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Table 1.  

Characteristic Patient no. and source
1 (10) 2 (10) 3 (12) 4 (13) 5 6 7 8 (11) 9 10
Age, y 62 50 74 53 70 54 69 32 59 30
Sex M F M M M M M F M F
Rural location No No No Yes Yes Yes Yes No Yes No
Date 2016 Aug 2016 Aug 2018 Jul 2018 Aug 2020 Jun 2020 Jul 2020 Aug 2013 May 2021 Apr 2021 Jun
Risk factors† Leisure Nurse Hunting Ag Ag Ag Leisure Leisure Ag Leisure
Comorbidities HTN, OSA None None Hepatic steatosis, active drinker Tongue cancer TB,
HTN None Diabetes mellitus, dyslipemia Diabetes mellitus
Bakir scale at admission 7 0 7 6 6 4 8 5 2 5
Outcome Died Good Died Good Good Good Died Good Good Good

Table 1. Main epidemiologic data of patients with Crimean-Congo hemorrhagic fever, Spain, 2013–2021*

*Source is indicated if other than this study. Ag, agriculture; HTN, hypertension; OSA, obstructive sleep apnea. †Risk factors include high-risk occupations; agriculture includes shepherding activities.

Table 2.  

Characteristic Patient no. and source
1 (10) 2 (10) 3 (12) 4 (13) 5 6 7 8 (11) 9 10
Main clinical data                    
   Tick bite Y N Y N Y Y Y Y Y Y
   First symptom Fever Fever Fever Fever Fever Fever Fever Fever Fever Fever
   Fever duration, d 4 5 6 6 9 5 4 4 4 5
   Days from first symptom to admission 3 2 4 5 9 7 3 2 4 12
   Digestive symptoms Y Y Y N Y N Y Y Y Y
   Any bleeding Y Y Y N Y N Y Y N Y
Laboratory data†                    
   Hemoglobin, g/dL 13.4 13.9 13.5 14.1 14.6 15.5 13.4 14.4 17 17
   Leukocytes, × 103 cells/mm3 13.9 6.2 10.7 3.1 2.4 2.3 5.5 1.5 2.8 11.1
   Neutrophils, % 85.5 83 90 62 33 66.4 69 63 68.5 90
   Lymphocytes, % 7.9 10.2 5 27 38 26.1 25 31 24.4 4
   Platelets, × 103/mm3 30 174 229 41 44 32 7 44 76 159
   Glucose, mg/d 80 102 83 135 110 134 280 106 116 491
   Creatinine, mg/dL 1.69 1.24 0.83 1.33 0.92 0.75 4.8 0.67 0.85 1.1
   CRP, mg/L 87.6 2.9 ND 15.2 0.3 0.65 3.72 0.6 0.55 52
   AST, U/L 203 24 20 347 273 273 1,305 494 107 72
   ALT, U/L 88 37 9 161 281 135 347 171 141 70
   Ferritin, ng/mL ND ND >40,000‡ 15,718 34,044 28,393 60,000 ND 7,878 1,147
   Bilirubin, mg/dL 0.9 0.5 0.5 0.7 0.43 0.35 1.4 0.29 0.58 ND
   GGT, U/L ND ND ND 425 272 132 1,420 77 136 ND
   ALP, U/L ND ND ND 103 84 59 239 58 72 91
   LDH, U/L ND ND 172 721 358 589 2,311 1,085 341 272
   Triglycerides, mg/dL ND ND ND ND ND 407‡ ND ND 164‡ ND
   Prothrombin time, s 18.1 15.6 10.7 10.2 10 12 13 12 11 ND
   Prothrombin activity, % 52.8 62 104 106 123 99 86 81 102 84
   Partial thromboplastin time, s 18.1 48.7 26.2 43.8 30.2 52.7 61.4 128 ND 29
   Functional fibrinogen, mg/dL ND 265.9 320 605 281 304 156 141 272 325
   D-dimer, ng/mL ND 35,200 ND ND ND 1.3 5.5 3.48 ND ND
   Genotype III III IV V III III III ND V ND
Treatment DOX; support DOX; Ribavirin ev/orally for 9 d DOX; support DOX DOX; ribavirin orally for 10 d§ DOX; ribavirin orally for 10 d§ DOX support DOX; support DOX DOX; support
Length of stay, d 9 23 8 6 22 9 2 17 9 8

