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Characteristic Value
Sex  
F 51 (52.0, 41.7–62.2)
M 47 (48.0, 37.8–58.3)
Median age, y (IQR) 51 (37–60.75)
Underlying illnesses 38 (38.8, 29.1–49.2)
History of tick bite† 86 (88.7, 80.6–94.2)
Median incubation period, d (IQR)‡ 6 (4–9.75)
Median duration of illness before first evaluation, d (IQR) 5 (4–6)
Clinical manifestation  
Body temperature >37.5°C 95 (96.9, 91.3–99.4)
Median body temperature, °C (IQR)§ 38.3 (37.8–38.9)
Chills 19 (19.4, 12.1–28.6)
Headache 84 (85.7, 77.2–92.0)
Myalgia 53 (54.1, 43.7–64.2)
Arthralgia 42 (42.9, 32.9–53.3)
Gastrointestinal symptoms 45 (45.9, 35.8–56.3)
Abdominal pain 2 (2.0, 0.3–7.2)
Nausea, vomiting 37 (37.8, 28.2–48.1)
Diarrhea 16 (16.3, 9.6–25.2)
Malaise and fatigue 96 (98.0, 92.8–99.8)
Respiratory symptoms 18 (18.4, 11.3–27.5)
Sore throat 11 (11.2, 5.7–19.2)
Cough 10 (10.2, 5.0–18.0)
Median duration of illness, initial phase, d (IQR)¶ 7 (6–8)
Hospitalization  
No. hospitalized patients 37 (37.8, 28.2–48.1)
Median duration of hospitalization, d (IQR)# 3 (1–5)

Table 1. Demographic and clinical data on adult patients who had febrile illness caused by tick-borne encephalitis virus without central nervous system involvement at the time of evaluation, Slovenia*

*Values are no. (%, 95% CI) except as indicated. IQR, interquartile range.
†Tick bite within 4 weeks before onset of illness. Data available for 97 patients.
‡Time (days) from tick bite to onset of illness calculated only in patients with 1 bite. Data available for 54 patients.
§Highest temperature in the course of the illness.
¶Data available for 82 patients.
#Data available for 33 patients.

 

Laboratory findings Value
Median blood leukocyte count, × 109/L (IQR)† 2.3 (1.8–3.125)
Blood leukocyte count <4 × 109/L 84 (87.5, 79.2–93.4)
Blood leukocyte count >10 × 109/L 0 (0, 0–3.8)
Median blood neutrophil count, × 109/L (IQR)‡ 1.22 (0.9–1.7)
Blood neutrophil count <1.5 × 109/L 55 (65.5, 54.3–75.5)
Blood neutrophil count >7.4 × 109/L 0 (0, 0–4.3)
Median blood lymphocyte count, × 109/L (IQR)‡ 0.88 (0.5–1.1)
Blood lymphocyte count <1.1 × 109/L 61 (72.6, 61.8–81.8)
Blood lymphocyte count >3.5 × 109/L 1 (1.2, 0–6.5)
Median blood monocyte count, × 109/L (IQR)‡ 0.29 (0.2–0.4)
Blood monocyte count <0.21 × 109/L 34 (40.5, 29.9–51.8)
Blood monocyte count >0.92 × 109/L 0 (0, 0–4.3)
Median blood platelet count, × 109/L (IQR)† 132 (110.5–157)
Blood platelet count <140 × 109/L 57 (59.4, 48.9–69.3)
Serum C-reactive protein level >5 mg/L†§ 9 (9.4, 4.4–17.1)
Liver test results, µkat/L (IQR)¶  
Median alkaline phosphatase¶ 0.93 (0.755–1.06)
Elevated >1.92 0 (0, 0–4.6)
Median aspartate aminotransferase# 0.615 (0.4575–0.8325)
Elevated >0.58 44 (55.0, 43.5–66.2)
Median alanine aminotransferase# 0.53 (0.37–0.805)
Elevated >0.77 21 (26.3, 17.0–37.3)
Median gamma-glutamyl transferase¶ 0.37 (0.265–0.595)
Elevated >0.92 9 (11.4, 5.3–20.5)
Median lactate dehydrogenase** 3.48 (2.92–4.82)
Elevated >4.13 12 (36.4, 20.4–54.9)
No. patients with >1 abnormal function test result†† 50 (62.5, 51.0–73.1)

Table 2. Laboratory data on adult patients who had febrile illness caused by tick-borne encephalitis virus without central nervous system involvement at the time of evaluation, Slovenia*

*Values are no. (%, 95% CI) unless otherwise noted. IQR, interquartile range.
†Data available for 96 patients.
‡Data available for 84 patients.
§Median 7, range 6–45.
¶Data available for 79 patients.
#Data available for 80 patients.
**Data available for 33 patients.
††Data available for 80 patients.

