Discovery of circulating miRNAs as biomarkers of chronic Chagas heart disease via a small RNA-Seq approach.

Chagas disease affects approximately 7 million people worldwide in Latin America and is a neglected tropical disease. Twenty to thirty percent of chronically infected patients develop chronic Chagas cardiomyopathy decades after acute infection. Identifying biomarkers of Chagas disease progression is necessary to develop better therapeutic and preventive strategies. Circulating microRNAs are increasingly reliable biomarkers of disease and therapeutic targets. To identify new circulating microRNAs for Chagas disease, we performed exploratory small RNA sequencing from the plasma of patients and performed de novo miRNA prediction, identifying potential new microRNAs. The levels of the new microRNAs temporarily named miR-Contig-1519 and miR-Contig-3244 and microRNAs that are biomarkers for nonchagasic cardiomyopathies, such as miR-148a-3p and miR-224-5p, were validated by quantitative reverse transcription. We found a specific circulating microRNA signature defined by low miR-Contig-3244, miR-Contig-1519, and miR-148a-3 levels but high miR-224-5p levels for patients with chronic Chagas disease. Finally, we predicted in silico that these altered circulating microRNAs could affect the expression of target genes involved in different cellular pathways and biological processes, which we will explore in the future.

Chagas Disease in Europe.

Chagas disease is currently present in many non-endemic countries and remains a neglected tropical disease globally. A review of the literature identified significant gaps and scarcity of updated information from European countries, with most studies reporting data from Spain and Italy. The index of underdiagnosis may be as high as 70%, affecting mainly females of child-bearing age. Standardized screening of fertile, non-pregnant, women from endemic countries and subsequent treatment is considered an essential strategy to control transmission and prevent new cases, yet no uniform legislation for screening risk groups exists. There is heterogeneity in Europe in terms of preventive strategies to avoid transfusion-related transmission of Chagas disease, not necessarily in line with the European directives, with some countries conducting systematic screening for T. cruzi infection in blood donors, whilst others rely on pre-transfusion questionnaires. The growing burden of the infection in resource-rich areas may provide an opportunity for progress in certain aspects of control and prevention. Options for improving screening strategies, management and linkage to care are reviewed.

Cystic echinococcosis of the bone.

PURPOSE OF REVIEW: Cystic echinococcosis (CE) has a wide world distribution causing important morbidity. Osseous involvement is present in less than 4% of the CE cases. Its diagnosis and therapeutic management is full of challenges and low grade of evidence. RECENT FINDINGS: The study summarizes literature evidence on the management of osseous CE with particular emphasis on new data regarding diagnosis and treatment. SUMMARY: Clinical presentation of osseous CE depends on the skeletal area affected. Diagnosis is mostly based on radiological findings and serology. Recent advances with qPCR on osseous tissue samples seem to be a good option for diagnosis confirmation. Complete resection of the cystic lesion is the only curative option, but it is usually not possible performing palliative surgery and prolonged albendazole intake in most cases. Radiotherapy could be an option, but experience to date is only based on clinical cases.

Chagas disease is related to structural changes of the gut microbiota in adults with chronic infection (TRIPOBIOME Study).

BACKGROUND: The implications of the gut microbial communities in the immune response against parasites and gut motility could explain the differences in clinical manifestations and treatment responses found in patients with chronic Chagas disease. METHODOLOGY/PRINCIPAL FINDINGS: In this pilot prospective cross-sectional study, we included 80 participants: 29 with indeterminate CD (ICD), 16 with cardiac CD (CCD), 15 with digestive CD (DCD), and 20 controls without CD. Stool was collected at the baseline visit and faecal microbial community structure DNA was analyzed by whole genome sequencing. We also performed a comprehensive dietary analysis. Ninety per cent (72/80) of subjects were of Bolivian origin with a median age of 47 years (IQR 39-54) and 48.3% (29/60) had received benznidazole treatment. There were no substantial differences in dietary habits between patients with CD and controls. We identified that the presence or absence of CD explained 5% of the observed microbiota variability. Subjects with CD exhibited consistent enrichment of Parabacteroides spp, while for Enterococcus hirae, Lactobacillus buchneri and Megamonas spp, the effect was less clear once excluded the outliers values. Sex, type of visceral involvement and previous treatment with benznidazole did not appear to have a confounding effect on gut microbiota structure. We also found that patients with DCD showed consistent Prevotella spp enrichment. CONCLUSIONS: We found a detectable effect of Chagas disease on overall microbiota structure with several potential disease biomarkers, which warrants further research in this field. The analysis of bacterial diversity could prove to be a viable target to improve the prognosis of this prevalent and neglected disease.

