Tuesday, May 30, 2023
| 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.
| 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.
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We extracted data for patients 1, 2, 3, 4, and 8 from published papers[10–13]. In turn, we conducted retrospective analysis on the medical records of all other patients with CCHF identified from Hospital Universitario de Salamanca and Hospital del Bierzo; we recorded demographic patient data, case history, symptoms, clinical signs, laboratory results, and outcomes for each patient (Table 1). Patient median age was 56.5 years (range 30–74 years); 7 were men and 3 women. Six patients had been infected in urban areas. The distribution of cases during the year was as follows: 1 case in April, 1 in May, 2 in June, 2 in July, and 4 in August (Figure 1).
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EnlargeFigure 1. Locations of CCHF cases (A) and phylogenetic tree of CCHFV (B) in Spain, 2013–2021. Dots on the map indicate patients with a CCHF diagnosis in Spain: black dots indicate cases from this study, and colored dots indicate cases previously described. Two cases (patients 8 and 10) were not sequenced. The phylogenetic tree was constructed by the neighbor-joining method based on sequences of the small segment of the virus. The numbers on the right indicate bootstrap values for the groups; values <75 are not shown. Other sequences are listed by GenBank accession number, strain, geographic origin, and sampling year. Genotypes are indicated by Roman numerals according to Carroll et al.[14] with the equivalent clade nomenclature according to Chamberlain et al.[15] in brackets; I, West Africa (Africa 1); III, South and West Africa (Africa 3); IV, Middle East/Asia, divided into 2 groups (Asia 1/Asia 2); V, Europe/Turkey (Europe 1); VI, Greece (Europe 2). New lineage, Africa 4 described by Negredo et al.[12]. CCHF, Crimean-Congo hemorrhagic fever; CCHFV, CCHF virus.
Eight of the 10 patients reported tick bites (Table 2). The mean +SD time from the bite to the onset of symptoms was 5.1 + 3.4 days (range 2–12 days). The median duration between the onset of symptoms and hospital admission was 5.1 + 3.1 days (range 2–12 days). All case-patients had sought care for fever and exanthema with a mean duration of 5.2 + 1.64 days (Figure 2). Eight patients had muscle soreness; 4 patients had diarrhea, and 4 had vomiting, nausea, or both. Three case-patients (5, 6, and 9) underwent bone marrow biopsy; 2 of them, patients 5 and 9, had hemophagocytosis, which fulfilled the criteria for hemophagocytic syndrome (Figure 3). Ferritin serum level was elevated in 7 patients.
;)
EnlargeFigure 2. Images of patients in study of Crimean-Congo hemorrhagic fever, Spain, 2013–2021. A) Details of a slightly purpuric rash on the leg of patient 8. B) Ecchymosis on the arm of patient 5. C) Mild rash on the chest of patient 9.
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EnlargeFigure 3. Bone marrow biopsy findings from patient 5 (A) and patient 9 (B) in study of Crimean-Congo hemorrhagic fever, Spain, 2013–2021. Arrows indicate macrophages with hemophagocytosis phenomena of red blood cells and platelets.
All patients received antimicrobial treatment with doxycycline while hospitalized. In addition, 5 patients received supportive treatment, 4 patients had taken treatment for bleeding, and 3 patients received ribavirin. None of those receiving antiviral treatment died; however, the sample size was small.
The mean +SD score on the Bakir prognostic scale[16] was 5.0 + 2.3. Seven patients survived with full recovery, whereas the other 3 died. Those 3 patients who died had the highest scores on the Bakir scale (1 patient scored 8 and the other 2 scored 7).
In most cases (patients 1, 2, 5, 6, and 7), disease was caused by CCHFV genotype III (Africa 3). Patient 3 had a new lineage, Africa 4 (Figure 1) within genotype IV. Isolates from patients 4 and 9 belonged to genotype V (Europe 1). We did not identify the genotype for patients 8 and 10. Of note, genotypes III and V were found to circulate in the same geographic area. We deposited the sequences into GenBank under accession nos. KY492290 (patient 1), KY492289 (patient 2), MN689739 (patient 3), ON227355 (patient 4), OP776634 (patient 5), OP776632 (patient 6), OP776631 (patient 7), and OP776633 (patient 9).
