Urmite

Cléa Melenotte
email: melenotteclea@gmail.com

Michel Drancourt

Jean Pierre Gorvel

Jean Louis Mège

Didier Raoult

Le syndrome de fatigue chronique post infection bactérienne n'est pas une infection latente

Keywords: Lyme disease, latent infection, post-infectious chronic fatigue syndrome maladie de Lyme, infection latente, syndrome de fatigue chronique post-infectieux Post-bacterial infection chronic fatigue syndrome

Post-infectious chronic fatigue syndrome is a public health problem. Etiologies and physiopathological mechanisms are unknown. Some viruses are known to be involved in post-infectious chronic fatigue syndrome, but the role of bacterial infection is still questionned, especially in cases of post-treatment Lyme disease syndrome where subjective symptoms are regularly attributed to the presence of the dormant bacterium without scientific evidence.

However, the medical experience of recalcitrant infections, relapses, and reactivations questions the role of "dormant bacteria" in asymptomatic latent infections as well as in subjective symptoms. We summarized scientific literature data on post-bacterial infection chronic fatigue syndrome, the role of dormant bacteria in latent infections, and bacterial asymptomatic carriage. Subjective symptoms described in postinfectious chronic fatigue syndromes are still misunderstood and there is no evidence suggesting that such symptoms could be related to dormant bacterial infection or carriage of viable bacteria. Psychological trauma may be part of these subjective symptoms. Post-infectious chronic fatigue syndrome could nonetheless be due to unknown microorganisms. Antibiotic treatment is not required for latent infections, except for latent syphilis and latent tuberculosis infections to prevent, after the primary infection, progression to the secondary or tertiary stage of the disease.

Résumé

Le syndrome de fatigue chronique post-infectieux représente un enjeu de santé publique. Ses étiologies et mécanismes pathophysiologiques restent inconnus. Certains virus sont impliqués dans le syndrome de fatigue chronique post-infectieux, mais le rôle de l'infection bactérienne est encore remis en question notamment dans le cadre du « Lyme tardif post-thérapeutique » lors duquel les symptômes subjectifs sont régulièrement attribués à la présence de la bactérie dormante, sans preuve scientifique.

Toutefois, l'expérience médicale des infections réfractaires au traitement, des rechutes et des réactivations met en doute le rôle de la « bactérie dormante » dans les infections latentes asymptomatiques ainsi qu'en cas de symptômes subjectifs. Nous résumons les données scientifiques issues de la littérature sur le syndrome de fatigue chronique post infection bactérienne, le rôle des bactéries dormantes dans les infections latentes et le portage bactérien asymptomatique. Les symptômes subjectifs décrits en cas de syndromes de fatigue chronique post-infectieux restent peu compris et aucune donnée ne suggère que ces symptômes peuvent être liés à une infection bactérienne dormante ou au portage de bactéries viables. Un traumatisme psychologique pourrait en partie expliquer ces symptômes subjectifs. Le syndrome de fatigue chronique post-infectieux pourrait néanmoins être dû à des micro-organismes inconnus. Aucun traitement antibiotique n'est requis en cas d'infections latentes, à l'exception d'une syphylis latente ou d'une infection tuberculeuse latente afin de prévenir la progression vers les stades secondaires et tertiaires de la maladie, après l'infection primaire.

I. Introduction

Chronic fatigue syndrome is defined by unexplained disability syndrome and a combinaison of non-specific subjective symptoms including fatigue, headache, musculoskeletal pain, neurocognitive disorders, sleeping disorders, mood disorders, and even respiratory tract disorders. Chronic fatigue syndrome represents a major public health problem, but its etiologies remain poorly understood. Post-infectious chronic fatigue syndrome has been reported after viral infections such as Epstein-Barr virus infection, Chikungunya virus infection, and hepatitis A and B infections [START_REF] Duvignaud | Rheumatism and chronic fatigue, the two facets of postchikungunya disease: the TELECHIK cohort study on Reunion island[END_REF][START_REF] Jason | Predictors of Post-Infectious Chronic Fatigue Syndrome in Adolescents[END_REF][START_REF] Berelowitz | Post-hepatitis syndrome revisited[END_REF]. Regarding bacterial infections, post-infectious chronic fatigue syndrome may be suspected after brucellosis, Q fever caused by Coxiella burnetii, and Lyme disease caused by Borrelia burgdorferi group (Borreliae). However, no evidence of a progressive infection can explain chronic fatigue syndrome (no clinical or biological inflammatory syndrome, no evidence of bacterial multiplication, and no evidence of antibiotic effectiveness). Post-infectious chronic fatigue syndrome therefore remains a crucial and unsolved issue. The question currently raised is whether latent infection could be responsible for subjective syndrome, as told in the post-treatment Lyme disease syndrome.

However, the medical experience of recalcitrant infections, relapses, and reactivations observed in cases of bone and joint infections even decades after the primary infection, underlines that some bacteria could persist in a dormant stage. These dormant bacteria remain quiescent and viable, without any clinical manifestation. Several factors can promote reactivation such as immunosuppression and pregnancy, but no reactivation factors can sometimes be identified. Some bacterial infections occur in several stages, with latency periods in-between some stages. This is the case for Lyme disease, tuberculosis, and syphilis. The primary infection is self-limiting, but if left untreated the disease can quiescently progress to secondary or tertiary manifestations. Finally, the identification of pathogenic bacteria in asymptomatic and healthy individuals, as asymptomatic carriage, led us to re-interrogate Koch's postulates.

To find out whether these latent infections, dormant bacteria, or asymptomatic carriages may have a role in post-infectious chronic fatigue syndrome, we performed a literature review. We searched Medline and Googlescholar databases for references with no language restriction and no restriction of publication time nor status, with the following keywords: dormant bacteria, latent infection, post-infectious chronic fatigue syndrome, chronic fatigue syndrome, asymptomatic carriage, post-treatment lyme disease syndrome, post-Q fever fatigue syndrome, latent tuberculosis, Mycobacterium tuberculosis, Brucella spp., Tropheryma whipplei, Bartonella spp., Staphylococcus aureus. A total of 119 references were included in the final qualitative synthesis.

II. Post-bacterial infection chronic fatigue syndrome

Coxiella burnetii: the Q fever fatigue syndrome

First described in 1992, the Q fever fatigue syndrome (QFS) is a health challenge as it is responsible for impaired quality of life and absenteeism [START_REF] Keijmel | Effectiveness of Long-term Doxycycline Treatment and Cognitive-Behavioral Therapy on Fatigue Severity in Patients with Q Fever Fatigue Syndrome (Qure Study): A Randomized Controlled Trial[END_REF][START_REF] Keijmel | The Qure study: Q fever fatigue syndrome-response to treatment; a randomized placebo-controlled trial[END_REF]. QFS is characterized by subjective symptoms for at least six months after acute Q fever. It is responsible for significant disability in daily living and it is not associated with objective symptoms nor organic lesions [START_REF] Keijmel | Effectiveness of Long-term Doxycycline Treatment and Cognitive-Behavioral Therapy on Fatigue Severity in Patients with Q Fever Fatigue Syndrome (Qure Study): A Randomized Controlled Trial[END_REF][START_REF] Parker | Q fever[END_REF][START_REF] Morroy | Fatigue following Acute Q-Fever: A Systematic Literature Review[END_REF]. The diagnosis should rule out other somatic and psychiatric etiologies of chronic fatigue syndrome. QFS also does not correlate with the anti-C. burnetii phase I IgG levels, which are insufficient and erroneous to conclude to the persistence or lack of persistence of the infection.

