Aspergillosis in anorexia nervosa: a report of two cases and review of the literature

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The disorder is characterised by dietary restriction or purges leading to malnutrition with subsequent metabolic anomalies, changes in immune function and increased mortality for the most severe forms of the disease. The changes in immune function may lead to increased susceptibility to bacterial infections or, more rarely, fungal infections, where only seven cases of chronic pulmonary aspergillosis (CPA) and one case of invasive pulmonary aspergillosis (IPA) have been described in the literature. Case Presentation Two cases of CPA occurring in the context of extreme AN according to the DSM5 classification are described. These two cases are compared to eight cases described in the literature. Clinical, biological and radiological data were collected. The majority of the patients (9/10) were female. AN was considered to be extreme in seven patients, severe in one patient and undetermined in 2 patients (BMI missing). Preexisting lesions were mentioned in four patients and in our two cases. Computed tomography scans demonstrated the presence of endocavitary material in two cases in the literature. The presence of anti- Aspergillus antibodies (IgG and IgE) was reported in 6/10 patients. Galactomannan was detected in serum and bronchoalveolar lavage fluid in respectively 1 and 3 patients. An Aspergillus spp. was recovered from fungal culture in six cases including: Aspergillus niger (n=1), Aspergillus fumigatus (n=3). Four patients underwent surgical removal of the mass and two of these were also treated with voriconazole (VCZ). Four patients received antifungal treatment alone, including VCZ monotherapy (n=1), or a combination of antibiotic and antifungal with either VCZ (n=2) or amphotericin B (n=1). One patient received liposomal amphotericin B then oral voriconazole and another one received voriconazole before micafungin due to panazole-resistant Aspergillus strain associated with treatment for nontuberculous mycobacteria. Regression of the lesions was confirmed radiologically in two patients. The evolution was favourable for 8/10 cases. One death occurred in the context of IPA and the second after the patient left hospital against medical advice. Conclusions These observations illustrate the possibility of CPA, or more rarely IPA, in patients with extreme AN. Evolution is usually favourable and rarely fatal. This complication should be considered in a patient with extreme AN in the presence of a preexisting cavity. Management should be multidisciplinary, involving personalised refeeding, medical treatment of aspergillosis associated with surgical treatment depending on the clinical context. anorexia nervosa malnutrition aspergillosis cavities invasive pulmonary aspergillosis chronic pulmonary aspergillosis diagnosis treatment outcomes Figures Figure 1 Figure 2 Highlights Anorexia nervosa (AN) is an eating disorder, which mainly affects adolescents and young women and may lead to changes in innate immunity. Fungal infections should be considered in the context of malnutrition and AN in particular. Chronic pulmonary aspergillosis is rare in AN and is most prevalent in patients with severe AN. Background Anorexia nervosa (AN) is a multifactorial eating disorder that mainly affects adolescents and young women ( 1 ). This psychiatric disorder is characterised by the drastic control of calorie consumption associated with severe food restriction or purges as well as intense and excessive physical activity ( 2 , 3 ). AN leads to malnutrition, which may be severe with serious consequences in terms of metabolic anomalies or morbidity-mortality ( 4 – 6 ). Severe malnutrition may be responsible for changes in innate immune function with a decrease in chemotaxis, bactericidal activity of neutrophils, and a decrease in complement C3 fraction. In addition, adaptive or humoral immunity is compromised with a decrease in serum levels of IgG and IgM and a change in the cooperation of T and B lymphocytes ( 7 ). In this context, infectious complications have been reported in malnourished patients with AN and these patients appear to be more susceptible to bacterial infections with an increase in number of cases of pulmonary tuberculosis and skin infections secondary to Staphyloccocus spp. ( 8 , 9 ). Although more rare, cases of fungal infection, including candidaemia or chronic pulmonary aspergillosis (CPA) have been reported ( 10 – 12 ). The aim of the present study is to describe two cases of CPA, in the context of extreme AN (BMI < 15 kg/m 2 ) according to the DSM-5 classification, treated in our centre, and to compare them with cases previously described in the literature. Methods Clinical, radiological and biological data for the two patients treated in Lille Teaching Hospital were collected from the patients’ electronic medical files stored on MOLIS® and SILLAGE®. Anti- Aspergillus spp. antibodies IgG and galactomannan levels were measured using PLATELIA ™ Aspergillus IgG (positive ≥ 10 AU/mL) and Biorad Aspergillus Ag® (positive index ≥ 0.5) kits respectively in serum or bronchoalveolar lavage (BAL) fluid. Aspergillus fumigatus DNA was detected by quantitative PCR (qPCR) targeting a mitochondrial gene coding for transfer RNA. Double immunodiffusion (DID or the Ouchterlony method) was carried out using A. fumigatus antigen (FSK1 MICROGEN BIOPRODUCT) and A. flavus antigen (in-house preparation from strain IHEM 5904 ). The AN severity was categorised according to the DSM-5 classification ( 13 ). The classification of CPA subtype was established according to European Society for Clinical Microbiology and Infectious Diseases (ESCMID) and European Respiratory Society (ESR) recommendations ( 14 ). One of the two patients was informed and gave their consent to the use of their personal data for research purposes, conforming to a document of non-opposition. The second patient who died, she had not explicitly expressed her opposition to the use of her data in medical correspondence. Cases reported in the literature were identified via PubMed® using a combination of the following keywords: « anorexia nervosa », « aspergillosis » and « aspergilloma ». Case report 1 The first case was a 26-year-old male non-smoker with a history of hyperinsulinism, restrictive AN (BMI: 12 kg/m 2 ) and an atypical mycobacteria pulmonary infection due to Mycobacterium szulgai treated for 18 months with clarithromycin, ethambutol and rifampicin. During follow-up, after treatment for 1 year with antitubercular treatment, a thoracic computed tomography (CT) scan revealed the presence of endocavitary material within cavities localises in the right upper lobe. Aspergillus serology by ELISA showed the presence of anti- Aspergillus IgG antibodies (19 AU/mL) associated with the presence of five precipitin bands specific to A. fumigatus on DID, of which one precipitin band had catalase activity. The clinical, biological and CT picture pointed to a diagnosis of probable aspergilloma. In the absence of clinical symptoms, and in view of severe malnutrition increasing the risk of surgical complications, the plan by the medical team was to carry out close surveillance. After 2 years of surveillance, the patient presented with a dry cough associated with scanty bloody sputum and a thoracic CT scan revealed an increase in number and size of the pulmonary lesions, some of which were associated with the presence of endocavitary material suggesting progression of the Aspergillus infection (Fig. 1 a). The patient was admitted to our hospital for the management of haemoptysis in the context of probable chronic cavitary pulmonary aspergillosis. Bronchial fibroscopy was carried out and direct microscopic examination of BAL, after staining with Toluidine Blue, revealed the presence of Aspergillus -type mycelial elements (Fig. 1 b). Culture of BAL revealed the presence of several colonies of A. fumigatus and an antifungal susceptibility test showed a multi-sensitive strain. Serum galactomannan assay was negative, but BAL was strongly positive (index: 5.88; positive ≥ 0.5). Anti- A. fumigatus IgG antibodies were present with a high serum titre and nine precipitin band by the Ouchterlony method, of which two had specific enzyme activity (chymotrypsin and catalase). Levels of ß-( 1 – 3 )-D-glucan, initially equivocal, were positive after 10 days of hospitalisation (114 pg/mL; positive ≥ 80 pg/mL). qPCR for A. fumigatus DNA in BAL was positive (Ct: 32.82) while PCR for Pneumocystis jirovecii DNA was negative. Complementary bacteriological and virological biological analyses were also carried for CMV, HSV, VZV, EBV, HHV6 and panel PCR for respiratory viruses and were all negative. An increased level of total IgE was observed at 599 kIU/L (normal < 114). Immunophenotyping by flux cytometry showed lymphopenia (305/mm 3 ; normal 1100–2500/ mm 3 ) with a collapse of B (23/mm 3 ; normal 100–400/mm3), CD4+&CD8 + T (172/mm3 and 76/mm3 respectively; normal 400–1300&200–700/ mm 3 ) and NK (68/mm 3 ; normal 100–400/ mm3) lymphocyte populations. Treatment was initiated with amoxicillin-clavulanic acid (3 g/day), voriconazole (VCZ; 400 mg/day) and cotrimoxazole (800/160* 2 mg morning and evening). There was no indication for surgery. The patient was transferred to a continuous care unit for enteral refeeding via a nasogastric tube and then by mouth. The clinical and radiological evolution was favourable with regression of the cavities and cavitary refilling on CT scans after 2 weeks of treatment. However, the development of several adverse events linked to VCZ required close and regular follow-up of residual plasma concentrations with values between 0.27 and 8 mg/L (effective therapeutic concentrations between 1 and 5.5 mg/L). The adverse events observed with VCZ included digestive or visual problems as well as photosensitivity leading to its replacement, after 6 months of treatment, with isavuconazole (200 mg/day) which was continued for nearly 3 years. In the absence of clinical relapse, it was decided to stop isavuconazole despite the persistence of a raised titre of anti- A. fumigatus antibodies (> 80 AU/mL; 6 precipitin bands on DID) and the persistence of cavitary lesions containing endocavitary material. A metabolic follow-up was undertaken during his therapeutic management and no anomaly of glucocorticoid or phospho-calcium metabolism was observed. In addition, hormonal investigations for phospho-calcium, glycaemia, food intake (leptin), thyroid and gonadotropin were normal. Levels of growth factors IGFBP-3 and IGF-1 were also normal. After 3 years of treatment no relapse was noted. Biological and radiological follow-up was carried out every 6 months and showed negative galactomannan but the persistence of anti- Aspergillus antibodies (60 AU/mL) and DID oscillating between 3 and 6 precipitin bands. Case report 2 This was a 24-year-old female with a history of AN, non-fracturing osteoporosis and an episode of Pneumocystosis jirvecii pneumonia (PjP) treated with cotrimoxazole for 3 weeks and complicated by cavitary sequelae in the right upper lobe. Four years after the episode of acute PjP, the patient was admitted to of our hospital with asthenia and an alteration of the general condition change in her general state which had developed over the past month, associated with low abundance haemoptysis. A thoracic CT scan was performed and compared with her previous scan demonstrating the aggravation of preexisting cavitary lesions by an increase in their size and cavitary filling suggestive of aspergillosis or a new PjP (Fig. 2 a). On admission significant levels of galactomannan (2.91; positive index ≥ 0.5) was found. High levels of anti- A. fumigatus IgG antibodies were also detected (> 80 AU/mL; positive > 10 AU/mL) with six precipitin bands (chymotrypsin and catalase positive). ß-( 1 – 3 )-D-glucan level was equivocal (69 pg/mL; positive ≥ 80 pg/mL). Due to a major change in her general state, in the context of restrictive AN with BMI of 10 kg/m 2 , the patient was quickly transferred to intensive care. Galactomannan was strongly positive in BAL (> 6; positive index 0.5) and direct microscopic examination of BAL discovered occasional mycelial elements resembling mould (Fig. 2 b). A. fumigatus PCR was positive in BAL while Pneumocystis and Mucorales qPCR were negative. Culture of BAL and antifungal susceptibility testing yielded many colonies of multi-sensitive A. fumigatus. Anti- A. fumigatus antibodies persisted at high levels (> 80 AU/mL) with nine precipitin bands (chymotrypsin and catalase positive). Serum galactomannan test was negative (index: 0.08) and serum ß-( 1 – 3 )-D-glucan persisted at equivocal levels (70 pg/mL with a doubtful interpretation between 60 and 80 pg/mL). Bacteriological and virological investigations (CMV, HSV, VZV, EBV, HHV6 and PCR panel for respiratory viruses) on BAL were negative. Electrophoresis of serum proteins showed the presence of hypoalbuminemia (29.1 g/L; normal 38–47.6 g/L), hyperalpha-1 and − 2 as well as gammaglobulinemia with the fusion of beta and gamma blocks. The investigations were completed by immunophenotyping, which showed lymphopenia (275/mm 3 ; normal 1100–2500/ mm 3 ) with a fall in B (35/mm 3 ; normal 100–400/mm3, CD4+/CD8 + T (189/mm3 and 37/mm3 respectively ; normal 400–1300&200–700/ mm 3 ) and NK(13/mm 3 ; normal 100–400/ mm3) lymphocyte populations. Hormonal investigations revealed hyperaldosteronism secondary to vomiting and infraclinical hypothyroidism, which did not justify supplementation or a gonadic investigation. The patient was treated with oral VCZ (200 mg/day), with an effective dose (residual of 1.65 mg/L [1–5.5 mg/L]), amoxicillin/clavulanic acid (500 mg/3 times/day) as well as feeding management for 7 days. After 9 days of hospitalisation the patient returned home against medical advice, supervised for home management by a healthcare provider for the continuation of anti-infective treatment and nutritional management. The patient died several days after leaving our hospital. Discussion AN is an eating disorder characterised by malnutrition, which may be severe and increase morbidity and mortality ( 4 , 5 ). Dysfunction of the immune system has been reported in these patients. Leukopenia has been observed consecutive to an alteration of the bone marrow, which becomes gelatinous and is responsible for hypocellularity through the accumulation of gelatinous substances in the extracellular spaces. This non-specific observation is reported in malnourished patients or those with chronic nutritional deficiency in the specific context of AN ( 15 ). A group of experts has suggested that modification of the bone marrow is not exclusively linked to chronic severe malnutrition or cachexia, but the pathogenesis of this condition could be attributed to other factors such as chronic inflammation or concomitant infections ( 16 ). Furthermore, other anomalies of innate immunity have been observed such as a qualitative deficit of polynuclear neutrophils ( 17 , 18 ) and a quantitative deficit of complement proteins ( 19 ) ( 20 ). Adaptative immunity also appears to be altered because changes in cellular immunity including leukopenia or a decrease in T lymphocyte sub-populations CD3, CD8 or CD4 have been reported. Some authors have observed a significant increase in CD4/CD8 ratio ( 9 ) and for one recent case reduce CD4 + and CD8 + lymphophocytes cells ( 21 ). In our two patients, immunophenotyping was concordant with data in the literature showing lymphopenia affecting B, T and NK cell populations. Furthermore, some authors have reported a modification of the cytokine profile with significantly decreased blood concentrations of IL6 and TNF-α in contrast, in some cases, to an increase in IL-1β ( 22 – 24 ). However, these parameters were not explored in our two patients and were not reported in the published cases. Furthermore, studies on humoral immunity in the context of AN are controversial or even contradictory since the small size of the cohorts studied did not allow the authors to draw any definitive conclusions ( 7 ). Infectious complications are regularly described in patients with malnutrition. However, patients with AN seem to stand out in this population ( 8 , 25 ). These patients do not appear to have an increased risk of developing common viral ( 26 ) or bacterial infections ( 9 ). Nevertheless, many cases of opportunistic infections have been described, notably involving Mycobacterium tuberculosis ( 27 , 28 ), atypical mycobacteria ( 29 – 31 ), Candida albicans ( 12 ), Pneumocystis jirovecii ( 11 ) or even Exophiala dermatitidis ( 32 ). Our two patients had a previous infection due to M. szulgai and P. jirovecii before the development of pulmonary aspergilloma in a preformed cavity. Filamentous fungi of the genus Aspergillus are ubiquitous saprophytic species belonging to the phylogenetic group, Ascomycetes. Among Aspergillus genus A. fumigatus is the most frequent species implicated in human infection. Aspergillosis are mainly linked to the inhalation of spores and can cause a spectrum of diseases which depend on the immune status of the host and the presence of preexisting lesions, as in our two patients ( 33 ). Taking into account the high mortality of CPA, estimated at 7% at 1 year and up to 32% at 5 years, its diagnostic and therapeutic management represents a real challenge because these infections constitute a spectrum of several clinical entities requiring a precise classification for each one ( 34 ). To date, only eight cases of respiratory infection due to Aspergillus spp. have been reported in the literature in patients with AN and have involved exclusively female patients, aged 19–44 years. These include four cases of pulmonary aspergilloma, two necrotising chronic pulmonary aspergillosis, and one IPA ( 21 ). The clinical, biological, radiological and therapeutic data for our patients (n = 2) and those reported in the literature (n = 8) are summarised in Table 1 . In 7/10 cases ( 21 , 35 – 41 ), AN was severe because BMI was < 15 and notion of cachexia for two cases. In our patients as well as those in the