Pulmonary tuberculosis: Diagnostic delay in Tunisia

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Original article

Pulmonary tuberculosis: Diagnostic delay in Tunisia Tuberculose pulmonaire : causes du retard diagnostique en Tunisie J. Ben Amar a,∗ , M. Hassairi b , N. Ben Salah b , R. Charfi b , F. Tritar b , R. Fourati b , D. Gamara b , H. Aouina a , H. Bouacha a a

Service de pneumologie, hôpital Charles-Nicolle, 1009, Baab Saadoun, Tunis, Tunisia b Service d’épidémiologie, institut Salah Azaiz, Tunis, Tunisia

Received 18 June 2015; received in revised form 2 September 2015; accepted 26 November 2015

Abstract Objective. – Early diagnosis and prompt effective therapy are crucial to fight against tuberculosis (TB), particularly in regions with a high prevalence. We aimed to evaluate TB diagnostic delays and identify the associated risk factors. Methods. – We conducted a survey in various health facilities in Tunisia between March 24th and October 30th, 2014. We included all patients aged ≥ 18 years who presented with pulmonary TB (PTB) and who had been initiated on an anti-TB treatment. We evaluated the time between respiratory symptom onset and treatment initiation. Treatment delays were divided into three categories: delays due to the patient, to the healthcare system, and overall delays. Results. – We included 352 patients in the study (242 men and 110 women). The mean age was 42.2 years ± 17.7. The median time from symptom onset to treatment initiation was 52.56 days. Patient delays were longer for men, for patients presenting with alcohol dependence, and for patients who already knew they were sick. Healthcare system delays were associated with older age, female patients, patients consulting a private physician, and outpatients. Conclusion. – TB symptoms should be better explained to the population and healthcare professionals should be better trained to both reduce such delays and initiate treatment as early as possible. © 2015 Published by Elsevier Masson SAS. Keywords: Diagnostic delay; Tuberculosis; Diagnosis

Résumé Objectif. – Un diagnostic précoce de tuberculose (TB) et un traitement efficace et rapide sont nécessaires pour lutter au mieux contre la maladie. L’objectif de cette étude était de décrire et d’évaluer les retards diagnostiques de la TB et d’identifier les facteurs associés à ce retard. Méthodes. – Enquête dans différents centres de santé tunisiens du 24 mars au 30 octobre 2014. Nous avons inclus tous les patients âgés ≥ 18 ans atteints de TB pulmonaire (avec ou sans documentation bactériologique). Nous avons mesuré le délai entre l’apparition des premiers symptômes respiratoires et l’instauration du traitement. Trois catégories de retard ont été définies : retard dû au patient, retard dû au système de santé, retard global. Résultats. – Nous avons inclus 352 patients dans l’étude (242 hommes et 110 femmes). L’âge moyen était de 42,2 ans ± 17,7. Le retard médian entre l’apparition des premiers symptômes et l’instauration du traitement était de 52,56 jours. Les retards dus aux patients étaient plus fréquemment observés chez les hommes, les patients alcooliques et les patients se sachant malades. Les retards dus au système de santé étaient plus fréquemment observés chez les personnes âgées, les femmes, les patients ayant consulté dans un cabinet privé et chez les patients traités en ambulatoire. Conclusion. – Une meilleure sensibilisation de la population quant aux symptômes de la TB est recommandée et une meilleure formation des professionnels de santé devrait être mise en place afin de réduire ces retards et d’instaurer un traitement aussi vite que possible. © 2015 Publi´e par Elsevier Masson SAS. Mots clés : Retard diagnostique ; Tuberculose ; Diagnostic ∗

Corresponding author. E-mail address: [email protected] (J. Ben Amar).

http://dx.doi.org/10.1016/j.medmal.2015.11.012 0399-077X/© 2015 Published by Elsevier Masson SAS.