In the Netherlands, after the 2007-2011 epidemiological outbreaks, QFS developped in 20% of patients who had been diagnosed with acute Q fever as compared with 4% of healthy controls [START_REF] Keijmel | The Qure study: Q fever fatigue syndrome-response to treatment; a randomized placebo-controlled trial[END_REF]. In Australia, QFS developped in 28% of patients who had been diagnosed with acute Q fever versus 0% of controls [START_REF] Marmion | Q fever: persistence of antigenic non-viable cell residues of Coxiella burnetii in the host--implications for post Q fever infection fatigue syndrome and other chronic sequelae[END_REF]. Pentillas et al. provided the first broad description of QFS in Australia, but their report can be questioned as they included patients presenting with objective symptoms (diarrhea, swollen superficial lymph node) [START_REF] Penttila | Cytokine dysregulation in the post-Q-fever fatigue syndrome[END_REF]. Just like post-treatment Lyme disease syndrome (PTLDS), the persistence of living microbes has been suggested to be involved in QFS, but never confirmed [START_REF] Penttila | Cytokine dysregulation in the post-Q-fever fatigue syndrome[END_REF]. A fundamental and dangerous confusion may thus be observed between latent infections and QFS. This confusion leads to misdiagnosing C. burnetii persistent latent infection as illustrated by the fatal case recently reported by Sudocheva et al.: a 19-year-old man was diagnosed with post-Q fever fatigue syndrome and died from disseminated C. burnetii infection 10 years after acute Q fever infection [START_REF] Sukocheva | Coxiella burnetii dormancy in a fatal ten-year multisystem dysfunctional illness: case report[END_REF][START_REF] Raoult | Q Fever: Confusion Between Chronic Infection and Chronic Fatigue[END_REF]. C. burnetii was identified by immunohistochemistry (IHC) and polymerase chain reaction (PCR) targeting the COM1 and IS1111 sequences in all post-mortem investigated organs [START_REF] Sukocheva | Coxiella burnetii dormancy in a fatal ten-year multisystem dysfunctional illness: case report[END_REF]. Marmion et al. also reported two cases of patients misdiagnosed with chronic fatigue syndrome instead of persistent C. burnetii endocarditis (one fatal case) [START_REF] Marmion | Q fever: persistence of antigenic non-viable cell residues of Coxiella burnetii in the host--implications for post Q fever infection fatigue syndrome and other chronic sequelae[END_REF][START_REF] Harris | Long-term persistence of Coxiella burnetii in the host after primary Q fever[END_REF]. These three cases argue in favor of long-term latent and asymptomatic C. burnetii infection. This infection is different from QFS as it only affects patients presenting with subjective signs and symptoms, with no detected living bacteria. Experimental studies on tissues distinguished living bacteria from dead bacteria using fluorescence in situ hybridization targeting the bacterial ribonucleic acid [START_REF] Melenotte | B-cell non-Hodgkin lymphoma linked to Coxiella burnetii[END_REF]. As C. burnetii was not isolated from these blood samples in case of QFS, persistent C. burnetii cell components are probably residues of the original heavy seeding during bacteremia rather than a renewed production of viable bacteria [START_REF] Morroy | Fatigue following Acute Q-Fever: A Systematic Literature Review[END_REF]. The long-term persistence of non-viable in situ or circulating C. burnetii cell components including antigens or DNA is the sole biological finding currently correlating with these subjective symptoms. The circulation of these bacterial cell components could result in an altered cell immunity and in an altered cytokine production [START_REF] Harris | Long-term persistence of Coxiella burnetii in the host after primary Q fever[END_REF][START_REF] Keijmel | Altered interferon-γ response in patients with Q-fever fatigue syndrome[END_REF][START_REF] Kato | Detection of Coxiella burnetii specific DNA in blood samples from Japanese patients with chronic nonspecific symptoms by nested polymerase chain reaction[END_REF][START_REF] Harris | Long-term persistence of Coxiella burnetii in the host after primary Q fever[END_REF]. The subsequent ongoing production of pro-inflammatory cytokines could then be responsible for fatigue. Patients presenting with QFS were described as differing in the frequency of HLA-DRB1*11 carriage and the 2/2 genotype of the IFNγ intron 1 microsatellite when compared with controls [START_REF] Helbig | Immune response genes in the post-Q-fever fatigue syndrome, Q fever endocarditis and uncomplicated acute primary Q fever[END_REF]. In addition, cytokine release pattern of peripheral blood monocyte cells of QFS patients was reported as aberrant with an increased IL-6 release, a decreased level of IL2 release, and an increased INFγ and CXCL10 production [START_REF] Raijmakers | Interferon-γ and CXCL10 responses related to complaints in patients with Q fever fatigue syndrome[END_REF].

Just like PTLDS, it is unknown whether QFS is a direct consequence of the non-viable or viable bacteria or if its origin is psychological.

Predictors of QFS are contradictory, and factors such as female sex and young adult have been associated with QFS [START_REF] Morroy | Fatigue following Acute Q-Fever: A Systematic Literature Review[END_REF]. The severity of the acute illness as well as preexisting health problems and hospitalization have been reported as QFS predictors [START_REF] Strauss | Are fatigue symptoms and chronic fatigue syndrome following Q fever infection related to psychosocial variables?[END_REF][START_REF] Morroy | The health status of Q-fever patients after long-term follow-up[END_REF].

Borrelia burgdorferi and post-treatment Lyme disease syndrome

Post-treatment Lyme disease syndrome (PTLDS) is characterized by the late onset of musculoskeletal symptoms and antibiotic treatment failures. PTLDS is estimated to affect 10% to 20% of patients treated with antibiotics effective against Lyme disease [START_REF] Goodlet | Adverse Events Associated with Antibiotics and Intravenous Therapies for Post-Lyme Disease Syndrome in a Commercially Insured Sample[END_REF][START_REF] Cairns | Post-Lyme borreliosis syndrome: a meta-analysis of reported symptoms[END_REF]. PTLDS is a public and political challenge as compared with C. burnetii infection, but few studies have been conducted to identify B. burgdorferi cell components or to understand the physiological and immune mechanisms involved in PTLDS [START_REF] Cervantes | Doctor says you are cured, but you still feel the pain. Borrelia DNA persistence in Lyme disease[END_REF]. Picha et al. performed a study with B. burgdorferi-infected patients, and identified B. burgdorferi DNA up to six months after the administration of an effective antimicrobial treatment. However, this result does not indicate the presence of living bacteria, and all patients with a positive B. burgdorferi PCR did not present with subjective symptoms [START_REF] Pícha | DNA persistence after treatment of Lyme borreliosis[END_REF][START_REF] Iyer | Detection of Borrelia burgdorferi nucleic acids after antibiotic treatment does not confirm viability[END_REF]. Autoimmune diseases are believed to be involved in patients diagnosed with PTLDS. Maccallini et al. hypothetized that such patients exhibited auto-immunity against γ-enolase, the neuron-specific isoenzyme of the glycolytic enzyme enolase [START_REF] Maccallini | Autoimmunity against a glycolytic enzyme as a possible cause for persistent symptoms in Lyme disease[END_REF].

Cabello et al. explained that in the absence of sterilizing immunity a strong antibody response was observed. They suggested that B. burgdorferi is located in a niche where it could be protected from the adaptive immune response [START_REF] Cabello | Hidden in plain sight: Borrelia burgdorferi and the extracellular matrix[END_REF]. The extracellular matrix, rich in collagen such as tendon and ligaments, was suspected to be the niche of B. burgdorferi in mice [START_REF] Cabello | Hidden in plain sight: Borrelia burgdorferi and the extracellular matrix[END_REF]. Crossland et al. recently identified persistent nonviable Borrelia in the central nervous system, joint-associated tissues, and urinary bladder of rhesus macaques following doxycycline therapy [START_REF] Crossland | Late Disseminated Lyme Disease: Associated Pathology and Spirochete Persistence Posttreatment in Rhesus Macaques[END_REF]. Hodzic et al. demonstrated that after ceftriaxone therapy in a mouse model, B. burgdorferi could not be cultured from tissues while low copy number of specific DNA sequences could be detected two, four, and eight months after treatment completion [START_REF] Hodzic | Resurgence of persisting non-cultivable Borrelia burgdorferi following antibiotic treatment in mice[END_REF].

Interestingly, Iyer et al. demonstrated in vitro that B. burgdorferi could not be cultured three days after ceftriaxone antibiotic treatment, but positive B. burgdorferi DNA was detected up to 56 days after antibiotic treament [START_REF] Iyer | Detection of Borrelia burgdorferi nucleic acids after antibiotic treatment does not confirm viability[END_REF]. These results are at odds with experimental data reported by Caskey et al. showing the doxycycline inability to kill quiescent B. burdgorferi, which newly developed after antimicrobial therapy [START_REF] Caskey | Persister Development by Borrelia burgdorferi Populations In Vitro[END_REF]. The lack of studies in humans does not allow scientific support for the responsibility of quiescent B. burgdorferi or dormant bacteria in PTLDS.

Brucella spp. and post-infectious fatigue syndrome

Chronic fatigue syndrome after Brucella infection has been reported in patients with poor health, musculoskeletal pain, depression, or anxiety without any infectious focus of the disease [START_REF] Castaño | Chronic brucellosis and persistence of Brucella melitensis DNA[END_REF]. However, the definition and description of persistent subjective symptoms after brucellosis is often mistaken with chronic brucellosis. Historically, antigen therapy was suggested to patients presenting with chronic brucellosis following antibiotic therapy [START_REF] Boura | Effect of bacterial extracts on the immunologic profile in chronic relapsing brucellosis patients[END_REF][START_REF] Roux | Antigen therapy in chronic brucellosis[END_REF][START_REF] Benning | Chronic brucellosis; success of treatment with brucellin[END_REF]. The term "post-brucellosis fatigue syndrome" could be more appropriate to differentiate subjective symptoms without detectable organic lesions following infection from chronic persistent Brucella infection. Some studies focused on post-brucellosis disease. The persistent detection of Brucella spp. DNA after an effective antibiotic therapy was initially related to relapses. Castano et al. recently identified the presence of Brucella spp. DNA in the blood and serum of patients presenting with persistent focalized infection, with non-focal disease and with subjective symptoms. This finding was even observed in the group of asymptomatic subjects with a history of brucellosis, but not in the control group [START_REF] Castaño | Chronic brucellosis and persistence of Brucella melitensis DNA[END_REF]. The authors reported that the proportion of individuals with Brucella melitensis DNA was significantly higher in symptomatic non-focal disease patients (patients with subjective symptoms and without identified focus) than in asymptomatic subjects [START_REF] Castaño | Chronic brucellosis and persistence of Brucella melitensis DNA[END_REF]. Brucella abortus has been widely used to study chronic fatigue syndrome in animal models.

An impaired mouse running activity has been described when animals were inoculated with B. abortus antigens [START_REF] Ottenweller | Mouse running activity is lowered by Brucella abortus treatment: a potential model to study chronic fatigue[END_REF]. Potential oxidative stress and immunological activation as assessed by an increase in tumor necrosis factor alpha are involved in chronic fatigue syndrome induced by B. abortus [START_REF] Gupta | Possible role of oxidative stress and immunological activation in mouse model of chronic fatigue syndrome and its attenuation by olive extract[END_REF].

Whether for Brucella spp., C. burnetii, or B. burgdorferi, the persistence of bacterial DNA copies in blood samples remains poorly understood.

We do not know if these DNA sequences are associated with subjective symptoms and the expression of viable dormant bateria.

