Diagnostic challenges in Ixodes tick-borne Lyme disease presenting with atypical erythema migrans: a clinical case

Background

In Russia, Ixodes tick-borne borreliosis (ITBB) is the most common tick-borne infection. In 2024, the number of ITBB cases in the Russian Federation was 7104, identified in 78 federal subjects. The highest incidence rates were recorded in four federal districts: the Central, Volga, Siberian, and Northwestern Federal Districts. The Central Federal District (CFD) accounts for the majority of ITBB cases — 46.8% — a trend that has been observed since 2018.[^1] In 2024, the highest ITBB rates in the CFD were registered in Moscow (13.91 per 100,000 population), Kostroma Oblast (12.35), Kaluga Oblast (10.07), Oryol Oblast (8.79), Lipetsk Oblast (8.74), and Voronezh Oblast (8.72). In Yaroslavl Oblast, the incidence of Ixodes tick-borne borreliosis decreased compared to the previous year (5.5 per 100,000 population in 2024 vs. 7.94 in 2023).

In the Russian Federation, adults predominate among ITBB cases (90%), with individuals aged 60-69 years most commonly affected, accounting for 23.6% of the age structure, followed by persons aged 50-59 years (17.2%) and 40-49 years (16.1%). In our country, the incidence of tick-borne borreliosis follows a spring-autumn seasonality, starting in March and ending in November, with 85.3% of all ITBB cases registered from June to October. In 2024, cases among the population in the CFD, Northwestern Federal District, Southern Federal District, and Volga Federal District were registered from January to November.

According to laboratory data, the infection rate of Ixodes ticks with Borrelia varies in different regions of Russia from 33.1% to 54%. In the Central Federal District, it ranges from 25.9% to 46.2%.

In Yaroslavl Oblast, ITBB is the leading tick-borne infection and also ranks first among natural-focal zoonoses. The incidence rate in the region in recent years has exceeded the national average by 1.5 times, although in the mid-2000s it was 4-6 times higher. In 2023, 98 cases of tick-borne borreliosis were registered. Laboratory testing of ticks for tick-borne pathogens is widespread in the region. Annually, about 15,000 people seek testing at regional laboratories. Vectors are examined by PCR for Borrelia, tick-borne encephalitis virus, Anaplasma, and Ehrlichia. The infection rate of Ixodes ticks with Borrelia in the region is high, ranging from 31.8% to 34.2% in different years (data from the State Report on the Sanitary and Epidemiological Welfare of the Population of Yaroslavl Oblast in 2023).

In 2023, Russia recorded the highest incidence of tick-borne borreliosis in the last 10 years (6.22 per 100,000 population) and the third highest since the beginning of the century. Many specialists associate the activation of natural disease foci and the emergence of new ones with changing climatic conditions. Due to global warming, the habitats of plants, animals, and vectors (ticks, mosquitoes) are expanding, especially northward and to higher altitudes. Predictions suggest that the expansion of vector habitats will lead to the spread of tick-borne infection nosoareals in a northerly direction [1].

Clinical observation

A 34-year-old female patient was under observation. She consulted an infectious disease specialist at a polyclinic on the 3rd day of illness. From the history, it is known that on August 18, 2024, she noticed a red patch measuring 9 by 4 cm in the left popliteal fossa, which gradually increased in size and became brighter in color (Fig. 1). During the collection of epidemiological history, it was determined that she did not recall any tick bite. She believed it was a bite from an unknown insect. The patient goes jogging in a forest-park area.

Examination by the infectious disease specialist on 21.08.24: body temperature 36.5°C, no catarrhal symptoms, pulse 84 per minute. Local status: in the left popliteal fossa, a hyperemic lesion measuring 14 by 6 cm, i.e., the erythema had increased in size (day 3 of illness). No bite mark or site of insect attachment was found within the lesion.

The infectious disease specialist doubted the diagnosis of tick-borne borreliosis and made a preliminary diagnosis: Local infections of the skin and subcutaneous tissue. Dynamic observation with a follow-up examination in 2 days was recommended.

On the same day, the patient was consulted by a dermatovenereologist. The physician learned that the patient had subjective sensations in the area of redness, such as itching and burning. In the local status, the dermatologist described pink papular rashes in the center of the erythema (Fig. 2). The physician diagnosed Allergic contact dermatitis, acute. Treatment prescribed: Candid cream (beclomethasone + gentamicin + clotrimazole) to apply twice daily for 14 days and levocetirizine 5 mg once daily for 10 days.

Fig. 1. Local erythema migrans	Fig. 2. Increased erythema migrans, appearance of papules

On the 5th day of illness (22.08.24), the patient's body temperature rose to 38°C, accompanied by a sore throat and dry cough. A district therapist was called to the home. Examination revealed mild hyperemia and granularity of the posterior pharyngeal wall mucosa. Vesicular breathing was present in the lungs, no wheezes. Body temperature was 37°C. A preliminary diagnosis was made: COVID-19, virus not identified. Acute pharyngitis. Local infections of the skin and subcutaneous tissue. A nasopharyngeal swab for COVID-19 by PCR was ordered. Pharyngosept and ciprofloxacin 500 mg twice daily were added to the treatment.