Table 2. Main clinical and laboratory data of patients with Crimean-Congo hemorrhagic fever, Spain, 2013–2021*

*Source is indicated if other than this study. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; DOX, doxycycline; GGT, gamma-glutamyl transferase; LDH, lactate dehydrogenase; ND, no data. †Analysis upon admission or during the first 24 hours. ‡Analysis performed during hospital admission. §In accordance with World Health Organization guidelines.

CME / ABIM MOC

Crimean-Congo Hemorrhagic Fever, Spain, 2013–2021

  • Authors: Helena Miriam Lorenzo Juanes, PharmD, PhD Student; Cristina Carbonell, MD, PhD; Begoña Febrer Sendra, BSc, PhD Student; Amparo López-Bernus, MD, PhD; Alberto Bahamonde, MD, PhD; Alberto Orfao, MD, PhD; Carmen Viera Lista, BSc, PhD Student; María Sánchez Ledesma, MD, PhD; Ana Isabel Negredo, PhD; Beatriz Rodríguez Alonso, MD, PhD; Beatriz Rey Bua, MD; María Paz Sánchez-Seco, PhD; Juan Luis Muñoz Bellido, MD, PhD; Antonio Muro, MD, PhD; Moncef Belhassen-García, MD, PhD
  • CME / ABIM MOC Released: 1/23/2023
  • Valid for credit through: 1/23/2024, 11:59 PM EST
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  • Credits Available

    Physicians - maximum of 1.00 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 1.00 ABIM MOC points

    You Are Eligible For

    • Letter of Completion
    • ABIM MOC points

Target Audience and Goal Statement

This activity is intended for infectious disease specialists and other clinicians who take care of patients who may develop Crimean-Congo hemorrhagic fever.

The goal of this activity is for learners to be better able to evaluate the clinical presentation and common genotypes of Crimean-Congo hemorrhagic fever.

Upon completion of this activity, participants will:

  • Analyze the disease condition of Crimean-Congo hemorrhagic fever
  • Assess the epidemiology of Crimean-Congo hemorrhagic fever in the current study
  • Assess the clinical presentation of Crimean-Congo hemorrhagic fever in the current study
  • Distinguish the most common genotype of Crimean-Congo hemorrhagic fever in the current study


Disclosures

Medscape, LLC requires every individual in a position to control educational content to disclose all financial relationships with ineligible companies that have occurred within the past 24 months. Ineligible companies are organizations whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

All relevant financial relationships for anyone with the ability to control the content of this educational activity are listed below and have been mitigated. Others involved in the planning of this activity have no relevant financial relationships.


Faculty

  • Helena Miriam Lorenzo Juanes, PharmD, PhD Student

    Servicio de Microbiología y Parasitología
    Hospital Universitario de Salamanca
    Instituto de Investigación Biomédica de Salamanca
    Centro de Investigación en Enfermedades Tropicales
    Universidad de Salamanca, Salamanca, Spain

  • Cristina Carbonell, MD, PhD

    Servicio de Medicina Interna
    Unidad de Infecciosas
    Hospital Universitario de Salamanca
    Instituto de Investigación Biomédica de Salamanca
    Centro de Investigación en Enfermedades Tropicales
    Universidad de Salamanca
    Salamanca, Spain

  • Begoña Febrer Sendra, BSc, PhD Student

    Grupo Enfermedades Infecciosas y Tropicales
    Instituto de Investigación Biomédica de Salamanca
    Centro de Investigación en Enfermedades Tropicales
    Facultad de Farmacia
    Universidad de Salamanca
    Salamanca, Spain

  • Amparo López-Bernus, MD, PhD

    Servicio de Medicina Interna
    Unidad de Infecciosas
    Hospital Universitario de Salamanca
    Instituto de Investigación Biomédica de Salamanca
    Centro de Investigación en Enfermedades Tropicales
    Universidad de Salamanca
    Salamanca, Spain

