Murine Typhus as the Leading Cause of Non-focalized Fever in the Canary Islands

doi:10.21203/rs.3.rs-4714528/v1

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Murine Typhus as the Leading Cause of Non-focalized Fever in the Canary Islands

https://doi.org/10.21203/rs.3.rs-4714528/v1

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The present prospective study aims to diagnose, through serology and PCR, the etiology of non-focalized fever lasting between 5 and 28 days in the islands of La Palma and El Hierro (Canary Islands, Spain) during the year 2021. The etiological profile described in this study is similar to that described in studies of fever of intermediate duration (FDI), with zoonoses being the main cause. Murine typhus (MT) is identified as the primary cause, followed by Q fever (QF). The incidence of MT is the highest published nationally and similar to the highest in Europe, with 39.6 cases in La Palma and 79.7 cases in El Hierro. QF, known to be endemic to the Canary Islands, presents incidences of 26.5 cases in La Palma and 15.6 cases in El Hierro. MT does not present gender differences, and its geographical distribution is homogeneous. However, QF is more prevalent in men and has a heterogeneous geographical distribution.

The high incidence of MT found in both urban and peri-urban areas is particularly noteworthy, and its possible connection with climate change and/or the growth of the reservoir population in the Canary Islands is unknown. Its similarity with QF in terms of clinical signs and treatment, in addition to the absence of a specific protocol for early diagnosis, may have contributed to its underdiagnoses. MT can produce health concerns with risk of hospitalization, complications, and even death. Hence, the registration of cases for epidemiological control is deemed essential.

Fever is the most frequent reason of medical consultation, both in Primary Care and the Emergency Department. The scientific literature provides different ways of defining fever. For the purpose of this study, non-focalized fever is defined as fever with a temperature higher than 38ºC and absence of signs or symptoms indicating its origin. Based on the duration of the fever, the following are included: short-duration fever (SDF), defined as fever lasting less than 7 days, and fever of intermediate duration (FID). The latter is a term used in Spain which refers to fever lasting between 7 and 28 days without a history of hospital stay, immunodeficiency or other chronic underlying disease that may justify its presence. After a basic clinical and complementary evaluation, the fever remains without diagnosis. SDF frequently has an infectious, viral or bacterial origin, and follows an often unsubstantial clinical evolution. However, in other instances, the duration of fever is prolonged, and a diagnosis cannot be identified with the initial diagnostic tests performed [1–2].

Research conducted in southern Spain have indicated a predominance of acute systemic infectious diseases as the main causes of FID, with zoonoses being the principal cause. Among them, the most frequent are: Q Fever (QF), brucellosis (Br), Mediterranean spotted fever (MSF), Murine Typhus (MT) and, among the least frequent, typhoid fever, Epstein-Barr virus (EBV) mononucleosis, Cytomegalovirus (CMV), human immunodeficiency virus (HIV) or toxoplasmosis (Tox) and leptospirosis (Lpt). Furthermore, there is a much lower percentage of causes associated with non-infectious pathologies and a variable percentage, depending on each study, of unknown cause (19–66%) [3–4]. The etiological spectrum of FID varies according to multiple factors, including time and geographic location [5]. Nonetheless, the number of national and international studies [1] on this subject is scarce.

Publications have reported cases of QF [6–9] and, in recent years, of MT [9–12] in the Canary Islands as sources of FID. On an international level, cases of MT have also been reported as a cause of FID in travelers from the Canary Islands [13–14]. There is however a lack of prospective and incidence studies on the main sources of FID in the archipelago [11–12].

The aim of this study is to analyze in detail the etiologic spectrum of non-focalized fever lasting from 5 to 28 days on the islands of La Palma and El Hierro. Their insularity, combined with their small and approachable population, make them ideal locations for said purpose. For methodological considerations, a broader spectrum was encompassed, starting at 5 days following the onset of fever, and incorporating cases of FID. This was undertaken with the aim of identifying and quantifying the incidence of its most prevalent etiologies, determining their geographical distribution and the population at risk.