III. Dormant bacteria and latent infection: a reversible aliveness

In 1944 Joseph Bigger led the founding stone of the concept of "dormant bacteria", with a microbiological definition. He observed that penicillin lysed a growing population of Staphyloccocus spp. but only a small proportion, although not resistant to antibiotics and not in a fission stage, survived [START_REF] Bigger | Treatment of Staphyloeoeeal Infections with Penicillin by Intermittent Sterilisation[END_REF]. This data suggested that penicillin was only effective in dividing bacteria. "Dormant bacteria" are characterized by a nongrowing and non-replicating stage, by viability (but unable to grow on usual culture media), and by tolerability to stress including stress-induced antibiotics [START_REF] Kell | Individuality, phenotypic differentiation, dormancy and "persistence" in culturable bacterial systems: commonalities shared by environmental, laboratory, and clinical microbiology[END_REF][START_REF] Barer | Viable but non-culturable and dormant bacteria: time to resolve an oxymoron and a misnomer[END_REF]. Consequently, they could be responsible for antibiotic treatment failure to eradicate the infection. At the "dormant" stage, bacteria are also non-virulent and bypass the innate immune system response. These bacteria could return to growth and normal activity when original conditions are restored [START_REF] Kell | Individuality, phenotypic differentiation, dormancy and "persistence" in culturable bacterial systems: commonalities shared by environmental, laboratory, and clinical microbiology[END_REF].

Staphylococcus aureus bone and joint infection

Since the description of Staphylococcus aureus as a "dormant" bacterium, mechanisms used to achieve its intracellular persistence have been partially identified. S. aureus small colony variant (SCV) is a quiescent metabolic state related to persistence, recurrence, and antibiotic resistance [START_REF] Barer | Viable but non-culturable and dormant bacteria: time to resolve an oxymoron and a misnomer[END_REF][START_REF] Kell | A Dormant Microbial Component in the Development of Preeclampsia[END_REF][START_REF] Proctor | Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections[END_REF]. Small colonies are also distinguished from usual S. aureus colonies on agar plates by their decreased pigmentation and reduced hemolysis [START_REF] Barer | Viable but non-culturable and dormant bacteria: time to resolve an oxymoron and a misnomer[END_REF][START_REF] Kell | A Dormant Microbial Component in the Development of Preeclampsia[END_REF][START_REF] Proctor | Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections[END_REF]. S. aureus SCVs are then characterized by a low metabolic activity. Proctor et al. showed that S. aureus SCVs settled in an intracellular niche and that 25% of the initial inoculum switched to SCVs [START_REF] Proctor | Persistent and relapsing infections associated with smallcolony variants of Staphylococcus aureus[END_REF][START_REF] Proctor | Staphylococcus aureus Small Colony Variants (SCVs): a road map for the metabolic pathways involved in persistent infections[END_REF].

In humans, S. aureus SCVs were recovered from abscess, bone and joint, blood, catheters, heart, and respiratory tract. All presented auxotrophic defects accounting for their low metabolic activities [START_REF] Kahl | Small colony variants (SCVs) of Staphylococcus aureus--a bacterial survival strategy[END_REF]. Non-professional phagocytic cells such as endothelial cells, epithelial cells, fibrobasts, osteoblasts, and keratinocytes were identified as host cells for intracellular persistence of S. aureus SCVs [START_REF] Proctor | Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections[END_REF]. In vitro, keratinocytes and endothelial cells infected with S. aureus SCVs did not present any sign of damaged cells unlike cells infected with the usual S. aureus which underwent cell apoptosis or necrosis [START_REF] Proctor | Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections[END_REF]. This data supports the role of these cells as latent niches for S. aureus infection.

Latent bacterial infection a. Syphilis

Treponema pallidum is responsible for syphilis and is characterized by its ability to invade the human body and escape the immune system. It is also characterized by a latent stage following the secondary stage and preceding the tertiary stage of the infection [START_REF] Peeling | Syphilis[END_REF]. Early latent syphilis is defined by a positive serology without clinical symptoms. Late latency may start one or two years after exposure and may last up to several decades. It is estimated that 15-40% of untreated individuals develop tertiary syphilis characterized by cardiac, neurological, skin, and bone involvement with destructive syphilitic gumma, hemiparesis, aphasia, aortitis, aortic aneurysm, and congestive heart failure or coronary disease [START_REF] Peeling | Syphilis[END_REF]. As a global worldwide re-emerging disease, latent T. pallidum infection is still challenging physicians because of two critical complications.

In immunocompromised hosts, malignant syphilis has been described as a severe cutaneous complication of syphilis in AIDS patients, and we recently observed neurological syphilis involvement in HIV-infected patients with low CD4 level (<350/mm 3 ). These reports demonstrated that immunosuppression is a factor promoting awakening of the latent form [START_REF] Dos Santos | Malignant syphilis in an AIDS patient[END_REF][START_REF] Hobbs | Neurosyphilis in patients with HIV[END_REF]. Pregnant women presenting with latent syphilis can transmit the infection in utero leading to recent dramatic outbreaks of congenital syphilis in Australia and the United States [START_REF] Cooper | The Re-Emergence of Congenital Syphilis in Ohio[END_REF][START_REF] Plotzker | Congenital Syphilis Prevention: Strategies, Evidence, and Future Directions[END_REF][START_REF] Nogrady | Sixth child dies from congenital syphilis in northern Australia[END_REF][START_REF] Diorio | Social Vulnerability in Congenital Syphilis Case Mothers: Qualitative Assessment of Cases in Indiana, 2014-2016[END_REF].

The detection of T. pallidum DNA in patients with latent stage of the disease was only observed in blood and ear scraping [START_REF] Castro | Detection of Treponema pallidum sp pallidum DNA in latent syphilis[END_REF]. Only former animal studies aimed to understand T. pallidum quiescent surviving. One century ago, Pearce and Brown described the rabbit's large and indurated lymph nodes (inguinal, popliteal, submental, auricular, axillary, and large flanck) as the latent niches of the bacterium [START_REF] Pearce | A STUDY OF THE RELATION OF TREPONEMA PALLIDUM TO LYMPHOID TISSUES IN EXPERIMENTAL SYPHILIS[END_REF]. Inoculation of the emulsion of resected asymptomatic lymph nodes induced the development of syphilis in previously uninfected animals [START_REF] Pearce | A STUDY OF THE RELATION OF TREPONEMA PALLIDUM TO LYMPHOID TISSUES IN EXPERIMENTAL SYPHILIS[END_REF]. In another experimental work, Collart et al. showed that corticosteroids reactivated latent syphilis in two of 12 rabbits [START_REF] Collart | SIGNIFICANCE OF SPIRAL ORGANISMS FOUND, AFTER TREATMENT, IN LATE[END_REF]. During this latent stage, the authors pointed out the morphological transformation of Treponema [START_REF] Collart | SIGNIFICANCE OF SPIRAL ORGANISMS FOUND, AFTER TREATMENT, IN LATE[END_REF]. T. pallidum is supposed to survive extracellulary, in areas rich in connective tissues and relatively inaccessible to circulating immune cells (tunica albuginea, tunica media of the aorta, testes) [START_REF] Collart | SIGNIFICANCE OF SPIRAL ORGANISMS FOUND, AFTER TREATMENT, IN LATE[END_REF]. Cerebrospinal fluid and lymphoid sites act as reservoirs for spirochetes, and maintain the disease in a quiescent state. The latent stage is characterized by the absence of symptoms and the reactivation may be promoted by immunosuppression or other hitherto unknown factors.

b. Lyme disease

Borrelia burgdorferi infection is characterized by symptom-free stages and several years may go by between the early localized and late disseminated stages [START_REF] Albert | Lyme arthritis in a 12-year-old patient after a latency period of 5 years[END_REF]. There is no documented case of bacterial presence at the latent stage. Reports rather focus on descriptions of the secondary or tertiary stage of the infection [START_REF] Pfister | Latent Lyme neuroborreliosis: presence of Borrelia burgdorferi in the cerebrospinal fluid without concurrent inflammatory signs[END_REF][START_REF] Fand | Pruritus in latent Lyme disease[END_REF]. Several animal models tried to identify the persistent niche of B. burgdorferi but most of these models focused on explaining PTLDS in mice, dogs, and macaques, and provided evidence of persistent bacteria by immunofluorescence and PCR after antibiotic therapy [START_REF] Crossland | Late Disseminated Lyme Disease: Associated Pathology and Spirochete Persistence Posttreatment in Rhesus Macaques[END_REF]. As previously discussed, the presence of B. burgdorferi DNA does not indicate bacterial viability.

As B. burgdorferi is probably present at a latent stage before the tertiary stage of the infection, its niche has not been identified. Although speculative works using mathematical models studied dormant properties of B. burgdorferi in vitro and in vivo, only migratory birds have been reported as able to carry B. burgdorferi at a latent stage for several months [START_REF] Gylfe | Reactivation of Borrelia infection in birds[END_REF][START_REF] Caskey | Persister Development by Borrelia burgdorferi Populations In Vitro[END_REF]. Moreover, immunosuppression has not been described as favoring the reactivation of B. burgdorferi, nor has it been described as influencing the acute phase of the infection [START_REF] Fürst | The impact of immunosuppression on erythema migrans. A retrospective study of clinical presentation, response to treatment and production of Borrelia antibodies in 33 patients[END_REF]. This was anecdotically described for B. miyamotoi reactivation in a patient presenting with follicular lymphoma treated with chemotherapy [START_REF] Boden | Borrelia miyamotoi-Associated Neuroborreliosis in Immunocompromised Person[END_REF]. Finally, evidence for latent Lyme disease reactivation in immunocompromised patients is scarce.

c. Tuberculosis

Mycobacterium tuberculosis is a global health challenge, with 10.4 milion new cases diagnosed in 2016 and 1.3 million deaths [START_REF]Global tuberculosis report[END_REF]. It has been estimated that one third of the global population carries latent M. tuberculosis infection -representing an enormous reservoir of potential tuberculosis cases -after initial infection usually occurring during childhood [START_REF] Hernández-Pando | Persistence of DNA from Mycobacterium tuberculosis in superficially normal lung tissue during latent infection[END_REF]. The infection is almost kept under control by the immune system and leads to disease in only 10% of cases [START_REF] Hernández-Pando | Persistence of DNA from Mycobacterium tuberculosis in superficially normal lung tissue during latent infection[END_REF]. Hundreds of million of tuberculosis reactivation cases are expected in future decades, representing a public health challenge [START_REF]Global tuberculosis report[END_REF]. The term "latent tuberculosis" was coined by Clemens von Pirquet (the inventor of the tuberculin skin test [TST]) in 1907. He described children with a positive TST presenting without any clinical symptoms [START_REF] Daniel | The history of tuberculosis[END_REF]. The current definition of latent tuberculosis combines a positive TST or positive interferon gamma release assay without clinical nor active radiological signs of the disease. Patients presenting with latent tuberculosis cannot transmit the disease but are subject to reactivation, with an estimated 2% to 23% of lifetime risk in developped countries [START_REF] Tufariello | Latent tuberculosis: mechanisms of host and bacillus that contribute to persistent infection[END_REF].