literature, no concomitant infection was documented despite repeated microbiological investigations except for the most recent case described by Vidmar et al . that is coinfected by a nontuberculous mycobacteria ( Mycobacterium celatum ) ( 21 ) Among the ten patients, eight were female suggesting a role of hormonal status in the pathogenesis of susceptibility to this infection. This theory is inscribed in a marked epidemiological context: the sex-ratio of AN is estimated to be between 10/1 and 15/1 in favour of females ( 42 ). Females with AN in the age range 15–24 years have a mortality rate 12-times higher than the general female population of the same age ( 39 ). Severe malnutrition leading to a decrease in concentrations of oestrogen and a deregulation of other hormones of the neuroendocrine axis could be implicated in the modulation of the immune response ( 43 , 44 ). Our patient 2 had a history of major oestrogen deficiency with osteoporosis of the spine consecutive to hypogonadism (oestradiolemia < 4 pg/mL; luteinising hormone < 0.1 IU/L; follicle stimulating hormone < 0.2 IU/L). Investigations for these factors were not mentioned in any of the previous cases in the literature. Preexisting cavitary lesions were present in 4 cases, but the information was not reported in the other six cases. Nevertheless, all of the patients had radiological anomalies including images of endocavitary material, nodules, condensations on CT scans, or opacities or masses on thoracic radiography ( Table 1 ). An infectious aetiology that could have been responsible for the formation of cavities was reported in our two patients as well as the two other cases described by Noter et al. ( 36 ) and Enriquez-Estrada et al. ( 39 ). Investigations for anti- Aspergillus IgG antibodies were positive in our two patients and confirmed by DID by the presence of at least six precipitin bands. In the literature, the presence of antibodies was only mentioned in two patients ( 37 , 41 ) but without specifying whether any complementary test had been performed. Absence of precipitation antibodies was mentioned in one patient of the literature ( 38 ). Investigations for specific IgE against A. fumigatus was only described in a single case which detected a high level ( 36 ). This examination was not carried out in our two patients at the time of diagnosis. Galactomannan assay was positive in both BAL in our two patients as well as in the BAL of one patient reported in the literature ( 39 ). Conversely, it was negative in the serum of three patients like case 1 ( 35 , 37 , 41 ) and not available in one ( 38 ) and not mentioned in three ( 21 , 36 , 40 ) ( Table 1 ). Fungal culture was positive in seven patients. Our two patients had a fungal culture positive for multi-sensitive A. fumigatus . In the other cases there was one case of A. niger ( 40 ), three cases of A. fumigatus ( 21 , 39 , 41 ) and one case of Aspergillus spp. ( 36 ). Culture was negative in one case ( 35 ) and not mentioned in two cases ( 37 , 38 ). Investigations for A. fumigatus DNA in BAL by PCR was carried out in our two patients and was positive. This investigation does not appear to have been carried out or is not mentioned in the other six cases in the literature (Table 1). Concerning the management of aspergillosis, four patients underwent a surgical intervention ( 35 – 37 , 41 ) of which two were associated with per operative antifungal treatment with VCZ ( 36 , 41 ). The team of Pagès retrospectively studied the effect of per operative antifungal treatment on postoperative morbidity and survival after a pulmonary resection in 113 patients with aspergilloma. In this study, the authors suggested that per operative antifungal treatment did not appear to modify postoperative morbidity and survival long-term in these patients ( 45 ). However, the study population consisted predominantly of men (71%) and their nutritional state was not specified. Although it is a rare event, studies focussing specifically on a population of patients suffering from malnutrition associated with chronic aspergillosis will help to evaluate the interest of antifungal treatment in this setting. The recommendations of the ESCMID-ECMM published in 2017 recommended as first line, if possible, surgical management of aspergilloma (ideally by video-assisted thoracic surgery (VATS)). As second line, prolonged antifungal treatment, with either itraconazole or VCZ for at least 6 months, is recommended ( 46 ). In this series, six patients out of ten had exclusively medical treatment (VCZ alone, n = 1; or an antifungal/antibiotic combination with VCZ, n = 2, or amphotericin B and antibiotic, n = 1). One patient received liposomal amphotericin B then oral voriconazole and another one received voriconazole before micafungin due to panazole-resistant Aspergillus strain associated with treatment for nontuberculous mycobacteria ( 21 ). VCZ is an antifungal used since 2002 which requires therapeutic surveillance due to well documented dose-dependent toxicity. Its most frequently reported side-effects are hepatotoxicity, visual problems and phototoxicity ( 47 ). Isavuconazole, which is a more recent triazole, has a more favourable safety profile as well as weaker drug interactions than VCZ ( 48 ) which may justify its use in a population of fragile and malnourished patients. However, isavuconazole was only documented in a single patient (case n°1). The use of this drug could be an alternative interesting therapy in this specific population. Radiological regression of lesions is specifically mentioned in one case in the literature ( 37 ) and stabilisation in our two patients. Data are missing in the other cases. Nevertheless, the evolution appears to be favourable in eight patients. Two deaths were reported including our second patient and one patient with the context of IPA and severe hypoglycaemia complicated by respiratory distress and cardiovascular collapse. However, due to the small number of patients overall, no definitive conclusion can be drawn. Conclusion The two cases reported and those described in the literature illustrate the possible development of CPA or, more exceptionally IPA in patients with AN. Although rare, this association seems to evolve favourably and severe forms with a fatal outcome are exceptional. The management of these patients depends on a multidisciplinary approach including specific psychiatric follow-up, adapted refeeding and antifungal treatment sometimes associated with surgery depending on the context. Prolonged clinical, biological and radiological follow-up is important in order to detect as early as possible any relapse or complications. Abbreviations AN: Anorexia nervosa; BAL: Bronchoalveolar lavage; BMI: Body mass index; CPA: Chronic pulmonary aspergillosis; CT: Computed tomography; DID: Double immunodiffusion; ESCMID: European Society for Clinical Microbiology and Infectious Diseases; ESR: European Respiratory Society; GM: galactomannan; IPA: Invasive pulmonary aspergillosis; N/A: not available; ND: not done; PCR: polymerase chain reaction; PjP: Pneumocystosis jirvecii pneumonia; qPCR: Quantitative PCR; TDM: tomodensitometry; VATS: Video-assisted thoracic surgery; VCZ: Voriconazole Declarations Ethics approval and consent to participate: the living patient was informed and gave their written and signed consent to the use of their personal data for research purposes, conforming to a document of non-opposition. The deceased patient did not express any objection to the use of the research data. This study was accepted by the ethical board (CNIL registration number n°73 - DEC25-172). Consent for publication: The second patient died and had not explicitly expressed opposition to the use of her medical data in medical correspondence during her lifetime. The use of her personal health data for research purposes was therefore permitted in accordance with current French legislation (The Data Protection Act – Article 86 (1978), amended on December 12, 2018, and MR 004 (CNIL) – Article 2.5.1). Availability of data and materials Competing interests: not applicable Funding; the authors have disclosed no relevant financial relationships Author contributions: AM and JL wrote the article. SL, CC, MC, MT, OC and BS reviewed the article. MT and OC contributed to the medical management of the patient. JBG contributed to histological investigation. References Steinhausen HC, Jensen CM. Time trends in lifetime incidence rates of first-time diagnosed anorexia nervosa and bulimia nervosa across 16 years in a Danish nationwide psychiatric registry study. 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Radiol Case Rep [Internet]. 2019 Jan 29 [cited 2023 Nov 22];14(3). Available from: https://pubmed.ncbi.nlm.nih.gov/30766647/ Hotta M, Minami Y, Itoda I, Yoshimori K, Takano K. A young female patient with anorexia nervosa complicated by Mycobacterium szulgai pulmonary infection. Int J Eat Disord. 2004 Jan;35(1):115–9. Shah K, Siglin J, Patel DM. Mycobacterium szulgai pulmonary infection in a woman with anorexia nervosa. IDCases. 