This project is the result of a co-operation agreement between the Canary Islands Health Service (Servicio Canario de la Salud, SCS), the University of Barcelona (Universidad de Barcelona, UB) and the Institute of Tropical Diseases and Public Health of the Canary Islands (Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, IUETSPC), at the University of La Laguna (Universidad de La Laguna, ULL).

Prospective study on the diagnosed cases of non-focalized fever lasting between 5 and 28 days on the islands of La Palma and El Hierro in the year 2021.

The present study was conducted amidst the SARS-Cov-2 pandemic, characterized by a clinical suspicion of coronavirus infection among cases presenting fever. The patients sought clinical consultation at early stages, often within the first 24 hours of the fever onset. During the case recruitment stage, defining criteria of FID was incorporated. However, considering the vast amount of patients with prolonged non-focalized fever within 7 days of onset, it was determined to incorporate patients experiencing fever persisting for a duration of 5 days.

The Spanish islands of El Hierro and La Palma are located in the Canary Archipelago, one of the outermost regions of the European Union. The islands are situated in the Atlantic Ocean, in the northwest of Africa and close to the south coast of Morocco. They have subtropical climate.

The Canary Islands Health Service is organized geographically into seven different Healthcare Divisions, one for each island. Within each Healthcare Division there is, at least, one General Hospital, providing services tailored to the specific health needs and demographic characteristics of the local population. Additionally, each Healthcare Division is further organized into Basic Health Areas, administrative subdivisions that comprise a group of Primary Care Health Centers and professionals operating under its functional and organizational jurisdiction.

La Palma is the second westernmost island of the archipelago and has a surface area of 708.33 km². The Healthcare Division of La Palma is organized into 7 Basic Health Areas and one General Hospital, the University Hospital of La Palma.

El Hierro is the smallest and westernmost island, with a surface of 268.71 Km².The Healthcare Divsion of El Hierro is organized into two Basic Health Areas and one hospital, the Nuestra Señora de los Reyes Hospital.

The study population comprises the entire population of the islands of La Palma and El Hierro, corresponding to 83,380 and 11,298 inhabitants respectively, as of January 1^st, 2021 according to data from the Canary Islands Statistic Institute (Instituto Canario de Estadística, ISTAC) [15].

For the recruitment and sample submission process, a sentinel primary care physicians network was created in each Basic Health Area of La Palma and El Hierro. The Internal Medicine Services, the Emergencies Departments and the COVID-19 units were also included in this network. The sentinel physicians were study referrers in their respective areas. The inclusion criteria are defined in Table 1.

Table 1. Inclusion Criteria.

>38ºC fever, without obvious source of infection from 5 to 28 days of duration.

No hospital admission in the last 2 weeks.
No HIV with CD4<500 or other known immunodeficiencies.
Non-diagnosis despite basic preliminary studies, including clinical history, physical examination, complete blood count, urine sediment, basic biochemistry with liver function test, kidney function test, PCR, and chest X-ray.
Immigrants with more than 6 months residency.
Patients with no oncological pathology or immunosuppressive oncological treatments.
Patients who are not on dialysis or with intravascular catheters.
Non-active drug users
Not having travelled outside Spain in the last 3 months.
Only patients above 14 years of age are included.

In the Health Service System, a standardized protocol was implemented to dismiss SARS-Cov-2 infection in individuals presenting with fever. Within the initial 24 hours of fever onset, patients undergo a SARS-Cov-2 PCR test, with a follow-up test scheduled 72 hours thereafter if the initial result is negative. Patients without evidence of SARS-Cov-2 infection who continue to exhibit fever symptoms were referred to the sentinel network of physicians for further evaluation to exclude focal fever. Those patients with persisting fever beyond 5 days despite negative findings were enrolled in the study. Patients diagnosed with SARS-Cov-2 infection, focal fever, or those who become afebrile prior to the 5-day mark were excluded from the study. Treatment decisions for patients not meeting the study criteria were determined based on clinical judgement by the attending physician.