Reactivation of M. tuberculosis is triggered when the host's immune response is weakened or suppressed. Patients with high risk of reactivation have HIV co-infection, lymphoma, leukemia, neck cancer, or underwent transplantation or chemotherapy, or received TNF-alpha inhibitor treatment [START_REF] Wood | Risk factors for developing tuberculosis in HIV-1-infected adults from communities with a low or very high incidence of tuberculosis[END_REF][START_REF] Cheng | Risk of Active Tuberculosis in Patients with Cancer: A Systematic Review and Meta-Analysis[END_REF][START_REF] Aguado | Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain. Spanish Transplantation Infection Study Group, GESITRA[END_REF][START_REF] Keane | Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent[END_REF]. Patients with a moderate risk of reactivation are patients with diabetes mellitus and patients treated with systemic glucocorticoids [START_REF] Jick | Glucocorticoid use, other associated factors, and the risk of tuberculosis[END_REF][START_REF] Lee | Diabetes Mellitus and Latent Tuberculosis Infection: A Systemic Review and Metaanalysis[END_REF]. The success of M. tuberculosis is first based on its capacity to avoid the microbicidal activity of macrophages [START_REF] Neyrolles | Bacterial pathogenesis: A sand grain in antigen processing[END_REF][START_REF] Pires | Role of Cathepsins in Mycobacterium tuberculosis Survival in Human Macrophages[END_REF].

The reduction of MHC II expression by macrophages prevents the recognition of infected macrophages by CD4+ T lymphocytes and the activation of the adaptive immune response especially. In addition, M. tuberculosis inhibits the phagolysosome fusion avoiding the vacuole acidification and clearance of the ingested microorganism. It has been demonstrated that M. tuberculosis further prevents host cell apoptosis by enhancing the release of the membrane-bound TNFR2 receptors and by upregulating the expression of Mcl-1 (Bcl2 family protein) [START_REF] Peddireddy | Mycobacterial Dormancy Systems and Host Responses in Tuberculosis[END_REF]. In response to environmental stress, M. tuberculosis mycobacteria shut down and close tight causing thickening and decreased permeability of the cell wall [START_REF] Peddireddy | Mycobacterial Dormancy Systems and Host Responses in Tuberculosis[END_REF]. M. tuberculosis turns down its own central metabolism and survives for a long time in a dormant non-replicating stage.

Interestingly, the toxin-antitoxin system is involved in the persistence of Mycobacterium sp. in a dormant non-replicating stage [START_REF] Peddireddy | Mycobacterial Dormancy Systems and Host Responses in Tuberculosis[END_REF]. At a physiological stage, the long-lived "toxin" protein is neutralized by the short-lived "antitoxin" protein. However, at the dormant stage M. tuberculosis represses the expression of the antitoxin protein, which results in the accumulation of the "toxin" protein [START_REF] Peddireddy | Mycobacterial Dormancy Systems and Host Responses in Tuberculosis[END_REF]. The toxin protein, as a ribonuclease, cleaves free and ribosomal-bound single-stranded mRNA, inhibiting protein synthesis and bacterial growth [START_REF] Peddireddy | Mycobacterial Dormancy Systems and Host Responses in Tuberculosis[END_REF]. A group of proteins called the resuscitation promoting factors (encoded by rpf genes) also induce M. tuberculosis out of the dormant stage [START_REF] Gupta | Mycobacterium tuberculosis: immune evasion, latency and reactivation[END_REF]. When the stress agent is removed, rpf genes are activated, proteins are produced, and the bacterium is able to re-enter a replicative phase [START_REF] Gupta | Mycobacterium tuberculosis: immune evasion, latency and reactivation[END_REF]. The wellorganized granuloma confers a confined environment for the survival of the bacterium and Mycobacterium can be released as a serpentine cord in the granuloma, a morphological presentation which is not recognized and not phagocyted by macrophages [START_REF] Gupta | Mycobacterium tuberculosis: immune evasion, latency and reactivation[END_REF].

The cellular niches of M. tuberculosis have been revisited at the beginning of this century by Hernandez-Pando et al.. They identified M. tuberculosis DNA in macrophages and in non-professional phagocytic type II pneumocytes, endothelial cells, and fibroblasts [START_REF] Hernández-Pando | Persistence of DNA from Mycobacterium tuberculosis in superficially normal lung tissue during latent infection[END_REF]. Neyrolles et al. observed non-replicating M. tuberculosis mycobacteria within adipocytes where they exhibited increased resistance to isoniazid and a diminished resistance to pyrazinamide. This result is consistent with the hydrophilic property of isoniazid [START_REF] Neyrolles | Is adipose tissue a place for Mycobacterium tuberculosis persistence?[END_REF]. Furthermore, Ayyappan et al.

showed that in experimentally infected rabbits, M. tuberculosis modulated differently the adipocyte signalling according to the latent or active infections [START_REF] Ayyappan | Effect of Mycobacterium tuberculosis infection on adipocyte physiology[END_REF].

Nonetheless, animal models tried to reproduce latent M. tuberculosis infection, but none was truly contributory and representative as "latency" was drug-induced [START_REF] Mccune | Microbial persistence. I. The capacity of tubercle bacilli to survive sterilization in mouse tissues[END_REF][START_REF] Mccune | Microbial persistence. II. Characteristics of the sterile state of tubercle bacilli[END_REF].

d. Rickettsiosis, the Brill-Zinsser disease

Rickettsia prowazekii is responsible for epidemic typhus and is transmitted by body lice. It has deeply marked the history of medicine, war, famine, and migration [START_REF] Bechah | Epidemic typhus[END_REF]. In addition to its typical presentation including abrupt fever, rashes, and headaches, recurrent presentations of epidemic typhus have been reported such as Brill-Zinsser disease [START_REF] Bechah | Epidemic typhus[END_REF]. First described in 1934, Brill-Zinsser disease is unrelated to louse infestation but also presents as fever, headache, and cutaneous rash [START_REF] Murray | Brill's disease. IV. Study of 26 cases in Yugoslavia[END_REF]. The reactivation of R. prowazekii can occur even 40 years after the acute infection. Bacteremia can be detected and IgG antibodies serum reactivation assessed, with no detectable IgM antibodies, demonstrating the reactivation of the infection [START_REF] Stein | Brill-Zinsser disease in France[END_REF]. It has been hypothetized that after the initial contamination, the bacterium spreads via the lymphatic route and blood towards endothelial cells [START_REF] Bechah | Epidemic typhus[END_REF]. Some authors showed that Rickettsia spp. could be found in lymph nodes years after the acute infection, suggesting this lymphoid organ as a niche for bacterial survival and dormancy [83]. In mice, adipocytes were demonstrated to be the specific cell type for R. prowazekii dormancy [START_REF] Bechah | Adipose tissue serves as a reservoir for recrudescent Rickettsia prowazekii infection in a mouse model[END_REF]. Latent typhus infection was identified in two animal models: mice and cotton rats. R. prowazekii was reactivated using dexamethasone, which induced an anti-inflammatory effect on the host's innate immune response [START_REF] Stein | Brill-Zinsser disease in France[END_REF]83]. However, the mechanism of R. prowazekii dormancy and reactivation in humans has not been established. e. Brucella spp.

