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Year : 2022  |  Volume : 59  |  Issue : 3  |  Page : 298-301

A case of Mediterranean spotted fever mimicking severe sepsis

1 Istanbul Medeniyet University, Göztepe Prof. Dr. Süleyman Yalçin City Hospital, İnternal Medicine, Istanbul, Turkey
2 Istanbul Medeniyet University, Göztepe Prof. Dr. Süleyman Yalçin Şehir Hastanesi, Clinical Microbiology and infection Diseases, Istanbul, Turkey

Date of Submission12-Feb-2022
Date of Acceptance31-Aug-2022
Date of Web Publication08-Dec-2022

Correspondence Address:
Erhan Eken
Medeniyet University Medical Faculty Göztepe Prof. Dr. Süleyman Yalçin City Hospital Depart ment of Internal Medicine-34000, İstanbul
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0972-9062.355965

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Mediterranean spotted fever (MSF) is a tick-borne acute endemic infectious disease caused by Rickettsia conorii. While MSF may progress asymptomatically, it may lead to clinical pictures like severe hemorrhagic fever. In this article, we are presenting an MSF case with signs of high fever, headache, nausea, weakness and generalized maculopapular rash. The diagnosis of the female patient who had a history of contact with a tick-infested dog was confirmed with her clinical and laboratory data. The clinical and laboratory findings of the patient who was given doxycycline by 200 mg/day for 7 days were improved in a short time. Rickettsia conorii serology by indirect immunofluorescence assay method confirmed the diagnosis of MSF. In cases of severe sepsis accompanied by high fever and generalized maculopapular rash where the source of the infection cannot be determined in the short term, carefully questioning exposure to ticks by considering the existing geographical, seasonal and endemic environmental factors may be life-saving in terms of early diagnosis and treatment of MSF, which may become fatal even in the absence of eschars (tache noire). The symptomatology of hemorrhagic fever associated with Rickettsia conorii may be confused with that of sepsis in clinical practice.

Keywords: Mediterranean spotted fever; severe sepsis; tick-borne diseases

How to cite this article:
Uzunlulu M, Eken E, Gönenç &, Kaya S, Selvi E, Arslan F. A case of Mediterranean spotted fever mimicking severe sepsis. J Vector Borne Dis 2022;59:298-301

How to cite this URL:
Uzunlulu M, Eken E, Gönenç &, Kaya S, Selvi E, Arslan F. A case of Mediterranean spotted fever mimicking severe sepsis. J Vector Borne Dis [serial online] 2022 [cited 2023 Feb 2];59:298-301. Available from: http://www.jvbd.org//text.asp?2022/59/3/298/355965

  Introduction Top

Mediterranean spotted fever (MSF), a tick-borne acute endemic infectious disease that is seen in the summer especially in the Mediterranean region including Turkey, is caused by Rickettsia conorii carried by Rhipicephalus sanguineus, known as brown dog tick[1],[2]. It is typically characterized by high fever, headache, maculopapular rash, myalgia, diarrhea, vomiting, and though not in every case, the formation of an eschar (tache noire) at the location of a tick bite[3]. The diagnosis of MSF depends on epidemiological, clinical and laboratory criteria. The immunofluorescence assay (IFA) method is the reference serological method recommended for detecting IgM and IgG antibodies that have formed against Rickettsia species in acute and convalescent phase serum samples[4]. The gold standard antibiotic agent in the treatment of MSF is doxycycline[5]. Although MSF is commonly considered a benign disease, it has been reported that it may lead to life-threatening clinical manifestations such as sepsis, shock and multiorgan failure[6],[7],[8]. Delay in diagnosis and failure to provide the right antibiotic treatment increase the risk of mortality in these cases. In this study, we report a 49-year-old female patient who was hospitalized with the symptomatology of severe sepsis, had a history of coming in contact with a tick-infested dog, and whose diagnosis of MSF was made based on clinical and laboratory findings. Our objective in presenting this case is to emphasize that the clinical picture in severe MSF cases may be confused with the clinical picture of sepsis.