2020;21:e00883. K O, Y N, H S, H B, H K, T A, et al. Pulmonary infection caused by Mycobacterium marinum in a patient with anorexia nervosa. ERJ Open Res [Internet]. 2021 Mar 15 [cited 2023 Nov 22];7(1). Available from: https://pubmed.ncbi.nlm.nih.gov/33748256/ Yoshinouchi T, Yamamoto K, Migita M, Yokoyama T, Nakamura T, Matsuoka M. Diagnosis and clinical management of Exophiala dermatitidis pneumonia in a patient with anorexia nervosa: A case report. Med Mycol Case Rep. 2023 Dec;42:100617. Latgé JP, Chamilos G. Aspergillus fumigatus and Aspergillosis in 2019. Clin Microbiol Rev. 2019 Dec 18;33(1):e00140-18. Tashiro M, Takazono T, Izumikawa K. Chronic pulmonary aspergillosis: comprehensive insights into epidemiology, treatment, and unresolved challenges. Ther Adv Infect Dis. 2024;11:20499361241253751. Takushima M, Haraguchi S, Hioki M, Endou N, Kawamura J, Yamashita Y, et al. Video-assisted thoracic surgery for pulmonary aspergilloma in patients with anorexia nervosa. J Nippon Med Sch Nippon Ika Daigaku Zasshi. 2004 Oct;71(5):333–6. Noter SL, Hendriks ER, Steup WH, Pahlplatz PVM, Beverdam FH. Aspergilloma of the lung due to aspiration during nasal tube feeding. Gen Thorac Cardiovasc Surg. 2009 Mar;57(3):169–70. Mogi A, Kosaka T, Yamaki E, Kuwano H. Pulmonary aspergilloma in patient with anorexia nervosa: case report. Ann Thorac Cardiovasc Surg Off J Assoc Thorac Cardiovasc Surg Asia. 2012;18(5):465–7. Pejčić TA, Stanković I, Djordjević I, Pavlović D, Petković TR, Stoimenov TJ, et al. Necrotizing pulmonary aspergillosis caused by anorexic syndrome — a case report. Cent Eur J Med. 2012 Feb 1;7(1):108–11. Enriquez-Estrada VM, Tapia-de la Barrera L, Rubio-Fuentes OJ, Brito-Citalan S, Corlay-Noriega I. Comorbid pulmonary aspergillosis as a justifier for weight loss in anorexia nervosa. Actas Esp Psiquiatr. 2019 July;47(4):165–70. Shimoni Z, Goldenberg A, Niven M. Fatal invasive pulmonary aspergillosis presenting as profound hypoglycemia in a patient with anorexia nervosa. Eur J Intern Med. 2006 July;17(4):295–7. Shirahata T, Akimoto M, Minegishi K, Endo S, Nakamura H, Nagata M. Video‐assisted thoracic surgery for a case of chronic progressive pulmonary aspergillosis undergoing haemodialysis complicated by anorexia nervosa: a case report. Respirol Case Rep. 2021 Feb 22;9(4):e00727. Treasure J, Zipfel S, Micali N, Wade T, Stice E, Claudino A, et al. Anorexia nervosa. Nat Rev Dis Primer. 2015 Nov 26;1(1):1–21. Singhal V, Misra M, Klibanski A. Endocrinology of anorexia nervosa in young people: recent insights. Curr Opin Endocrinol Diabetes Obes. 2014 Feb;21(1):64–70. Harding AT, Heaton NS. The Impact of Estrogens and Their Receptors on Immunity and Inflammation during Infection. Cancers. 2022 Feb 12;14(4):909. Pagès PB, Grima R, Mordant P, Grand B, Badia A, Le Pimpec-Barthes F, et al. [Does antifungal therapy influence postoperative morbidity or long-term survival after surgical resection for pulmonary aspergilloma?]. Rev Pneumol Clin. 2014 Dec;70(6):322–8. Ullmann AJ, Aguado JM, Arikan-Akdagli S, Denning DW, Groll AH, Lagrou K, et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2018 May;24 Suppl 1:e1–38. Levine MT, Chandrasekar PH. Adverse effects of voriconazole: Over a decade of use. Clin Transplant. 2016;30(11):1377–86. Maertens JA, Raad II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet Lond Engl. 2016 Feb 20;387(10020):760–9. Table Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1Aspergillosisinanorexianervosa.docx Table 1. Clinical, biological, radiological and therapeutic data for patients with anorexia nervosa (AN) presenting with chronic aspergillosis. *: Fungitell ® ; positive >80 pg/mL; ǂ: Elisa Platelia ® Aspergillus IgG, Bio-Rad; positive >10 AU; §: Elisa Platelia ® Aspergillus Ag, Bio-Rad, cut-off 0.5; #: 28S RNA gene. VATS: video-assisted thoracic surgery; GM: galactomannan; BAL: bronchoalveolar lavage; PCR: polymerase chain reaction; CT: computed tomography; TDM: tomodensitometry; ND: not done; N/A: not available; Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 30 Mar, 2026 Reviews received at journal 29 Mar, 2026 Reviews received at journal 29 Mar, 2026 Reviewers agreed at journal 27 Mar, 2026 Reviewers agreed at journal 27 Mar, 2026 Reviewers invited by journal 13 Feb, 2026 Editor assigned by journal 13 Feb, 2026 Editor invited by journal 11 Feb, 2026 Submission checks completed at journal 10 Feb, 2026 First submitted to journal 10 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8657208","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":591311290,"identity":"9374a540-3246-426c-ae39-3c0244f8087d","order_by":0,"name":"Ambroise Mercier","email":"","orcid":"","institution":"Centre Hospitalier Universitaire de Lille","correspondingAuthor":false,"prefix":"","firstName":"Ambroise","middleName":"","lastName":"Mercier","suffix":""},{"id":591311291,"identity":"b1900dc8-0c66-4949-a936-1971ee97a98e","order_by":1,"name":"Séverine Loridant","email":"","orcid":"","institution":"University of Lille","correspondingAuthor":false,"prefix":"","firstName":"Séverine","middleName":"","lastName":"Loridant","suffix":""},{"id":591311292,"identity":"fd8e9de3-3c11-4e3c-a15e-5ca17e1aee37","order_by":2,"name":"Macha Tetart","email":"","orcid":"","institution":"Hôpital Gustave Dron","correspondingAuthor":false,"prefix":"","firstName":"Macha","middleName":"","lastName":"Tetart","suffix":""},{"id":591311293,"identity":"f20d6e0f-a4b0-4c0b-967f-713858666d13","order_by":3,"name":"Olivier Cottencin","email":"","orcid":"","institution":"University of Lille","correspondingAuthor":false,"prefix":"","firstName":"Olivier","middleName":"","lastName":"Cottencin","suffix":""},{"id":591311294,"identity":"32d7ea38-8084-4839-b807-d013f87db7fc","order_by":4,"name":"Jean-Baptiste Gibier","email":"","orcid":"","institution":"University of Lille","correspondingAuthor":false,"prefix":"","firstName":"Jean-Baptiste","middleName":"","lastName":"Gibier","suffix":""},{"id":591311295,"identity":"24dffcce-5007-4eda-938c-9edf4e16489b","order_by":5,"name":"Camille Cordier","email":"","orcid":"","institution":"University of Lille","correspondingAuthor":false,"prefix":"","firstName":"Camille","middleName":"","lastName":"Cordier","suffix":""},{"id":591311296,"identity":"61cf9c4c-2e05-4878-be25-a5ac284936ed","order_by":6,"name":"Marjorie Cornu","email":"","orcid":"","institution":"University of Lille","correspondingAuthor":false,"prefix":"","firstName":"Marjorie","middleName":"","lastName":"Cornu","suffix":""},{"id":591311297,"identity":"dc7624af-8044-4f37-9a21-a0e190e173bb","order_by":7,"name":"Boualem Sendid","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFUlEQVRIie3PPWrDMBiA4a8I7EXgVYU2voKCIXEgtFeRCLSLh04mQweDIV7cvVuvECi0dHMwZBLOqqLFB+jg0UMplZL+LHK6dtA7mE/CD5IAXK5/GDWf9mtBmDcHQGaHxmcAJ+0gYb/k6kAYJVhP9G8CXn2YGAyTqV+OO7Z8grC428g23fFnH1NgNwQHgLzOQmaliAgTCqhoFjFrFH/JDdEXO80QurddTCaU8JUmJJmYga9r77o3hFZBbX2LTKKefygIH94MaQxh+1MuK4QGiP4zUwASG1Jpgqo9oWAns3KbxmyrMBVJpN+yiH4Iqe1k6uePsrtVo7AQ49c+vThf7zYZdO/zUVDkVvIdtuwdBS6Xy+U61idQDV2AUgsT+gAAAABJRU5ErkJggg==","orcid":"","institution":"University of Lille","correspondingAuthor":true,"prefix":"","firstName":"Boualem","middleName":"","lastName":"Sendid","suffix":""},{"id":591311298,"identity":"891ad83a-c7a6-4b15-b03e-eff684980ea5","order_by":8,"name":"Jordan Leroy","email":"","orcid":"","institution":"University of Lille","correspondingAuthor":false,"prefix":"","firstName":"Jordan","middleName":"","lastName":"Leroy","suffix":""}],"badges":[],"createdAt":"2026-01-21 08:41:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8657208/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8657208/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102982298,"identity":"a0b12102-990c-42c2-a388-f4d2ebacc584","added_by":"auto","created_at":"2026-02-19 09:14:38","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":580211,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(a) Thoracic CT scan of patient no. 1, axial section. (b) Microscopic examination (x200) of bronchoalveolar lavage stained with Gomori-Grocott.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe red arrow indicates the cavity observed on the CT scan.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8657208/v1/ca904c340e86838471232e02.png"},{"id":102982300,"identity":"c94813d3-d1e4-49f8-9a15-2b73fee97d69","added_by":"auto","created_at":"2026-02-19 09:14:38","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":410635,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(a) Thoracic CT scan of patient no. 2, axial section. (b) Microscopic examination (x400) of bronchoalveolar lavage stained with toluidine blue.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe red arrow shows the cavity observed on the CT scan.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8657208/v1/e8f3ac46310ad904f57c6cc3.png"},{"id":103050916,"identity":"1fc545f6-fcdd-4188-a2da-a2a4d6e01282","added_by":"auto","created_at":"2026-02-20 07:56:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1709779,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8657208/v1/430b96a9-f5f4-426f-b0ce-1a96fcaf4a3f.pdf"},{"id":103049401,"identity":"3a952e40-868f-4e5b-912d-36aba1c9f33b","added_by":"auto","created_at":"2026-02-20 07:40:48","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":41989,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e \u003cstrong\u003eClinical, biological, radiological and therapeutic data for patients with anorexia nervosa (AN) presenting with chronic aspergillosis.