Brucella spp. are able to induce latent infections [START_REF] Meneses | Brucella bacteremia reactivation 70 years after the primary infection[END_REF][START_REF] Ögredici | Brucellosis reactivation after 28 years[END_REF]. Brucella spp. reactivation as a gall bladder infection has been reported 28 years after primary infection in a non-endemic region [START_REF] Meneses | Brucella bacteremia reactivation 70 years after the primary infection[END_REF][START_REF] Ögredici | Brucellosis reactivation after 28 years[END_REF]. Immunossupression such as chemotherapy (cyclophosphamide, vincristine, methotrexate, 5fluorouracil, etoposide, doxorubicin, and cisplatin and dexamethasone), transplantation, and anecdotically during pregnancy, has been reported [START_REF] Sari | Brucellosis in the etiology of febrile neutropenia: case report[END_REF][START_REF] Metan | Brucellosis in all patients with febrile neutropenia[END_REF][START_REF] Ertem | Brucellosis transmitted by bone marrow transplantation[END_REF]. Although the latency niche has not been well-established in humans, in animals bacteria were isolated from vaginal secretion and milk of asymptomatic sheep up to three years after the infection of the flock [START_REF] Tittarelli | The persistence of Brucella melitensis in experimentally infected ewes through three reproductive cycles[END_REF]. Rats born from Brucella abortus-infected mothers have been reported as latent carriers of Brucella. Cervical lymph nodes are described as an initial efficient trap for Brucella, and were also identified as a potential reservoir niche for chronic pathogen persistence [START_REF] Von Bargen | Cervical Lymph Nodes as a Selective Niche for Brucella during Oral Infections[END_REF]. Brucella can survive for a while in the host cell macrophages and dendritic plasmacytoid cells. It highlights their ability to induce chronic and life-long infections. Just like C. burnetii and M. tuberculosis, Brucella spp. can prevent apoptosis of the macrophage, through Bcl2A1 upregulation [START_REF] Gross | In vitro Brucella suis infection prevents the programmed cell death of human monocytic cells[END_REF]. Brucella thus persists in tissues and induces granulomatous inflammation. The latter inflammation restricts bacterial replication but is insufficient to kill the bacterium [START_REF] Atluri | Interactions of the human pathogenic Brucella species with their hosts[END_REF]. In addition to macrophages, dendritic cells and microglia, non-phagocytic cells such as fibroblasts, epithelial cells, osteoblastic cell lines, trophoblasts, and astrocytes have been suggested as niches [START_REF] Atluri | Interactions of the human pathogenic Brucella species with their hosts[END_REF]. Jacob et al. have shown that Brucella spontaneous smooth small colony variants were characterized by a less effective clearance from spleen and liver in experimentally infected mice [START_REF] Jacob | In vitro and in vivo characterization of smooth small colony variants of Brucella abortus S19[END_REF].

f. Coxiella burnetii

The latent C. burnetii infection stage has been suspected after relapses were observed in patients presenting with an apparent Q fever recovery [START_REF] Sidwell | STUDIES OF LATENT Q FEVER INFECTIONS. II. EFFECTS OF MULTIPLE CORTISONE INJECTIONS[END_REF][START_REF] Beck | Q fever studies in Southern California; an epidemiological study of 300 cases[END_REF][START_REF] Bertrand | Isolation of a strain of Coxiella burnetii on the occasion of a relapse of human Q fever[END_REF]. The placenta was described as a latent niche for C. burnetii, insofar as the bacterium was isolated from the placenta of women with a history of Q fever, but without clinical manifestations of the disease [START_REF] Syrucek | B. Studies on the microscopic slide-agglutination test for Q fever[END_REF][100][101]. The latent presentation could be reactivated by immunosuppression or pregnancy and could infect placenta, heart valve, vascular, bones, or liver.

In the 1940s, it was demonstrated that C. burnetii persisted in animals after an initial clinical or subclinical infection. Its persistence was first explored in guinea pigs where the rickettsial agent of American and Australian Q fever was present in various organs up to 110 days after the primary infection and after defervescence [102]. The experimental works of Sidwell described the latent infection as an unapparent infection in which host equilibrium is established. C. burnetii reactivation was described with deep infectious focus after whole body irradiation, or after repeated injections of corticosteroids in guinea pigs and, to a lesser extent, in mice three months after the primary C. burnetii infection [START_REF] Sidwell | STUDIES OF LATENT Q FEVER INFECTIONS. II. EFFECTS OF MULTIPLE CORTISONE INJECTIONS[END_REF]103].

In a study inoculating C. burnetii in pregnant sheep (early stage of pregnancy), the bacterium was detected up to 13 weeks in the bone marrow, spleen, liver, kidney, and in placenta just before parturition and at 20 weeks post delivery [START_REF] Harris | Long-term persistence of Coxiella burnetii in the host after primary Q fever[END_REF]104]. This data argues in favor of the reactivation of a cryptic infection and of the existence of latent niches for C. burnetii. All infectious agents mentioned in the present article are able to induce primary infection and persistent focalized infection. The primary infection could be separated from the persistent focalized infection by a free phase, during which no clinical symptoms are observed. This phase could be called the latency phase. Table 1 summarizes the site of latency and the evidence for bacterial survival without clinical symptoms in humans.

IV. Bacterial carriage without symptoms

1. Bartonella species Unlike bacterial DNA detection in asymptomatic patients with a history of infectious diseases, Bartonella spp. were isolated from the blood of asymptomatic donors. Bacteria were identified by culture and real-time PCR from the blood of 3.2% of asymptomatic healthy blood donors [106,107]. Bartonella spp. could therefore be transmitted during transfusion [106, 107].

Tropheryma whipplei in asymptomatic carriers

Whipple's disease was first considered a chronic digestive disease and was then considered an acute pneumonia or epidemic fever [108,109,110]. Although the typical presentation includes diarrhea, weight loss, abdominal pain, and arthralgia, T. whipplei asymptomatic carriage in middle-aged men remains intriguing [111]. Two per cent to 44% of the population carries the bacterium in stools without clinical symptoms, but the worldwide annual incidence of the disease is only estimated at 12 new cases [112]. Immunosuppression has been shown to promote the activation of the disease as reported by various authors, with almost 50% of patients presenting with T. whipplei infection treated with immunosuppressive therapy before Whipple's disease diagnosis [113,114,115]. Genetic background, corticosteroids, and tumor necrosis factor inhibitors (10%) lead to a more rapid clinical progression and a clear onset [115,116].

V. What is the rationale for treatment?

The international scientific community only recommends antibiotic treatment for two latent infections: latent syphilis and latent tuberculosis infection.

Treatment of latent syphilis to prevent late relapse and complications

Regarding the dramatic consequences of tertiary syphilis and the resurgence of congenital syphilis in developped countries, the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) both recommend treating this latent infection (Table 2) [117,118].

Treatment of latent tuberculosis infection to prevent relapses in high priority groups

Patients with positive TST or positive interferon-gamma assay should undergo medical evaluation to rule out active tuberculosis. When active tuberculosis has been ruled out, the CDC and WHO recommend initiating an antibiotic therapy in patients belonging to high priority groups (Table 2) [119].

No evidence of antibiotic efficacy on subjective symptoms a) Q fever chronic fatigue

Some studies have supported a biopsychological etiology for Q fever syndrome [START_REF] Morroy | Fatigue following Acute Q-Fever: A Systematic Literature Review[END_REF]. Although the benefits of the antibiotic therapy were controversially reported in the literature, a randomized study recently concluded on the issue. Cognitive behavioral therapy was effective in reducing fatigue severity in Q fever syndrome patients whereas prolonged therapy with doxycycline was not [START_REF] Keijmel | Effectiveness of Long-term Doxycycline Treatment and Cognitive-Behavioral Therapy on Fatigue Severity in Patients with Q Fever Fatigue Syndrome (Qure Study): A Randomized Controlled Trial[END_REF].

b) PTLDS

On the basis of the heterogeneous accuracy of serological testing for Lyme disease and the variety of subjective symptoms wrongly attributed to Lyme disease, no antibiotic treatment should be proposed in the absence of active infection confirmation (positive microbiological test and detection of an organic lesion).

In addition, a recent study performed by Goodlet et al. reported that oral or intravenous antibiotic therapies in cases of post-treatment Lyme disease symptoms were associated with an increased morbidity within 90 days [START_REF] Goodlet | Adverse Events Associated with Antibiotics and Intravenous Therapies for Post-Lyme Disease Syndrome in a Commercially Insured Sample[END_REF].

Conclusion

Post-infectious chronic fatigue syndrome is characterized by subjective symptoms without evidence of living bacteria as the disease is not associated with relapses. Conversely, latent infection could be defined as an asymptomatic disease prone to reactivation in which the microorganisms are likely to be dormant. Furthermore, asymptomatic carriage is not associated by definition with subjective symptoms.

The subjective symptoms described in post-bacterial infection chronic fatigue syndrome are still misunderstood and no evidence is currently available to demonstrate that such symptoms could be related to a dormant bacterial infection or to carriage of viable bacteria. Other etiologies including psychological trauma may be part of these subjective symptoms. Post-infectious chronic fatigue syndrome could nonetheless be due to yet unknown microorganisms. Latent syphilis is defined as syphilis characterized by seroreactivity without other evidence of primary, secondary, or tertiary disease.

• Early latent syphilis: during the year preceding the diagnosis, they had 1) a documented seroconversion or a sustained (>2 week) fourfold or greater increase in nontreponemal test titers; 2) unequivocal symptoms of primary or secondary syphilis; or 3) a sex partner documented to have primary, secondary, or early latent syphilis.

In addition, for persons with reactive nontreponemal and treponemal tests whose only possible exposure occurred during the previous 12 months, early latent syphilis can be assumed.

Early latent syphilis

Benzathine penicillin G 2.4 million units IM in a single dose

Late latent syphilis or latent syphilis of unknown duration

Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals

  The biological form of the persistent organism is unknown. It was hypothesized that C. burnetii survives in macrophages as resistant small-cell variants. In a mouse model, Bechah et al. demonstrated the persistence of C. burnetii in abdominal inguinal and dorsal adipose tissues and in macrophages up to four months after the primary infection [105]. C. burnetii inhibits the fusion with lysosome in the late phagosome of cultured adipocytes, and inhibits apoptosis [105]. Further clinical investigations are required to identify the organ of latent C. burnetii infection and the biological form of the persistent organism.

Table 2 .

 2 Treatment recommendation for latent infection in adults Tableau 2. Recommandations thérapeutiques en cas d'infection latente chez l'adulte Recent contacts of a TB case • Persons with fibrotic changes on chest radiograph consistent with old TB • Organ transplant recipients • Persons who are immunosuppressed for other reasons (e.g., taking the equivalent of >15 mg/day of prednisone for 1 month or longer, taking TNF-α antagonists) People with a positive IGRA result or a TST reaction of 10 or more millimeters • Persons from high-prevalence countries • Injection drug users • Residents and employees of high-risk congregate settings (e.g., correctional facilities, nursing homes, homeless shelters, hospitals, and other health care facilities) • Mycobacteriology laboratory personnel • Children under 4 years of age, or children and adolescents exposed to adults in highrisk categories

	Infection	CDC recommendations

In the absence of these conditions, an asymptomatic person should be considered to have latent syphilis.