 

Characteristic Febrile illness followed by CNS involvement, n = 52 Febrile illness with possible later CNS involvement, n = 4 Febrile illness without later CNS involvement, n = 6
Sex      
F 26 (50.0, 35.8–64.2) 2 (50.0, 6.8–93.2) 3 (50.0, 11.8–88.2)
M 26 (50.0, 35.8–64.2) 2 (50.0, 6.8–93.2) 3 (50.0, 11.8–88.2)
Median age, y (IQR) 50 (40.75–62) 52 (51.75–55) 45.5 (34.5–55)
Underlying illnesses 22 (42.3, 28.7–56.8) 0 (0, 0–60.2) 3 (50.0, 11.8–88.2)
History of tick bite† 45/51 (88.2, 76.1–95.6) 3/4 (75.0, 19.4–99.4) 5/6 (83.3, 35.9–99.6)
Median incubation period, d (IQR)‡ 6 (4.5–9.5)§ 9 (9–9)¶ 6.5 (3–11)#
Median duration of illness before first evaluation, d (IQR) 5 (3.75–7) 5.5 (5–6.25) 5 (4.25–6.5)
Clinical manifestation      
Body temperature >37.5°C 51/52 (98.1, 89.7–100) 3/4 (75.0, 19.4–99.4) 6 (100, 54.1–100)
Median body temperature, °C (IQR)** 38.5 (38–39) 38.3 (38.05–38.45) 39 (38.625–39)
Chills 10 (19.2, 9.6–32.5) 1 (25.0, 0.6–80.7) 1 (16.7, 0.4–64.1)
Headache 47 (90.4, 79.0–96.8) 2 (50.0, 6.8–93.2) 6 (100, 54.1–100)
Myalgias 27 (51.9, 37.6–66.0) 3 (75.0, 19.4–99.4) 3 (50.0, 11.8–88.2)
Arthralgias 22 (42.3, 28.7–56.8) 3 (75.0, 19.4–99.4) 2 (33.3, 4.3–77.7)
Gastrointestinal symptoms 24 (46.2, 32.2–60.5) 2 (50.0, 6.8–93.2) 3 (50.0, 11.8–88.2)
Abdominal pain 1 (1.9, 0.1–10.3) 1 (25.0, 0.6–80.7) 0 (0, 0–45.9)
Nausea, vomiting 22 (42.3, 28.7–56.8) 2 (25.0, 0.6–80.7) 2 (33.3, 4.3–77.7)
Diarrhea 6 (11.5, 4.4–23.4) 2 (50.0, 6.8–93.2) 1 (16.7, 0.4–64.1)
Malaise or fatigue 52 (100, 93.2–100) 4 (100, 39.8–100) 5 (83.3, 35.9–99.6)
Respiratory symptoms 7 (13.4, 5.6–25.8) 0 (0, 0–60.2) 1 (16.7, 0.4–64.1)
Sore throat 7 (13.4, 5.6–25.8) 0 (0, 0–60.2) 1 (16.7, 0.4–64.1)
Cough 1 (1.9, 0.1–10.3) 0 (0, 0–60.2) 0 (0, 0–45.9)
Median duration of illness, d (IQR) 7 (6–8)†† 8 (7–9)‡‡ 9 (7.5–9.75)
Hospitalization      
No. hospitalized patients 20 (38.5, 25.3–53.0) 2 (50.0, 6.8–93.2) 3 (50.0, 11.8–88.2)
Median duration, d (IQR) 4 (1–6)§§ 4.5 (3.75–5.25) 4 (2.5–5)
Laboratory findings      
Median blood leukocyte count, × 109/L (IQR) 2.2 (1.8–2.85)¶¶ 1.7 (1.675–1.95) 2.95 (2.5–4.15)
Blood leukocyte count <4 × 109/L 50 (100, 92.9–100) 4 (100, 39.8–100) 4 (66.7, 22.3–95.7)
Blood leukocyte count >10 × 109/L 0 (0, 0–7.1) 0 (0, 0–60.2) 0 (0, 0–45.9)
Median blood platelet count, × 109/L (IQR) 125.5 (108.25–152.75)¶¶ 110 (86–134.25) 139 (118.5–162.5)
Blood platelet count <140 × 109/L 34 (68.0, 53.3–80.5) 3 (75.0, 19.4–99.4) 3 (50.0, 11.8–88.2)
Serum C-reactive protein elevated, >5 mg/L 3/50 (6.0, 1.3–16.6)## 0 (0, 0–60.2) 1 (16.7, 0.4–64.1)***
Liver tests, µkat/L (IQR)      
Median aspartate aminotransferase 0.605 (0.4575–0.84)††† 1.05 (0.59–3.55) 0.62 (0.5075–0.845)
Elevated >0.58 26 (54.2, 39.2–68.6) 3 (75.0, 19.4–99.4) 4 (66.7, 22.3–95.7)
Median alanine aminotransferase 0.535 (0.4–0.82)††† 1.285 (0.48–3.5225) 0.56 (0.3475–0.78)
Elevated >0.77 µkat/L 13 (27.1, 15.3–41.9) 2 (50.0, 6.8–93.2) 2 (33.3, 4.3–77.7)
No. patients with >1 abnormal liver test result 29/48 (60.4, 45.3–74.2) 3 (75.0, 19.4–99.4) 4 (66.7, 22.3–95.7)