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e*: Fungitell\u003csup\u003e®\u003c/sup\u003e; positive \u0026gt;80 pg/mL; ǂ: Elisa Platelia\u003csup\u003e®\u003c/sup\u003e Aspergillus IgG, Bio-Rad; positive \u0026gt;10 AU; §: Elisa Platelia\u003csup\u003e®\u003c/sup\u003eAspergillus Ag, Bio-Rad, cut-off 0.5; #:\u0026nbsp; \u003cem\u003e28S RNA\u003c/em\u003e gene.\u003c/p\u003e\n\u003cp\u003eVATS: video-assisted thoracic surgery; GM: galactomannan; BAL: bronchoalveolar lavage; PCR: polymerase chain reaction; CT: computed tomography; TDM: tomodensitometry; ND: not done; N/A: not available;\u003c/p\u003e","description":"","filename":"Table1Aspergillosisinanorexianervosa.docx","url":"https://assets-eu.researchsquare.com/files/rs-8657208/v1/f973c0e3512af8b3e2be13db.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Aspergillosis in anorexia nervosa: a report of two cases and review of the literature","fulltext":[{"header":"Highlights","content":"\u003cul\u003e\n \u003cli\u003eAnorexia nervosa (AN) is an eating disorder, which mainly affects adolescents and young women and may lead to changes in innate immunity.\u003c/li\u003e\n \u003cli\u003eFungal infections should be considered in the context of malnutrition and AN in particular. \u0026nbsp;\u003c/li\u003e\n \u003cli\u003eChronic pulmonary aspergillosis is rare in AN and is most prevalent in patients with severe AN.\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Background","content":"\u003cp\u003eAnorexia nervosa (AN) is a multifactorial eating disorder that mainly affects adolescents and young women (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). This psychiatric disorder is characterised by the drastic control of calorie consumption associated with severe food restriction or purges as well as intense and excessive physical activity (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). AN leads to malnutrition, which may be severe with serious consequences in terms of metabolic anomalies or morbidity-mortality (\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Severe malnutrition may be responsible for changes in innate immune function with a decrease in chemotaxis, bactericidal activity of neutrophils, and a decrease in complement C3 fraction. In addition, adaptive or humoral immunity is compromised with a decrease in serum levels of IgG and IgM and a change in the cooperation of T and B lymphocytes (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). In this context, infectious complications have been reported in malnourished patients with AN and these patients appear to be more susceptible to bacterial infections with an increase in number of cases of pulmonary tuberculosis and skin infections secondary to \u003cem\u003eStaphyloccocus\u003c/em\u003e spp. (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Although more rare, cases of fungal infection, including candidaemia or chronic pulmonary aspergillosis (CPA) have been reported (\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe aim of the present study is to describe two cases of CPA, in the context of extreme AN (BMI\u0026thinsp;\u0026lt;\u0026thinsp;15 kg/m\u003csup\u003e2\u003c/sup\u003e) according to the DSM-5 classification, treated in our centre, and to compare them with cases previously described in the literature.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eClinical, radiological and biological data for the two patients treated in Lille Teaching Hospital were collected from the patients\u0026rsquo; electronic medical files stored on MOLIS\u0026reg; and SILLAGE\u0026reg;. Anti-\u003cem\u003eAspergillus spp.\u003c/em\u003e antibodies IgG and galactomannan levels were measured using PLATELIA\u003cb\u003e\u0026trade;\u003c/b\u003e \u003cem\u003eAspergillus\u003c/em\u003e IgG (positive\u0026thinsp;\u0026ge;\u0026thinsp;10 AU/mL) and Biorad \u003cem\u003eAspergillus\u003c/em\u003e Ag\u0026reg; (positive index\u0026thinsp;\u0026ge;\u0026thinsp;0.5) kits respectively in serum or bronchoalveolar lavage (BAL) fluid. \u003cem\u003eAspergillus fumigatus\u003c/em\u003e DNA was detected by quantitative PCR (qPCR) targeting a mitochondrial gene coding for transfer RNA. Double immunodiffusion (DID or the Ouchterlony method) was carried out using \u003cem\u003eA. fumigatus\u003c/em\u003e antigen (FSK1 MICROGEN BIOPRODUCT) and \u003cem\u003eA. flavus\u003c/em\u003e antigen (in-house preparation from strain \u003cem\u003eIHEM 5904\u003c/em\u003e). The AN severity was categorised according to the DSM-5 classification (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). The classification of CPA subtype was established according to European Society for Clinical Microbiology and Infectious Diseases (ESCMID) and European Respiratory Society (ESR) recommendations (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). One of the two patients was informed and gave their consent to the use of their personal data for research purposes, conforming to a document of non-opposition. The second patient who died, she had not explicitly expressed her opposition to the use of her data in medical correspondence.\u003c/p\u003e \u003cp\u003eCases reported in the literature were identified via PubMed\u0026reg; using a combination of the following keywords: \u0026laquo; \u003cem\u003eanorexia nervosa\u003c/em\u003e \u0026raquo;, \u0026laquo; \u003cem\u003easpergillosis\u003c/em\u003e \u0026raquo; and \u0026laquo; \u003cem\u003easpergilloma\u003c/em\u003e \u0026raquo;.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eCase report 1\u003c/h2\u003e \u003cp\u003eThe first case was a 26-year-old male non-smoker with a history of hyperinsulinism, restrictive AN (BMI: 12 kg/m\u003csup\u003e2\u003c/sup\u003e) and an atypical mycobacteria pulmonary infection due to \u003cem\u003eMycobacterium szulgai\u003c/em\u003e treated for 18 months with clarithromycin, ethambutol and rifampicin. During follow-up, after treatment for 1 year with antitubercular treatment, a thoracic computed tomography (CT) scan revealed the presence of endocavitary material within cavities localises in the right upper lobe. \u003cem\u003eAspergillus\u003c/em\u003e serology by ELISA showed the presence of anti-\u003cem\u003eAspergillus\u003c/em\u003e IgG antibodies (19 AU/mL) associated with the presence of five precipitin bands specific to \u003cem\u003eA. fumigatus\u003c/em\u003e on DID, of which one precipitin band had catalase activity. The clinical, biological and CT picture pointed to a diagnosis of probable aspergilloma. In the absence of clinical symptoms, and in view of severe malnutrition increasing the risk of surgical complications, the plan by the medical team was to carry out close surveillance. After 2 years of surveillance, the patient presented with a dry cough associated with scanty bloody sputum and a thoracic CT scan revealed an increase in number and size of the pulmonary lesions, some of which were associated with the presence of endocavitary material suggesting progression of the \u003cem\u003eAspergillus\u003c/em\u003e infection (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). The patient was admitted to our hospital for the management of haemoptysis in the context of probable chronic cavitary pulmonary aspergillosis. Bronchial fibroscopy was carried out and direct microscopic examination of BAL, after staining with Toluidine Blue, revealed the presence of \u003cem\u003eAspergillus\u003c/em\u003e-type mycelial elements (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). Culture of BAL revealed the presence of several colonies of \u003cem\u003eA. fumigatus\u003c/em\u003e and an antifungal susceptibility test showed a multi-sensitive strain. Serum galactomannan assay was negative, but BAL was strongly positive (index: 5.88; positive\u0026thinsp;\u0026ge;\u0026thinsp;0.5). Anti-\u003cem\u003eA. fumigatus\u003c/em\u003e IgG antibodies were present with a high serum titre and nine precipitin band by the Ouchterlony method, of which two had specific enzyme activity (chymotrypsin and catalase). Levels of \u0026szlig;-(\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)-D-glucan, initially equivocal, were positive after 10 days of hospitalisation (114 pg/mL; positive\u0026thinsp;\u0026ge;\u0026thinsp;80 pg/mL). qPCR for \u003cem\u003eA. fumigatus\u003c/em\u003e DNA in BAL was positive (Ct: 32.82) while PCR for \u003cem\u003ePneumocystis jirovecii\u003c/em\u003e DNA was negative. Complementary bacteriological and virological biological analyses were also carried for CMV, HSV, VZV, EBV, HHV6 and panel PCR for respiratory viruses and were all negative. An increased level of total IgE was observed at 599 kIU/L (normal\u0026thinsp;\u0026lt;\u0026thinsp;114).