IGRA: inter feron-gamma release assays; TST: tuberculin skin test; HIV: human immunodeficiency virus; TB: tuberculosis; TNF: tumor necrosis factor.


VITROME Patrick Peretti-Watel
email: patrick.peretti-watel@inserm.fr

Jeremy Ward

Romain Lutaud

Valérie Seror

MALADIE DE LYME : LE REGARD DES SCIENCES SOCIALES LYME DISEASE: INSIGHT FROM SOCIAL SCIENCES

Keywords: maladie de Lyme, sciences sociales, Borrelia Lyme disease, social science, Borrelia

This article is a selective literature review of social science works published on Lyme disease, that draws on other articles published on similar health hazards. These works present Lyme borreliosis as an "archetypal" example of modern infectious risks. It is an "invisible" risk resulting from interactions between human activities, ecosystems, and pathogens. To tackle this risk, health authorities promote individual-based prevention measures. Perceptions of the general population should thus be better understood: different from the perceptions of experts, the general population's perceptions are socially differentiated, inclined to an "optimism bias", and influenced by personal stories. One should also not forget the dilemmas faced by the general population when contemplating preventive behavior. The "chronic Lyme disease" controversy illustrates the modern disappointment in science, the leveling of the general population's and experts' relative opinions, and the progressive interference of the former with expert matters.

1

Résumé

Cet article propose une revue de littérature sélective des travaux de sciences sociales consacrés à la maladie de Lyme, en mobilisant également d'autres travaux menés sur des risques sanitaires similaires. Ces travaux montrent que la borréliose de Lyme constitue un exemple « archétypal » des risques infectieux contemporains. C'est tout d'abord un risque « invisible », dont l'émergence résulte des interactions entre activités humaines, écosystèmes et pathogènes, et pour lequel les autorités de santé privilégient la prévention individuelle. Ce choix implique de mieux connaître les perceptions profanes : distinctes de celles des experts, ces perceptions sont socialement différenciées, sujettes au « biais d'optimisme » et influencées par les récits personnels. De plus, il ne faut pas oublier les dilemmes auxquels sont confrontés les profanes qui envisagent une conduite préventive. Enfin, la controverse sur le « Lyme chronique » illustre bien le désenchantement contemporain à l'égard de la science, le nivellement des positions relatives de l'expert et du profane, et l'immixtion progressive du second sur le terrain du premier.

Introduction

Lyme disease may now be viewed as a unique nosological entity. Transmitted by Borrelia burgdorferi following an infected tick bite, the infection is usually considered benign and curable with a few weeks of antibiotic therapy. The annual incidence of Lyme disease is around tens of thousands of cases in France, with great regional disparities. Little attention was paid to this infection in France, either in the research field or in the media, until the end of the years 2000. However, Lyme disease is now the object of scientific controversies and heated public debates. Patients' associations condemn the attitudes of health authorities and physicians, whom they believe refuse to acknowledge and treat a chronic presentation of the disease that they claim to be highly debilitating. Health authorities regret the tension and acrimony of patients' associations, and their "resentment against the medical profession and experts" [START_REF] Hcsp | La borréliose de Lyme[END_REF]. The French High Council for Public Health (French acronym HCSP) published a first short report on Lyme disease in 2010, where no mention of these heated debates was made [START_REF] Hcsp | Mieux connaître la borréliose de Lyme pour mieux la prévenir[END_REF]. Another longer report was published in 2014, with a whole chapter dedicated to patients and associations [START_REF] Hcsp | La borréliose de Lyme[END_REF]. This article reviews human and social science works on Lyme disease. Our aim was twofold: on the one hand, we aimed to demonstrate how Lyme disease and the associated perceptions, reactions, and debates illustrate several events characteristic of modern societies: when considering this point of view, Lyme disease is not an abnormality but rather an excellent example of new health hazards -particularly infectious -faced by modern societies; on the other hand, by putting Lyme disease into perspective with other health hazards, we hope to demonstrate how human and social sciences help better understand the various perceptions of and reactions to Lyme disease.

We will first see that Lyme disease is an emerging risk, boosted by human activities and thus "manufactured" to some extent, and an invisible risk or at least only accessible via scientific tools. This emerging and invisible nature of risk results in chronic and endogenous health crises. As health policies are increasingly based on individual-based preventive behaviors, one should focus on understanding the general population's understanding of risks: studies performed on Lyme disease-associated perceptions remind us of a few major results on risk perceptions. We will finally contextualize the controversy on the chronic presentation of Lyme disease at a time of modern disappointment in science.

Emerging risks and health crises: Lyme borreliosis, an archetypal case

A "manufactured" risk?

Anthony Giddens and Ulrich Beck, two major sociologists of the end of the 20 th century, believed modern societies to be threatened by new risks. These new risks are no longer natural disasters but "manufactured" threats, i.e. generated by technologies and human activities [START_REF] Giddens | Modernity and self-identity[END_REF][START_REF] Beck | Risk Society. Towards a new modernity[END_REF]. One may of course think about the nuclear risk, the various sources of pollution, and the mad cow disease crisis. The latter was highlighted by Beck as it is also an example of people's disappointment in science.

However, this observation should be nuanced and updated in light of the past few decades.

New infectious risks, caused by preexisting pathogens that were previously unknown or poorly known, have indeed emerged because of human activities (legionellosis bacterium, Lyme disease bacterium, Ebola virus, HIV) [START_REF] Schwartz | Les nouvelles maladies infectieuses. Questions de Santé Publique[END_REF]. The mad cow disease is an example of these new risks, as the incriminated prion has not been created by men but disseminated following transformations of the bovine industry in Great Britain [START_REF] Peretti-Watel | La crise de la vache folle : une épidémie fantôme ?[END_REF]. As for Lyme disease, the loss of agricultural lands and the suburban reforestation -in the Ile-de-France region and in New England, United States, for instance -led to the proliferation of deer and rodents, acting as reservoirs for Borrelia burgdorferi and feeding the ticks by infecting them. Population settlement near forests and the growing taste of city-dwellers for outdoor activities in this environment, have considerably increased human exposure to tick bites [START_REF] Hcsp | La borréliose de Lyme[END_REF][START_REF] Schwartz | Les nouvelles maladies infectieuses. Questions de Santé Publique[END_REF][START_REF] Barbour | The Biological and Social Phenomenon of Lyme Disease[END_REF]. Merrill Singer's anthropology of infectious diseases describes how this new ecology of human activities, combined with climate changes, resulted in a new epidemiology of vector-borne diseases in Northern countries. This was brought about by the modified hosts/parasites and pathogen/pathogen (coinfections) interactions, and affects differently the various social groups. Patients presenting with Lyme disease in the United States are, for instance, more likely to belong to the upper middle class living in the suburb and to present with a coinfection (Lyme disease and babesiosis) [START_REF] Singer | Ectoparasitic Syndemics: Polymicrobial Tick-borne Disease Interactions in a Changing Anthropogenic Landscape[END_REF]. Merrill Singer thus reminds us that humans both contribute to and suffer from environmental changes.

An invisible risk, that can only be unveiled by science

Beck believes new risks of the modern world to be remarkable as they are invisible: whether it is microorganisms or radiations, these imperceptible risks can only be understood with scientific tools, and yet often indirectly [START_REF] Beck | Risk Society. Towards a new modernity[END_REF]. Besides contributing to their proliferation, the invisible nature of these risks also contributes to the volatility and diversity of risk perceptions, even more so as science -the only tool able to detect them -is weakened and contested.

Lyme disease is a great example of an invisible risk, as the serological diagnosis consists in detecting in the patient's serum the presence of specific antibodies produced by the organism to fight against the infection caused by Borrelia burgdorferi. Yet, part of the controversy between patients and physicians focuses on the diagnostic approach as the bacterium may be present without the antibodies (especially at the early stage of the infection) and conversely, antibodies may persist after the bacterium disappearance (knowing that some also say that the other diagnostic methods -culture or gene amplification -are not optimal [START_REF] Hcsp | La borréliose de Lyme[END_REF]).

An endogenous and chronic health "crisis"

The common-sense definition of a health crisis involves a major sudden threat with great impact on our daily lives. However, this general conception is not in agreement with the analysis of modern crises [START_REF]La gestion des crises sanitaires[END_REF]. Modern crises do not necessarily take a heavy toll on human lives (e.g., mad cow disease crisis or avian flu virus or H1N1 virus). Similarly, when considering the less controverted acute presentation of Lyme disease, the infection annual incidence is modest (<30,000 cases) and is not supposed to be fatal.

Considering the relative absence of victims, the outbreak of a crisis usually comes from the media coverage of a controversy or from scientific uncertainty. Such controversies or uncertainties are usually pointed out by health authorities (e.g., the mad cow disease crisis was triggered by British authorities themselves in March 1996) or by associations acting as whistle-blowers (e.g., impact of electromagnetic waves on health). Increased health surveillance and media coverage of controversies tend to "chronicize" crises, which thus stand the test of time. For instance, the early warning phase of the H1N1 crisis in France lasted for almost a year, from April 2009 to January 2010. Although the urgency factor is still characteristic of a crisis, crises are increasingly becoming endogenous: no longer triggered by a sudden massive external event, but by social stakeholders [START_REF] Gilbert | Quelques apports des sciences humaines et sociales à l'analyse des dynamiques de crise[END_REF].