Case report

In May 2021, a 49-year-old female patient with known essential thrombocythemia (followed up without medication), hypertension (using candesartan 16 mg/day) and type 2 diabetes (using metformin 2 g/day) presented to the emergency department with fever lasting 10 days accompanied by chills, intermittent headache, nausea, weakness and generalized myalgia. The patient’s physical examination in the emergency room revealed a fever of 39.3°C, hypotension (88/55 mmHg), tachycardia (125 beats/min), maculopapular rash on the torso, limbs, palm and foot [Figure 1] & [Figure 2]. Her consciousness status indicated a tendency to sleep, and her Glasgow Coma Scale score was 14. Laboratory tests revealed an elevated C-reactive protein level (215.11 mg/L, normal value: <5 mg/L), an increased blood lactate level at 1.5 mmol/L, an increased erythrocyte sedimentation rate at 70 mm/h, an increased procalcitonin level (1.58 ng/mL, normal value: <0.5ng/mL), mildanemia, hyponatremia (sodium level: 125mmol/L), renal dysfunction (creatinine: 1.61 mg/dL) and abnormal liver biochemical tests (alanine aminotransferase: 178 IU/L, aspartate aminotransferase: 162 IU/L, alkaline phosphatase: 215 IU/L and gammaglutamyl transpeptidase: 154 IU/L). The coagulation test results of the patient were abnormal (international normalized ratio: 1.42, activated partial thromboplastin time: 41.8 sec). Her chest x-ray, computed brain tomography, brain diffusion magnetic resonance, electrocardiography and echocardiography results were normal. The patient was admitted to the internal medicine clinic with diagnosis of severe sepsis. Sepsis, systemic vasculitis and conditions progressing with hemorrhagic fever (Crimean Congo hemorrhagic fever (CCHF), leptospirosis) were included in the differential diagnosis. The patient was stabilized by fluid resuscitation, a series of blood and urine cultures was taken, and with the specialist recommendation of the infectious disease clinic, antibiotic treatment was started with meropenem by 3x1 g and linezolid by 2x600 mg. In terms of vasculitis, the patient’s antinuclear antibody and extractable nuclear antigen (ENA) profiles were found negative, and a skin biopsy was taken from her maculopapular rash.
Figure 1: Maculopapular rash in the leg of the patients.

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Figure 2: Maculopapular rash all over the body.

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When the history of this patient, whose fever did not go down despite antibiotic treatment for two days, was detailed, it was learned that her home was in a forested area, she had a dog, she had seen ticks on her dog, and she had noticed a tick bite on her abdomen one week before her symptoms started. The patient, for whom the diagnosis of MSF was suspected based on her clinical symptoms, history and laboratory results, was referred to the infectious disease clinic again. The antibiotics she had been receiving were stopped, and doxycycline treatment at the dose of 200 mg/day was started. As a result of two days of treatment with doxycycline, the fever of the patient went down, her vital signs stabilized, her general status improved, her rashes regressed, and her lactate and serum creatinine levels went back to normal in a short time. The other abnormal laboratory results of the patient also improved gradually. There was no reproduction in her blood and urine cultures. CCHF and leptospirosis serological tests were negative. Her skin biopsy result was compatible with leukocytoclastic vasculitis. Her Rickettsia conorii serology by indirect IFA confirmed the diagnosis with the positivity of immunoglobulin G at 1:160 and immunoglobulin M at 1:768. The patient’s Rickettsia conorii IgM ELISA test was also positive. After 7 days of treatment with doxycycline, the patient was discharged with full recovery.

  Discussion Top

Although Mediterranean spotted fever (MSF) is gen-erally considered a benign disease, its severe forms and mortalities have also been reported in the literature. In a large case series where 250 cases diagnosed with MSF between 1989 and 2012 were evaluated, the rates of intensive care admission and mortality were found to be 5% and 3.6%, respectively[9]. Risk factors that have been defined for the severe forms of MSF are old age, immunosuppression, diabetes mellitus, heart failure, respiratory failure, chronic alcoholism, glucose-6-phosphate dehydrogenase deficiency, delay in treatment and inadequate antimicrobial treatment[10]. The predisposing factors in our patient were type 2 diabetes and essential thrombocythemia.

It is suggested that the high rate of mortality associated with sepsis and multiorgan failure in MSF is related to generalized vasculitis accompanying an increase in microvascular capillary permeability caused by the proliferation of Rickettsia in vascular endothelial cells[4]. Moreover, the broad spectrum of the complications of the condition mainly based on the organs that are damaged may be explained by reports on the autopsy series of cases involving mortality showing generalized vascular infection including vascular lesions in the brain (meningoencephalitis), heart, kidneys, lungs, liver, gastrointestinal system, pancreas, spleen and skin[11]. In our case, in addition to multiorgan involvement, the skin biopsy result of the patient that was indicative of leukocytoclastic vasculitis was compatible with the pathogenesis of the disease.