\u003c/p\u003e \u003cp\u003eImmunophenotyping by flux cytometry showed lymphopenia (305/mm\u003csup\u003e3\u003c/sup\u003e; normal 1100\u0026ndash;2500/ mm\u003csup\u003e3\u003c/sup\u003e) with a collapse of B (23/mm\u003csup\u003e3\u003c/sup\u003e; normal 100\u0026ndash;400/mm3), CD4+\u0026amp;CD8\u0026thinsp;+\u0026thinsp;T (172/mm3 and 76/mm3 respectively; normal 400\u0026ndash;1300\u0026amp;200\u0026ndash;700/ mm\u003csup\u003e3\u003c/sup\u003e) and NK (68/mm\u003csup\u003e3\u003c/sup\u003e; normal 100\u0026ndash;400/ mm3) lymphocyte populations. Treatment was initiated with amoxicillin-clavulanic acid (3 g/day), voriconazole (VCZ; 400 mg/day) and cotrimoxazole (800/160* 2 mg morning and evening). There was no indication for surgery. The patient was transferred to a continuous care unit for enteral refeeding via a nasogastric tube and then by mouth. The clinical and radiological evolution was favourable with regression of the cavities and cavitary refilling on CT scans after 2 weeks of treatment. However, the development of several adverse events linked to VCZ required close and regular follow-up of residual plasma concentrations with values between 0.27 and 8 mg/L (effective therapeutic concentrations between 1 and 5.5 mg/L). The adverse events observed with VCZ included digestive or visual problems as well as photosensitivity leading to its replacement, after 6 months of treatment, with isavuconazole (200 mg/day) which was continued for nearly 3 years. In the absence of clinical relapse, it was decided to stop isavuconazole despite the persistence of a raised titre of anti-\u003cem\u003eA. fumigatus\u003c/em\u003e antibodies (\u0026gt;\u0026thinsp;80 AU/mL; 6 precipitin bands on DID) and the persistence of cavitary lesions containing endocavitary material. A metabolic follow-up was undertaken during his therapeutic management and no anomaly of glucocorticoid or phospho-calcium metabolism was observed. In addition, hormonal investigations for phospho-calcium, glycaemia, food intake (leptin), thyroid and gonadotropin were normal. Levels of growth factors IGFBP-3 and IGF-1 were also normal. After 3 years of treatment no relapse was noted. Biological and radiological follow-up was carried out every 6 months and showed negative galactomannan but the persistence of anti-\u003cem\u003eAspergillus\u003c/em\u003e antibodies (60 AU/mL) and DID oscillating between 3 and 6 precipitin bands.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCase report 2\u003c/h3\u003e\n\u003cp\u003eThis was a 24-year-old female with a history of AN, non-fracturing osteoporosis and an episode of \u003cem\u003ePneumocystosis jirvecii\u003c/em\u003e pneumonia (PjP) treated with cotrimoxazole for 3 weeks and complicated by cavitary sequelae in the right upper lobe. Four years after the episode of acute PjP, the patient was admitted to of our hospital with asthenia and an alteration of the general condition change in her general state which had developed over the past month, associated with low abundance haemoptysis. A thoracic CT scan was performed and compared with her previous scan demonstrating the aggravation of preexisting cavitary lesions by an increase in their size and cavitary filling suggestive of aspergillosis or a new PjP (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). On admission significant levels of galactomannan (2.91; positive index\u0026thinsp;\u0026ge;\u0026thinsp;0.5) was found. High levels of anti-\u003cem\u003eA. fumigatus\u003c/em\u003e IgG antibodies were also detected (\u0026gt;\u0026thinsp;80 AU/mL; positive\u0026thinsp;\u0026gt;\u0026thinsp;10 AU/mL) with six precipitin bands (chymotrypsin and catalase positive). \u0026szlig;-(\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)-D-glucan level was equivocal (69 pg/mL; positive\u0026thinsp;\u0026ge;\u0026thinsp;80 pg/mL). Due to a major change in her general state, in the context of restrictive AN with BMI of 10 kg/m\u003csup\u003e2\u003c/sup\u003e, the patient was quickly transferred to intensive care. Galactomannan was strongly positive in BAL (\u0026gt;\u0026thinsp;6; positive index 0.5) and direct microscopic examination of BAL discovered occasional mycelial elements resembling mould (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). \u003cem\u003eA. fumigatus\u003c/em\u003e PCR was positive in BAL while \u003cem\u003ePneumocystis\u003c/em\u003e and Mucorales qPCR were negative. Culture of BAL and antifungal susceptibility testing yielded many colonies of multi-sensitive \u003cem\u003eA. fumigatus.\u003c/em\u003e Anti-\u003cem\u003eA. fumigatus\u003c/em\u003e antibodies persisted at high levels (\u0026gt;\u0026thinsp;80 AU/mL) with nine precipitin bands (chymotrypsin and catalase positive). Serum galactomannan test was negative (index: 0.08) and serum \u0026szlig;-(\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)-D-glucan persisted at equivocal levels (70 pg/mL with a doubtful interpretation between 60 and 80 pg/mL). Bacteriological and virological investigations (CMV, HSV, VZV, EBV, HHV6 and PCR panel for respiratory viruses) on BAL were negative. Electrophoresis of serum proteins showed the presence of hypoalbuminemia (29.1 g/L; normal 38\u0026ndash;47.6 g/L), hyperalpha-1 and \u0026minus;\u0026thinsp;2 as well as gammaglobulinemia with the fusion of beta and gamma blocks. The investigations were completed by immunophenotyping, which showed lymphopenia (275/mm\u003csup\u003e3\u003c/sup\u003e; normal 1100\u0026ndash;2500/ mm\u003csup\u003e3\u003c/sup\u003e) with a fall in B (35/mm\u003csup\u003e3\u003c/sup\u003e; normal 100\u0026ndash;400/mm3, CD4+/CD8\u0026thinsp;+\u0026thinsp;T (189/mm3 and 37/mm3 respectively ; normal 400\u0026ndash;1300\u0026amp;200\u0026ndash;700/ mm\u003csup\u003e3\u003c/sup\u003e) and NK(13/mm\u003csup\u003e3\u003c/sup\u003e ; normal 100\u0026ndash;400/ mm3) lymphocyte populations. Hormonal investigations revealed hyperaldosteronism secondary to vomiting and infraclinical hypothyroidism, which did not justify supplementation or a gonadic investigation. The patient was treated with oral VCZ (200 mg/day), with an effective dose (residual of 1.65 mg/L [1\u0026ndash;5.5 mg/L]), amoxicillin/clavulanic acid (500 mg/3 times/day) as well as feeding management for 7 days. After 9 days of hospitalisation the patient returned home against medical advice, supervised for home management by a healthcare provider for the continuation of anti-infective treatment and nutritional management. The patient died several days after leaving our hospital.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAN is an eating disorder characterised by malnutrition, which may be severe and increase morbidity and mortality (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Dysfunction of the immune system has been reported in these patients. Leukopenia has been observed consecutive to an alteration of the bone marrow, which becomes gelatinous and is responsible for hypocellularity through the accumulation of gelatinous substances in the extracellular spaces. This non-specific observation is reported in malnourished patients or those with chronic nutritional deficiency in the specific context of AN (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). A group of experts has suggested that modification of the bone marrow is not exclusively linked to chronic severe malnutrition or cachexia, but the pathogenesis of this condition could be attributed to other factors such as chronic inflammation or concomitant infections (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Furthermore, other anomalies of innate immunity have been observed such as a qualitative deficit of polynuclear neutrophils (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) and a quantitative deficit of complement proteins (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Adaptative immunity also appears to be altered because changes in cellular immunity including leukopenia or a decrease in T lymphocyte sub-populations CD3, CD8 or CD4 have been reported. Some authors have observed a significant increase in CD4/CD8 ratio (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) and for one recent case reduce CD4\u0026thinsp;+\u0026thinsp;and CD8\u0026thinsp;+\u0026thinsp;lymphophocytes cells (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). In our two patients, immunophenotyping was concordant with data in the literature showing lymphopenia affecting B, T and NK cell populations. Furthermore, some authors have reported a modification of the cytokine profile with significantly decreased blood concentrations of IL6 and TNF-α in contrast, in some cases, to an increase in IL-1β (\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). However, these parameters were not explored in our two patients and were not reported in the published cases. Furthermore, studies on humoral immunity in the context of AN are controversial or even contradictory since the small size of the cohorts studied did not allow the authors to draw any definitive conclusions (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eInfectious complications are regularly described in patients