Kamila Kolanska

Jaume Alijotas-Reig

Jonathan Cohen

Meryem Cheloufi

Lise Selleret

Emmanuelle D'argent

Gilles Kayem

Enrique Esteve Valverde

Olivier Fain

Marie Bornes

Emile Darai

Arsene Mekinian
email: arsene.mekinian@aphp.fr

Endometriosis with infertility: a comprehensive review on the role of immune deregulation and immunomodulation therapy

Keywords: endometriosis, infertility, immune dysregulation, TNFα antagonists

Background

Endometriosis is a multifactorial pathology dependent on intrinsic and extrinsic factors, but the immune deregulation seems to play a pivotal role. In endometriosis-associated infertility this could raise the benefit of immunomodulatory strategies to improve the results of ART. In this review, we will describe (1) sera and peritoneal fluid cytokines and immune markers; (2) autoantibodies; (3) immunomodulatory treatments in endometriosis with infertility.

Methods

The literature research was conducted in Medline, Embase and Cochrane Library with keywords: "endometriosis", "unexplained miscarriage", "implantation failure", "recurrent implantation failure » and « IVF-ICSI », « biomarkers of autoimmunity", "TNF-α", "TNF-α antagonists", "infliximab", "adalimumab", "etanercept", "immunomodulatory treatment", "steroids", "intralipids", "intravenous immunoglobulins", "G-CSF", "pentoxyfylline".

Results

Several studies analyzed the levels of pro-inflammatory cytokines in sera and peritoneal fluid of endometriosis-associated infertility, in particular TNF-α. Various autoantibodies have been found in peritoneal fluid and sera of infertile endometriosis women even in the absence of clinically defined autoimmune disease, as antinuclear, anti-SSA and antiphospholipid autoantibodies. In few uncontrolled studies, steroids and TNF-α antagonists could increase the pregnancy rates in endometriosis-associated infertility, but well-designed trials are lacking.

Conclusion

Endometriosis is characterized by increased levels of cytokines and autoantibodies. This suggests the role of inflammation and immune cell deregulation in infertility associated to endometriosis. The strategies of immunomodulation to regulate these immune deregulations are poorly studied and well-designed studies are necessary.

Introduction

Endometriosis is an inflammatory oestrogen-dependent chronic disease defined by the presence of endometrial glands and stroma at extra-uterine sites [1]. The prevalence vary from 5-10% in women with pain symptoms, dyspareunia and dysmenorrhea, and at least one third of them suffer from infertility [START_REF] De Ziegler | Endometriosis and infertility: pathophysiology and management[END_REF]. Besides chronic pain representing an important challenge in these young women, another important problem is the management of endometriosisassociated infertility. Reduced fertility in women with endometriosis can be related to mechanical distortions with pelvic adhesions, occlusions of the tubal ostia and decreased folliculogenesis. Chronic intraperitoneal inflammation is another important feature of endometriosis and can impair the fertility by increasing the concentration of pro-inflammatory cytokines. This pro-inflammatory environment can interfere with oocyte-sperm interactions, embryo development and implantation [START_REF] Tanbo | Endometriosis-associated infertility: aspects of pathophysiological mechanisms and treatment options[END_REF]. Moreover, increased prevalence of various autoantibodies and autoimmune diseases such as systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis or chronic inflammatory bowel disease in endometriosis women raise the possible autoimmune link with endometriosis-associated infertility [START_REF] Lin | Risk of systemic lupus erythematosus in patients with endometriosis: A nationwide population-based cohort study[END_REF][START_REF] Shigesi | The association between endometriosis and autoimmune diseases: a systematic review and meta-analysis[END_REF].

The physiopathological mechanism involved in endometriosis-associated infertility is not clearly elucidated. The hypothesis of altered oocyte quality is frequently raised, as the pregnancy rates in egg donation tend to be decreased if the donor has the history of endometriosis [START_REF] Hauzman | Oocyte donation and endometriosis: What are the lessons?[END_REF][START_REF] Katsoff | Evaluation of the effect of endometriosis on oocyte quality and endometrial environment by comparison of donor and recipient outcomes following embryo transfer in a shared oocyte program[END_REF]. On the other hand the endometrial alterations involved in embryo implantation process in women with endometriosis are debatable [START_REF] Lessey | Endometrial receptivity in the eutopic endometrium of women with endometriosis: it is affected, and let me show you why[END_REF][START_REF] Miravet-Valenciano | Endometrial receptivity in eutopic endometrium in patients with endometriosis: it is not affected, and let me show you why[END_REF]. Nevertheless, the immune profile alteration observed in women with endometriosis could play an important role in the infertility.

As far as medical management of endometriosis is concerned, the handling of chronic pain is mainly based on hormonal therapies, such as contraceptive pill, progestogens, GnRH agonists and anti-aromatase inhibitors. These therapies, however, are inconvenient for the management of infertility. The management of endometriosis-associated infertility combine the selective surgery and the Assisted Reproductive Technology (ART). The place of immunomodulatory therapies has been raised for the endometriosis-associated infertility but remain poorly studied [START_REF] Muñoz-Hernando | Endometriosis: alternative methods of medical treatment[END_REF]. Among the potential immunomodulatory therapies, the value of steroids and TNF-α antagonists have been previously studied, but their potential efficacy remains to be determined in well-designed studies [START_REF] Mekinian | Unexplained Recurrent Miscarriage and Recurrent Implantation Failure: Is There a Place for Immunomodulation?[END_REF]. Even if the use of assisted reproductive technologies (ART) in endometriosis-associated infertility increases the pregnancy rates, effective combined strategies to improve the results of ART in endometriosis-associated infertility are still lacking.

The aim of this review is to describe sera and peritoneal fluid cytokines, autoantibodies and immunomodulatory treatments in endometriosis-associated infertility.

Methods

Search strategy

Data for this review were obtained through a systematic and comprehensive literature search using the keywords to identify articles published in English from PubMed (MEDLINE) , Embase and Cochrane Library and limited to studies published in French or English between 1990 and 2020. Selection criteria included randomized clinical trials, observational openlabelled studies, case-reports and retrospective case-series related to endometriosis-associated infertility. The "Mesh Database" of Pubmed helped steer the search by combining Mesh keywords: "endometriosis", "unexplained miscarriage", "implantation failure", "recurrent implantation failure" and "IVF-ICSI", "biomarkers of autoimmunity", "TNF-α", "cytokines", "TNF-α antagonists", "infliximab", "adalimumab", "etanercept", "immunomodulatory treatment", "steroids", "intralipids", "intravenous immunoglobulins", "hydroxychloroquine", "G-CSF"; pentoxifylline". Research was carried out with the following keywords in the title, abstract or keywords in articles. A first selection was made by eliminating redundant articles and in this case, the most recent publication was taken into account.

Cytokines and other immune factors in sera and peritoneal fluid of endometriosisassociated infertility: possible biomarkers

Several studies analyzed the levels of pro-inflammatory cytokines in sera and peritoneal fluid of endometriosis-associated infertility [12, 13] [14]. Increased levels in peritoneal fluids of TNF-α, interleukin-1 (IL)-1, IL-6, IL-10, TGF-β1 and IL-8 were demonstrated in infertile women with endometriosis [START_REF] Wu | The role of cytokines in endometriosis[END_REF]. In comparison to women with tubal infertility, women with endometriosis-associated infertility have increased follicular fluid levels of TNF-α, granulocyte-macrophage-colony stimulating factor (GM-CSF) and IL-15, whereas IL-10 levels were significantly decreased [START_REF] Falconer | IVF outcome in women with endometriosis in relation to tumour necrosis factor and anti-Müllerian hormone[END_REF]. Whereas IL-6 follicular fluid levels were not significantly increased in women with endometriosis-associated infertility [START_REF] Falconer | IVF outcome in women with endometriosis in relation to tumour necrosis factor and anti-Müllerian hormone[END_REF], endometrial stromal cells from endometriosis implants secreted significantly higher levels of IL-6 at baseline and after IL-1 stimulation than cells from endometrium of women with endometriosis and normal controls [START_REF] Tseng | Interleukin-6 secretion in vitro is upregulated in ectopic and eutopic endometrial stromal cells from women with endometriosis[END_REF].

