of the infection.