For instance, patients' associations obviously played a crucial role in the media coverage of Lyme disease [START_REF] Hcsp | La borréliose de Lyme[END_REF]. Conversely, this media coverage was also endogenous as it was delayed and structured by organizational factors. The surveillance of health hazards caused by vectorborne diseases in France has long been focused on diseases transmitted by mosquitoes coming from warm countries, at the cost of diseases transmitted by other vectors in the Northern Hemisphere. Different institutional and scientific authorities were thus responsible for defining recommendations to tackle the issue, with specific perspectives, methods, and measures [START_REF] Massart | La maladie de Lyme entre cadrage infectieux, vectoriel et zoonotique : vers une écologisation des problèmes sanitaires ?[END_REF]. For Lyme disease, the focus has first been put on the infectious risk (targeted at the bacterium, diagnosis, and care) and then on the disease vector (reservoirs, interactions between ecosystems and lifestyles). Both of these priorities have long ignored each other.

Conversely, for the chikungunya epidemic observed in Reunion in 2005, priority was given to fighting the disease vector, i.e. the Aedes mosquito [START_REF] Metzger | L'épidémie de chikungunya : un problème de moustiques ?[END_REF]. Drawing on another field, the 2003 heat wave crisis was declared too late by health authorities, which had reviewed their priorities the year before and decided to exclude climate changes [START_REF] Got | Comment tuer l'Etat[END_REF].

Preventive actions involving the general population

Programs aimed to tackle a specific health hazard often entail the general population to follow recommendations issued by the authorities, e.g. by urgently complying with a mass vaccination campaign [START_REF]La gestion des crises sanitaires[END_REF]. In line with the modern risk culture asking everyone to take themselves in hand and to take responsibility of their own health, these measures often focus on individual-based preventive behaviors that need to be promoted via information and awareness campaigns [START_REF] Peretti-Watel | Le principe de prévention[END_REF].

Lyme disease prevention programs, in France and elsewhere, are in line with this principle as they focus on individual-based preventive behaviors (wearing clothes with long sleeves, using insect repellent, staying on the main forest paths, looking for ticks on one's skin, etc.) rather than environmental changes (treating deer, building fences, etc.) [START_REF] Piesman | Prevention of tick-borne diseases[END_REF][START_REF] Aenishaenslin | From Lyme disease emergence to endemicity: a cross sectional comparative study of risk perceptions in different populations[END_REF].

In the United States this desire to increase people's autonomy related to preventive measures is also illustrated by some pharmaceutical companies who tried to commercialize a vaccine against Lyme disease at the end of the 1990s. As Lyme disease is considered a benign disease restricted to specific geographical areas and as infected people cannot transmit the disease (no herd immunity), this vaccine was not presented as a public health requirement but as an "à la carte" optional vaccine left to the individual's choice based on the need for control and protection [START_REF] Aronowitz | The Rise and Fall of the Lyme Disease Vaccines: A Cautionary Tale for Risk Interventions in American Medicine and Public Health[END_REF].

Perceptions of the general population

Pluralist perceptions, different from the perceptions of experts

To involve the general population in the fight against Lyme borreliosis, one should first understand how the general population perceives the risk associated with this disease. The general population's perceptions of Lyme disease are heterogeneous: levels of perception and associated factors depend on the context, for instance on whether or not interviewed people live in an endemic or emergent region for Lyme disease [START_REF] Aenishaenslin | Factors associated with preventive behaviors regarding Lyme disease in Canada and Switzerland: a comparative study[END_REF][START_REF] Aenishaenslin | From Lyme disease emergence to endemicity: a cross sectional comparative study of risk perceptions in different populations[END_REF]. However, despite disparities, constant factors of risk perception analysis are observed in studies focusing on the "Lyme disease risk". These constant factors had already been observed in various fields -more than 40 years ago for some -, at the crossroads of economics and psychology: i.e., the general population and experts do not have the same perception of a given risk [START_REF] Aenishaenslin | From Lyme disease emergence to endemicity: a cross sectional comparative study of risk perceptions in different populations[END_REF][START_REF] Slovic | Rating the Risks[END_REF]; risks are more acutely perceived by women or people with low socioeconomic level [START_REF] Aenishaenslin | From Lyme disease emergence to endemicity: a cross sectional comparative study of risk perceptions in different populations[END_REF][START_REF] Phillips | Lyme disease and preventive behaviors in residents of Nantucket Island, Massachusetts[END_REF][22][START_REF] Gustafson | Gender differences in risk perception: theoretical and methodological perspectives[END_REF][START_REF] Slovic | Emotion, Sex, Politics, and Science: Surveying the. Risk-Assessment Battlefield[END_REF]; the risk perceived for oneself is almost always lower than that perceived for others (i.e., "optimism bias" [START_REF] Aenishaenslin | From Lyme disease emergence to endemicity: a cross sectional comparative study of risk perceptions in different populations[END_REF][START_REF] Weinstein | Unrealistic Optimism About Future Life Events[END_REF]). How do the general population's perceptions differ from experts' perceptions? The psychometric paradigm indicates that the general population does not think about a risk just in terms of probability and severity. They also take into consideration other factors: whether it is viewed as manageable at the individual level; whether the risk exposure is perceived as voluntary or involuntary, fair or unfair; whether consequences are immediate or delayed, frightening or insignificant; whether the risk is perceived as familiar or mysterious; whether the risk is based on established scientific knowledge or on controverted scientific knowledge [START_REF] Slovic | Perception of Risk[END_REF]. Some of these factors are mentioned in studies on the risk perception of Lyme disease [START_REF] Aenishaenslin | From Lyme disease emergence to endemicity: a cross sectional comparative study of risk perceptions in different populations[END_REF]. This risk is associated with several characteristics that may startle the general population: still largely unknown by the general public, Lyme disease is associated with a multitude of troubling symptoms, including atypical neurological disorders [START_REF] Hcsp | La borréliose de Lyme[END_REF], and it can be perceived as particularly unfair and out of control as it now mainly affects children (at least in France and in the United States) [START_REF] Hcsp | La borréliose de Lyme[END_REF][START_REF] Bacon | Surveillance for Lyme disease--United States, 1992-2006[END_REF].

Perception biases: personal stories

Studies conducted on risk perceptions at the crossroads of economics and psychology reported on perception biases very early on. They mainly reported that a given piece of information does not have the same impact on risk perception depending on how it is presented (i.e., can it be acted upon?; is it striking or spectacular?) [START_REF] Tversky | Judgment under Uncertainty: Heuristics and Biases[END_REF]. With the development of the Internet, this type of bias is now particularly well illustrated by the multiplication of and access to personal stories. The general population highly enjoys this type of information sources, at the detriment of more "objective" pieces of information disseminated by health authorities. The same holds for vaccination: websites supporting a critical standpoint on vaccines give priority to this type of testimonials [START_REF] Grant | Vaccination persuasion online: a qualitative study of two provaccine and two vaccine-skeptical websites[END_REF].

Similarly, a qualitative survey performed in Connecticut, United States, reported the greater trust of people in the experiences of close relatives who contracted Lyme disease than in information disseminated by health professionals and health authorities [START_REF] Macauda | Long-term Lyme disease antibiotic therapy beliefs among New England residents[END_REF]. A recent study reported that this type of stories was particularly searched for on the Internet [START_REF] Yiannakoulias | Celebrity over science? An analysis of Lyme disease video content on YouTube[END_REF]. The authors assessed a random sample of 700 videos on Lyme disease (out of more than 150,000 videos on YouTube), with a total of approximately 13 million views. Ninety-two per cent of these videos had been uploaded by private individuals, and almost two-thirds related personal stories. Analyses revealed that, compared with a video posted by a governmental agency on epidemiological data and prevention advice, a video figuring celebrities talking about their personal experience with Lyme disease will be viewed 18 more times and will be twice more likely to be "liked" by viewers.

Dilemmas and competing risk perceptions

Studies conducted on risk perceptions revealed that informing the general population is not enough for them to "adequately" perceive a threat and to effectively follow preventive advice: for Lyme disease, several studies highlighted that people with very good knowledge of the disease do not necessarily follow the recommendations [START_REF] Shadick | Determinants of tick-avoidance behaviors in an endemic area for Lyme disease[END_REF]33]. This seeming inertia is better understood if we consider what prevention experts often forget, namely that recommendations drafted by health professionals or health authorities leave individuals facing dilemmas [START_REF] Peretti-Watel | Le principe de prévention[END_REF]. Preventive behaviors may indeed be problematic because they disrupt our daily life, prevent the fulfillment of some objectives, break certain values, or just because they are themselves viewed as risky by people. For instance, vaccination refusal may result from philosophical or religious beliefs, or may be based on fear of potential adverse effects [START_REF] Fournet | Under-vaccinated groups in Europe and their beliefs, attitudes and reasons for non-vaccination; two systematic reviews[END_REF][START_REF] Velan | Major motives in non-acceptance of A/H1N1 flu vaccination: the weight of rational assessment[END_REF].

A recent study on Lyme disease reminded that the determinants related to preventive behaviors imply that people believe that the benefits of such approach overcomes its disadvantages [START_REF] Shadick | Determinants of tick-avoidance behaviors in an endemic area for Lyme disease[END_REF]. Thus, the most frequently followed precaution measure is checking one's skin following exposure and by contrast, the least followed measure is spraying acaricides in gardens or lands, probably because of their toxicity [START_REF] Aenishaenslin | Factors associated with preventive behaviors regarding Lyme disease in Canada and Switzerland: a comparative study[END_REF][START_REF] Phillips | Lyme disease and preventive behaviors in residents of Nantucket Island, Massachusetts[END_REF][START_REF] Herrington | Risk perceptions regarding ticks and Lyme disease: a national survey[END_REF]. Similarly, people practicing outdoor activities in forests are reluctant to preventive measures during such activities because they fear that it might impair the associated enjoyment (for instance, protecting oneself by wearing ample clothes when the weather is hot) [START_REF] Marcu | Making sense of unfamiliar risks in the countryside: the case of Lyme disease[END_REF][START_REF] Marcu | Experience of Lyme disease and preferences for precautions: a cross-sectional survey of UK patients[END_REF].