The exact role of IL-1 and IL-6 in infertility is not completely elucidated. IL-6 promotes the acute phase of inflammatory response by inducing the differentiation of B and cytotoxic T cells and reducing the NK cell cytotoxic activity [START_REF] Kang | An increased level of IL-6 suppresses NK cell activity in peritoneal fluid of patients with endometriosis via regulation of SHP-2 expression[END_REF]. High concentrations of IL-6 might inhibit the proliferation of endometrial stromal cells [START_REF] Zarmakoupis | Inhibition of human endometrial stromal cell proliferation by interleukin 6[END_REF]. Although the presence of IL-6 is required for the promotion of blastocyst development, its might limit the blastocyst interaction with matrix substrates during the process of adhesion [START_REF] Prins | Interleukin-6 in pregnancy and gestational disorders[END_REF]. On the other hand, IL-6 could reduce significantly the motility of sperm [START_REF] Yoshida | A combination of interleukin-6 and its soluble receptor impairs sperm motility: implications in infertility associated with endometriosis[END_REF]. Interleukin-6 is involved in various pathologies of pregnancy such as miscarriage, preeclampsia or preterm birth [START_REF] Prins | Interleukin-6 in pregnancy and gestational disorders[END_REF]. As far as IL-1 is concerned, its role in disrupting of the endometrial decidualisation has been demonstrated [START_REF] Frank | Interleukin-1 beta and the endometrium: an inhibitor of stromal cell differentiation and possible autoregulator of decidualization in humans[END_REF]. IL-1β seems to inhibit estrogen receptor-α and progesterone receptors thus modifying hormonally induced signalization pathways [START_REF] Yu | Interleukin-1β inhibits estrogen receptor-α, progesterone receptors A and B and biomarkers of human endometrial stromal cell differentiation: implications for endometriosis[END_REF].

Among women undergoing laparoscopy for pain, infertility or tubal ligation, serum and peritoneal fluid TNF-α and IL-6 levels were significantly increased in women with final diagnosis of endometriosis [START_REF] Bedaiwy | Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial[END_REF]. In in vitro studies TNF-α increases the transcriptional activity in endometrial epithelial cells and modulates the expression of estrogen-regulated genes, which are implicated in growth, proliferation and tissue invasion [START_REF] Gori | Tumor necrosis factor-α activates estrogen signaling pathways in endometrial epithelial cells via estrogen receptor α[END_REF]. Higher peritoneal fluid IL-8 levels were induced by exposure to TNF-α [START_REF] Arici | Interleukin-8 concentration in peritoneal fluid of patients with endometriosis and modulation of interleukin-8 expression in human mesothelial cells[END_REF]. Basal synthesis of TNF-α, IL-6, and IL-8 and the LPS-stimulated synthesis of TNF-α by blood monocytes from women with endometriosis was significantly greater in comparison to fertile controls, whereas no changes were noted for IL-10 [START_REF] Braun | Spontaneous and induced synthesis of cytokines by peripheral blood monocytes in patients with endometriosis[END_REF].

It is not well established if those cytokine local and general changes are the reason or the consequence of endometriosis. Nevertheless, the presence of ectopic endometrium promotes a highly inflammatory, pro-angiogenic and hormone-rich microenvironment [START_REF] Miller | Implications of immune dysfunction on endometriosis associated infertility[END_REF].These increased cytokines may be secreted by peritoneal macrophages, lymphocytes, endometrial implants and mesothelial cells of the peritoneum which are recruited and activated in endometriosis [15] [29]. The consequence of increased proinflammatory cytokine levels in peritoneal fluid could result in diminished quality of oocyte and, consequently, embryos, even if the precise mechanisms are not established [14] [28]. The impaired adhesion, implantation and angiogenesis are among the various mechanisms implicated in the endometriosisassociated infertility, an increased inflammatory status is probably one of the corner mechanism for the decreased fertility in endometriosis [15] [14].

Proangiogenic factors such as VEGF and PlGF have been proposed as the principal molecules involved in the neovascularization necessary for the implantation, establishment and development of ectopic endometriotic tissue [30] [31]. The role of PlGF in the induction of inflammation has been suggested in cutaneous inflammation [START_REF] Oura | A critical role of placental growth factor in the induction of inflammation and edema formation[END_REF]. Their concentrations were found to be increased in peritoneal fluid of women with endometriosis, as well as that of IL-8

which is a potent chemo-attractant for numerous immune cells [33] [START_REF] Attar | Experimental treatments of endometriosis[END_REF].

Other factors such as antioxidant agents, chemokines, adhesion molecules (sICAM-1) and chemotactic proteins such as monocyte chemoattractant protein-1(MCP-1), regulated upon activation, normal T cell (RANTES or CCL5) could be impaired in endometriosis-associated infertility [33] [34] [START_REF] Hornung | Chemokine bioactivity of RANTES in endometriotic and normal endometrial stromal cells and peritoneal fluid[END_REF]. Even if the levels of these various cytokines and factors could be dysregulated in endometriosis, the cytokines measurement in peritoneal fluid and serum is not actually used in routine screening to demonstrate the underlying inflammation and determine women that could benefit from immunomodulation strategies. Many biomarkers for endometriosis have been investigated, but no biomarker has been validated and a panel of biomarkers will most likely be necessary for a complex disease such as endometriosis. [START_REF] Df | Noninvasive diagnosis of endometriosis: Review of current peripheral blood and endometrial biomarkers. Best practice & research[END_REF]

Prevalence of autoantibodies in endometriosis-associated infertility

Various autoantibodies have been found in peritoneal fluid and sera of infertile endometriosis women even in the absence of clinically defined autoimmune disease [START_REF] Tomassetti | Endometriosis, recurrent miscarriage and implantation failure: is there an immunological link?[END_REF]. Antinuclear (ANA), anti-SSA/Ro and antiphospholipid autoantibodies (aPL) were more frequent in women with endometriosis than controls [START_REF] Taylor | Autoreactivity in women with endometriosis[END_REF]. Anti-cardiolipin antibodies and anti-sperm antibodies were both more frequent in sera and peritoneal fluids of 323 various stage endometriosis women comparatively to infertile non-endometriosis patients [START_REF] Ulcová-Gallová | Endometriosis in reproductive immunology[END_REF].

Even if the exact mechanism of autoimmunity in infertility is not completely elucidated, its role in pregnancy loss has been widely accepted. aPL might be responsible for the damage of the trophoblast and provoke premature aging and necrosis of the villi [39] [40].The presence of aPL could be associated to a lower ovarian reserve [START_REF] Vega | Anti-mullerian hormone levels decline with the presence of antiphospholipid antibodies[END_REF]. The ANA, on the other hand, could impact the embryo development as the development of murine embryos is blocked while incubating with ANA [START_REF] Ying | Antinuclear antibodies predicts a poor IVF-ET outcome: impaired egg and embryo development and reduced pregnancy rate[END_REF].A recent systematic review shows that the presence of ANA could be correlated to poorer IVF outcomes [START_REF] Simopoulou | The Impact of Autoantibodies on IVF Treatment and Outcome: A Systematic Review[END_REF].

Laminins are an important and biologically active part of the basal lamina, influencing cell differentiation, migration, adhesion as well as phenotype and cell survival. In addition, laminins enhance trophoblast adhesion in the peri-implantation period, and anti-laminin-1 autoantibodies have been evaluated in endometriosis women. Both levels and prevalence of these autoantibodies were increased in endometriosis-associated infertility, even if their presence was not predictive of IVF failure [START_REF] Caccavo | Antilaminin-1 antibodies in sera and follicular fluid of women with endometriosis undergoing in vitro fertilization[END_REF][START_REF] Inagaki | A possible mechanism of autoimmunemediated infertility in women with endometriosis[END_REF]. Anti-ovary, anti-theca, anti-granulosa cells and anti-endometrium autoantibodies have been also more prevalent in infertile women with endometriosis although their pathogenic and clinical value are uncertain [START_REF] Mathur | Autoimmunity to endometrium and ovary in endometriosis[END_REF]. Those autoantibodies may target ooplasm, zona pellucida and granulosa cells and alter the ovarian reserve and the IVF outcomes [START_REF] Carp | The autoimmune bases of infertility and pregnancy loss[END_REF] [47]. Among 23 women with endometriosis-associated infertility, aPL, ANA antibodies were significantly more frequent than in infertile controls, except for lupus anticoagulant (LAC) and anti-thyroid antibodies [START_REF] Kaider | Immunodiagnostic evaluation in women with reproductive failure[END_REF]. Among 35 IVF cycles with at least one autoantibodies, 8 (23%) women became pregnant, versus 16 (46%) in autoantibodies-negative ones (p=0.04) [START_REF] Dmowski | The effect of endometriosis, its stage and activity, and of autoantibodies on in vitro fertilization and embryo transfer success rates[END_REF]. Anti-GM-CSF antibodies levels were evaluated in 106 sera of endometriosis women and were significantly increased in patients with endometriosis compared to controls and were associated with the severity of the disease [50].

