Article, Infectious Diseases

Predicting tularemia with clinical, laboratory and demographical findings in the ED

a b s t r a c t

Introduction: We aimed to determine clinical, laboratory and Demographical characteristics of tularemia on ad- mission to Emergency Department (ED).

Material and Methods: Medical data of 317 patients admitted to ED and subsequently hospitalized with suspected tularemia between January 1, 2011, and May 31, 2015, were collected. Patients were divided into 2 groups ac- cording to microagglutination test results, as tularemia (+) and tularemia (-).

Results: Of the 317 patients involved, 49 were found to be tularemia (+) and 268 were tularemia (-). Mean age of the tularemia (+) patients was found to be higher than that of tularemia (-) patients. When compared to tu- laremia (-) patients, a significant portion of patients in tularemia (+) patients were elderly, living in rural areas and had contact with rodents. When clinical and laboratory findings of the 2 groups were compared, any statis- tical significance could not be determined.

Conclusion: Tularemia is a disease of Elderly people living in rural areas. Contact with rodents also increases risk of tularemia in suspected patients.

(C) 2015

Introduction

Tularemia is a zoonotic disease caused by a a highly infectious, facul- tative intracellular, Gram-negative coccobacillus named Francisella tularensis. The disease is common in Turkey and throughout the World, particularly in North America, Europe, and Asia. It is also known as “rabbit fever”, “hunters’ disease”, “deerfly fever”, “tick fever”, “O’Hara’s Disease” and “Francis’ Disease” [1-3].

Transmission of the disease to humans occur through tick bites, con- tact with contaminated animals, consumption of infected animals’ meat, drinking contaminated water, and inhalation [4,5]. Even though a definitive reservoir has not been determined, arthropods, birds, ro- dents, lagomorphs, carnivores and ruminants, are known to carry Francisella[6].

Depending on the route of exposure and type of bacteria, clinical presentation of the disease vary from mild skin lesions and lymphade- nopathy to pneumonia and/or septicemia which threatens life [7].

? Conflict of interests and funding: None to declare.

* Corresponding author. Tel.: +90 5324475563; fax: +90 3642230323.

E-mail addresses: [email protected] (D. Yapar), [email protected] (A.K. Erenler), [email protected] (O. Terzi), [email protected] (O. Akdogan), [email protected] (Y. Ece), [email protected] (N. Baykam).

The main forms of the disease are ulceroglandular, glandular, oculoglandular, oropharyngeal, pneumonic, and typhoidal (septicemic). The majority of the cases in Europe and Turkey are known to be in the form of oropharyngeal tularemia [2]. Oropharyngeal tularemia is char- acterized by swollen ear, nose and throat lymph nodes develops after the ingestion of the bacterium, and oculoglandular tularaemia when eyelids and other periorbital structures are infected, usually through aerosols or contact with fingers carrying the bacterium [8].

Due to infection capacity of F tularensis in low doses and ease of

dissemination by aerosols, it is also used as a biological weapon, hence this bacterium was categorized as a highly dangerous biological agent by the Centers for Disease Control in Atlanta, Georgia [3].

In this article, we aimed to determine clinical and Laboratory features of tularemia on admission in the Emergency Department (ED) and clar- ify predictors of the disease in order to prevent misdiagnoses.

Material and methods

Medical data of 317 patients admitted to ED of Hitit University Corum Education and Research Hospital with suspected tularemia between January 1, 2011, and May 31, 2015, were collected, retrospec- tively. Presumeptive diagnosis of tularemia on admission to ED was based on suspicion of the clinicians in patients with regional