Please cite this article in press as: Ben Amar J, et al. Pulmonary tuberculosis: Diagnostic delay in Tunisia. Med Mal Infect (2015), http://dx.doi.org/10.1016/j.medmal.2015.11.012

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1. Introduction

2. Patients and methods

In 2012, the World Health Organization (WHO) estimated at 8.6 million the number of newly diagnosed tuberculosis (TB) case patients and at 1.3 million the number of deaths due to TB [1]. The highest prevalence was observed in Asia and Africa (24%) with most of these case patients in India and China (40%). Tunisia is an intermediate TB endemic country with a 2012reported incidence of 30/100,000 population. A partnership program with the Global Fund was established in 2008. It aims at reducing the incidence of TB and at reaching the objectives set by the Stop TB strategy by 2015 (i.e., reducing prevalence and deaths due to TB by 50% compared with the 1990 baseline, building on existing achievements to eliminate TB as a public health problem by 2050, ensuring detection of at least 70% of TB patients excreting BK in sputum, and successfully treating at least 85% of them. The Tunisian TB plan is a threefold strategy:

We conducted a questionnaire-based study between March and October 2014 with newly diagnosed pulmonary TB (PTB) patients consulting in all Tunisian treatment facilities entitled to diagnose and provide care to TB patients. Bacteriological confirmation was not required for inclusion in the study but all patients had to be initiated on an anti-TB treatment.

• early TB detection of presumptive patients, household and close contacts, and at-risk groups; • implementation of the directly observed treatment control strategy (DOTS) until complete recovery; • BCG vaccination. Identifying and treating TB patients are defined as the most effective measures to combat the disease. Controlling TB epidemic can indeed only be achieved by limiting the transmission of the bacillus [2]. Diagnostic delays result in individual (increased morbidity and mortality) [3] and collective consequences (increased contagiousness) [4]. This is why time to diagnosis is a key indicator of the quality of TB control programs. Many TB studies focused on diagnostic delays as it is one of the main factors preventing disease eradication [5,6]. Patients at an early stage of the disease produce very few bacteria. The risk of transmission is therefore limited. As the disease progresses, the number of excreted bacteria increases and patients become increasingly contagious. Our aim was to evaluate the extent of TB diagnostic delays in Tunisia and to identify associated risk factors to effectively adapt TB control measures.

2.1. Inclusion criteria We included patients aged ≥ 18 years who received a PTB diagnosis during the study period, with or without bacteriological confirmation. We did not include patients presenting with latent TB or patients who had already been on an anti-TB treatment for more than a month. We also did not include patients who did not hold the Tunisian nationality. Patients were recruited in pulmonology wards and TB clinics. 2.2. Data collection We collected data from the patients’ medical records and using a standardized patient questionnaire administered by a trained healthcare worker. The questionnaire was designed on the basis of a literature review aiming at identifying existing factors associated with diagnostic delays. Collected data included patient- and disease-related data as well as any consequences due to substantial diagnostic delays (hospitalization, severe clinical presentations). Questions related to symptoms frequently associated with PTB were included in the questionnaire (cough, hemoptysis, night sweat, etc.). Two types of diagnostic delays were identified (Fig. 1 [7]): • diagnostic delay due to the patient (PD) corresponds to the time between symptom onset and the first consultation; • diagnostic delay due to the healthcare system (HSD) corresponds to the time between the first consultation and treatment initiation. We also made a distinction between: • treatment delay (TD): time between diagnosis and treatment initiation;

Fig. 1. Diagnostic and treatment delays for TB patients according to Okür et al. [7]. Retard de prise en charge de la tuberculose selon Okür et al. [7].

Please cite this article in press as: Ben Amar J, et al. Pulmonary tuberculosis: Diagnostic delay in Tunisia. Med Mal Infect (2015), http://dx.doi.org/10.1016/j.medmal.2015.11.012

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J. Ben Amar et al. / Médecine et maladies infectieuses xxx (2015) xxx–xxx Table 1 Sociodemographic characteristics of included patients. Caractéristiques sociodémographiques des patients inclus dans l’étude.