Upon inclusion in the study, patients were required to sign an informed consent form and 2 ml of blood was drawn into an Ethylenediaminetetraacetic acid (EDTA) tube which was frozen at -80°C for molecular detection [16] of: Coxiella burnetii, Rickettsia spp., Bartonella spp. and Anaplasma/Ehrlichia spp. at the Institute of Tropical Diseases and Public Health of the Canary Islands (IUETSPC). Serological studies were conducted regularly by the Canary Islands Health Service. At first, serologies for Coxiella burnetii, Rickettsia typhi, Cytomegalovirus and Epstein-Barr virus were requested. When no diagnosis was found, serial serology for rickettsiosis or QF was performed between 14 and 30 days after the first serology. In cases with negative results, the serological study was extended to include Chlamydophila pneumoniae, Mycoplasma pneumonieae, HIV, Parvovirus B19, Treponema pallidum, Borrelia burgdorferi, and Brucella melitensis.

Table 2.

Microorganism	Technical Serology	Cutoff points
Coxiella burnetii	IIF (Vircell Laboratories)	IgM ≥1/64 and/or IgG≥1/1024 or quadrupling of IgG titers between 2 consecutive samples.
Rickettsia typhi	IIF (Pasteur Laboratories)	IgM≥1/192 or quadrupling of IgG titers in 2 consecutive samples.
Rickettsia conorii	IIF (Pasteur Laboratories)	IgM≥1/192 or quadrupling of IgG titers in 2 consecutive samples.
EBV	ELISA CL (Abbott Laboratories)	Qualitative
CMV	ELISA CL (Abbott Laboratories)	Qualitative
Chlamydophila pneumoniae	IIF (Vircell Laboratories)	IgM≥ 1/64 y/o IgG≥1/512
Mycoplasma pneumonieae	ELISA CL (Vircell Laboratories)	Qualitative
Parvovirus B19	ELISA CL (Vircell Laboratories)	Qualitative
Treponema pallidum	ELISA CL (Abbott Laboratories)	Qualitative
Borrelia burgdorferi	ELISA CL (Vircell Laboratories)	Qualitative
HIV	ELISA CL and Western- Blot (Abott Laboratories)	Qualitative
Brucella melitensis	Rosa Bengala agglutination test (Linear)	Qualitative

Table 2. Serological techniques used. IIF: Indirect immunofluorescence, ELISA: enzyme-linked immunosorbent assay, CL: chemiluminescence

All patients who met the inclusion criteria and had clinical suspicion of rickettsiosis or QF were administered Empirical Antimicrobial Therapy with doxycycline after blood sampling. All cases diagnosed by serology and/or PCR test were considered positive.

The design of this work conforms to European legal and ethical standards and was approved by Comité de Ética de la Investigación con Medicamentos (CEIm) of Hospital Universitario de Canarias (Tenerife, Spain) and coded 2017_81. All patient’s written consents were obtained.

Statistical Analysis: quantitative variables were described by calculating their means, standard deviations, maximum and minimum values. On the other hand, qualitative variables were represented with frequency tables. The subpopulations were compared using Chi-squared test, Student's t-distribution and logistic regression models. Statistical analyses were performed with the R 4.2.2 package, hypothesis tests were evaluated with an alpha risk of 5% and confidence intervals (CI) were computed at the 95% level.

During the year 2021, 79 patients were registered, 65 of them on the island of La Palma and 14 on the island of El Hierro. Among the cases selected, 48 cases (60.7%) derive from the Emergency Department, 21 cases (26.6%) from Internal Medicine hospitalization and 3 cases (3.8%) from the Intensive Care Unit (ICU). The remaining cases came from Primary Care (8.9%). 88.6% of the cases were registered with 10 or fewer days of progress since the onset of fever and 45.6% of them between 5 and 6 days.

Among the 79 cases, PCR combined with amplicon sequencing was conducted on 71 patients, while serology was performed on 73 individuals. Serological analysis revealed 23 cases of Rickettsia typhi, 13 cases of Coxiella burnetii, 8 cases of Mycoplasma pneumoniae, 5 cases of cytomegalovirus (CMV), 3 cases of Epstein-Barr virus (EBV), 3 cases of Parvovirus B19, 2 cases of Chlamydia pneumoniae, and 2 cases of Rickettsia conorii. The molecular diagnosis identified 38 cases of Rickettsia typhi, 10 cases of Coxiella burnetii, and 1 case of Bartonella henselae, with no detections of Anaplasma/Ehrlichia spp. No species of Rickettsia other than Rickettsia typhi were identified. Nineteen patients tested positive for Rickettsia typhi and 7 patients tested positive for Coxiella burnetii by both PCR and serology. Blood cultures from one patient yielded Enterococcus faecalis. Thirteen patients exhibited negative results on both PCR and serological testing, with one patient clinically diagnosed with Central Fever. Table 3. provides a detailed description of patient diagnoses, including 13 cases with two or more positive results.