The estimated distribution of autochthonous leishmaniasis by Leishmania infantum in Europe in 2005-2020.

BACKGROUND: This study describes the spatial and temporal distribution between 2005 and 2020 of human and animal leishmaniasis by Leishmania infantum in European countries reporting autochthonous cases, and highlights potential activities to improve disease control. METHODOLOGY/PRINCIPAL FINDINGS: It was based on a review of the scientific literature and data reported by the World Health Organization (WHO), the World Organization for Animal Health (WOAH) and the Ministries of Health, including hospital discharges in some countries. Autochthonous infections were reported in the scientific literature from 22 countries, including 13 and 21 countries reporting human and animal infections, respectively. In contrast, only 17 countries reported autochthonous human leishmaniasis cases to the WHO and 8 countries animal infections to the WOAH. The number of WOAH reported cases were 4,203, comprising 4,183 canine cases and 20 cases in wildlife. Of 8,367 WHO reported human cases, 69% were visceral leishmaniasis cases-of which 94% were autochthonous-and 31% cutaneous leishmaniasis cases-of which 53% were imported and mostly in France. The resulting cumulative incidence per 100,000 population of visceral leishmaniasis between 2005-2020, was highest in Albania (2.15 cases), followed by Montenegro, Malta, Greece, Spain and North Macedonia (0.53-0.42), Italy (0.16), Portugal (0.09) and lower in other endemic countries (0.07-0.002). However, according to hospital discharges, the estimated human leishmaniasis incidence was 0.70 in Italy and visceral leishmaniasis incidences were 0.67 in Spain and 0.41 in Portugal. CONCLUSIONS/SIGNIFICANCE: Overall, there was no evidence of widespread increased incidence of autochthonous human leishmaniasis by L. infantum in European countries. Visceral leishmaniasis incidence followed a decreasing trend in Albania, Italy and Portugal, and peaked in Greece in 2013, 2014 and 2017, and in Spain in 2006-2007 and 2011-2013. Animal and human cutaneous leishmaniasis remain highly underreported. In humans, hospital discharge databases provide the most accurate information on visceral leishmaniasis and may be a valuable indirect source of information to identify hotspots of animal leishmaniasis. Integrated leishmaniasis surveillance and reporting following the One Health approach, needs to be enhanced in order to improve disease control.

Rickettsioses imported by travellers and migrants to Spain attended in the +Redivi network, 2009-2020.

BACKGROUND: Rickettsioses are emerging zoonotic diseases with worldwide prevalence, recognized as a cause of imported fever in travellers and migrants. Our objective is to describe the microbiological, clinical and epidemiological characteristics of imported rickettsioses in travellers and migrants included in a Spanish collaborative network database. METHODS: This multicentre retrospective observational study was nested in +Redivi, the Cooperative Network for the Study of Infections Imported by Immigrants and Travellers. We asked collaborating centres for microbiological, clinical and epidemiological data on the rickettsiosis cases from the inception of the network in 2009 to December 2020. RESULTS: Fifty-four cases of imported rickettsioses were included; 35 (64.8%) patients were men, and the median age was 37 years (interquartile range 26, 51.2). Only 7.4% of patients were travellers visiting friends and relatives, and 5.6% were migrants. The most frequent travel destination (38.9%) was South Africa, and 90.7% engaged in a high-risk activity. Twenty-seven patients (50.0%) started presenting symptoms after their return to Spain. The most frequent symptoms were febrile syndrome (55.6%) and cutaneous manifestations (27.8%). Most diagnoses (63.0%) were confirmed by serology. Only a few cases (9.3%) required hospitalization. All participants had a full recovery. CONCLUSIONS: Clinicians should suspect rickettsial diseases in travellers coming from high-risk areas, especially Southern Africa, who have engaged in activities in rural areas and natural parks. Doxycycline should be considered in the empiric treatment of imported fever of travellers coming from those areas or who have engaged in high-risk activities. There is a need to improve access to molecular diagnosis of rickettsiosis in Spain.