Despite the increased prevalence of these various autoantibodies, the predictive value of these autoantibodies on the issue of IVF remain to be determined.

Immunomodulatory therapies

Steroids

In a murine embryo assay, the addition of dexamethasone to murine embryo culture with endometriotic peritoneal fluid improved the rates of blastocyst development [START_REF] Heitmann | Dexamethasone attenuates the embryotoxic effect of endometriotic peritoneal fluid in a murine model[END_REF]. Few studies evaluated the benefit of steroids for endometriosis-associated infertility. Twenty-one patients with endometriosis received steroids before IVF, at 10mg/day from the 3 rd day of the cycle until the day of oocyte retrieval and the dosage was increased to 60 mg/day from the evening of oocyte retrieval and for 4 days [START_REF] Kim | The immunotherapy during in vitro fertilization and embryo transfer cycles in infertile patients with endometriosis[END_REF]. The rates of clinical pregnancies after IVF were compared to 44 controls with IVF without steroids. The clinical pregnancies rates were at 42.6% in the steroid treated group vs. 22.8% in the absence of steroid therapy (p<0.05), without differences in the miscarriage rates. In women with positives autoantibodies the clinical pregnancy rates were higher in steroid treated group as compared to non-treated group (40.9% vs 14.8%; p<0.05). In 84 infertile women with endometriosis, steroids were added during the entire IVF cycle or 5 days before embryo transfer and various autoantibodies were tested before IVF cycle [START_REF] Dmowski | The effect of endometriosis, its stage and activity, and of autoantibodies on in vitro fertilization and embryo transfer success rates[END_REF]. In 35 autoantibodies-positives patients, steroid use during IVF cycle was associated with clinical pregnancy in 8/10 cases versus 0/25 in those without steroid treatment (80% vs 0% p < 0.05). In 35 autoantibody-negative patients, pregnancy was obtained in 7/15 cases with steroid treatment during IVF versus 9/20 in the group without steroid treatment (46.7% vs 45%, p=NS) [START_REF] Dmowski | The effect of endometriosis, its stage and activity, and of autoantibodies on in vitro fertilization and embryo transfer success rates[END_REF]. No randomized trial is available to confirm the potential benefit of steroid treatment in these women.

TNF-α antagonists

Several studies showed an abnormal inflammation status in women with endometriosis and demonstrated increased levels of various pro-inflammatory cytokines, such as TNF-α, IL-6, TGF-β and IL-1β, in sera and peritoneal fluids as has previously been mentioned [START_REF] Falconer | IVF outcome in women with endometriosis in relation to tumour necrosis factor and anti-Müllerian hormone[END_REF]. TNF-α is usually expressed by human oocytes, corpus luteum and it is present in the follicular fluid [START_REF] Falconer | IVF outcome in women with endometriosis in relation to tumour necrosis factor and anti-Müllerian hormone[END_REF]. In a baboon model of endometriosis, the neutralization of TNF-α activity with recombinant TNFRSF1A (the soluble form of TNF receptor type 1) significantly decreased the endometriotic lesions without causing the hypoestrogenic effects [START_REF] Tomassetti | Endometriosis, recurrent miscarriage and implantation failure: is there an immunological link?[END_REF] [53] [54] [START_REF] Barrier | Efficacy of anti-tumor necrosis factor therapy in the treatment of spontaneous endometriosis in baboons[END_REF].

Monoclonal anti-TNF-α in endometriosis baboons also reduced significantly the induced peritoneal endometriosis [START_REF] Falconer | Treatment with anti-TNF monoclonal antibody (c5N) reduces the extent of induced endometriosis in the baboon[END_REF]. In a model of murine embryos cultured with different concentrations of TNF-α, the blastocyst development ratio was significantly decreased in the presence of TNF-α. The increased apoptosis and embryotoxicity of TNF-α was abrogated by the addition of adalimumab, a human monoclonal anti-TNF-α antibody [START_REF] Chen | A tumor necrosis factor-α inhibitor reduces the embryotoxic effects of endometriotic peritoneal fluid[END_REF]. In a randomized placebo-controlled blinded study using rat endometriosis model, female rats were randomized to receive either etanercept 0.4 mg/kg etanercept sc once weekly during 4 weeks or placebo [START_REF] Islimye | Regression of endometrial autografts in a rat model of endometriosis treated with etanercept[END_REF]. The volume and extension of endometrial implants were significantly reduced in female rats under etanercept in comparison to untreated controls, but the effect on the clinical pregnancy was not analyzed in this study.

A randomized trial analyzed the efficacy of infliximab versus placebo in 21 patients with endometriosis and chronic pelvic pain prior to surgery [START_REF] Koninckx | Anti-TNFalpha treatment for deep endometriosis-associated pain: a randomized placebocontrolled trial[END_REF]. The decrease of pain severity was noted in 30% of infliximab treated women and was similar to those under placebo. The volume of endometriotic nodules, the lesions extension evaluated during the surgery and the extent of endometriosis were not significantly changed after infliximab use in comparison to placebo. The impact on the infertility was not analyzed in this trial.

So far no well-designed studies evaluated the clinical value of TNF-α antagonists in women with endometriosis-associated infertility. In a woman with severe endometriosis under etanercept for rheumatoid arthritis, no spontaneous pregnancy occurred, and she became pregnant several months later after IVF preceded by laparoscopic surgery [START_REF] Shakiba | Tumour necrosis factor-alpha blockers: potential limitations in the management of advanced endometriosis? A case report[END_REF]. The analysis of NK cell activity in a woman with extensive endometriosis and fifteen failed IVF and oocyte donation cycles showed increased NK cell activity before subsequent IVF. She received four doses of etanercept twice a week 6 month, which resulted in a successful birth [START_REF] Jerzak | First successful pregnancy after addition of enoxaparin to sildenafil and etanercept immunotherapy in woman with fifteen failed IVF cycles -case report[END_REF]. Nineteen women with endometrioma received etanercept 50 mg on the second day of the menstrual cycle preceding IVF cycle. The clinical pregnancy rate was higher in patients who received etanercept as compared to non-treated women, with odd ratio 4.17 [95% CI 1.23-14.14) [START_REF] Önalan | Effect of Etanercept on the Success of Assisted Reproductive Technology in Patients with Endometrioma[END_REF].

Data about the safety of TNF-α antagonists during the pregnancy are extensively reported, in particular in women with Crohn's disease and rheumatoid arthritis [START_REF] Mekinian | Unexplained Recurrent Miscarriage and Recurrent Implantation Failure: Is There a Place for Immunomodulation?[END_REF]. The main concern is the increased risk of infectious adverse events. In the only trial of infliximab in 21 women with endometriosis, an acute tonsillitis and a mild infusion reaction were noted [START_REF] Koninckx | Anti-TNFalpha treatment for deep endometriosis-associated pain: a randomized placebocontrolled trial[END_REF]. From the actually available data, we can conclude that TNF-α blockers can be safely used during the implantation period and pregnancy [START_REF] Alijotas-Reig | Tumor Necrosis Factor-Alpha and Pregnancy: Focus on Biologics. An Updated and Comprehensive Review[END_REF] Intralipids Increased NK cells rates and cytotoxicity have been demonstrated in endometriosis-associated infertility, and in vitro and clinical studies raise the potential interest to use intravenous intralipid infusion to modulate the NK cells cytotoxicity in infertility [64, 65] [15]. The data about the use of intralipids in endometriosis-associated infertility report 3 women with increased uterine NK (uNK) which received intralipid infusion on the day of the embryo transfer in frozen embryo transfer cycles, 2nd infusion after the positive pregnancy test and following infusions every 2 weeks until 12th week of pregnancy which resulted in live birth in 2 cases [START_REF] Freitag | Are uterine natural killer and plasma cells in infertility patients associated with endometriosis, repeated implantation failure, or recurrent pregnancy loss?[END_REF]. However, uNK cells are necessary to achieve a normal implantation and further correct placentation. Like this, only cases with high uNK cells in endometrial fluid could be suitable for a treatments directed to reduce them. Thus, the role played for intralipids appears to be anecdotic.