Table 3

**Distribution of diagnosed cases, ICU admissions, and deaths for each pathology diagnosed.** The most common causes of non-focalized fever were MT and QF, accounting for 73.4% of all cases. Up to 15.2% of fever cases are of unknown cause. The incidence of MT was 39.6 cases per 100,000 inhabitants/year in La Palma (95% CI, 25–54) and 79.7 cases per 100,000 inhabitants/year in El Hierro (95% CI, 23–136). The second most common cause is QF with 26.5 cases per 100,000 inhabitants/year in La Palma (95% CI, 5–78) and 15.6 cases per 100,000 inhabitants/year in El Hierro (95% CI, 7–25). In both etiologies, the island of El Hierro has the highest occurrences, approximately twice the incidence of La Palma. Table 4.
Diagnoses	No. of cases	Hospitalization	ICU	Deaths
Rickettsia typhi	34	16	3	2
Coxiella burnetii	12	2
Rickettsia typhi & Coxiella burnetii	2
Rickettsia typhi + Parvovirus B19 + Mycoplasma pneumoniae	1	1
Rickettsia typhi + Chlamydia pneumoniae	1	1
Rickettsia typhi + Cytomegalovirus + Mycoplasma pneumoniae	1
Rickettsia typhi + Mycoplasma pneumoniae	2
Rickettsia conorii	1	1
Rickettsia conorii & Rickettsia typhi	1
Coxiella burnetii + Cytomegalovirus + Parvovirus B19 + Mycoplasma pneumoniae	1	1
Coxiella burnetii + Chlamydia pneumoniae	1	1
Cytomegalovirus	1
Cytomegalovirus + Epstein Barr Virus + Mycoplasma pneumoniae	1
Cytomegalovirus + Epstein Barr Virus	2
Mycoplasma pneumoniae	2
Parvovirus B19	1	1
Bartonella henselae	1	1
Enterococcus bacteremia	1	1
Central Fever	1	1		1
Unknown Origin	12	4
Total	79	31	3	3

Table 4

Incidences by pathology on the islands of La Palma and El Hierro. Confidence interval (CI) at 95% level.
	LA PALMA		EL HIERRO
Diagnoses	N	Incidence per 100000 CI (95%)	N	Incidence per 100000 CI (95%)
Q fever	13	15.59 (7–25)	3	26.55 (5–78)
Murine Typhus	33	39.58 (25–54)	9	79.66 (23–136)
Rickettsia spp.	1	1.20 (0–7)	0	0
Cytomegalovirus Mononucleosis	5	6.00 (2–14)	1	8.85 (0–49)
Epstein Barr Virus Mononucleosis	3	3.60 (1–11)	0	0
Parvovirosis	3	3.60 (1–11)	0	0
Mycoplasmosis	8	9.59 (2–17)	0	0
Bartonellosis	0		1	8.85 (0–49)
Bacteriemia	1	1.20 (0–7)	0	0
Unknown origin	12	13.19 (5–22)	1	8.85 (0–49)
Non-infectious cause	1	1.20 (0–7)	0	0

Out of 79 cases, 51 were males (64.6%) and 28 females (35.4%). There were no significant differences in age between men and women, (p = 0.39) with a mean age of 49.6, a minimum of 14 and a maximum of 90. There were no differences in age between men and women diagnosed with MT (p = 0.45), with a mean of 45.7 years with CI (39.2 and 52.2), or with QF (p = 0.67) with a mean of 54 years and CI (44.2–63.8). No differences were found between men and women with MT (p = 0.12) although significant differences were found with QF (p = 0.05), the latter with 3 times more men than women.

