Tularemia Epidemic in Northwestern Spain: Clinical Description and Therapeutic Response

BRIEF REPORT Tularemia Epidemic in Northwestern Spain: Clinical Description and Therapeutic Response José Luis Pérez-Castrillón, Pablo Bachiller-Luque, Miguel Martı́n-Luquero, Francisco Javier Mena-Martı́n, and Vicente Herreros Department of Internal Medicine, Rio Hortega Hospital, University of Valladolid, Valladolid, Spain Tularemia is a zoonosis caused by Francisella tularensis, a small gram-negative coccobacillus that is highly infective. The principal vectors are ticks and wild rabbits, and the natural hosts are lagomorphs and other rodents. The 2 principal biogroups are Francisella tularensis biovar tularensis (type A) and Francisella tularensis biovar palaearctica (type B) [1]. Here, the clinical characteristics of 142 patients from the area of Tierra de Campos (Valladolid, northwestern Spain) diagnosed with tularemia between December 1997 and February 1998 are described. Special reference is made to the therapeutic response and to the use of ciprofloxacin in the treatment of the illness. Patients and methods. In total, 142 patients diagnosed with tularemia were studied in the Department of Internal Medicine of the Rio Hortega Hospital (Valladolid, Spain). By use of a clinical history protocol, the following data were collected for all patients: symptoms; physical signs; and results of laboratory tests, including IgG serology for F. tularensis. Samples of exudates and lymph node aspirations (n p 25) were sent for culture in Bcye media (Oxoid) for Legionella, in a BacTReceived 11 September 2000; revised 28 December 2000; electronically published 6 July 2001. Reprints or correspondence: Dr. José Luis Pérez-Castrillón, Departamento de Medicina Interna, Hospital Universitario Rio Hortega, Cardenal Torquemada s/n, 47010 Valladolid, Spain (). Clinical Infectious Diseases 2001; 33:573–6  2001 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2001/3304-0024$03.00 BRIEF REPORTS • CID 2001:33 (15 August) • 573 This study describes the clinical characteristics of tularemia in Spain’s first epidemic outbreak and the therapeutic response and compares the efficacy of 3 antibiotics (streptomycin, ciprofloxacin, and doxycycline). For 142 cases of tularemia, the therapeutic failure rate was 22.5%; ciprofloxacin was the antibiotic with the lowest percentage of therapeutic failures and with the fewest side effects. Alert blood culture bottle (Organon Teknika), and on cystine enriched chocolate agar. Direct immunofluorescence was performed on 20 aspirates. The diagnosis of tularemia was considered positive when the patient had an F. tularensis antibody titer of IgG ⭓1:160 or when the patient had seroconversion or F. tularensis was isolated from a clinical sample. Six clinical forms of disease were defined: ulceroglandular, glandular, typhoidal, oculoglandular, pharyngeal, and pneumonic. The patients were treated with intramuscularly administered streptomycin at a dosage of either 1 g every 24 h or 500 mg every 12 h for 7–10 days. For patients who refused parenteral treatment or for whom aminoglycosides were contraindicated, doxycycline (100 mg orally every 12 h for 2 weeks) or ciprofloxacin (750 mg orally every 12 h for 14–28 days) was administered. The therapeutic response could not be assessed for 6 patients. Therapeutic failure was defined by the presence of 1 of the following findings: persistence or recurrence of fever, increase in the size or appearance of new lymphadenopathies, and persistence of the constitutional syndrome with elevation of the levels of the proteins associated with the acute phase of infection [2]. The therapeutic option used in cases of treatment failure was ciprofloxacin at the above-described dose or streptomycin, if it had not been used previously. We used the Kolmogorov-Smirnov test to compare normality of the variables. The x2 test and Fisher exact test were used for variables with a normal distribution, and the Kruskal-Wallis test and the Mann-Whitney U test were used for variables that did not fit this distribution. Results. A total of 142 patients was included in the study. The mean age (SD) of the patients was 52  14 years (range, 14–82 years). There were more females than males (89 vs. 53, respectively). A total of 138 patients (97.2%) had previous contact with hares, 119 (83.8%) had prepared hare carcasses, and 19 (13.3%) had handled hare meat. For 4 patients (2.8%), animal contact could not be confirmed. The number of hunters affected was 16 (11.3%), all of whom were male. Tularemia was diagnosed on the basis of the following findings: culture of F. tularensis biovar palaearctica for 3 patients (2.1% of the patients and 12% of the cultures performed); seroconversion for 19 patients (13.4%); and a compatible clinical picture associated with an elevated F. tularensis antibody titer for 120 patients (84.5%). Direct immunofluorescence of aspirates had results positive for F. tularensis for 7 of the 20 patients for whom this test was carried out (35%); all these patients had high titers of positive antibodies to F. tularensis. The mean delay (SD) Table 1. Clinical manifestations in patients with tularemia during an outbreak in Spain (n p 142). Symptoms or signs No. (%) of patients Symptoms Asthenia 73 (51.4) Weight loss 55 (38.7) Myalgia 36 (25.4) Cough 34 (24) Odynophagia 24 (16.9) Nausea or vomiting 22 (15.5) Arthralgia 21 (14.8) Headache 14 (9.9) Chills 12 (8.5) Dyspnea 5 (3.6) Diarrhea 3 (2.1) Signs Lymphadenopathy 129 (90.8) 99 (69.7) Cutaneous ulcer 87 (61.4) Other cutaneous lesions 25 (17.6) Oral ulcer 23 (16.2) Conjunctivitis 9 (6.3) between the onset of symptoms and diagnosis was 47.5  31 days (range, 3–145 days). The symptoms and signs of the patients are presented in table 1. The most frequent symptoms were asthenia and weight loss, but no relationship was found between the constitutional syndrome and other data. Fever was the most frequent sign (present in 90.8% of patients), with a mean duration of 13 days. The lymphadenopathies were localized in the epitrochlea, axillary, and cervical regions. The findings of laboratory tests were normal, except for an increase in the levels of fibrinogen and variant surface glycoprotein. Table 2 shows the distribution of the different clinical forms of disease. The ulceroglandular form was the most frequent (87 cases). Analysis of the differences between the clinical forms showed that the glandular form was associated with a lower frequency of fever and a longer diagnostic delay (mean  SD, 82.8  42.5 days vs. 43.4  29.1 days for the ulceroglandular form; P p .016). The ulceroglandular form showed a higher frequency of therapeutic failure, compared with the typhoidal form (RR, 10.1; P p 0.028). The treatments used are shown in table 3, together with the rates of therapeutic failure for the different antibiotics. There were no differences in the treatments used for the different clinical forms of disease, except for t (...truncated)