23.08.24: Examined by the infectious disease specialist. The patient reported pain, itching, and burning in the area of redness, and pain during movement in the left knee joint. Local changes: the patch had increased in size, reaching 18 by 11 cm in diameter, and took on the characteristic appearance of annular erythema migrans (EM); hyperemia had spread to the lower leg and the lower part of the thigh. Papules and vesicles were visible in the center of the erythema (Fig. 3). Blood tests (complete blood count and comprehensive metabolic panel) were ordered. Treatment: ciprofloxacin was discontinued and doxycycline 100 mg twice daily was started.

24.08.24 (day 7 of illness): The patient was re-examined by the infectious disease specialist. Body temperature was 37.1°C, pain in the erythema area was reduced, and mobility in the knee joint had improved. Local status: the left lower leg was slightly edematous; in the area of the left popliteal fossa extending to the lower leg and lower thigh, annular EM was observed, with bright red hyperemia in the central part (diameter about 20 cm) and a pale peripheral rim, with multiple vesicles in the center (Fig. 4). Due to the absence of a tick bite in the epidemiological history and the appearance of atypical elements within the hyperemic lesion, the infectious disease specialist doubted the diagnosis of tick-borne borreliosis.

Fig. 3. Erythema migrans with papules and vesicles	Fig. 4. Annular erythema migrans

Examined by the infectious disease specialist on 26.08.24. Body temperature 36.8°C, the patient complained of a dry cough, weakness, and reduced pain in the area of redness. Local status: the size of the annular erythema was unchanged, hyperemia was less intense, vesicles and papules were flattening. An ELISA blood test for antibodies to Borrelia (IgM and IgG) was ordered. The C-reactive protein (CRP) level was elevated in the comprehensive metabolic panel (23.6 mg/L). It was recommended to continue the course of doxycycline.

Examination by the infectious disease specialist on 30.08.24 (day 13 of illness). The patient complained of a sore throat, weakness, and slight nasal discharge. PCR of a nasopharyngeal swab from 28.08.24 detected SARS-CoV-2 RNA. ELISA from 01.09.24 revealed IgM class antibodies to Borrelia. Local status: the erythema was the same size, quite bright with a cyanotic hue; papules and vesicles persisted (Fig. 5 and 6).

Fig. 5. Erythema migrans with a cyanotic tint and vesicles	Fig. 6. A view of erythema migrans with a cyanotic tint and vesicles

The infectious disease specialist made the diagnosis: Tick-borne borreliosis, acute course, erythematous form, moderate severity. COVID-19, virus identified (SARS-CoV-2 RNA positive from 28.08.24), mild severity.

It was recommended to continue doxycycline 200 mg daily for a total of 14 days to treat tick-borne borreliosis, and favipiravir was prescribed according to the regimen for the new coronavirus infection.

Against the background of continued doxycycline therapy, the EM decreased in size, acquired a stagnant-cyanotic hue, and small hemorrhagic elements were observed at the periphery (Fig. 7 and 8). Upon active questioning (after treatment), the patient mentioned that she had continued to apply Candid cream to the erythema site concurrently with taking the antibiotic.

Fig. 7. Erythema migrans with hemorrhagic rash	Fig. 8. Erythema migrans with a cyanotic tint and hemorrhages at the periphery

The patient was under our observation for several months. The EM gradually faded; crusts formed at the site of the papulovesicular eruptions (Fig. 9), followed by large-plate scaling and pigmentation (Fig. 10). Subsequently, no further changes remained at the EM site.

Fig. 9. Formation of crusts in the center of erythema migrans and pigmentation	Fig. 10. Scaling and pigmentation at the site of erythema migrans

Discussion

In the presented case, we encountered difficulty in the clinical diagnosis of the erythematous form of tick-borne borreliosis.

The difficulties arose primarily because the patient did not see an attached tick. According to the literature, in the erythematous form of ITBB, about 70% of patients report a tick bite [2, 3, 4]. These patients were present in areas endemic for tick-borne infections during the vector activity season (spring-summer-autumn). In this clinical case, the patient lives in an endemic region (Yaroslavl city) and jogs in park areas during the warm months, i.e., during the period of tick activity. The fact that she did not see the vector may be because it could have detached from the skin or could have been brushed off by clothing. There is evidence that not only female Ixodes ticks, which feed for a long time, are epidemiologically dangerous, but also males capable of multiple brief attachments [2].

The localization of EM, related to the site of tick attachment, must be considered. In adults, ticks most often attach to the lower limbs and trunk, while in children, they attach to the head, neck, and trunk [3]. Consequently, EM is most often found in these anatomical areas.