Regarding seasonality, no significant statistical differences were observed in the distribution of cases per month (p = 0.10), likely due to insufficient statistical power. Nevertheless, for MT peaks were noted during the summer and fall months (p = 0.06) and, regarding QF, seasonality was evident with a peak occurring during the winter months (p = 0.01). Figure 1.

Table 5

Illustrates the case and incidence distribution by municipality.

Municipalities	Population	No. of cases	Case incidence per 100000 inhabitants	I/100000 MT	I/100000 QF
Los Llanos	20648	17	82.33	48.43 (10)	9.69 (2)
Santa Cruz /Puntallana	17995	18	100.02	33.34 (6)	2223 (4)
Las Breñas	13062	5	38.28	7.66 (1)	22.97 (3)
El Paso	7745	10	129.12	90.38 (7)	25.82 (2)
Tazacorte	4558	6	134.59	87.76 (4)	---
Mazo /Fuencaliente	6631	5	75.4	47.47 (2)	23.74 (1)
Tijarafe /Puntagorda	4794	2	41.71	41.71 (2)	20.86 (1)
Garafía	1813	2	110.31	55.16 (1)	---
Barlovento /Los Sauces	6134	---	---	---	---
Valverde	5084	4	78.68	39.34 (2)	19.67 (1)
La Frontera	4276	6	140.32	116.93 (5)	---
El Pinar	1936	4	206.61	103.31 (2)	103.31 (2)

I:Incidence; TM : ; FQ: ; ( ) no. of cases

Cases of MT were registered in all the Basic Health Areas, with average incidences of 30 and 50 cases per 100,000 inhabitants/year in urban and peri-urban areas and 50 and 120 cases in rural areas. In La Palma, the highest incidence was noted in El Paso and Tazacorte, while in El Hierro it was identified in El Pinar and La Frontera.

Regarding QF, the incidences typically range between 20 and 25 cases per 100,000 inhabitants/year, with the highest rate registered in El Pinar and an absence of cases in several municipalities. Table 5.

The number of hospitalized cases was 31 (39.2%), their diagnoses are described in Table 3. The majority of these cases were associated with MT (58.1%). 33% of cases developed medical complications: 42.5% were respiratory (pneumonia, pneumonitis and pleural effusion), 24% alterations in renal function and 1% cardiac decompensation.

Out of the cases with MT, 42.8% were hospitalized and 3 patients had to be admitted to the ICU. There were 16 cases who presented complications: 8 of them were respiratory, 2 were heart failure and 4 were renal failure. Two patients with Murine Typhus passed away, both over 80 years of age, of whom one case came from the ICU and the other from Internal Medicine.

Regarding patients with QF, 25% of them were hospitalized, and only 1 case presented complications with infrarenal aortic aneurysm.

The implementation of a specific protocol via a network of sentinel physicians has facilitated the early detection of cases of non-focalized fever. Ninety percent of cases were identified within 10 days, with 46% diagnosed within 5–6 days of fever onset. Early blood collection, conducted prior to any therapeutic intervention, enabled the acquisition of an optimal sample for molecular diagnosis [17], resulting in a 67.7% positivity rate among the total PCR tests conducted.

The present prospective study is the first published in the Canary Islands to describe the etiological profile of non-focalized fever and, despite including cases from 5 days of fever onset, all identified diagnoses align with the FID profile. The primary cause of fever with unknown origin are zoonoses, with MT emerging as the predominant etiology, followed by QF. Previous publications have not reported such a high prevalence of MT, despite its consideration as an emerging cause of FID [11–12]. These disparities may stem from the prospective nature of this study, incorporating molecular diagnosis [16] and earlier case recruitment. Notably, despite the significant number of rickettsiosis cases in our series, Rickettsia felis was not detected. Although human cases of R. felis have been documented in the Canary Islands via serology [18], its absence in our series could be attributed to stringent clinical recruitment criteria, primarily focused on high and persistent fever. Consequently, these findings lend support to the hypothesis that the potential pathology of R. felis in humans may be less aggressive than that of R. typhi, albeit this remains an unresolved question [19]. No cases of anaplasmosis, brucellosis, or Mediterranean spotted fever were reported, although some positive results have been described in some studies conducted in the Spanish Peninsula [3–4, 20]. Additionally, although two cases of positive serology for R. conorii were found, they were considered to be false positives in relation to cross-reactions between rickettsia species, already described in other publications [12]. Furthermore, several cases of mycoplasmosis associated with other infections were identified. Nevertheless, as the diagnostic approach for mycoplasmosis has been solely serological, the possibility of serological cross-reactivity should also be contemplated in future investigations to elucidate its role as an etiological factor in FID or non-focalized fever.