http://dx.doi.org/10.1016/j.ajem.2015.10.034

0735-6757/(C) 2015

D. Yapar et al. / American Journal of Emergency Medicine 34 (2016) 218221 219

lymphadenopathy, painful maculopapular lesions, rodent and/or tick exposure, unexplained fever and symptoms of upper respiratory system disorders. Suspected patients were hospitalized after Infectious Dis- eases consultation. From the medical records of the patients, initial clin- ical and laboratory characteristics in ED were collected. Then, tularemia test results for tularemia microagglutination (MA) titration of the pa- tients were collected. Patients were divided into two subgroups accord- ing to test results as tularemia (+) and tularemia (-). Two groups were compared according to clinical and laboratory findings. Patients were investigated for age, complaints on admission, location, occupation, properties of water used for drink, contact with animals, tick bite, farm- ing, contact with rodents, family or neighbourhood history for similar diseases and outcome (hospitalization, transfer to an advanced center or death). For definite diagnosis of tularemia, agglutination titrates were studied from blood serum samples of the patients. In patients with agglutination titrates above 1:160, those with positive polymerase chain reaction or cultural reproduction were confirmed as tularemia. Statistical analyses were performed using SPSS 22.0. Descriptive data were given as arithmetic mean +- standart deviation, minimum- maxiumum and percentages. For statistical evaluation ?2, Mann- Whitney U tests, and stepwise logistic regression analysis were used. p b 0,05 was considered statistically significant.

Results

Of the 317 patients involved, 49 (15.5%) were found to be tularemia (+) and 268 (84.5) were tularemia (-). When distribution of the tula- remia (+) patients in according to years was investigated, it was found that 9 patients (18,4%) in 2011, 14 patients (28.6%) in 2012, 10 patients (20.4%) in 2013, 13 patients (26.5%) in 2014, and 3 patients (6.1%) in the first half of 2015 were tularemia (+). A statistical significance could not be found in incidence according to years (P N .05).

While 36.7% of the tularemia (+) patients was male, 45.5% of the tu- laremia (-) patients was male (P N .05). Mean age was 42.7 +- 15.1 (min:6-max:81) in tularemia (+) and 36.0 +- 21.1 (min,0; max,94) in tularemia (-) patients. This finding was found to be statistically signif- icant. In tularemia (+) group, 14.3% of the patients were between 0 and 5 years of age, 8.2% were students and 8.2% were in agriculture agricul- ture work. In tularemia (-) group, 10.8% were between 0-5 years of age, 7.5% were students, and 5.6% were in agriculture work. When occu- pational status of the groups were compared, a statistical significant dif- ference could not be found (P N .05). When living environment (rural area or city center) of the groups were compared, it was determined that 65.3% of the tularemia (+) patients were living in rural areas while 31.3% of the tularemia (-) patients were living in rural areas. This finding was also statistically significant (P = .000). Majority of the tularemia (+) patients was living in rural areas. Only in 4 villages, 2 or more cases were determined.

No significant differences were found between those patients with tularaemia and those without, with regard to such symptoms as sore throat, fever, myalgia, nausea anorexia lymphadenopathy, oral or skin ulceration, nor between tularaemia and contact with livestock, ground game, outdoor activities or tick bites (P N .05). Table 1 summarizes the comparison of clinical findings of groups on admission. We also could not determine any statistical significance between patients admitted to the hospital and those discharged to home according to their demo- graphical, clinical and laboratory characteristics.

In logistic regression analysis, living in rural areas and contact with rodents were found to have statistical significance (P = .000, OR: 0.19, 95% CI [0.08-0.4]; P = 0.02, OR: 9.4, 95% CI [1.3-66.2], respectively). Pa-

rameters involved in the logistic regression analysis are summarized in Table 2.

When types of tularemia were investigated it was determined that majority of the cases was glandular form (n = 25, 51%) followed up by oropharyngeal form (n = 19, 38.8%), oculoglandular form (n = 1, 2%) and ulceroglandular form (n = 1,2%), respectively. Of 3 patients

Table 1

Comparison of clinical findings of groups on admission

(6.1%), clinical definite diagnosis could not be made. While 47 of the tu- laremia (+) patients (95.9%) were followed up as outpatients, 2 of them (4.1%) were hospitalized. On the other hand, 228 (85.1%) of tularemia (-) patients were followed up as outpatients and 40 (14.9%) were hospitalized.

Any statistical significance in regards to laboratory findings could not be determined between two groups.