Screening of imported malaria infection in asymptomatic migrants from Sub-Saharan Africa: A retrospective analysis of a 2010-2019 cohort.

BACKGROUND: Up to 40% of cases of imported malaria in Europe are diagnosed in recently arrived migrants, who generally exhibit asymptomatic or mild symptoms and show low parasitaemia (submicroscopic). The study describes the prevalence of malaria infection among asymptomatic Sub-Saharan African migrants (ASSAM) and compares asymptomatic malaria-infected (AMI) vs non-malaria infected patients. METHODS: An observational, comparative, retrospective study was carried out in ASSAM who underwent a medical examination, between 2010 and 2019 at the National Reference Unit for Tropical Diseases (NRU-Trop) in Madrid, Spain. Medical examination and systematic screening protocol for infectious diseases, including screening for malaria infection by Polymerase Chain Reaction (PCR) was performed. RESULTS: During the study period, 632 out of 1061 ASSAM were screened for malaria, median age: 24 years (IQR:1-5); median time from arrival to diagnosis: 2 months (IQR:1-5). P. falciparum was the most frequent species: 61 patients (67.8%). Compared to non-malaria infected, AMI subjects had: higher rate of co-infection with S. stercoralis (41.1%VS 22.9%;p < 0.001) and filariae (8.9% VS 2.4%;p = 0.006), lower erythrocyte corpuscular volume (83.6 VS 84.4;p = 0.008) and lower levels of cholesterol (151.0 VS 167.3;p < 0.001). CONCLUSIONS: We observed a high prevalence of AMI among ASSAM. This highlights the need to consider routing screening of migrants from endemic areas and to study if such screening could avoid the potential morbidities associated with chronic infection, reduce morbi-mortality of acute malaria and the risk of transmission in host communities.

Anfotericina B liposomal en el tratamiento de la leishmaniasis visceral.

A review on the current evidence of the efficacy and security of liposomal amphotericinB (L-AmB) for the treatment of visceral leishmaniasis (VL) has been performed. In the Indian subcontinent, a single dose of 10mg/kg has shown effectiveness in the treatment of VL due to Leishmania donovani. In contrast, higher doses of L-AmB (up to 30mg/kg) are required in Africa to treat a VL of the same etiology. When treating VL by Leishmania infantum acquired in the Americas and Europe the usual dose of L-AmB is 20-21mg/kg. In HIV co-infected patients the required doses are usually higher, up to 60mg/kg, and if it is administered in a prophylactic schedule after the treatment of VL relapses are reduced. L-AmB has shown synergism with other antiparasitic drugs, especially with paromomycin in the Indian subcontinent and with miltefosin in patients coinfected with HIV in East Africa. Due to its efficacy and safety profile, L-AmB is the first therapeutic option for VL.

Leishmaniases in the European Union and Neighboring Countries.

A questionnaire survey of animal and human health authorities in Europe revealed that leishmaniases are not notifiable in all countries with autochthonous cases. Few countries implement surveillance and control targeting both animal and human infections. Leishmaniases are considered emergent diseases in most countries, and lack of resources is a challenge for control.

Autoantibodies against the immunodominant sCha epitope discriminate the risk of sudden death in chronic Chagas cardiomyopathy.

In Chagas disease (ChD) caused by Trypanosoma cruzi, new biomarkers to predict chronic cardiac pathology are urgently needed. Previous studies in chagasic patients with mild symptomatology showed that antibodies against the immunodominant R3 epitope of sCha, a fragment of the human basic helix-loop-helix transcription factor like 5, correlated with cardiac pathology. To validate sCha as a biomarker and to understand the origin of anti-sCha antibodies, we conducted a multicenter study with several cohorts of chagasic patients with severe cardiac symptomatology. We found that levels of antibodies against sCha discriminated the high risk of sudden death, indicating they could be useful for ChD prognosis. We investigated the origin of the antibodies and performed an alanine scan of the R3 epitope. We identified a minimal epitope MRQLD, and a BLAST search retrieved several T. cruzi antigens. Five of the hits had known or putative functions, of which phosphonopyruvate decarboxylase showed the highest cross-reactivity with sCha, confirming the role of molecular mimicry in the development of anti-sCha antibodies. Altogether, we demonstrate that the development of antibodies against sCha, which originated by molecular mimicry with T. cruzi antigens, could discriminate electrocardiographic alterations associated with a high risk of sudden death.