Disappointment in science and controversies: "Chronic Lyme disease"

A controversial chronic presentation

Within months or years following a tick bite, some patients report a variety of symptoms, often highly subjective and poorly specific to the physician's opinion (myalgia, cognitive symptoms, asthenia, etc.). Some patients, but also some physicians, are convinced to have a chronic presentation of Lyme disease, even though the serological tests (or any other diagnostic methods) cannot confirm the disease. These patients and physicians thus believe that these tests are highly imperfect. These patients are asking for long-term antibiotic treatments, that may sometimes be effective -at least temporarily. However, even though this effectiveness reinforces these people's conviction, it does not have any diagnostic value because the treatment may target another disease or disorder (even more so as ticks carry many bacteria, viruses, and parasites).

For most physicians and health authorities, this chronic presentation of Lyme disease does not exist. It is considered a "catch-all disease" for people presenting with unexplained symptoms, and antibiotic prescription would not be justified: it would lead to unnecessary costs to society, while antibiotic consumption contributes to antibiotic resistance and could be harmful for patients [START_REF] Hcsp | La borréliose de Lyme[END_REF][START_REF] Feder | A Critical Appraisal of "Chronic Lyme Disease[END_REF]. However, patients believe that physicians do not listen to them, do not understand their pain, and refuse to treat them, even though their symptoms greatly impact their daily life -sometimes leading to loss of employment. These patients gathered together and created patients' associations in the years 2000 in France and 30 years earlier in the United States. They advocate for the recognition of "chronic Lyme disease" and are highly active on the Internet and social media.

Disappointment in science and controversies

The "chronic Lyme disease" presentation also divides physicians and experts, resulting in a major media and scientific controversy [START_REF] Hcsp | La borréliose de Lyme[END_REF][START_REF] Massart | La maladie de Lyme entre cadrage infectieux, vectoriel et zoonotique : vers une écologisation des problèmes sanitaires ?[END_REF][START_REF] Aronowitz | The Rise and Fall of the Lyme Disease Vaccines: A Cautionary Tale for Risk Interventions in American Medicine and Public Health[END_REF]. In the United States the controversy mainly opposes a learned society known as the Infectious Diseases Society of America (IDSA) to a physicians' association known as the International Lyme and Associated Diseases Society (ILADS). The debate around "chronic Lyme disease" is the perfect example of the disappointment in modern science, which was highlighted by Ulrich Beck [START_REF] Beck | Risk Society. Towards a new modernity[END_REF]. Both the general population and the scientific community are disappointed in modern science as it generates a multitude of highly specialized, fragmented, temporary, and often contradictory results, especially in the biomedical field [START_REF] Peretti-Watel | Du recours au paradigme épidémiologique pour l'étude des conduites à risque[END_REF]. Science can no longer decide between contradictory opinions or invalidate biases, quite the opposite: every opinion can be supported by scientific arguments found among the excessive amount of scientific data. This "balkanization of knowledge" is reinforced by new information and communication technologies. They contribute to the proliferation of controversies and to further weakening experts' knowledge, resulting in the general population's mistrust in experts' knowledge [START_REF]La perception des risques et de la sécurité par les Français[END_REF]. Indeed, every modern controversy now has its "own" experts. During the mad cow disease crisis, some experts questioned the responsibility of the mad cow prion in the transmission to humans while others foresaw hundreds of thousands of victims in the near future. Similarly, what many experts called the "H1N1 flu pandemic" was actually just a minor flu [START_REF]La gestion des crises sanitaires[END_REF].

Controversies discussing science

Although disappointment in science feeds controversies, the latter provide the opportunity to confront competing conceptions of science. Each side reproaching the other to lack scientific ground. For instance, two American physicians published an article on the "chronic Lyme disease" controversy. They considered that supporters of a chronic presentation and their "pseudo-science" have declared war to scientific culture and evidence-based medicine. To better invalidate the opinions of supporters of a chronic presentation, the authors referred to another previous controversy: i.e., the relation between vaccination and autism, which was proven as a scientific fraud [START_REF] Auwaerter | Bullying Borrelia : when the culture of science is under attack[END_REF]. Similarly, the HCSP mentioned in its 2014 report that associations advocating for the recognition of "chronic Lyme disease" are trying "to undermine the legitimacy of professional expert assessment" and have an "anti-science" stance similar to those against vaccination [START_REF] Hcsp | La borréliose de Lyme[END_REF]. As for the associations, they frown upon the contempt, denial, and ignorance of Lyme disease that they believe the HCSP experts display [START_REF] Lyme | Audition Haut Conseil de la Santé Publique[END_REF].

Debates on vaccination, for instance, often present as a defense of science and its principles, especially on the social media: advocates of vaccination try to depict their detractors as an "anti-vaccination" cult associated with an "anti-science" stance. Detractors of vaccination, on the other hand, point to the dogmatism and lack of critical mind of vaccination advocates and highlight the need to enhance technical skills and independence of judgment [START_REF] Ward | Les critiques de la (dé)raison vaccinale. Quelles luttes pour le monopole de « la Science » dans les controverses sur les vaccins ?[END_REF].

The upsurge of the general population and patients in the scientific field is far from new. The general population has long learned how to imitate experts to be able to promote their cause.

They collect their own data and perform their own analyses to alert public authorities: this is what the American sociologist, Phil Brown, calls "popular epidemiology". This term was first coined in the 1980s to describe the investigation work performed by residents living next to a contaminated site to study the prevalence of pediatric leukemia cases near this site [START_REF] Brown | Popular Epidemiology: Community Response to Toxic Waste-Induced Disease in Woburn[END_REF]. Not only does the general population mimic epidemiology, but they are also trying to change the scientific rules. In the 1990s for instance, associations of HIV-infected patients fiercely negotiated with scientists and pharmaceutical companies to change the "good practices" of clinical trials (randomization, double blind, and placebo) conducted to assess the effectiveness of new treatments in order to speed up access to such treatments [START_REF] Barbot | Les malades en mouvement. La médecine et la[END_REF].

When patients want to establish their own diagnosis: science and life story

The "chronic Lyme disease" controversy highlights a new step in the interference of the general population in the scientific field. We have already mentioned the importance of personal stories related to "chronic Lyme disease" posted on the Internet. Patients are claiming legitimacy for establishing their own diagnosis based on personal experience [START_REF] Aronowitz | The Rise and Fall of the Lyme Disease Vaccines: A Cautionary Tale for Risk Interventions in American Medicine and Public Health[END_REF][START_REF] Aronowitz | The Social Construction of a New Disease and Its Social Consequences[END_REF]. This is not an isolated example as associations of patients with electromagnetic hypersensitivity are striving to obtain official recognition of a disease associated with highly subjective symptoms that cannot be recognized and validated by physicians. Other examples are veterans convinced to have Gulf War syndrome or resident associations convinced to be physically affected by incinerators or motorway intersections. Confronted with an "invisible" disease, which signs and effects cannot be proven by scientific tools, the general population tries to gather testimonials and to undertake the "public socialization" of their own experiences to obtain recognition of a new disease [START_REF] Chateauraynaud | Le partage de l'hypersensible : le surgissement des électrohypersensibles dans l'espace public[END_REF].

This "patient-inherent legitimacy", which pretends to present patients' testimonials as sources of knowledge, was already in gestation among HIV-infected activists at the end of the 1980s [START_REF] Pollak | Une identité blessée[END_REF]. It is now clearly advocated by associations campaigning for the recognition of a "chronic Lyme disease" presentation. When the France Lyme association was heard by the HCSP, they chose to present the testimonial of a physician believing to be suffering from Lyme disease for six years [START_REF] Lyme | Audition Haut Conseil de la Santé Publique[END_REF]. Similarly, in 2001, the relevant official authority of the United States investigated the effectiveness of a vaccine accused of causing "chronic Lyme disease". During the hearings, the pharmaceutical company commercializing the vaccine presented the statistical results of a clinical trial while patients' associations had people believing to be victims of this vaccine testifying [START_REF] Aronowitz | The Rise and Fall of the Lyme Disease Vaccines: A Cautionary Tale for Risk Interventions in American Medicine and Public Health[END_REF]. Although this patients' "pretentiousness" could upset physicians, several studies suggest that physicians also tend to rather trust personal experiences than literature data (e.g., for the treatment of depression) [START_REF] Andersson | Conceptions of depressive disorder and its treatment among 17 Swedish GPs. A qualitative interview study[END_REF][START_REF] Dumesnil | General Practitioners' Choices and their Determinants when Starting Treatment for Major Depression: A Cross Sectional, Randomized Case-Vignette Survey[END_REF].

Conclusion

Far from being an abnormality, Lyme borreliosis represents an "archetypal" risk with numerous characteristics of modern risks and modern societies. Lyme borreliosis is an infectious risk resulting from the interactions between human activities and preexisting pathogens, that were until now unknown or forgotten. The "invisible" nature of Lyme borreliosis and some organizational factors delayed its media coverage.

Priority was then given to individual-based prevention, which requires understanding the general population's perceptions: studies performed abroad suggest that these perceptions differ from that of experts (socially differentiated, based on personal stories instead of expert data, and subject to an "optimism bias"). Besides, one should also not forget the dilemmas faced by the general population contemplating a preventive approach to understand these perceptions.

The highly controversial issue of "chronic Lyme disease" highlights the modern disappointment in science and the numerous resulting controversies. Just like any other controversy, this controversy focuses on modern debates on science and shows the leveling of the general population's and experts' relative opinions, and the progressive interference of the former with expert matters.