with malnutrition. However, patients with AN seem to stand out in this population (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). These patients do not appear to have an increased risk of developing common viral (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) or bacterial infections (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Nevertheless, many cases of opportunistic infections have been described, notably involving \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e), atypical mycobacteria (\u003cspan additionalcitationids=\"CR30\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e), \u003cem\u003eCandida albicans\u003c/em\u003e (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e), \u003cem\u003ePneumocystis jirovecii\u003c/em\u003e (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) or even \u003cem\u003eExophiala dermatitidis\u003c/em\u003e (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Our two patients had a previous infection due to \u003cem\u003eM. szulgai\u003c/em\u003e and \u003cem\u003eP. jirovecii\u003c/em\u003e before the development of pulmonary aspergilloma in a preformed cavity. Filamentous fungi of the genus \u003cem\u003eAspergillus\u003c/em\u003e are ubiquitous saprophytic species belonging to the phylogenetic group, Ascomycetes. Among \u003cem\u003eAspergillus\u003c/em\u003e genus \u003cem\u003eA. fumigatus\u003c/em\u003e is the most frequent species implicated in human infection. Aspergillosis are mainly linked to the inhalation of spores and can cause a spectrum of diseases which depend on the immune status of the host and the presence of preexisting lesions, as in our two patients (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Taking into account the high mortality of CPA, estimated at 7% at 1 year and up to 32% at 5 years, its diagnostic and therapeutic management represents a real challenge because these infections constitute a spectrum of several clinical entities requiring a precise classification for each one (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). To date, only eight cases of respiratory infection due to \u003cem\u003eAspergillus\u003c/em\u003e spp. have been reported in the literature in patients with AN and have involved exclusively female patients, aged 19\u0026ndash;44 years. These include four cases of pulmonary aspergilloma, two necrotising chronic pulmonary aspergillosis, and one IPA (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). The clinical, biological, radiological and therapeutic data for our patients (n\u0026thinsp;=\u0026thinsp;2) and those reported in the literature (n\u0026thinsp;=\u0026thinsp;8) are summarised in \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eIn 7/10 cases (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan additionalcitationids=\"CR36 CR37 CR38 CR39 CR40\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e), AN was severe because BMI was \u0026lt;\u0026thinsp;15 and notion of cachexia for two cases. In our patients as well as those in the literature, no concomitant infection was documented despite repeated microbiological investigations except for the most recent case described by Vidmar \u003cem\u003eet al\u003c/em\u003e. that is coinfected by a nontuberculous mycobacteria (\u003cem\u003eMycobacterium celatum\u003c/em\u003e) (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) Among the ten patients, eight were female suggesting a role of hormonal status in the pathogenesis of susceptibility to this infection. This theory is inscribed in a marked epidemiological context: the sex-ratio of AN is estimated to be between 10/1 and 15/1 in favour of females (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). Females with AN in the age range 15\u0026ndash;24 years have a mortality rate 12-times higher than the general female population of the same age (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). Severe malnutrition leading to a decrease in concentrations of oestrogen and a deregulation of other hormones of the neuroendocrine axis could be implicated in the modulation of the immune response (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). Our patient 2 had a history of major oestrogen deficiency with osteoporosis of the spine consecutive to hypogonadism (oestradiolemia\u0026thinsp;\u0026lt;\u0026thinsp;4 pg/mL; luteinising hormone\u0026thinsp;\u0026lt;\u0026thinsp;0.1 IU/L; follicle stimulating hormone\u0026thinsp;\u0026lt;\u0026thinsp;0.2 IU/L). Investigations for these factors were not mentioned in any of the previous cases in the literature.\u003c/p\u003e \u003cp\u003ePreexisting cavitary lesions were present in 4 cases, but the information was not reported in the other six cases. Nevertheless, all of the patients had radiological anomalies including images of endocavitary material, nodules, condensations on CT scans, or opacities or masses on thoracic radiography (\u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e). An infectious aetiology that could have been responsible for the formation of cavities was reported in our two patients as well as the two other cases described by Noter et al. (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e) and Enriquez-Estrada et al. (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). Investigations for anti-\u003cem\u003eAspergillus\u003c/em\u003e IgG antibodies were positive in our two patients and confirmed by DID by the presence of at least six precipitin bands. In the literature, the presence of antibodies was only mentioned in two patients (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e) but without specifying whether any complementary test had been performed. Absence of precipitation antibodies was mentioned in one patient of the literature (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). Investigations for specific IgE against \u003cem\u003eA. fumigatus\u003c/em\u003e was only described in a single case which detected a high level (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). This examination was not carried out in our two patients at the time of diagnosis. Galactomannan assay was positive in both BAL in our two patients as well as in the BAL of one patient reported in the literature (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). Conversely, it was negative in the serum of three patients like case 1 (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e) and not available in one (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e) and not mentioned in three (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e) (\u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e). Fungal culture was positive in seven patients. Our two patients had a fungal culture positive for multi-sensitive \u003cem\u003eA. fumigatus\u003c/em\u003e. In the other cases there was one case of \u003cem\u003eA. niger\u003c/em\u003e (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e), three cases of \u003cem\u003eA. fumigatus\u003c/em\u003e (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e) and one case of \u003cem\u003eAspergillus\u003c/em\u003e spp. (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). Culture was negative in one case (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e) and not mentioned in two cases (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e). Investigations for \u003cem\u003eA. fumigatus\u003c/em\u003e DNA in BAL by PCR was carried out in our two patients and was positive. This investigation does not appear to have been carried out or is not mentioned in the other six cases in the literature \u003cb\u003e(Table\u0026nbsp;1).\u003c/b\u003e\u003c/p\u003e \u003cp\u003eConcerning the management of aspergillosis, four patients underwent a surgical intervention (\u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e) of which two were associated with per operative antifungal treatment with VCZ (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). The team of Pag\u0026egrave;s retrospectively studied the effect of per operative antifungal treatment on postoperative morbidity and survival after a pulmonary resection in 113 patients with aspergilloma. In this study, the authors suggested that per operative antifungal treatment did not appear to modify postoperative morbidity and survival long-term in these patients (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e). However, the study population consisted predominantly of men (71%) and their nutritional state was not specified. Although it is a rare event, studies focussing specifically on a population of patients suffering from malnutrition associated with chronic aspergillosis will help to evaluate the interest of antifungal treatment in this setting. The recommendations of the ESCMID-ECMM published in 2017 recommended as first line, if possible, surgical management of aspergilloma (ideally by video-assisted thoracic surgery (VATS)). As second line, prolonged antifungal treatment, with either itraconazole or VCZ for at least 6 months, is recommended (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e). In this