In the presented case, the disease began with local manifestations, namely the appearance of a patch larger than 5 cm in diameter. Subsequently, the patch increased in size from the center to the periphery (centrifugally), which is characteristic of erythema migrans — a reliable symptom of the disease. The patient experienced itching, burning, and pain in the area of redness, which is also characteristic of the erythematous form of ITBB. There was no general intoxication syndrome at the onset of the disease. According to our observations, normal temperature in the erythematous form is observed in 45% of cases. The subsequent rise in body temperature was likely associated with the concurrent new coronavirus infection. A primary affect — a mark from the tick bite — may be visible in the center of the erythema, but it may also be absent. In this case, it was absent.

The appearance of atypical rashes against the background of EM, as well as the absence of a reported tick bite, complicated timely diagnosis. The literature describes atypical elements within the EM area, such as papules, vesicles, pustules, purpura, and necrosis. They occur rarely — in 4.8% of cases [4, 5]. According to our observations from 2001 to 2008, out of 319 patients with the erythematous form of TB, only 3 patients had papules, vesicles, and hemorrhages in the EM area.

The diagnosis of the erythematous form of tick-borne borreliosis can be made based on clinical and epidemiological data. Laboratory diagnosis of the disease is necessary in cases of non-erythematous forms, atypical erythema migrans (as in this case), and in disseminated and chronic courses of ITBB [6].

The difficulty of laboratory diagnosis in the acute course of the disease is due to the fact that even in the presence of EM, laboratory confirmation of the diagnosis is observed in only 50-80% of patients [2, 3]. This is associated with the delayed production of IgM and IgG in borreliosis. IgM appears on average 1-1.5 months after infection, and IgG after 2-3 months [2, 7]. According to data from Sayfullin R.F., IgM and/or IgG were detected in only 76% of cases at 4-6 weeks after a tick bite, and starting from the 7th week — in 93%. Seronegativity in patients during the acute period should be regarded as a false-negative result, as IgM and IgG have not yet had time to form. In this case, laboratory testing was not performed immediately, but 12 days after the onset of the disease (infection occurred even earlier, but since the patient did not see the tick, the incubation period and, consequently, the duration of infection cannot be determined). The serological test (ELISA) detected IgM antibodies to Borrelia, which definitively confirmed the diagnosis.

For the treatment of the erythematous form of ITBB, antibiotics that accumulate in the skin and also act on intracellular forms of bacteria, characteristic of Borrelia, are preferred. The drug of choice for treating acute borreliosis in adults is doxycycline [2, 6, 8]. In this case, from the 3rd day of observation, the infectious disease specialist prescribed treatment with doxycycline, presumably suspecting ITBB. However, while taking this drug, the erythema continued to enlarge, became brighter, acquired a cyanotic hue, and vesicles persisted and increased. This may have been because the patient continued to apply a cream containing glucocorticosteroids to the hyperemic area. She also reported sun exposure. The infrequent side effect of doxycycline, namely photosensitization, should be mentioned here. Possibly, the influence of these factors affected the intensity of the erythema's color, the appearance and increase of vesicles and papules, and the presence of hemorrhagic elements at the periphery.

The effectiveness of a standard course of antibiotic therapy (14 days) for ITBB is high. Local treatment using creams and ointments for the erythematous form is not recommended. If the EM was homogeneous, during antibiotic therapy it often takes on an annular character and gradually fades. Slight scaling may sometimes be observed at the site of hyperemia; it is most often seen in annular EM, while homogeneous EM usually resolves without a trace [5]. In some patients, pigmentation may be observed, which subsequently disappears. In the clinical case presented, the patient simultaneously experienced large-plate scaling and pigmentation at the EM site, which later disappeared without a trace.

It is noteworthy that this case involved a combination of two infections — tick-borne borreliosis and new coronavirus infection.

Conclusion

Thus, tick-borne borreliosis should be clinically suspected upon finding a patch at least 5 cm in diameter that enlarges from the center to the periphery. EM may be homogeneous, i.e., uniformly colored, or annular. A primary affect — a mark from the tick bite — may be visible in the center of the erythema, but it may also be absent. Patients may experience subjective sensations in the area of erythema, such as itching, pain, and burning. In rare cases, atypical elements may be present against the background of EM, such as papules, vesicles, pustules, and hemorrhages. General intoxication syndrome is not observed in all patients with the erythematous form of ITBB. Attention should be paid to the localization of EM: in adults, it is more often on the skin of the trunk and lower limbs; in children, on the skin of the head, neck, and trunk.

It should be remembered that even in the absence of a reported tick bite, a diagnosis of tick-borne borreliosis cannot be excluded. It is necessary to consider the patient's stay in a region endemic for tick-borne infections, namely walks in forest-park areas, visits to suburban areas, and recreational camps, and to take into account the seasonality of the disease associated with the period of tick activity.