Sex Male Female Age 18–39 years 40–59 years 60–69 years 70 years and above Education level Never been to school Primary school Secondary school University Missing data Occupation Unemployed Manual workers Civil servants Housewives Other Missing data Medical coverage Medical care free of charge Social security coverage Other Missing data

3

3. Ethical considerations

n

%

242 110

68.8 31.2

166 110 18 58

50.3 33.4 5.6 16

52 106 129 31 34

16.4 33.5 40.4 9.7

79 145 33 31 60 4

22.6 41.7 9.6 8.8 17.4

82 173 56 41

26.4 55.6 18.1

The present study was conducted within the frame of the grant awarded by the Global Fund and was approved by the Tunisian Ministry of Health. Patients were made aware of the study processes and of the type of data required. 4. Results 4.1. Patients’ characteristics

Lengthy PD and HSD were defined as > 30 days [8] and > 7 days, respectively. They were defined on the basis of delays reported in the literature.

A total of 352 patients were included in the study; 68.8% were men. The mean age was 42.2 years ± 17.7 (range: 18–92 years). Most patients held secondary education diploma (53.2%) and were from low socioeconomic backgrounds (Table 1). We observed that 6.8% of male patients had a history of TB compared with 3.1% of female patients. A reported 26% of male patients presented with alcohol dependence. Most patients were diagnosed in community health centers (73.8%) or by TB screening (21%). TB detection by screening methods was significantly more frequent in male patients (23.4% vs. 15.9%; P = 0.11), while TB detection in a community health center was significantly higher for female patients (79.3% vs. 71.3%; P = 0.11). TB detection during a contact investigation represented 11.6% of case patients. This figure corresponds to three-quarters (74.1%) of patients detected by screening methods. TB detection following an occupational screening accounted for 17.5% of patients while screening in school settings only accounted for 0.8% (Fig. 3). Symptoms driving patients to consult included asthenia (91.2%), weight loss (90.1%), feeling sick (89%), cough (88.7%), and hemoptysis (34.6%). The feeling of being sick was more frequently observed in female patients (94.1% vs. 86.7%; P = 0.04).

2.3. Data analysis

4.2. Diagnostic and treatment delays

Quantitative data was expressed as the mean ± SD with extreme and median values. Categorical data was expressed as percentage calculation. We used Student’s t-test to compare mean data and Pearson’s Chi2 test to compare percentages. A P-value of 5% was considered statistically significant. Data capture was performed using the Epi Data software and data analysis using the STATA software.

Delays due to patients (PD) and to the healthcare system (HSD) are presented in Table 2. PD distribution is detailed in Fig. 2. We observed that 24.2% of patients experienced diagnostic delays. Significantly higher delays were observed in male patients (27.5% vs. 18.4%; P = 0.10). The length of PD was, however, shorter for patients benefiting from a health insurance

• and overall delay (OD): time between symptom onset and treatment initiation.

Table 2 Diagnosis and treatment delays. Retards de diagnostic et de prise en charge. Delay

Minimum

Maximum

Mean

Standard deviation

Overall delay (days): date of symptom onset/treatment initiation Patient delay (days): symptom onset/first consultation Healthcare system delay (days): first consultation/treatment initiation Delay first consultation/specialist consultation Delay specialist consultation/diagnostic date Delay diagnostic date/treatment initiation

0.00 0.00 0.00 0.00 0.00 0.00

541.88 344.81 468.56 285.94 293.38 70.88

56.52 29.54 29.71 14.11 14.93 1.86

65.77 43.96 51.89 33.57 33.62 6.70

Please cite this article in press as: Ben Amar J, et al. Pulmonary tuberculosis: Diagnostic delay in Tunisia. Med Mal Infect (2015), http://dx.doi.org/10.1016/j.medmal.2015.11.012

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J. Ben Amar et al. / Médecine et maladies infectieuses xxx (2015) xxx–xxx 12.6 >2 months

5.8 16.4 11.6 12.5 11.1

Paent delay

30-59 days

32.2

Total

15-29 days

45.5

Female

24.6

Male 14.9 7-14 days

7.6 19 28.8 28.5 28.9

<7 days

0

5

10

15

20

25

30

35

40

45

50

Percentage of paents

Fig. 2. Patient delay (in days) by sex. Retard patient (jours) selon le sexe.