Discussion

Tularemia is a zoonosis caused by the bacterium F tularensis; the main forms of disease that occur in humans are ulceroglandular/glandular, oculoglandular, oropharyngeal, and respiratory. In Turkey, tularemia outbreaks were described as early as 1936 to 1938, but tularemia was not reportable until 2004. Recently, multiple tularemia outbreaks in Turkey have been described, including in regions where the disease has not been previously reported; it is now considered a reemerging zoo- notic disease in Turkey [9,10]. The only F. tularensis subspecies found in most of Eurasia, including Turkey, is holarctica[11,12]. Our study revealed that incidence of the disease does not increase significantly by years. This finding also demonstrates that we could not achieve a significant decrease in incidence of the disease, as well. So, more rigorious measures must be taken in warfare against tularemia.

In the literature, oropharyngeal form of tularemia is reported to be more common in Turkey than in other countries. In contrast, the ulceroglandular form is the most common type of tularemia in other countries; it is caused by blood-sucking insects or arthropods. The oro- pharyngeal form of tularemia is common in regions dominating aquatic cycle and is caused by the consumption of contaminated water or food. Urine, excrement or other excretions of animals involved in the aquatic cycle such as beaver, muskrat, and voles can contain the causative agent and infect surface waters after rainfall in the winter months. The main reason for the oropharyngeal form is the consumption of contaminated water by people [1,13]. Our finding that tularemia is more frequently seen in rural areas is compatible with the fact that contamination of water and contact with contaminated meat and animals are more fre- quent in rural areas. This finding shows that education of people in rural areas play an essential role in warfare against tularemia.

The clinical manifestations of tularemia depend on the route through which the bacterium entered the body and are usually ulceroglandular or typhoidal, although oculoglandular, oropharyngeal, and pneumonic forms have also been reported [14]. The ulceroglandular form, which represents 75 to 85% of all tularemia cases, corresponds to a regional lymphadenopathy with a painful maculopapular lesion that evolves to an eschar at sites of skin infection; it can also occasionally develop into systemic disease with a 5 to 15% case fatality rate [15]. In ED diagnosis of tularemia is based on suspicion of clinicians as it represents a wide range of symptoms mimicking other common diseases. It is known that up to 68% of the patients may initially be diagnosed with more com- mon but clinically similar infections other than tularemia, particularly gram-positive lymphadenitis or cellulitis, cat-scratch disease, and Epstein-Barr virus infection [16].

220 D. Yapar et al. / American Journal of Emergency Medicine 34 (2016) 218221

Table 2

Logistic regression analysis of parameters associated with tularemia

p

OR

95% CI

Age

0.1

1,014

0.9

1.0

Gender

0.2

0.6

0.3

1.3

Location?

0.0

0.1

0.0

0.4

Contact with polluted water

0.5

0.6

0.1

2.8

Living in rural areas

0.6

0.7

0.2

2.1

Livestock

0.7

1.1

0.3

3.5

Farming

0.5

0.7

0.2

2.2

Hunting

0.7

0.7

0.1

4.4

Contact with rodents?

0.0

9.4

1.3

66.2

Outdoor activities

0.6

0.7

0.1

2.8

OR, odds ratio; CI, confidence interval.

* Statistical significance.

However, in a study by Mailles et al, it was reported that the most frequent clinical presentation was found to be glandular tularaemia which is characterized by lymphadenopathy in axillary, inguinal, ear- nose-throat, epicondylar, mediastinal and popliteal regions. [8]. In an another study buy Grunaow et al, it was reported that 79% of the pa- tients presented with glandular form [17].

In our study, majority of the cases were found to be glandular form tularemia followed by oropharyngeal form. This finding may be linked to increasing socio-cultural status and awareness of farmers living in rural areas. However, high proportion of oropharyngeal form -as second common type- is still unacceptable.

The number of cases is higher (1.18 times) in females than males in Turkey [18]. However, outside of Turkey, the number of cases is higher in males than females [19]. The reason for higher female prevalence in Turkey may be due to the fact that women may be more active in house- hold chores, and have more contact with contaminated water and with animal excrement or urine in food storage areas [18]. Our findings are compatible with the literature that the disease is seen in females more commonly. We also think that female dominance may be linked to ac- tive role of Turkish women in social life.