Antimalarials: Hydroxychloroquine

Antimalarials particularly hydroxychloroquine (HCQ) exerts pleiotropic effects other than anti-infectious. Antimalarials have many anti-inflammatory, immune-regulatory and antiaggregant properties. Thus, they inhibit phospholipase activity, stabilize lysosomal membranes, block the production of several pro-inflammatory cytokines, impair complementdependent antigen-antibody reactions and attenuate antigen processing, and inhibit cellmediated cytotoxicity [START_REF] Mekinian | Obstetrical APS: is there a place for hydroxychloroquine to improve the pregnancy outcome?[END_REF]. Besides, HCQ reduce the proliferative response of T-lymphocytes and NK cell activity [START_REF] Ausiello | In vivo effects of chloroquine treatment on spontaneous and interferon-induced natural killer activities in rheumatoid arthritis patients[END_REF]. In addition, inhibition of autophagy prevents immune activation of different cell types, which inhibits cytokine production and modulates CD154 expression on the surface of T cells. HCQ also inhibits macrophage TNF mRNA transcription and endotoxin-induced secretion of TNF-α, IL-1, and IL-6 [START_REF] Karres | Chloroquine inhibits proinflammatory cytokine release into human whole blood[END_REF]. Studies of HCQ have yielded conflicting results in terms of the ability to inhibit TNF-α, but HCQ blocks IL-1, IL-6, and IFN-γ production by monocytes [START_REF] Sperber | Selective regulation of cytokine secretion by hydroxychloroquine: inhibition of interleukin 1 alpha (IL-1-alpha) and IL-6 in human monocytes and T cells[END_REF][START_REF] Van Den Borne | Chloroquine and hydroxychloroquine equally affect tumor necrosis factor-alpha, interleukin 6, and interferon-gamma production by peripheral blood mononuclear cells[END_REF]. Furthermore, HCQ include anti-inflammatory properties through the blocking effect on the arachidonic acid cascade (phospholipases A2 and C), which contribute to the down-regulation of pro-inflammatory prostaglandins.

Accordingly, the therapeutic effects of HCQ were assessed in an established mouse model of endometriosis [START_REF] Ruiz | Effect of hydroxychloroquine and characterization of autophagy in a mouse model of endometriosis[END_REF]. HCQ significantly altered the endometriotic cells survival, by interfering with the inflammatory response, altering the organization of ectopic growth and modulating the expression of autophagic markers. Nevertheless, clinical data about the potential benefit of hydroxychloroquine are lacking.

Other TNF-α inhibitor: Pentoxifylline

Pentoxifylline is a phosphodiesterase inhibitor commonly used in the treatment of peripheral vascular disease. A wide range of immunomodulatory properties has been described, including of down-regulating TNF-alpha synthesis [START_REF] Ng | Expression of intracellular Th1 and Th2 cytokines in women with recurrent spontaneous abortion, implantation failures after IVF/ET or normal pregnancy[END_REF]. Furthermore, animal models showed a reduction in fetal resorption, thereby diminishing TNF-alpha and increasing IL-10 and IL-4 placentally produced levels [74] [75]. Pentoxifylline has been used in cases of endometriosisrelated infertility [START_REF] Shaw | Immunological mechanisms of pentoxifylline in chronic heart failure[END_REF] [77] [START_REF] Creus | Combined laparoscopic surgery and pentoxifylline therapy for treatment of endometriosis-associated infertility: a preliminary trial[END_REF]. It had been used years ago in the treatment of certain forms of thrombotic APS [START_REF] Bick | Antiphospholipid thrombosis syndromes. Clinical and applied thrombosis/hemostasis[END_REF]. Given its capability to modify the Th1/Th2 cytokine balance together with its lack of adverse effects, pentoxifylline could be another useful drug to use in endometriosis. In nude mouse model with implanted human endometrial tissue from endometriosic women, the use of oral pentoxifylline reduced the number and the volume of endometriosis-like Lesions [START_REF] Perelló | Oral Administration of Pentoxifylline Reduces Endometriosis-Like Lesions in a Nude Mouse Model[END_REF]. Recent Cochrane review included four trials involving 334 participants and pentoxifylline had no significant effect on reduction in pain. There was no evidence of an increase in clinical pregnancy events in the pentoxifylline group compared with placebo [START_REF] Lv | Pentoxifylline versus medical therapies for subfertile women with endometriosis[END_REF].

Other immunomodulatory drugs

Other immunomodulatory therapies have been used in unexplained recurrent implantation failure and unexplained recurrent miscarriages presumed to be in relation with the breaking of immune tolerance [START_REF] Mekinian | Unexplained Recurrent Miscarriage and Recurrent Implantation Failure: Is There a Place for Immunomodulation?[END_REF]. However, no data are currently available about G-CSF, intravenous immunoglobulins, classic immunosuppressive drugs or IL-2 low dose for the management of endometriosis-associated infertility. Other strategies, such as various stem cell therapies, are not actually evaluated in the women with infertility [START_REF] Pourakbari | Cell therapy in female infertility-related diseases: Emphasis on recurrent miscarriage and repeated implantation failure[END_REF]. The increasing evidence of link between microbiota and uterine immunity could also discuss this possible immunomodulation strategy in the future [START_REF] Agostinis | Uterine Immunity and Microbiota: A Shifting Paradigm[END_REF].

Conclusion

Endometriosis is associated to a highly inflammatory, pro-angiogenic and hormone-rich microenvironment which may impair fertility by influencing oocyte and embryo quality, transport of gametes in the reproductive tract and embryo implantation by modifications in the eutopic endometrium. Even if the exact mechanisms of those changes remain unclear, the strategies of immunomodulation to regulate immune alterations involved in endometriosisassociated infertility have been proposed. The function of those therapies is still poorly studied and well-designed studies are necessary.

Co-authors contribution:

Conception and design of the study: KK, AM, JAR, JC, MC, LS, EDA, GK, EEV, OF, MB, ED.

Acquisition of data: KK, AM, JAR Analyze and interpretation of data: KK, AM, JAR Drafting of the manuscript: KK, AM, JAR, JC, MC, LS, EDA, GK, EEV, OF, MB, ED.

Final approval: KK, AM, JAR, JC, MC, LS, EDA, GK, EEV, OF, MB, ED.

Conflicts of interest:

AM is investigator of CELGENE, ROCHE, CHUGAI founded trials with APHP and Hopital 15-20 promotion; AM received several fees for congress travels and experts' use from LFB, SANOFI, SHIRE, and CELGENE. Funding: none.


M.D Jebrane Bouaoud
email: jebrane.bouaoud@gmail.com

student; Jean-Baptiste Belloc

Use of injectables in rhinoplasty retouching: towards an evolution of surgical strategy? Literature

Keywords: revision rhinoplasty, injectables, fillers, hyaluronic acid, calcium hydroxylapatite

Background: Surgical revision rate of rhinoplasty is from 5% to 15% in literature.

Objective of review: In the context of post-rhinoplasty deformities, we aim to investigate the modalities of using injectables, their impacts on revision rate of rhinoplasty as well as their influences on the surgical strategy.

Type of review: We realized an international literature review to collect informations on main studies reporting series of exclusive secondary medical rhinoplasties or mixed primary/secondary medical rhinoplasties, as well as per-operative injection.

Search strategy: The databases of the National Library of Medicine, Cochrane Library, Embase and Web of science were explored using the following Boolean string: (rhinoplasty OR nose) AND (injectable OR fillers OR hyaluronic acid OR calcium hydroxylapatite). The search was limited to the English language literature for studies published from 2007 up to December 2019.

Results: Fifteen cohort studies were included. Hyaluronic acid was the most commonly used injectable for rhinoplasty revision. Patient satisfaction rates varied between 80% and 100%. Reinjections were necessary in about 20 to 50% of cases whatever the used injectables. Minor complications (swelling, bruising, erythema) were frequent after filler injections (4%). Severe complications such granulomas or vascular embolism causing skin necrosis/visual impairment were rare (0.4%). Their physiopathology, management and prevention are detailed.

Conclusions. The use of injectables seems to reduce the need of secondary surgical rhinoplasties. It can be expected that an evolution in surgical practices will result from injectables using, but it will be possible only if the technique is perfectly understood to avoid potentially serious vascular complications.