(16.3% vs. 25.3% for precarious people; P = 0.02). We did not observe any significant association with other sociodemographic criteria, and especially with patients’ place of residence, age, or level of education. We observed that 18.5% of patients who experienced diagnostic delays (PD) did not actually think so. The main reasons for such delays included patients waiting for symptoms to spontaneously disappear (56.5%), financial reasons (22.3%), poor care usually received in healthcare facilities (9.5%), or fear of a severe diagnosis (4.69%). Differences were observed between sociodemographic variables: a significantly higher number of female patients thought that they were not delaying time to diagnosis (35% vs. 12.4%; P = 0.04). Alcohol dependence was also significantly associated with patient delays (40.4% vs. 21.1%; P = 0.009) (Fig. 3). We did not observe any significant association between PD and a history of TB, of chronic respiratory tract infection, or the presence of hemoptysis (25.3% vs. 22.5%; P = 0.62) (Table 3).

Negave repercussions on professional life

60.3

Paents’ opinion

Tendency to shut themselves away

34.0

High associated cost

Patients’ opinion on TB stigmatization is represented in Fig. 3. We observed that 60.3% of patients thought that TB negatively impacted their professional life, 60.1% thought that TB had an impact on their marital relationship, and 33.5% were ashamed of having TB. PDs were more frequently observed in patients who thought a TB diagnosis would result in being isolated from others (32.5% vs. 18.2% of other patients; P = 0.03). PDs were also more frequently observed in patients who first consulted a specialist instead of a family physician (36.1% vs. 17.8%; P = 0.007). This is most probably due to the long waiting time to get an appointment, especially in some governorates. We did not observe any significant difference between private and public facilities. HSD distribution is described in Fig. 4. Factors associated with HSD by clinical characteristics are described in Table 4. We observed that 70.5% of delays were due to the healthcare system. Such delays were most frequently observed in female patients (80.2% vs. 66.6%; P = 0.06) and they significantly increased with age (57.1% in patients aged under 40 years and 84.6% in patients aged above 60 years; P = 0.0008). However, we did not observe any significant difference between urban and rural areas (69.3% vs. 72.1%; P = 0.71). HSD was significantly associated with the use of a CT scan (96.1% vs.

29.2

Negave repercussions on marital relaonship

60.1

Tendency to hide the disease from others

35.8

Shame of having TB

33.5 0.0

50.0

100.0

Percentage of paents

Fig. 3. Patients’ opinion on TB stigmatization. Perception de la stigmatisation due à la tuberculose.

Fig. 4. Healthcare system delay distribution. Distribution du retard dû au système de santé.

Please cite this article in press as: Ben Amar J, et al. Pulmonary tuberculosis: Diagnostic delay in Tunisia. Med Mal Infect (2015), http://dx.doi.org/10.1016/j.medmal.2015.11.012

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Table 3 Patient delay by medical history. Retard diagnostique dû au patient selon les antécédents. Patient delay > 30 days n

%

P Odds ratio (OR) Univariate analysis (95% CI)

Chronic respiratory diseases 228 23.6 No Yes 16 36.5 Alcohol dependence No 200 21.1 44 40.4 Yes Other dependence 207 22.1 No Yes 37 36.5 TB history 227 23.3 No Yes 17 38.4 244 24.2 Total

P

Odds ratio (OR) Multivariate analysis (95% CI)

1 1.86 (0.54–6.40)

0.31

1 2.54 (1.25–5.20)

1 2.24 (1.07–4.68)

0.03

0.009

1 2.03 (0.96–4.29)

1 1.71 (0.79–3.74)

0.17

0.06

1 2.05 (0.67–6.31)

0.21

1 1.93 (0.61–6.09)

0.26

Table 4 Healthcare system delay by clinical characteristics. Retard dû au système de santé selon les caractéristiques cliniques. Delay between the first consultation and treatment initiation (> 7 days)

Hemoptysis No Yes TB history No Yes Patients hiding they have TB Yes No Unknown Facility of first consultation Not detailed Community health center Hospital Private practice Other First physician consulted Not detailed Family physician Specialist Hospitalization Not detailed Yes No Severe symptoms Not detailed Yes No Bacteriological confirmation No Yes Total

n

%

Odds ratio (OR) Univariate analysis (95% CI)

140 80

72 68

1 0.82 (0.45–1.51)

203 17

71.1 61.8

1 0.65 (0.22–2.00)

85 120 15

67.1 74.3 56.3

0.70 (0.38–1.32) 1 0.45 (0.13–1.50)