When age of patients with tularemia was investigated, in a study, it was reported that 19.3% of the patients were less than 20 years old. Most patients (53.8%) were in the age group of 30-64 years. This suggests that the disease usually affects adults. The average age is reported to be 38.7 years for women and 30.6 years for men [1,18]. Compatible with the literature, in our study, when groups were compared according to age, tularemia was most likely to occur in adult patients.

It is known that a wide range of animals, encompassing arthropods, birds, rodents, lagomorphs, carnivores and ruminants, can carry Francisella, but a definitive reservoir has not been identified [6].

The main transmission route in Turkey is through drinking contam-

inated water. It has been hypothesized that water becomes contaminat- ed by secretions from rodents and hares [20,5,21]. The potential role of migrating birds in the transmission of the disease may be explained through the transfer of infected ticks or the direct contamination of water [22].

In our study, accordingly, we could not determine exact reservoirs due to limited history obtained.

Laboratory workers, farmers, veterinarians, hunters, foresters, cooks, and butchers are known to be at risk of tularemia infection [23]. Because there are not any advanced laboratories hereabouts, majority of our pa- tients were young population living in rural areas or farmers. As a devel- oping country, in Turkey, contamination of water and meat is still a Public health problem. When once water is contaminated, exposure of a wide range of people happens to be possible.

The disease develops with fever, sore throat, and cervical and post- auricular lymphadenomegaly. In addition, in the course of tularemia, skin rashes (papular, vesiculopapular, or erythema nodosum) have been reported at rates of 5% to 42% [24-26]. Vesicular types of skin rashes can be confused with varicella zoster infection [27]. Lymphade- nopathy and sore throat were the leading Presenting complaints on

admission to ED in our study. Additionally, weakness and fever were common in patients with tularemia. When two groups were compared, any clinical or laboratory findings to differentiate tularemia could not be found. Tularemia remains as a disease that can be confused with many diseases and needs laboratory confirmation.

In a study from Turkey, it was reported that 68% of tularemia pa- tients lived in the rural area, 75% had rodents at home, 46% used natural water supplies, 53% fed animals, 15% had contact with game animals and 5% had contact with ticks [26]. Similarly in our study, after regres- sion analysis, contact with rodents as well as living in rural areas were found to be predictors of tularemia.

The diagnosis is presumed upon clinical grounds and confirmed by serological testing. According to published reports delayed diagnosis can result in an overall mortality rate of 7% of cases; however, early di- agnosis will lead to uncomplicated recovery in most cases [28]. In our study, none of the tularemia (+) patients died. However, we could not determine any clinical finding that may be useful in discriminating tularemia (+) patients from tularemia (-) patients. Diagnostic sensi- tivity may be increased by collection of a pertinent exposure history, recognition of variations in clinical presentation, and judicious applica- tion of laboratory tests [16].

The gold standard diagnostic method for tularemia is culture. The culture procedures should be conducted in level-3 biosafety laboratory conditions [29,30]. Due to the difficulty of reproduction of F. tularensis and the hazard it bears for laboratory personnel, serologic tests should be preferred in diagnosing the disease [10,31,24,32,30]. Microagglutination is being used as a diagnostic test for a long time. Among the patients with symptoms and findings matching with tulare- mia, 1:160 and above positivity titer in MA is sufficient to diagnose the disease [2]. Determination of tularemia was made by the same tech- nique. When required in some of patients, blood culture was also per- formed for confirmation of diagnosis.

Our study also has some limitations. Because there are no specific clinical and laboratory findings of tularemia, selection of patients group was based mainly on clinical suspect which may cause erroneous hospitalizations. Besides, a larger patients group could be obtained if misdiagnosed patients could have been involved into the study.

Conclusion

According to the results of our study, tularemia is a disease of elderly in contact with rodents living in rural areas. Contrary to literature, the most common type of disease was found to be glandular form in Mid- Anatolian city, Corum. Clinical manifestations of the disease are sore throat, lymphadenopathy, weakness, and fever. Due to its wide range of clinical characteristics, any specific finding to predict tularemia on ad- mission could not be determined. Blood culture and MA remain as mainstays of diagnosis of tularemia. Clinical suspect of physician seems to be the most important factor for diagnosis.

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