No reliable diagnostic test is available at the early stage of MSF, and its diagnosis is made based on epidemiological, clinical and laboratory data. The European Guidelines for the diagnosis of MSF (ESCMID Study Group on Coxiella, Anaplasma, Rickettsia and Bartonella) recommends a scoring system depending on epidemiological criteria, clinical criteria, non-specific laboratory findings, bacteriological criteria and serological criteria, and accordingly, total scores higher than 25 are accepted as adequate for diagnosis [Table 1][4]. According to this system, in our case, with seasonal conformity, the presence of exposure to a tick bite, the combination of high fever and maculopapular rash, high liver enzyme levels and positive serological results, the score was calculated to be 35. The characteristics of our case that were not compatible with the diagnostic criteria of the European Guidelines were the absence of thrombocytopenia and our failure to show the presence of eschars. While eschar presence is not necessarily seen in all cases, it is a significant physical examination finding for the diagnosis of MSF. The fact that an eschar could not be observed in our case may have been associated with the possibility that the patient removed the eschar tissue with her hands a few days after her exposure to the tick bite. Furthermore, the absence of thrombocytopenia in the patient may be explained by the fact that she had essential thrombocythemia. This is because we think that the presence of relative thrombocytopenia in the patient was confirmed with the fact that her platelet count was 192 10[9] cells per L at the time of admission, while it returned to basal levels (758 10[9] cells per L) after clinical improvements.
Table 1: Diagnostic criteria for Mediterranean spotted fever (MSF) caused by Rickettsia conorii

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The most specific method for the diagnosis of R. conorii infection is to identify the agent in tissue samples by immunostaining or polymerase chain reaction[12]. In addition to this, detecting antibodies formed against R. conorii with the IFA method is the most appropriate laboratory technique for the diagnosis of MSF. It is necessary to take two serum samples seven to ten days apart (considered positive if greater than or equal to 1/128) and test the presence of seroconversion, the presence of IgM or a significant increase of the titer of antibodies to establish the diagnosis[4]. In our case, both the positive result of the Rickettsia conorii IgM ELISA test and the positivity of immunoglobulin G and immunoglobulin M at high titers in the IFA test confirmed the diagnosis of MSF.

In cases suspected of MSF, it is recommended to start doxycycline treatment without waiting for laboratory confirmation. Especially in the case of fatal presentations of MSF including sepsis, septic shock and multiorgan failure, the recommended clinical approach is to quickly and carefully examine the patient as in our case and start the appropriate treatment on time by avoiding unnecessary use of broad-spectrum antimicrobial agents.

  Conclusion Top

MSF may display a highly diverse set of symptoms from a benign form to life-threatening developments. The case we have presented here has revealed the importance of taking a detailed history of the patient and conducting a comprehensive clinical examination. In sepsis cases accompanied by high fever and generalized maculopapular rash and especially when the source of the infection cannot be identified, carefully questioning the patient’s status of exposure to tick bites or their history of visiting regions where Rickettsia species are endemic especially in summer by considering the existing geographical conditions around the patient may be life-saving in terms of early diagnosis and treatment.

Ethical statement

The patient’s informed consent was taken and guidelines for general global ethical procedures was adhered to.

Conflict of interest: None

  References Top

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Kuloglu F, Rolain JM, Akata F, Eroglu C, Celik AD, Parola P. Mediterranean spotted fever in the Trakya region of Turkey. Ticks Tick Borne Dis 2012; 3: 298–304.  Back to cited text no. 2
Raoult D, Roux V Rickettsioses as paradigms of new or emerging infectious diseases. Clin Microbiol Rev 1997; 10: 694–719.  Back to cited text no. 3
Brouqui P, Bacellar F, Baranton G, Birtles RJ, Bjoërsdorff A, Blanco JR, et al. ESCMID Study Group on Coxiella, Anaplasma, Rickettsia and Bartonella; European Network for Surveillance of Tick-Borne Diseases. Guidelines for the diagnosis of tick-borne bacterial diseases in Europe. Clin Microbiol Infect 2004; 10: 1108–1132.  Back to cited text no. 4
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Abdeljelil M, Sakly H, Kooli I, Marrakchi W, Aouam A, Loussaief C, et al. Mediterranean spotted fever as a cause of septic shock. IDCases 2019; 15: e00528.  Back to cited text no. 6
Ghezala HB, Feriani N. Late diagnosis of fatal invasive rickettsial disease in the Intensive Care Unit. Pan Afr Med J 2016; 25: 211.  Back to cited text no. 7
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Crespo P, Seixas D, Marques N, Oliveira J, da Cunha S, MeliçoSilvestre A. Mediterranean spotted fever: case series of 24 years (1989-2012). Springerplus 2015; 4: 272.  Back to cited text no. 9
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Walker DH, Herrero-Herrero JI, Ruiz-Beltrán R, BullónSopelana A, Ramos-Hidalgo A. The pathology of fatal Mediterranean spotted fever. Am J Clin Pathol 1987: 87; 669–672.  Back to cited text no. 11
Torpiano P, Pace D. Clinically-diagnosed Mediterranean Spotted Fever in Malta. Travel Med Infect Dis 2018; 26: 16–24.  Back to cited text no. 12


  [Figure 1], [Figure 2]

  [Table 1]


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