According to the findings of this study, the incidence of non-focalized fever was higher in males than in females, although there were no differences in terms of age, with a mean age of 49.6 years. Notwithstanding, upon analysis by pathology, it was observed that this gender difference was attributed to QF (p < 0.05), with three times more cases in males than in females. Consistent with other series studied [7, 9, 21] QF was also more prevalent in males and is associated with occupations related to livestock farming. No gender disparities were identified in cases of MT, consistent with findings from other series [9, 11].

The highest nationally reported incidence of MT is documented at 39.6 cases per 100,000 inhabitants/year in La Palma and notably at 79.7 cases per 100,000 inhabitants/year on El Hierro. According to the study of Beatriz Rodríguez-Alonso et al., the Canary Islands exhibit the highest national incidence of MT, with a rate of 1.2 cases per 100,000 inhabitants/year, significantly lower than the findings of this study [12]. Such variations may originate from differences in sample study areas, sampling timeframes, the prospective design employed in this study, and the early diagnosis due to the implementation of molecular diagnostics. Thus, while the observed incidences are remarkably high, they may accurately reflect the realities of our geographic context.

On an international scale, the incidences reported may parallel to those of Croatia [22], with 57 cases per 100,000 inhabitants/year and Greece [23] with 87 cases per 100,000 inhabitants/year, published by Punda-Polic et al. and George Chaliotis et al.

The second most prevalent cause of non-focalized fever is QF, with reported incidences of 26.5 cases per 100,000 inhabitants/year on the island of La Palma and 15.6 cases per 100,000 inhabitants/year on El Hierro. These rates exceed those estimated in Gran Canaria (2003) and are comparable to those observed in Lanzarote (1997) with 5 and 12 cases per 100,000 inhabitants/year, respectively [7, 24]. However, they are lower than those reported by Vélez-Tobarias in 2013 in La Palma (43 cases per 100000 inhabitants/year) in thesis for the master's degree in International Health and Tropical Medicine at the University of Barcelona. The majority of published studies on QF consist of case series and prevalence investigations [21] Recent literature on the incidence of QF in the Canary Islands is scarce. Based on the available data, it could be interpreted that the incidence of QF is declining in the Canary Islands, possibly attributable to enhanced sanitary measures concerning the goat population. Internationally, there are documented case series detailing QF outbreaks and some incidence studies reporting lower rates than those observed in this study. Raoult et al. described a rate of 2.5 cases per 100,000 inhabitants/year in France [25], with even lower rates in Switzerland.

The geographical distribution of MT is notably high, with a remarkable absence of cases in the north of La Palma (Barlovento and Los Sauces), where temperatures are lower. Regarding QF, there is a spatial distribution by focus of infection, which could be associated with the animal health management of some goat herds. The highest incidence, about 100 cases per 100,000 inhabitants/year, was found in the municipality of El Pinar.

The incidence of QF displays a pronounced seasonal trend, particularly notable during the winter months. This pattern is subject to variation depending on the specific geographical location under examination [21, 25]. It is particularly associated with the annual goat kidding cycle that farmers establish for the sale of kid during Christmas. Conversely, in other islands, calving occurs biannually, resulting in concentrated cases during two distinct seasonal spikes [6–7, 9]. In contrast, cases of MT demonstrate a seasonal increase during the summer and fall months, aligning with the period of peak reproductive activity of its vector, the flea [9, 11]. This observation may account for the diminished presence of MT in colder regions and seasons. These biological cycles are in line with those described in previous studies [19].