0.19

4 46 97 68 5

66.3 65 85.4 38.8

1 0.94 (0.46–1.95) 2.97 (1.20–7.37) 0.32 (0.04–2.40)

0.87 0.01 0.26

4 140 76

74.1 64.8

1 0.64 (0.35–1.19)

1 166 53

67 80.7

0.48 (0.22–1.05) 1

0.06

107 22 91

52.7 74.1

0.39 (0.15–1.05) 1

0.06

133 87 220

77 61.4 70.5

1 0.47 (0.26–0.87)

P

0.53

0.45 0.27

0.15

0.01

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67.1%; P = 0.003). However, we did not observe any significant association between HSD and the use of bronchoscopy.

5. Discussion The results of our study reveal that both PD and HSD were quite lengthy. The average PD was 29.54 days ± 43.96 and the average HSD was 29.71 days ± 51.89. The mean treatment delay (TD) was 56.52 days ± 65.77. We observed that 25.8% of delays were due to patients and that 74.2% were due to the healthcare system.

5.1. Median diagnostic delays The results of our study indicate that the median overall diagnostic delay was 37.44 days. This figure is lower than the median delay observed in Storla’s review [5] conducted in 2008 (mean: 72 days). It is also lower than the delays reported in studies conducted in Italy (median delay of 65 days [9]), Norway (63 days) [10], and France (68 days) [11]. Our PD and HSD (11 and 14 days, respectively) are also lower than those reported in the above studies (7 and 36 days in Italy, 28 and 33 days in Norway, and 14 and 25 days in France). Storla et al. [5] observed a median overall delay of 72 days. The lowest median delays were observed in Pakistan (21 days) [12], China (31 days) [13], and in the United States (35 days) [14]. The highest median delays were observed in Tanzania (136 days) [8], the United Kingdom (126 days) [15], and Burkina Faso (120 days) [16]. The lowest median patient delays were observed in Taiwan [17], Italy [9], and New Zealand [18] (< 7 days). This may be partly explained by the vast majority of inhabitants living in urban areas and being better informed in terms of healthcare prevention. The highest median patient delays were observed in the United Kingdom (63 days) [15] and Ethiopia (60 days) [19]. Such diagnostic delay differences depend on various factors including access to healthcare facilities, quality of TB control programs, awareness of the population on TB issues, social, economic, and cultural status of the country. Lengthy diagnostic delays were observed in some industrialized countries, such as in the United Kingdom [15], probably because physicians and patients are not that familiar with TB and are thus less likely to diagnose or think about TB in the event of a persistent cough. Storla’s review highlighted the difficulty of precisely defining TB diagnostic delay [5]. Significant differences were observed between studies in terms of inclusion and exclusion criteria, of determining the date of symptom onset, and the date of the first consultation. A total of 58 studies were reviewed and the authors of 49 studies defined the date of symptom onset as the date of occurrence of any symptom; the authors of two studies defined that date as the date patients developed a cough, and it was pulmonary symptoms for another study. The authors of six studies could not determine symptom onset.