Table 3. Basic demographic, clinical, and laboratory characteristics of febrile illness caused by tick-borne encephalitis virus infection with or without subsequent central nervous system involvement*


*Values are no. (%, 95% CI) except as indicated. CNS, central nervous system; IQR, interquartile range.
†Tick bite within 4 weeks before onset of illness.
‡Time (d) from tick bite to onset of illness calculated only in patients with 1 bite.
§Data available for 27 patients.
¶Data available for 1 patient.
#Data available for 4 patients.
**The highest temperature in the course of the illness.
††Data available for 45 patients.
‡‡Data available for 2 patients.
§§Data available for 17 patients.
¶¶Data available for 50 patients.
##Median 6, range 6–9.
***Value 45.
†††Data available for 48 patients.

CME / ABIM MOC

Clinical and Laboratory Characteristics and Outcome of Illness Caused by Tick-Borne Encephalitis Virus Without Central Nervous System Involvement

  • Authors: Petra Bogovič, MD, PhD; Andrej Kastrin, PhD; Stanka Lotrič-Furlan, MD, PhD; Katarina Ogrinc, MD, PhD; Tatjana Avšič Županc, PhD; Miša Korva, PhD; Nataša Knap, PhD; Franc Strle, MD, PhD
  • CME / ABIM MOC Released: 1/21/2022
  • Valid for credit through: 1/21/2023
Start Activity

  • 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, neurologists, and other physicians who treat and manage patients at risk for tick-borne encephalitis virus.

The goal of this activity is to describe clinical findings in cases of tick-borne encephalitis virus.

Upon completion of this activity, participants will:

  • Distinguish the typical disease course of tick-borne encephalitis virus
  • Assess clinical characteristics of patients with tick-borne encephalitis virus
  • Analyze trends in laboratory values among patients with tick-borne encephalitis virus
  • Identify the rate of central nervous system involvement in the current case series of tick-borne encephalitis virus


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 according to Medscape policies. Others involved in the planning of this activity have no relevant financial relationships.


Faculty

  • Petra Bogovič, MD, PhD

    University Medical Center Ljubljana, Ljubljana, Slovenia

  • Andrej Kastrin, PhD

    Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

  • Stanka Lotrič-Furlan, MD, PhD

    University Medical Center Ljubljana, Ljubljana, Slovenia

  • Katarina Ogrinc, MD, PhD

    University Medical Center Ljubljana, Ljubljana, Slovenia

  • Tatjana Avšič Županc, PhD

    Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

  • Miša Korva, PhD

    Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

  • Nataša Knap, PhD

    Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

  • Franc Strle, MD, PhD

    University Medical Center Ljubljana, Ljubljana, Slovenia

CME Author

  • Charles P. Vega, MD

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

    Disclosures

    Disclosure: Charles P. Vega, MD, has disclosed the following relevant financial relationships:
    Served as an advisor or consultant for: Johnson & Johnson

Editor

  • Jill Russell, BA

    Copyeditor 
    Emerging Infectious Diseases 

    Disclosures

    Disclosure: Jill Russell, BA, has disclosed no relevant financial relationships.

CME Reviewer

  • Leigh A. Schmidt, MSN, RN, CMSRN, CNE, CHCP

    Associate Director, Accreditation and Compliance
    Medscape, LLC

    Disclosures

    Disclosure: Leigh A. Schmidt, MSN, RN, CMSRN, CNE, CHCP, has disclosed no relevant financial relationships.


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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

Clinical and Laboratory Characteristics and Outcome of Illness Caused by Tick-Borne Encephalitis Virus Without Central Nervous System Involvement

Authors: Petra Bogovič, MD, PhD; Andrej Kastrin, PhD; Stanka Lotrič-Furlan, MD, PhD; Katarina Ogrinc, MD, PhD; Tatjana Avšič Županc, PhD; Miša Korva, PhD; Nataša Knap, PhD; Franc Strle, MD, PhDFaculty and Disclosures

CME / ABIM MOC Released: 1/21/2022

Valid for credit through: 1/21/2023

processing....