Introduction

Rhinoplasties are surgical procedures widely described and commonly practiced [START_REF] Rudy | Rhinoplasty[END_REF]. However, postrhinoplasty deformities are frequent, even in the most experienced hands [START_REF] Bray | Injection rhinoplasty: non-surgical nasal augmentation and correction of post-rhinoplasty contour asymmetries with hyaluronic acid: how we do it[END_REF][START_REF] Kose | Use of hyaluronic acid in the correction of contour asymmetries following rhinoplasty[END_REF][START_REF] Stupak | Calcium hydroxylapatite gel (Radiesse) injection for the correction of postrhinoplasty contour deficiencies and asymmetries[END_REF][START_REF] Baptista | Correction of sequelae of rhinoplasty by lipofilling[END_REF][START_REF] Cárdenas | Refinement of rhinoplasty with lipoinjection[END_REF]. Thus, surgical revisions, or secondary rhinoplasties, could be necessary as evidenced by the rates of open or closed post rhinoplasty surgical revision ranging from 5 to 15% in the literature [START_REF] Bouaoud | Functional and Aesthetic Factors Associated with Revision of Rhinoplasty[END_REF].

Beside surgical rhinoplasty, injections of fillers to correct nasal deformities are currently emerging and become more and more popular [START_REF]Plastic Surgery Statistics[END_REF]. This emergence of injectables using may change our practices given their efficiency to correct some postoperative defects of rhinoplasties [START_REF] Kose | Use of hyaluronic acid in the correction of contour asymmetries following rhinoplasty[END_REF][START_REF] Stupak | Calcium hydroxylapatite gel (Radiesse) injection for the correction of postrhinoplasty contour deficiencies and asymmetries[END_REF][START_REF] Baptista | Correction of sequelae of rhinoplasty by lipofilling[END_REF][START_REF] Cárdenas | Refinement of rhinoplasty with lipoinjection[END_REF][START_REF] Hedén | Nasal Reshaping with Hyaluronic Acid: An Alternative or Complement to Surgery[END_REF][START_REF] Schuster | Injection Rhinoplasty with Hyaluronic Acid and Calcium Hydroxyapatite: A Retrospective Survey Investigating Outcome and Complication Rates[END_REF][START_REF] Erol | Microfat Grafting in Nasal Surgery[END_REF][START_REF] Solomon | Facial soft tissue augmentation with Artecoll®: A review of eight years of clinical experience in 153 patients[END_REF][START_REF] Monreal | Fat grafting to the nose: personal experience with 36 patients[END_REF][START_REF] Siclovan | Injectable calcium hydroxylapatite for correction of nasal bridge deformities[END_REF]. However, the iatrogenicity of injectable should not be underestimated and it is necessary to proceed with a rigorous technique to avoid complications, among which some may be serious [START_REF] Bray | Injection rhinoplasty: non-surgical nasal augmentation and correction of post-rhinoplasty contour asymmetries with hyaluronic acid: how we do it[END_REF][START_REF] Kose | Use of hyaluronic acid in the correction of contour asymmetries following rhinoplasty[END_REF][START_REF] Baptista | Correction of sequelae of rhinoplasty by lipofilling[END_REF][START_REF] Hedén | Nasal Reshaping with Hyaluronic Acid: An Alternative or Complement to Surgery[END_REF][START_REF] Schuster | Injection Rhinoplasty with Hyaluronic Acid and Calcium Hydroxyapatite: A Retrospective Survey Investigating Outcome and Complication Rates[END_REF][START_REF] Erol | Microfat Grafting in Nasal Surgery[END_REF][START_REF] Siclovan | Injectable calcium hydroxylapatite for correction of nasal bridge deformities[END_REF][START_REF] Thomas | Injectables in the Nose: Facts and Controversies[END_REF]. Thus, in the context of post-rhinoplasty deformities, two questions remain unanswered. Do injectables reduce the surgical revision rate of rhinoplasties? Will injectables lead to changes in our surgical strategy and management? To try to get some answers, we have decided to realize a literature review on the subject. The aims of this literature review were to investigate and understand the type, the indications, the outcomes and the complications of using injectables in rhinoplasty retouching. Furthermore, we report some advices to avoid and manage complications as well as some elements of responses for the two above mentioned questions.

Method

A literature review was realized to collect information on the interesting studies. The databases of the National Library of Medicine, Cochrane Library, Embase and Web of science were explored using the following Boolean string: (rhinoplasty OR nose) AND (injectable OR fillers OR hyaluronic acid OR calcium hydroxylapatite). Inclusion criteria were as following: series of exclusively secondary medical rhinoplasties or mixed primary or secondary medical rhinoplasties, as well as per-operative injection published in the last twelve years i.e. from 2007 up to December 2019. The search was limited to the English language literature. We also considered literature reviews for the discussion. Studies reporting only primary medical rhinoplasties were excluded, as well as those involving silicone, collagen or permanent injections. The study flow diagram is available (figure1). The included studies are listed in Table 1 [START_REF] Bray | Injection rhinoplasty: non-surgical nasal augmentation and correction of post-rhinoplasty contour asymmetries with hyaluronic acid: how we do it[END_REF][START_REF] Kose | Use of hyaluronic acid in the correction of contour asymmetries following rhinoplasty[END_REF][START_REF] Stupak | Calcium hydroxylapatite gel (Radiesse) injection for the correction of postrhinoplasty contour deficiencies and asymmetries[END_REF][START_REF] Baptista | Correction of sequelae of rhinoplasty by lipofilling[END_REF][START_REF] Cárdenas | Refinement of rhinoplasty with lipoinjection[END_REF][START_REF] Hedén | Nasal Reshaping with Hyaluronic Acid: An Alternative or Complement to Surgery[END_REF][START_REF] Schuster | Injection Rhinoplasty with Hyaluronic Acid and Calcium Hydroxyapatite: A Retrospective Survey Investigating Outcome and Complication Rates[END_REF][START_REF] Erol | Microfat Grafting in Nasal Surgery[END_REF][START_REF] Monreal | Fat grafting to the nose: personal experience with 36 patients[END_REF][START_REF] Siclovan | Injectable calcium hydroxylapatite for correction of nasal bridge deformities[END_REF][START_REF] Valente | Abstract: Dermal Fillers in Secondary Rhinoplasty[END_REF][START_REF] Jasin | Nonsurgical rhinoplasty using dermal fillers[END_REF][START_REF] Liapakis | Secondary rhinoplasty fixations with hyaluronic acid[END_REF][START_REF] Rivkin | Nonsurgical Injection Rhinoplasty With Calcium Hydroxylapatite in a Carrier Gel (Radiesse): A 4-Year, Retrospective, Clinical Review[END_REF][START_REF] Becker | Nasal augmentation with calcium hydroxylapatite in a carrier-based gel[END_REF].

Results of the literature review

History of injectables in rhinoplasty

Firstly, in 1904, Albert E. Stein injected paraffin to correct supratip depression (saddle nose) [START_REF] Stein | Paraffin-injektionen, Theorie und Praxis[END_REF]. Then, in 1919, P. Bruning used fat injections to correct rhinoplasty deformities [START_REF] Bruning | Contribution a l'etude des greffes adipeuses[END_REF]. Nasal injections really developed in the 1980s with silicone and bovine collagen [START_REF] Knapp | The augmentation of soft tissue with injectable collagen[END_REF][START_REF] Webster | Rhinoplastic revisions with injectable silicone[END_REF]. The recent emergence of new injectables such calcium hydroxylapatite (CaHA) and Hyaluronic acid (HA) has led to the concept of medical rhinoplasty [START_REF] Siclovan | Injectable calcium hydroxylapatite for correction of nasal bridge deformities[END_REF][START_REF] Tzikas | A 52-month summary of results using calcium hydroxylapatite for facial soft tissue augmentation[END_REF][START_REF] Carruthers | Advances in facial rejuvenation: botulinum toxin type a, hyaluronic acid dermal fillers, and combination therapies--consensus recommendations[END_REF][START_REF] Loghem | Calcium hydroxylapatite: over a decade of clinical experience[END_REF][START_REF] Pavicic | Calcium hydroxylapatite filler: an overview of safety and tolerability[END_REF][START_REF] Bertossi | Nonsurgical Rhinoplasty: Nasal Grid Analysis and Nasal Injecting Protocol[END_REF][START_REF] Jung | Minimally Invasive Rhinoplasty Technique Using a Hyaluronic Acid Filler and Polydioxanone Threads: An Effective Combination[END_REF][START_REF] Moon | Injection Rhinoplasty Using Filler[END_REF][START_REF] Johnson | Nonsurgical Rhinoplasty[END_REF][START_REF] Han | Multiplane hyaluronic acid (EME) in female Chinese rhinoplasty using blunt and sharp needle technique[END_REF][START_REF] Xue | Multiplane hyaluronic acid rhinoplasty[END_REF][START_REF] Redaelli | Medical rhinoplasty with hyaluronic acid and botulinum toxin A: a very simple and quite effective technique[END_REF][START_REF] Beer | Nasal reconstruction using 20 mg/ml cross-linked hyaluronic acid[END_REF].