Seroprevalence of vaccine-preventable and non-vaccine-preventable infections in migrants in Spain.

BACKGROUND: Updated seroprevalence studies of infections in migrants may aid the design of tailored vaccination and prevention programmes. The objective of this study was to describe the seroprevalence rates for potentially transmissible viral infections in migrants attended at a referral centre in a major European city. METHODS: Descriptive analysis of seroprevalence of vaccine-preventable and non-vaccine-preventable infections in migrants attended at a centre in Madrid, Spain (2018-19). Recorded variables included age, gender, country of birth/continent of origin, time from arrival to Spain until first clinic visit, rubella, measles, mumps, varicella (VZV), hepatitis B virus (HBV), hepatitis A virus (HAV), hepatitis C virus (HCV) and HIV serology. RESULTS: In total, 468 patients were included, 135 females (28.8%) and 333 males (71.2%), mean age 30.4 years. The majority of patients were from Africa (52.5%, of which 88.2% from sub-Saharan Africa), followed by Latin America (38.5%) and other areas (9%). Seroprevalence for tested migrants for rubella, measles and mumps was < 95% in the group overall (91% rubella, 88% measles, 83% mumps) and lower rates were observed in migrants >20 years (compared with those ≤ 20 years). Over 10% of females were potentially susceptible (negative/indeterminate serology) to rubella (11.4%), measles (12.7%) or mumps (10.3%). Lowest rates of rubella seropositivity were in Latin American migrants (over 12% potentially susceptible); measles and mumps seropositivity was lowest in migrants from areas other than Africa/Latin America (74% and 68%, respectively). Seroprevalence rates were 91% for VZV, 90% overall for HAV, ~6% for HBV chronic infection (~50% of migrants tested susceptible), 2% for HCV and 6% for HIV. CONCLUSIONS: Differences in seroprevalence for vaccine-preventable and transmissible infections according to gender, age range and area of origin were observed. Tailored screening, vaccination and prevention strategies in potentially vulnerable migrant groups should be designed.

Exploiting the Microbiota for the Diagnosis of Anal Precancerous Lesions in Men Who Have Sex With Men.

BACKGROUND: While the microbiota has been associated with human papillomavirus malignant transformation, it is unclear whether anal bacteria could improve the low specificity of anal cytology for the screening of high-grade intraepithelial squamous neoplasia (HSIL). METHODS: We recruited men who have sex with men undergoing anal cytology and high-resolution anoscopy. We assessed the microbiota composition from fecal samples and cytobrush anal samples using 16S ribosomal DNA sequencing in participants with or without biopsy-proven HSIL (bHSIL). We selected bacterial biomarkers based on their linear discriminant analysis. We assessed their predictive performance using logistic regression and bootstrap resampling. RESULTS: We included 128 individuals, 47 (36.7%) with bHSIL and 99 (77.3%) with human immunodeficiency virus. We detected 40 potential predictors of bHSIL. Ruminococcaceae NK4A214 group, Alloprevotella genus, Prevotella melanonigenica, and Ruminococcaceae UCG-014 were the most predictive of bHSIL. From 35 false-positive cytologic results, the combination of these 4 biomarkers with the anal cytology reclassified to true-negative 33 individuals (94%) and showed good diagnostic performance (area under the receiver operating characteristic curve, 0.805; 95% confidence interval, .728-.882). CONCLUSIONS: We found anal-associated bacteria indicative of a higher risk of precancerous anal lesions, which combination was highly specific. The microbiota could be developed as a complementary diagnostic tool to overcome the limitations of the current screening strategy for anal cancer.

COVID-19 and geographical area of origin.