  • Alberto Bahamonde, MD, PhD

    Servicio de Medicina Interna
    Hospital El Bierzo
    Ponferrada, Spain

  • Alberto Orfao, MD, PhD

    Centro de Investigación del Cancer
    Servicio de Citometría
    Centro de Investigación Biomédica en Red de Cáncer
    Instituto de Investigación Biomédica de Salamanca
    Universidad de Salamanca
    Salamanca, Spain

  • Carmen Viera Lista, BSc, PhD Student

    Grupo Enfermedades Infecciosas y Tropicales
    Instituto de Investigación Biomédica de Salamanca
    Centro de Investigación en Enfermedades Tropicales
    Facultad de Farmacia
    Universidad de Salamanca
    Salamanca, Spain

  • María Sánchez Ledesma, MD, PhD

    Servicio de Medicina Interna
    Unidad de Infecciosas
    Hospital Universitario de Salamanca
    Instituto de Investigación Biomédica de Salamanca
    Centro de Investigación en Enfermedades Tropicales
    Universidad de Salamanca
    Salamanca, Spain

  • Ana Isabel Negredo, PhD

    Arbovirus and Imported Viral Diseases Unit
    Centro Nacional de Microbiología
    Instituto de Salud Carlos III
    Red de Investigación Colaborativa en Enfermedades Tropicales
    Madrid, Spain

  • Beatriz Rodríguez Alonso, MD, PhD

    Servicio de Medicina Interna
    Unidad de Infecciosas
    Hospital Universitario de Salamanca
    Instituto de Investigación Biomédica de Salamanca
    Centro de Investigación en Enfermedades Tropicales
    Universidad de Salamanca
    Salamanca, Spain

  • Beatriz Rey Bua, MD

    Servicio de Haematología
    Hospital Universitario de Salamanca
    Instituto de Investigación Biomédica de Salamanca
    Universidad de Salamanca
    Salamanca, Spain

  • María Paz Sánchez-Seco, PhD

    Arbovirus and Imported Viral Diseases Unit
    Centro Nacional de Microbiología
    Instituto de Salud Carlos III
    Red de Investigación Colaborativa en Enfermedades Tropicales
    Madrid, Spain

  • Juan Luis Muñoz Bellido, MD, PhD

    Servicio de Microbiología y Parasitología
    Hospital Universitario de Salamanca
    Instituto de Investigación Biomédica de Salamanca
    Centro de Investigación en Enfermedades Tropicales
    Departamento de Ciencias Biomédicas y del Diagnóstico
    Universidad de Salamanca
    Salamanca, Spain

  • Antonio Muro, MD, PhD

    Grupo Enfermedades Infecciosas y Tropicales
    Instituto de Investigación Biomédica de Salamanca
    Centro de Investigación en Enfermedades Tropicales
    Universidad de Salamanca
    Salamanca, Spain

  • Moncef Belhassen-García, MD, PhD

    Servicio de Medicina Interna
    Unidad de Infecciosas
    Hospital Universitario de Salamanca
    Instituto de Investigación Biomédica de Salamanca
    Centro de Investigación en Enfermedades Tropicales
    Grupo Enfermedades Infecciosas y Tropicales
    Universidad de Salamanca
    Salamanca, Spain

CME Author

  • Charles P. Vega, MD

    Health Sciences Clinical Professor of Family Medicine
    University of California, Irvine School of Medicine

    Disclosures

    Charles P. Vega, MD, has the following relevant financial relationships:
    Consultant or advisor for: GlaxoSmithKline; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Editor

  • Dana C. Dolan, BS

    Copyeditor 
    Emerging Infectious Diseases

Compliance Reviewer

  • Amanda Jett, PharmD, BCACP

    Associate Director, Accreditation and Compliance, Medscape, LLC

    Disclosures

    Amanda Jett, PharmD, BCACP, has no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has no relevant financial relationships.


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Interprofessional Continuing Education

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    For Physicians

  • Medscape, LLC designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

    Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1.0 MOC points in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.

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CME / ABIM MOC

Crimean-Congo Hemorrhagic Fever, Spain, 2013–2021: Discussion

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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.