Selection of injectables

HA is the most commonly used injectable for rhinoplasty retouches (Table 1), in particular because of its safety, plasticity, durability, and the possibility of reversing the HA effects with hyaluronidase. The 2018 National Plastic Surgery Statistics reports the use of HA in 79.5% of cosmetic minimally-invasive procedures using fillers [START_REF]Plastic Surgery Statistics[END_REF]. On the other hand, CaHA, Platelet-Rich Plasma (PRP), Polylactic acid and fat injections are used for the same indications in 8.4%, 4.8%; 4.6% and 1.7% of cases respectively. Permanent injectables are not recommended because of the difficult removal in case of excess as well as because they could compromise a future surgery [START_REF] Humphrey | Soft tissue fillers in the nose[END_REF][START_REF] Kurkjian | Soft-tissue fillers in rhinoplasty[END_REF][START_REF] Lacerda | Filler Rhinoplasty[END_REF].

Indications of the injections

Injectables are used to correct low to moderate aesthetic disorders. Several nasal subunits may be injected after rhinoplasty such the dorsum (irregularities), the osseocartilaginous flaps (asymmetry), the upper lateral cartilage (inverted V deformity, "spreader graft"), the supratip region (saddle nose, pollybeak), the tip (asymmetry, hypo projection), the columella and the naso-labial angle. Severe aesthetic disorders or respiratory functional problems are usually surgically managed [START_REF] Stupak | Calcium hydroxylapatite gel (Radiesse) injection for the correction of postrhinoplasty contour deficiencies and asymmetries[END_REF].

Outcomes

Patient satisfaction rates vary from 80% to 100% [START_REF] Kose | Use of hyaluronic acid in the correction of contour asymmetries following rhinoplasty[END_REF][START_REF] Stupak | Calcium hydroxylapatite gel (Radiesse) injection for the correction of postrhinoplasty contour deficiencies and asymmetries[END_REF][START_REF] Baptista | Correction of sequelae of rhinoplasty by lipofilling[END_REF][START_REF] Cárdenas | Refinement of rhinoplasty with lipoinjection[END_REF][START_REF] Hedén | Nasal Reshaping with Hyaluronic Acid: An Alternative or Complement to Surgery[END_REF][START_REF] Schuster | Injection Rhinoplasty with Hyaluronic Acid and Calcium Hydroxyapatite: A Retrospective Survey Investigating Outcome and Complication Rates[END_REF][START_REF] Erol | Microfat Grafting in Nasal Surgery[END_REF][START_REF] Solomon | Facial soft tissue augmentation with Artecoll®: A review of eight years of clinical experience in 153 patients[END_REF][START_REF] Siclovan | Injectable calcium hydroxylapatite for correction of nasal bridge deformities[END_REF]. However, this rate is related to the importance of the corrected disorder. Indeed, the greater is the defects to be corrected, the lower is the satisfaction rate [START_REF] Erol | Microfat Grafting in Nasal Surgery[END_REF]. Other factors that influence this rate are the anatomic characteristics of the injected nose, the injection protocol and the experience of the injector [START_REF] Bertossi | Nonsurgical Rhinoplasty: Nasal Grid Analysis and Nasal Injecting Protocol[END_REF]. Reinjections are necessary in about 50% of cases for HA [START_REF] Kose | Use of hyaluronic acid in the correction of contour asymmetries following rhinoplasty[END_REF][START_REF] Hedén | Nasal Reshaping with Hyaluronic Acid: An Alternative or Complement to Surgery[END_REF] and 10 to 17% of cases for fat injections [START_REF] Baptista | Correction of sequelae of rhinoplasty by lipofilling[END_REF][START_REF] Monreal | Fat grafting to the nose: personal experience with 36 patients[END_REF]. Regarding longevity, results of nasal injections seem to be more stable than those observed for other anatomical regions of the face due to the immobility/low mobility of the injection areas [START_REF] Hedén | Nasal Reshaping with Hyaluronic Acid: An Alternative or Complement to Surgery[END_REF][START_REF] Thomas | Injectables in the Nose: Facts and Controversies[END_REF].

Complications

 Overview

Minor complications are frequent after filler injections with a mean rate of 4% (range 0-10). They are mainly swelling, bruising, erythema, hypersensitivity, nodules, lump and asymmetry, incomplete corrections, irregularities and asymmetries. Minor complications are most of the time transient. On the other hand, severe complications are rare with a mean rate of 0.4% (range 0-4) but they are most of the time critical. These are granulomas and vascular embolism causing skin necrosis or visual impairment [START_REF] Bertossi | Complications and management after a nonsurgical rhinoplasty: a literature review[END_REF][START_REF] Beleznay | Update on Avoiding and Treating Blindness From Fillers: A Recent Review of the World Literature[END_REF]. Anatomy of the nose and physiopathology of the complications are important to understand for managing fillers complications.

 Cutaneous and vascular anatomy of the nose

Between the skin and the bony-cartilaginous framework there are 4 layers: superficial fatty layer, fibromuscular layer or superficial muscular aponeurotic system (SMAS), deep fatty layer, and periosteum-perichondrium [START_REF] Bertossi | Nonsurgical Rhinoplasty: Nasal Grid Analysis and Nasal Injecting Protocol[END_REF][START_REF] Bertossi | Complications and management after a nonsurgical rhinoplasty: a literature review[END_REF].

The proximal part of the nose is vascularized by the internal carotid system via the ophthalmic artery.

The distal part of the nose is vascularized by the external carotid system via the facial artery. Major blood vessels are located in the SMAS layer or the superficial fatty layer [START_REF] Trenité | Rhinoplasty: A Practical Guide to Functional and Aesthetic Surgery of the Nose[END_REF]. The skin is thin and loose in the upper two thirds of the nose, while the skin is thick and inextensible in the tip and supra tip [START_REF] Tansatit | Safe Planes for Injection Rhinoplasty: A Histological Analysis of Midline Longitudinal Sections of the Asian Nose[END_REF].

 Physiopathology of the vascular complication complications [START_REF] Kose | Use of hyaluronic acid in the correction of contour asymmetries following rhinoplasty[END_REF][START_REF] Baptista | Correction of sequelae of rhinoplasty by lipofilling[END_REF][START_REF] Hedén | Nasal Reshaping with Hyaluronic Acid: An Alternative or Complement to Surgery[END_REF][START_REF] Schuster | Injection Rhinoplasty with Hyaluronic Acid and Calcium Hydroxyapatite: A Retrospective Survey Investigating Outcome and Complication Rates[END_REF][START_REF] Monreal | Fat grafting to the nose: personal experience with 36 patients[END_REF][START_REF] Siclovan | Injectable calcium hydroxylapatite for correction of nasal bridge deformities[END_REF][START_REF] Thomas | Injectables in the Nose: Facts and Controversies[END_REF][START_REF] Robati | The Risk of Skin Necrosis Following Hyaluronic Acid Filler Injection in Patients With a History of Cosmetic Rhinoplasty[END_REF][START_REF] Leupe | The injectable filler in rhinoplasty: not a complication-free alternative[END_REF][START_REF] Schanz | Arterial embolization caused by injection of hyaluronic acid (Restylane®)[END_REF][START_REF] Delorenzi | Complications of injectable fillers, part 2: vascular complications[END_REF][START_REF] Delorenzi | Complications of injectable fillers, part I[END_REF][START_REF] Park | Iatrogenic occlusion of the ophthalmic artery after cosmetic facial filler injections: a national survey by the Korean Retina Society[END_REF][START_REF] Walker | This month's guideline: Visual Loss Secondary to Cosmetic Filler Injection[END_REF] Vascular risk corresponds either to an arterial embolization or a vascular compression. Embolization of an artery in the proximal part of the nose can lead to blindness if the central artery of the retina is involved. Embolization of the distal part of the nose can lead to facial skin necrosis. Excess of injectables at the tip and supra tip may cause skin necrosis secondary to vascular compression due to the thickness and inextensibility of the skin at this level.