Abstract and Introduction

Information on febrile illness caused by tick-borne encephalitis virus (TBEV) without central nervous system involvement is limited. We characterized 98 patients who had TBEV RNA in their blood but no central nervous system involvement at the time of evaluation. Median duration of illness was 7 days; 37 (38%) patients were hospitalized. The most frequent findings were malaise or fatigue (98%), fever (97%), headache (86%), and myalgias (54%); common laboratory findings were leukopenia (88%), thrombocytopenia (59%), and abnormal liver test results (63%). During the illness, blood leukocyte counts tended to improve, whereas thrombocytopenia and liver enzymes tended to deteriorate. At the time of positive PCR findings, 0/98 patients had serum IgG TBEV and 7 serum IgM TBEV; all patients later seroconverted. Viral RNA load was higher in patients with more severe illness but did not differ substantially in relation to several other factors. Illness progressed to tick-borne encephalitis in 84% of patients within 18 days after defervescence.

Introduction

Tick-borne encephalitis virus (TBEV) is a member of the genus Flavivirus in the family Flaviviridae and is transmitted to humans predominantly through Ixodes spp. tick bites. In addition to 3 well-known subtypes of TBEV (European, Siberian, and Far Eastern) that cause disease in humans, other subtypes, including the currently named Baikalian and Himalayan subtypes, have been reported [1,2].

Infection with TBEV can be symptomatic or asymptomatic. As is the case for infections with other flaviviruses, most (70%–98%) persons infected with TBEV do not experience symptoms; however, some findings in blood donors suggest that asymptomatic infections might be rare [3]. Nevertheless, when infection with TBEV is symptomatic, it can manifest as a febrile illness without central nervous system (CNS) involvement (Figure 1, panel A) but often progresses to tick-borne encephalitis (TBE) (i.e., CNS involvement caused by the virus) (Figure 1, panel B). Clinical manifestation differs in some respects according to virus subtype. In 13%–44% of patients, TBE caused by the European subtype manifests with direct CNS involvement [4,15] (Figure 1, panel C), whereas in most patients, CNS inflammation is preceded by a febrile illness, resulting in a biphasic course (Figure 1, panel B). The initial phase, which corresponds to viremia, manifests as fever, fatigue, malaise, headache, and muscle and joint pain, but in the absence of CNS inflammation; this phase usually lasts <1 week [8], and the illness then improves over a few days. The hallmark of the second phase of the disease is CNS involvement. Meningitis is the predominant manifestation in children. In adults, meningitis occurs in ≈50% of patients, meningoencephalitis in ≈40%, and meningoencephalomyelitis in ≈5%–10%. The case-fatality rate of TBE caused by the European subtype of TBEV is 0.5%–2%. In addition, ≈5% of adult patients are affected by permanent pareses, and at least one third suffer from a postencephalitic syndrome [16,19].

Enlarge

Figure 1. Timelines of clinical manifestations of illness caused by TBEV. A) Febrile headache (fever form); B) biphasic course of TBE; C) monophasic course of TBE. CNS, central nervous system; TBE, tick-borne encephalitis; TBEV, tick-borne encephalitis virus.

In general, clinical manifestations and laboratory characteristics of symptomatic TBEV infection are well described. However, this statement is valid for cases with neurologic involvement (i.e., for TBE) but less so for the initial phase of TBE, and much less so for TBEV infection manifesting solely as febrile illness without later CNS involvement. That manifestation, also called isolated initial phase of TBE, abortive form of TBE, febrile headache, summer flu, or fever form, is postulated to match clinically and serologically the initial phase of TBE, with the exception that subsequent CNS involvement does not occur. TBEV infection manifesting as febrile illness without later CNS involvement is suggested to be frequent [20,23], although not in all reports [5,6,24,25], and the scientific basis for such a conclusion is unclear. Furthermore, although the outcome of symptomatic TBEV infection without CNS involvement is believed to be favorable, no reliable data on the outcome have been published. Because clinical symptoms and signs of the illness are nonspecific, and because, in parallel to the initial phase of TBE, serum antibodies to TBEV are not yet expected to have developed, the only option for diagnosis at the time of actual illness is demonstrating the presence of TBEV RNA in the blood. However, this approach is not routine and might have a low diagnostic yield owing to several other known or unknown causes of fever, even in a region that is highly endemic for TBE. Therefore, the possibility that a febrile illness is the result of TBEV infection is usually tested for and established only after signs or symptoms of CNS involvement appear, which does not happen in case of the fever form. In that case (and if PCR detection of viral RNA in blood is not available), further clinical and microbiologic (serologic) follow-up after improvement is needed to establish the diagnosis. In this study, we analyzed in detail the clinical and laboratory characteristics of febrile illness after tick bite or exposure to ticks and its outcome in patients in whom infection with TBEV was established by the presence of viral RNA in the blood.