OBJECTIVES: To describe and compare the main clinical characteristics and outcome measures in hospitalized patients with confirmed coronavirus disease 2019 (COVID-19) according to geographical area of origin. METHODS: A retrospective analysis of patients hospitalized with confirmed COVID-19 at a referral centre in Madrid, Spain, during March-May 2020 was performed. Recorded variables (age, gender, intensive care unit (ICU) admission, outcome), and geographical area of origin were compared for Europeans and non-Europeans (Latin Americans, Asians and Africans). RESULTS: In total, 2345 patients with confirmed COVID-19 hospitalized during the study period were included in the study. Of these, 1956 (83.4%) were European and 389 (16.6%) were non-European (of whom over 90%, 354/389, were Latin American). Non-Europeans were significantly younger than Europeans (mean 54 (SD 13.5) versus 70.4 (SD 15.1) years, p < 0.001); the majority were male (1420/2345, 60.6%), with no significant differences in gender between Europeans and non-Europeans (1197/1956 (61.2%) male in the European group versus 223/389 (57.3%) male in the non-European group, p 0.15). In-hospital mortality overall was higher in Europeans (443/1956, 22.7%) than in non-Europeans (40/389, 10.3%) (p < 0.001), but there were no significant differences when adjusted for age/gender (OR 1.27, 95% CI 0.86-1.88). Non-Europeans were more frequently admitted to ICU (71/389, 18.3%) compared with Europeans (187/1956, 9.6%) (p < 0.001) and a difference in ICU admission rate was also found when adjusted for age/gender (OR 1.43, 95% CI 1.03-1.98). CONCLUSIONS: No significant differences in mortality were observed between Europeans and non-Europeans (mainly Latin Americans), but an increase in ICU admission rate was found in non-Europeans.

Use of methotrexate for leprosy reactions. Experience of a referral center and systematic review of the literature.

BACKGROUND: Patients with leprosy can present with systemic inflammatory complications called leprosy reactions (LR), which can be severe and cause a loss of nerve function. The treatment of choice is prolonged corticosteroid therapy, frequently associated with severe side effects. We have used methotrexate as a corticosteroid-sparing regimen with good results. METHODS: To evaluate the role of methotrexate in managing LR, we performed a systematic review of the literature including our cases. We evaluated studies, prospective and retrospective, in both adults and children, which included any dose/regimen of methotrexate for the treatment of LR type 1 or 2. RESULTS: The systematic search revealed 261 records that yield 21 patients including our 3 cases (19 adults/two children), who were treated with methotrexate for LR type 1 and 2. There were 14 males. Median age was 35 years (P25-P75 28 to 52). Patients showed lepromatous (7), borderline lepromatous (9) or borderline tuberculoid (3) leprosy, among the 19 cases in which the type of leprosy was specified. As for the type of LR, 15 patients showed erythema nodosum leprosum (ENL), five showed LR type 1 and one showed polyarthritis and previous ENL. Methotrexate at weekly doses ranging from 7.5 mg to 20 mg (median 15 mg per week), typically administered with low-dose corticosteroids, was effective and safe as a corticosteroid-sparing agent. CONCLUSIONS: Methotrexate could be a suitable ancillary treatment or alternative to corticosteroids, especially in populations who are more prone to its adverse events. However, this evidence is based only on case reports and short clinical series.

Screening for Trypanosoma cruzi infection in immigrants and refugees: Systematic review and recommendations from the Spanish Society of Infectious Diseases and Clinical Microbiology.

BackgroundChagas disease has spread beyond its original borders on the American continent with migration. It can be transmitted from mother to child, through organ transplantation and transfusion of blood and blood products. It is necessary to determine when to screen for this infection.AimOur objective was to evaluate the appropriateness of screening for Trypanosoma cruzi infection in Latin American migrants and their descendants.MethodsWe reviewed the literature using rigorous criteria. The quality of evidence was ranked according to the GRADE classification. An evidence to decision framework was adopted to provide information on the most relevant aspects necessary to formulate recommendations.ResultsThe 33 studies evaluated revealed a prevalence of T. cruzi infection among Latin American migrants in Europe of 6.08% (95% confidence interval (CI): 3.24-9.69; 28 studies). Vertical transmission occurred in three of 100 live births (95% CI: 1-6; 13 studies). The prevalence of cardiovascular disease was 19% (95% CI: 13-27; nine studies), including only 1% severe cardiac events (95% CI: 0-2; 11 studies). The overall quality of evidence was low because of risk of bias in the studies and considerable heterogeneity of the evaluated populations. The recommendations took into account economic studies on the value of screening strategies and studies on acceptability of screening and knowledge of the disease in the affected population.ConclusionsWe identified five situations in which screening for T. cruzi infection is indicated. We recommend screening persons from endemic areas and children of mothers from these areas.

Latent and active tuberculosis infections in migrants and travellers: A retrospective analysis from the Spanish +REDIVI collaborative network.