 Prevention advices in literature

To reduce the risk of complications, it is necessary to perfectly understand the vascular anatomy of the nose. It is also important to consider changes induced by previous surgeries. It is essential to respect several rules to avoid these vascular risks: mark the midline (the linear threading technique), small amount of filler (0.1 to 1.0 mL per injection session), retrograde injection (withdrawal technique), without hyper pressure (slow and gentle injection), in depth just above the perichondrium or periosteum (to minimize damage to vessels and avoid intravascular injection), at best with blunt cannulas. Before injection, aspirate to verify a negative flashback. A permanent control of the appearance of the teguments should be realized during the procedure. Epinephrine may be added to filler for vessel constriction as well as compression of proximal ophthalmic anastomosing vessels with non-dominant hand. In all cases patients should be always informed about all the risks associated with fillers injection. Injections should be realized at least 3 to 6 months after the primary rhinoplasty and intervals of 4 to 6 weeks are necessary if serial injection are planned. [START_REF] Bray | Injection rhinoplasty: non-surgical nasal augmentation and correction of post-rhinoplasty contour asymmetries with hyaluronic acid: how we do it[END_REF][START_REF] Kose | Use of hyaluronic acid in the correction of contour asymmetries following rhinoplasty[END_REF][START_REF] Hedén | Nasal Reshaping with Hyaluronic Acid: An Alternative or Complement to Surgery[END_REF][START_REF] Schuster | Injection Rhinoplasty with Hyaluronic Acid and Calcium Hydroxyapatite: A Retrospective Survey Investigating Outcome and Complication Rates[END_REF][START_REF] Monreal | Fat grafting to the nose: personal experience with 36 patients[END_REF][START_REF] Siclovan | Injectable calcium hydroxylapatite for correction of nasal bridge deformities[END_REF][START_REF] Thomas | Injectables in the Nose: Facts and Controversies[END_REF][START_REF] Liapakis | Secondary rhinoplasty fixations with hyaluronic acid[END_REF][START_REF] Bertossi | Nonsurgical Rhinoplasty: Nasal Grid Analysis and Nasal Injecting Protocol[END_REF][START_REF] Bertossi | Nonsurgical Rhinoplasty: Nasal Grid Analysis and Nasal Injecting Protocol[END_REF][START_REF] Kurkjian | Soft-tissue fillers in rhinoplasty[END_REF][START_REF] Loh | Prevention and management of vision loss relating to facial filler injections[END_REF][START_REF] De Lacerda | Prevention and management of iatrogenic blindness associated with aesthetical filler injections[END_REF][START_REF] Woodward | Facial Filler Complications[END_REF][START_REF] Wang | Update on injectables in the nose[END_REF][START_REF] Cotofana | Midface: Clinical Anatomy and Regional Approaches with Injectable Fillers[END_REF].

 Management of complications in literature

The prognosis depends mainly on the early recognition of complications and their prompt managements. Thus, during and after the procedures, surgeons should research the alarm signs associated with these complications. Immediate localized or distant pain or other classic symptoms and signs (skin blanching, livedo reticularis, slow capillary refill, and dusky blue-red discoloration) are not always apparent, which sometimes makes diagnosis challenging. In case of vascular complication, immediate injection of 10 hyaluronidase units per 0.1mL of HA should be realized [START_REF] Kurkjian | Soft-tissue fillers in rhinoplasty[END_REF]. Topical nitropaste under occlusion, oral acetylsalicylic acid (aspirin), warm compresses, and vigorous massage are also useful. Secondary lines of treatment may involve intra-arterial hyaluronidase, hyperbaric oxygen therapy, and ancillary vasodilating agents (prostaglandin E1) [START_REF] Bertossi | Complications and management after a nonsurgical rhinoplasty: a literature review[END_REF][START_REF] Goodman | Experience and Management of Intravascular Injection with Facial Fillers: Results of a Multinational Survey of Experienced Injectors[END_REF][START_REF] Urdiales-Gálvez | Treatment of Soft Tissue Filler Complications: Expert Consensus Recommendations[END_REF][START_REF] Cavallini | The role of hyaluronidase in the treatment of complications from hyaluronic acid dermal fillers[END_REF][START_REF] Ciancio | Early hyaluronidase use in preventing skin necrosis after treatment with dermal fillers: Report of two cases[END_REF]. At all, reported management strategies vary greatly from surgeons and there is no treatment that is consistently successful [START_REF] Beleznay | Update on Avoiding and Treating Blindness From Fillers: A Recent Review of the World Literature[END_REF].

Discussion

Rhinoplasty is a challenging procedure and results sometimes in unsatisfaction, even in the most experienced hands [START_REF] Bray | Injection rhinoplasty: non-surgical nasal augmentation and correction of post-rhinoplasty contour asymmetries with hyaluronic acid: how we do it[END_REF][START_REF] Kose | Use of hyaluronic acid in the correction of contour asymmetries following rhinoplasty[END_REF][START_REF] Stupak | Calcium hydroxylapatite gel (Radiesse) injection for the correction of postrhinoplasty contour deficiencies and asymmetries[END_REF][START_REF] Baptista | Correction of sequelae of rhinoplasty by lipofilling[END_REF][START_REF] Cárdenas | Refinement of rhinoplasty with lipoinjection[END_REF]. A recent study reporting the causes for litigation in facial surgery showed that dissatisfaction about the esthetic or functional result topped the list and that rhinoplasty was by far the most common claim [START_REF] Brauwer | Causes for litigation and risk management in facial surgery: A review of 136 cases[END_REF]. Thus, surgical revisions are not so rare as evidenced by several studies reporting surgical revision rates ranging from 5 to 15% whether by open or closed techniques [START_REF] Bouaoud | Functional and Aesthetic Factors Associated with Revision of Rhinoplasty[END_REF]. The cost and complexity of secondary surgical rhinoplasty, as well as the possible non-operative management (low to moderate defects and/or difficult to access for surgery) or the patient's refusal, give full meaning to injectables for revision rhinoplasties [START_REF] Valente | Abstract: Dermal Fillers in Secondary Rhinoplasty[END_REF][START_REF] Cotofana | Midface: Clinical Anatomy and Regional Approaches with Injectable Fillers[END_REF][START_REF] Kontis | The Art of Camouflage: When Can a Revision Rhinoplasty Be Nonsurgical?[END_REF]. Injectables have already proven their effectiveness (high satisfaction rate), safety, simplicity of use and low cost [START_REF] Kose | Use of hyaluronic acid in the correction of contour asymmetries following rhinoplasty[END_REF][START_REF] Stupak | Calcium hydroxylapatite gel (Radiesse) injection for the correction of postrhinoplasty contour deficiencies and asymmetries[END_REF][START_REF] Baptista | Correction of sequelae of rhinoplasty by lipofilling[END_REF][START_REF] Cárdenas | Refinement of rhinoplasty with lipoinjection[END_REF][START_REF] Hedén | Nasal Reshaping with Hyaluronic Acid: An Alternative or Complement to Surgery[END_REF][START_REF] Schuster | Injection Rhinoplasty with Hyaluronic Acid and Calcium Hydroxyapatite: A Retrospective Survey Investigating Outcome and Complication Rates[END_REF][START_REF] Erol | Microfat Grafting in Nasal Surgery[END_REF][START_REF] Solomon | Facial soft tissue augmentation with Artecoll®: A review of eight years of clinical experience in 153 patients[END_REF][START_REF] Monreal | Fat grafting to the nose: personal experience with 36 patients[END_REF][START_REF] Siclovan | Injectable calcium hydroxylapatite for correction of nasal bridge deformities[END_REF]. Most of post-rhinoplasty defects are accessible to injectables in experienced hands. Resorbable injectables are recommended because they are reversible in case of excess and they do not compromise a future surgical revision [START_REF] Schuster | Injection Rhinoplasty with Hyaluronic Acid and Calcium Hydroxyapatite: A Retrospective Survey Investigating Outcome and Complication Rates[END_REF].

However, major defects are not an indication for injectable but require surgical rhinoplasty [START_REF] Kose | Use of hyaluronic acid in the correction of contour asymmetries following rhinoplasty[END_REF][START_REF] Stupak | Calcium hydroxylapatite gel (Radiesse) injection for the correction of postrhinoplasty contour deficiencies and asymmetries[END_REF][START_REF] Kurkjian | Soft-tissue fillers in rhinoplasty[END_REF].