Nearly 43% of MT cases were identified during hospitalization, with 38% experiencing medical complications, 7% required admission to the ICU and 4.7% resulted in fatalities. These findings are consistent with the existing literature [12, 26]. Notably, the two ICU deaths were diagnosed early and confirmed solely by molecular diagnosis. In other studies, death might not have been detected due to the absence of molecular diagnosis. Regarding QF, 25% of the cases were also identified during hospitalization, with 6% presenting complications. No ICU admissions or fatalities were attributed to QF. In contrast to other studies [6–9, 27], the earliest recruitment and treatment could explain the lowest number of admissions, complications and fatalities observed.

In conclusion, the most frequent causes of non-focalized fever in this region are zoonoses, as well as MT followed by QF.

Regarding QF, given its patched distribution, it is essential to define public health strategies targeting active emission sources. The absence of cases in certain municipalities suggests the effectiveness public health measures implemented.

Concerning MT, the results highlight its significant underestimation as a disease. There is a compelling need to establish an interdisciplinary epidemiological surveillance network. Additionally, reservoir and vector control measures, coupled with prompt case identification for appropriate therapeutic intervention to mitigate potential complications and mortality risks, should be implemented. While MT has been overlooked, the significantly high incidences warrant attention. Uncertainty persists regarding its potential correlation with climate change or the expanding reservoir population in the Canary Islands. Furthermore, the possibility of MT being a re-emerging disease influenced by uncontrolled variables cannot be dismissed. Rigorous case registration is paramount for effective epidemiological control.

Author Contribution

Conceptualization: M. V.-T., A.M. T.-V., C.A.-T.; methodology: M. V.-T., A.M. T.-V., J.M.-M, C.G.-H, E.C., J.A.P., and C.A.- T.; resources: M. V.-T., A.M. T.-V., C.G.-H, E.C., J.A.P., J.M.-M, and C.A.- T. ; writing—original draft preparation: M. V.-T., A.M. T.-V., and C.A.- T.; writing—review and editing: M. V.-T., A.M. T.-V., J.M.-M, C.G.-H, J.A.P., E.C., G.C. and C.A.- T.; visualization: M. V.-T., A.M. T.-V., G.C. and C.A.- T.; supervision: A.M. T.-V., E.C., G.C. and C.A.- T.; project administration: M.V.-T, A.M.T.-V, and C.A.- T.

Acknowledgement

This work is the result of a cooperation agreement between the University of Barcelona, the University of La Laguna and the Canary Health Service on May 27, 2020, being published in the Official Gazette of the Canary Islands (BOC) on June 9, 2020. We especially want to thank the Fever Working Group of the Canary Islands made up of primary care doctors, emergency services, laboratories and the data service. They have made possible the development of this project: Pedro Fonte García, Nieves Luisa Hernández Rodríguez, Isabel Saucedo Villanueva, Lucas Corral Neri, Juan Febles Guadarrama, Tomás Morales López, Diheva Fernández Luzúa, Eusebio Jiménez García, Mirkadeiny Cabrera Febles, Leopoldo Martín Martín, Miguel Moreno Moreno, Luis Humberto Vizcaíno, Lourdes Molina Bolaños, Carmen Eva de Paz Pérez, Ana Delia Afonso Pérez, Victoria Sánchez Martínez, Domingo Franciso Ramón, Jorge Díaz Muñoz, María Magdalena Pérez Rodríguez, Adrián Borrero Guillot, Dora Mª Torres Cabrera, José Fco Ferraz Jerónimo, Nuria Batista Medina, Rosa Delia Romero Romero, Cristina Moya Martín, Belkis M Sangil Valdivia, José Alfredo Rodríguez Guzmán, Natalia Díaz Ortega,Teresa Cotonat Vives, María Labrador Notario, Nadia Estefanía Van Moen Del Amo, Sonia Herrera Montesinos, Rafael Luis Fonseca Rodríguez, Nieves Rosa Arroyo Díaz, Tatiana Fernández Ávila, David Acedo Fuentes, Pablo Servando, Cristina Schiller, Elena María Rodríguez Fernández, Elena Benítez Rodríguez, Manoel Fandinho de Castro y Luis Curbelo Estévez.

Data Availability

Data is provided within the supplementary information

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Murine Typhus as the Leading Cause of Non-focalized Fever in the Canary Islands

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