BACKGROUND: Tuberculosis (TB) is the leading cause of infectious disease mortality worldwide. We analysed active and latent TB infections (LTBI) from the Spanish Network for the Study of Imported Infectious Diseases by Travellers and Immigrants (+REDIVI). METHODS: Observational, retrospective, multicentre study of TB and LTBI registered in the +REDIVI network from October 2009 to December 2016. RESULTS: Of 1008 cases of LTBI, 884 (87.7%) were immigrants; 93 (4.5%), immigrants visiting friends and relatives (VFR); 2 (0.9%), VFR-travellers; and 29 (1.1%), travellers. Absolute (N = 157 vs. N = 75) and relative (12.5% vs. 5.9%) frequency decreased over the study period (p = 0.003). Median time to diagnosis was 24.6 months (females 50.3 vs males 11.9; p < 0.001). Of 448 TB cases, 405 (90.4%) were in immigrants; 30 (6.7%), VFR-immigrants; 6 (1.3%), VFR-travellers; and 7 (1.6%), travellers. Median time to diagnosis was 62.5 months (females 86.6 vs males 70.1; p = 0.0075). There were 8 multidrug resistant TB cases and 1 extensively drug resistant case of TB, all in immigrants. CONCLUSION: TB was frequently diagnosed more than 5 years after arrival in Spain. Screening programmes for TB and LTBI in immigrants should be considered beyond this time point. Women showed a higher diagnostic delay for both latent and active TB.

Clinicoepidemiological characteristics of viral hepatitis in migrants and travellers of the +Redivi network.

BACKGROUND: Continuous growth of mobile populations has influenced the global epidemiology of infectious diseases, including chronic and acute viral hepatitis. METHOD: A prospective observational multicentre study was performed in a Spanish network of imported infections. Viral hepatitis cases from January 2009 to September 2017 were included. RESULTS: Of 14,546 records, 723 (4.97%) had imported viral hepatitis, including 48 (6.64%) acute cases and 675 (93.36%) chronic cases. Of the 48 acute cases, 31 were travellers and immigrants returning from visiting friends or relatives (VFR), while 19 (61%) were acute Hepatitis A or Hepatitis B. Only 18.2% of VFR immigrants and 35% of travellers received pre-travel advice. Acute hepatitis was more frequent in VFR immigrants (AOR 2.59, CI95% 1.20-5.60) and travellers (AOR 2.83, CI95% 1.46-5.50) than immigrants. Of the 675 Chronic cases, 570 were immigrants, and 439 (77%) had chronic Hepatitis B. Chronic hepatitis was more frequent in immigrants (AOR 20.22, CI95% 11.64-35.13) and VFR immigrants (AOR 11.12, CI95% 6.20-19.94) than travellers. CONCLUSIONS: Chronic viral hepatitis was typical of immigrants, acute viral hepatitis was common among travellers, and VFR immigrants had mixed risk. Improving pre-travel consultation and screening of immigrants may contribute to preventing new cases of viral hepatitis and avoiding community transmission.

Osseous cystic echinococcosis: A case series study at a referral unit in Spain.

BACKGROUND: Cystic echinococcosis (CE) is present in all continents, except for the Antarctica. Characteristically, CE lesions are found in the liver and the lungs, but virtually any part of the body may be affected (the spleen, kidneys, heart, central nervous system, bones, among others). It is estimated that the incidence of bone involvement in CE is 0.5% to 4%. METHODOLOGY: A retrospective study was performed of patients with osseous CE treated at the National Reference Unit of Tropical Diseases of the Ramon y Cajal Hospital, Madrid, Spain, between 1989 and December 2017. Epidemiological, clinical, diagnostic and therapeutic data of patients with long-term follow-up were collected. MAIN FINDINGS: During the study period, of the 104 patients with CE, 27 exhibited bone involvement (26%). The bones most frequently affected were the spine, followed by the ribs, pelvis, femur, tibia and the scapula. The most common symptom was pain followed by medullar syndrome and pathologic fracture. In total, 81.5% of patients underwent surgery for osseous CE at least once. As many as 96% received albendazol either in (mostly long-term) monotherapy or in combination with praziquantel. CONCLUSIONS: The diagnosis and management of osseous CE is challenging. In many cases osseous CE should be considered a chronic disease and should be managed on a case-by-case basis. Lifelong follow-up should be performed for potential recurrence and sequels.