Furthermore, the risk of serious vascular complications associated with injectables in the nasal area should not be omitted [START_REF] Bertossi | Complications and management after a nonsurgical rhinoplasty: a literature review[END_REF][START_REF] Beleznay | Update on Avoiding and Treating Blindness From Fillers: A Recent Review of the World Literature[END_REF]. The two main involved mechanisms are: i-embolization of a vessel by the injectable and ii-extrinsic vascular compression by excessive injections in an anatomic area recovered by inextensible skin. A perfect knowledge of the vascular anatomy and soft tissues of the nose, as well as a rigorous technique performed by trained hands, make it possible to avoid the main part of these complications In this review of the use of injectables for revision rhinoplasty, we noted some interesting information (Table 1). Firstly, the most commonly used injectable is HA followed by CaHA and fat. Furthermore, rhinoplasty using injectables is to be easy, safe, low cost, and becomes increasingly popular. This technique seems to be effectiveness for minor defects and provide a high satisfaction rate. Finally, few complications are reported in the literature.

With regard to question 1, "Do injectables reduce the rate of surgical revision?", the answer is yes.

Only one author of our review (Hedén) clearly answers this question [START_REF] Hedén | Nasal Reshaping with Hyaluronic Acid: An Alternative or Complement to Surgery[END_REF]. Given the large number of procedures reported, involving both minor and major defects, and high satisfaction rate, we can clearly hypothesize that injectables may reduce the rate of revision surgery. In addition, the number of rhinoplasty revisions using injectables is growing rapidly since this technique is increasingly popular among patients and surgeons. Indeed, injectables are no longer only indicated when surgical revision is refused but are primarily proposed as an effective therapeutic option and their indications are expanding [START_REF] Erol | Microfat Grafting in Nasal Surgery[END_REF][START_REF] Solomon | Facial soft tissue augmentation with Artecoll®: A review of eight years of clinical experience in 153 patients[END_REF][START_REF] Monreal | Fat grafting to the nose: personal experience with 36 patients[END_REF][START_REF] Kurkjian | Soft-tissue fillers in rhinoplasty[END_REF]. Moreover, some surgeons do not yet use this technique which suggests that more cases of injections will be performed once they will be convinced by injectables benefits [START_REF] Rosenberger | Controversies in Revision Rhinoplasty[END_REF].

Finally, given that respiratory functional disorders after primary rhinoplasty are a major cause of surgical revision [START_REF] Bouaoud | Functional and Aesthetic Factors Associated with Revision of Rhinoplasty[END_REF], the using of injectables to correct inspiratory collapse of the nasal valve, especially by using endonasal injection at its apex ("spreader graft") [START_REF] Bray | Injection rhinoplasty: non-surgical nasal augmentation and correction of post-rhinoplasty contour asymmetries with hyaluronic acid: how we do it[END_REF][START_REF] Kontis | The Art of Camouflage: When Can a Revision Rhinoplasty Be Nonsurgical?[END_REF][START_REF] Kontis | Filler Injection for Nasal Valve Stenting. Cosmetic Injection Techniques : A Text and Video Guide to Neurotoxins and Fillers[END_REF][START_REF] Nyte | Spreader graft injection with calcium hydroxylapatite: a nonsurgical technique for internal nasal valve collapse[END_REF][START_REF] Nyte | Hyaluronic acid spreader-graft injection for internal nasal valve collapse[END_REF] is promising.

Although the answer to this question is yes, we do not know the proportion. Prospective comparative studies should be designed, with sufficient follow-up time, to compare the surgical revision rates before and after the use of injectables for post-rhinoplasty retouching.

With regard to question 2, " Do injectables eventually lead to a change in our surgical strategy?", the answer is unclear. More and more surgeons use perioperative fat injections to prevent the occurrence of postoperative defects [START_REF] Cárdenas | Refinement of rhinoplasty with lipoinjection[END_REF][START_REF] Monreal | Fat grafting to the nose: personal experience with 36 patients[END_REF]. However, all the authors agree that surgery remains the gold standard [START_REF] Bray | Injection rhinoplasty: non-surgical nasal augmentation and correction of post-rhinoplasty contour asymmetries with hyaluronic acid: how we do it[END_REF][START_REF] Kose | Use of hyaluronic acid in the correction of contour asymmetries following rhinoplasty[END_REF][START_REF] Erol | Microfat Grafting in Nasal Surgery[END_REF][START_REF] Monreal | Fat grafting to the nose: personal experience with 36 patients[END_REF][START_REF] Siclovan | Injectable calcium hydroxylapatite for correction of nasal bridge deformities[END_REF][START_REF] Thomas | Injectables in the Nose: Facts and Controversies[END_REF] and that the rigor of the surgical technique should not be modified on the pretext that injectables can compensate its shortcomings [START_REF] Monreal | Fat grafting to the nose: personal experience with 36 patients[END_REF][START_REF] Siclovan | Injectable calcium hydroxylapatite for correction of nasal bridge deformities[END_REF]. Even if it is more complicated and more costly, surgery remains the most effective way to correct postoperative defects in rhinoplasty, especially when they are important [START_REF] Kose | Use of hyaluronic acid in the correction of contour asymmetries following rhinoplasty[END_REF][START_REF] Stupak | Calcium hydroxylapatite gel (Radiesse) injection for the correction of postrhinoplasty contour deficiencies and asymmetries[END_REF][START_REF] Baptista | Correction of sequelae of rhinoplasty by lipofilling[END_REF][START_REF] Monreal | Fat grafting to the nose: personal experience with 36 patients[END_REF][START_REF] Kurkjian | Soft-tissue fillers in rhinoplasty[END_REF].

Several questions remain unanswered and require serious considerations: i-What will be the place of injectables in perioperative surgery? At the end of the procedure, it is quite conceivable to correct a residual defect by injection especially if it appears too difficult or high-risk for surgically correcting it;

ii-Should we change our surgical management (i.e. more important resections) given that a residual depression is easier to correct using injectables comparing to residual excess? At all, injectables may be considered per or postoperatively [START_REF] Hedén | Nasal Reshaping with Hyaluronic Acid: An Alternative or Complement to Surgery[END_REF]. Some authors consider surgery for major architectural modifications of the nose and injectables for "finishing" [START_REF] Kurkjian | Soft-tissue fillers in rhinoplasty[END_REF]. Others believe that each rhinoplasty project should be subject to medical and surgical considerations from the beginning [START_REF] Siclovan | Injectable calcium hydroxylapatite for correction of nasal bridge deformities[END_REF].

Conclusion

Surgery aiming for excellence remains the gold standard to correct nose aesthetic and functional disorders, whether for primary or secondary rhinoplasties. However, using injectables easy, low-cost, and allow correcting low to moderate disorders. While it is established that injectables reduce the number of secondary rhinoplasties, the optimal time for injectables in rhinoplasty retouching is not yet clearly defined. It can be expected that an evolution in our surgical practices will emerge from results of large rhinoplasty cohorts with injectable using. In all cases, the anatomy and the technique should be perfectly understood to avoid potentially serious vascular complications.

Figure and table legends

Figure 1 :

 1 Figure 1: The study flow diagram.

Table 1 :

 1 Published studies in international literature concerning revision rhinoplasty with injectable (not mentioned in this table are studies with silicone, collagen or Polymethylmethacrylate[PMMA] injection, studies concerning only primary medical rhinoplasties and literature reviews) (Nb : number ; HA: hyaluronic acid; CaHA: Calcium Hydroxylapatite; NA: non-available; wk : weeks; periop: perioperative)

	Becker 2008 20	24	9 (37%) 15	0	CaHA	Temporary minor	0	78 % of the
				(63%)			pain, redness, and		patients rated
							swelling following		their
							injection		satisfaction as
									8/10 or better
	Cárdenas et	78	61	17	78 (100%)	Fat	0	0	99% of excellent
	Carvajal 2007 6		(78%)	(22%)					or	good
									satisfaction
	Stupak et al.,	13	0	13		CaHA	1 mild erythema for	0	85% of good to
	2007 4			(100%)			several days		excellent
									satisfaction
	*Not referenced on PubMed, no information on previous rhinoplasty was available for 27 patients
	(7.0%)

Table 1 :

 1 Published studies in international literature concerning revision rhinoplasty with injectable (not mentioned in this table are studies with silicone, collagen or Polymethylmethacrylate [PMMA] injection, studies concerning only primary medical rhinoplasties and literature reviews) (HA: hyaluronic acid; CaHA: Calcium Hydroxylapatite; n/a: non-available; wk : weeks;)

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.