5.2. Factors associated with substantial diagnostic delays We observed that PD was significantly lower for patients benefiting from a health insurance (16.3% vs 25.3% for precarious patients; P = 0.02). Healthcare expenses are directly paid by patients in most developing countries and these expenses can account for up to 127% of patients’ monthly income in some of these countries [20]. Although patients do not have to pay for TB management in Tunisia, some patients will have to spend significant extra-costs. In addition to being at higher risk of TB due to their living conditions, precarious people are also associated with the most important consultation delay. Potential risk factors for diagnostic delays reported in the literature vary between studies and contradictions are even observed for a single risk factor. For instance, the authors of some studies associated a specific risk factor with diagnostic delay while that same factor was thought to reduce diagnostic delays in other studies [21,22]. WHO conducted a study in Syria and concluded that HIV infection was a risk factor for a longer diagnostic delay [21]. However, the authors of three other studies came to the opposite conclusion [22]. The results of several studies revealed that patients presenting with chronic cough and/or other pulmonary diseases were at higher risk of diagnostic delays [23]. This may be due to the higher incidence of intercurrent diseases and comorbidities in these patients which make it more difficult to establish diagnosis. However, the authors of another study obtained once again opposite results [24]. Some authors indicated that negative smear tests were associated with diagnostic delays [25,26], while the results of another study indicated the opposite (WHO study conducted in Egypt [27]). The results of other studies revealed that alcohol dependence or drug addiction was associated with a higher diagnostic delay [28,29]. The financial impact of such dependences and their consequences on the patient’s health led the patient not to seek medical help and disturbed symptom identification [28,29]. Difficult access to health care was also mentioned as a potential cause for diagnostic delay [8,30]. Some authors observed higher diagnostic delays in elderly patients [9,31,32] while the results of two other studies pointed out to the opposite [33,34]. Young and employed patients are better taken care of as they can afford better health care. This relation may also be explained by them needing to be healthy to keep on working. Diagnostic delays in female patients have been reported in Burkina Faso [34] and in the United States [27]. Other studies came to the opposite conclusion [8,9,27,29–35] and the reason might be a more difficult access to health care for women, especially for women living in rural areas. This restricted access to health care may be due to cultural and social factors contributing to women’s limited independence, to financial and transportation difficulties, and to their free will to consult a physician. In some countries, immigrants are also frequently confronted to diagnostic delays [14]. Several studies highlighted the relation between low income/poverty and diagnostic delays [8,9,19–35]. Another risk

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factor for diagnostic delay lies in a low level of education and/or a poor awareness and poor knowledge of TB. Patients do not know the symptoms of TB or chronic signs similar to that of TB [36,37]. We observed that the healthcare system delay varies by type of first consultation. A higher delay was observed with patients first consulting a private physician. This may be explained by the physicians’ poor awareness of TB in private practices as reported by the authors of a study conducted in Malaysia [38]: only 17.8% of patients who first consulted a family physician had a chest xray and a smear microscopy performed. Greater awareness of family physicians is however needed to reduce HSD as most TB patients first come to them for a medical consultation. 6. Conclusion Although anti-TB treatment and care are free of charge in Tunisia, diagnostic delays are relatively lengthy. This delay seems to be largely due to the healthcare system. Untreated patients with positive smear test represent the main source of infection; diagnostic and treatment delays in those patients increase the risk of transmission. The Tunisian population should be better informed on TB and healthcare professionals should pay a closer attention to potential TB symptoms. Healthcare system delay should also be reduced by improving the coordination between the various players and by allocating more resources to laboratories. Authors’ contribution Mohamed Hassairi designed the questionnaire and performed the statistical analysis. Ben Amar Jihen, Mohamed Hassairi, and Bouacha Hend wrote the article. Ben Salah Nozha, Charfi Ridha, Fourati Rachid, Dhikrayet Gamara, and Aouina Hichem conducted the survey. Disclosure of interest The authors declare that they have no competing interest. References [1] WHO. Global tuberculosis report 2013. Geneva: WHO; 2013. [2] Lin X, Chongsuvivatwong V, Lin L, Geater A, Lijuan R. Dose-response relationship between treatment delay of smear-positive tuberculosis patients and intrahousehold transmission: a cross-sectional study. Trans R Soc Trop Med Hyg 2008;102:797–804. [3] Zafran N, Heldal E, Pavlovic S, Vuckovic D, Boe J. Why do our patients die of active tuberculosis in the era of effective therapy? Tubercle Lung Dis 1994;75:329–33. [4] El-Sony A, Enarson D, Khamis A, Baraka O, Bjune G. Relations of grading of sputum smears with clinical features of tuberculosis in patients in routine practice in Sudan. Int J Tuberc Lung Dis 2002;6:91–7. [5] Storla DG, Yimer S, Bjune GA. A systematic review of delay in the diagnosis and treatment of tuberculosis. BMC Public Health 2008;8:15. [6] Sreeramareddy CT, Panduru KV, Menten J, Van den Ende J. Time delays in diagnosis of pulmonary tuberculosis: a systematic review of literature. BMC Infect Dis 2009;9:91.

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Please cite this article in press as: Ben Amar J, et al. Pulmonary tuberculosis: Diagnostic delay in Tunisia. Med Mal Infect (2015), http://dx.doi.org/10.1016/j.medmal.2015.11.012