series, six patients out of ten had exclusively medical treatment (VCZ alone, n\u0026thinsp;=\u0026thinsp;1; or an antifungal/antibiotic combination with VCZ, n\u0026thinsp;=\u0026thinsp;2, or amphotericin B and antibiotic, n\u0026thinsp;=\u0026thinsp;1). One patient received liposomal amphotericin B then oral voriconazole and another one received voriconazole before micafungin due to panazole-resistant \u003cem\u003eAspergillus\u003c/em\u003e strain associated with treatment for nontuberculous mycobacteria (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). VCZ is an antifungal used since 2002 which requires therapeutic surveillance due to well documented dose-dependent toxicity. Its most frequently reported side-effects are hepatotoxicity, visual problems and phototoxicity (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e). Isavuconazole, which is a more recent triazole, has a more favourable safety profile as well as weaker drug interactions than VCZ (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e) which may justify its use in a population of fragile and malnourished patients. However, isavuconazole was only documented in a single patient (case n\u0026deg;1). The use of this drug could be an alternative interesting therapy in this specific population. Radiological regression of lesions is specifically mentioned in one case in the literature (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e) and stabilisation in our two patients. Data are missing in the other cases. Nevertheless, the evolution appears to be favourable in eight patients. Two deaths were reported including our second patient and one patient with the context of IPA and severe hypoglycaemia complicated by respiratory distress and cardiovascular collapse. However, due to the small number of patients overall, no definitive conclusion can be drawn.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe two cases reported and those described in the literature illustrate the possible development of CPA or, more exceptionally IPA in patients with AN. Although rare, this association seems to evolve favourably and severe forms with a fatal outcome are exceptional. The management of these patients depends on a multidisciplinary approach including specific psychiatric follow-up, adapted refeeding and antifungal treatment sometimes associated with surgery depending on the context. Prolonged clinical, biological and radiological follow-up is important in order to detect as early as possible any relapse or complications.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAN: Anorexia nervosa; BAL: Bronchoalveolar lavage; BMI: Body mass index; CPA: Chronic pulmonary aspergillosis; CT: Computed tomography; DID: Double immunodiffusion; ESCMID:\u0026nbsp;European Society for Clinical Microbiology and Infectious Diseases; ESR: European Respiratory Society; GM: galactomannan; IPA: Invasive pulmonary aspergillosis;\u0026nbsp;N/A: not available; ND: not done; PCR: polymerase chain reaction; PjP: \u003cem\u003ePneumocystosis jirvecii\u003c/em\u003e pneumonia; qPCR: Quantitative PCR; TDM: tomodensitometry; VATS: Video-assisted thoracic surgery; VCZ: Voriconazole\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u0026nbsp;\u003c/strong\u003ethe living patient was informed and gave their written and signed consent to the use of their personal data for research purposes, conforming to a document of non-opposition. The deceased patient did not express any objection to the use of the research data. This study was accepted by the ethical board (CNIL registration number n°73 - DEC25-172).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eThe second patient died and had not explicitly expressed opposition to the use of her medical data in medical correspondence during her lifetime. The use of her personal health data for research purposes was therefore permitted in accordance with current French legislation (The Data Protection Act – Article 86 (1978), amended on December 12, 2018, and MR 004 (CNIL) – Article 2.5.1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests: not\u0026nbsp;\u003c/strong\u003eapplicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding;\u003c/strong\u003e the authors\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ehave disclosed no relevant financial relationships\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003eAM and JL wrote the article. SL, CC, MC, MT, OC and BS reviewed the article. MT and OC contributed to the medical management of the patient. \u0026nbsp;JBG contributed to histological investigation.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSteinhausen HC, Jensen CM. Time trends in lifetime incidence rates of first-time diagnosed anorexia nervosa and bulimia nervosa across 16 years in a Danish nationwide psychiatric registry study. Int J Eat Disord. 2015 Nov;48(7):845\u0026ndash;50. \u003c/li\u003e\n\u003cli\u003eGibson D, Workman C, Mehler PS. Medical Complications of Anorexia Nervosa and Bulimia Nervosa. Psychiatr Clin North Am. 2019 June 1;42(2):263\u0026ndash;74. \u003c/li\u003e\n\u003cli\u003eZipfel S, Mack I, Baur LA, Hebebrand J, Touyz S, Herzog W, et al. Impact of exercise on energy metabolism in anorexia nervosa. J Eat Disord. 2013 Sept 4;1(1):37. \u003c/li\u003e\n\u003cli\u003eZipfel S, L\u0026ouml;we B, Reas DL, Deter HC, Herzog W. 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Immune disorders in anorexia. Cent-Eur J Immunol. 2017;42(3):294\u0026ndash;300. \u003c/li\u003e\n\u003cli\u003eAttalla El Halabieh N, Petrillo E, Laviano A, Delfino M, Rossi Fanelli F. A Case of Pneumocystis jirovecii Pneumonia in a Severely Malnourished, HIV-Negative Patient: A Role for Malnutrition in Opportunistic Infections? JPEN J Parenter Enteral Nutr. 2016 July;40(5):722\u0026ndash;4. \u003c/li\u003e\n\u003cli\u003eHanachi M, Bohem V, Bemer P, Kayser N, de Truchis P, Melchior JC. Negative role of malnutrition in cell-mediated immune response: Pneumocystis jirovecii pneumonia (PCP) in a severely malnourished, HIV-negative patient with anorexia nervosa. Clin Nutr ESPEN. 2018 June;25:163\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eYoshida K, Matsuda N, Sato T, Watanabe T, Nakamura K, Saito K, et al. Candida brain abscesses in a patient with anorexia nervosa receiving total parenteral nutrition. Clin Neurol Neurosurg. 2022 Jan;212:107058. \u003c/li\u003e\n\u003cli\u003eMoskowitz L, Weiselberg E. Anorexia Nervosa/Atypical Anorexia Nervosa. Curr Probl Pediatr Adolesc Health Care. 2017 Apr 1;47(4):70\u0026ndash;84. \u003c/li\u003e\n\u003cli\u003eDenning DW, Cadranel J, Beigelman-Aubry C, Ader F, Chakrabarti A, Blot S, et al. Chronic pulmonary aspergillosis: rationale and clinical guidelines for diagnosis and management. Eur Respir J. 2016 Jan;47(1):45\u0026ndash;68. \u003c/li\u003e\n\u003cli\u003eAbella E, Feliu E, Granada I, Mill\u0026aacute; F, Oriol A, Ribera JM, et al. Bone marrow changes in anorexia nervosa are correlated with the amount of weight loss and not with other clinical findings. Am J Clin Pathol. 2002 Oct;118(4):582\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eGunaratne MDSK, Shi M, Go RS. A comprehensive review on gelatinous transformation of the bone marrow. Expert Rev Hematol. 2024 July 26; \u003c/li\u003e\n\u003cli\u003ePalmblad J, Fohlin L, Lundstr\u0026ouml;m M. Anorexia nervosa and polymorphonuclear (PMN) granulocyte reactions. Scand J Haematol. 1977 Oct;19(4):334\u0026ndash;42. \u003c/li\u003e\n\u003cli\u003eGotch FM, Spry CJ, Mowat AG, Beeson PB, Maclennan IC. Reversible granulocyte killing defect in anorexia nervosa. Clin Exp Immunol. 1975 Aug;21(2):244\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eWyatt RJ, Farrell M, Berry PL, Forristal J, Maloney MJ, West CD. Reduced alternative complement pathway control protein levels in anorexia nervosa: response to parenteral alimentation. Am J Clin Nutr. 1982 May;35(5):973\u0026ndash;80. \u003c/li\u003e\n\u003cli\u003eElegido A, Graell M, Andr\u0026eacute;s P, Gheorghe A, Marcos A, Nova E. Increased naive CD4+ and B lymphocyte subsets are associated with body mass loss and drive relative lymphocytosis in anorexia nervosa patients. Nutr Res N Y N. 2017 Mar;39:43\u0026ndash;50. \u003c/li\u003e\n\u003cli\u003eVidmar P, Altenburg J, van Leeuwen EM, van Bellegem ACM, Verhoef C, de Bree GJ, et al. Lymphocyte subsets and the increased risk for opportunistic infections in severe restrictive anorexia nervosa. J Eat Disord. 2025 May 19;13(1):84. \u003c/li\u003e\n\u003cli\u003eSchattner A, Steinbock M, Tepper R, Schonfeld A, Vaisman N, Hahn T. Tumour necrosis factor production and cell-mediated immunity in anorexia nervosa. Clin Exp Immunol. 1990 Jan;79(1):62\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eCason J, Ainley CC, Wolstencroft RA, Norton KR, Thompson RP. Cell-mediated immunity in anorexia nervosa. Clin Exp Immunol. 1986 May;64(2):370\u0026ndash;5. \u003c/li\u003e\n\u003cli\u003eNova E, G\u0026oacute;mez-Mart\u0026iacute;nez S, Morand\u0026eacute; G, Marcos A. Cytokine production by blood mononuclear cells from in-patients with anorexia nervosa. Br J Nutr. 2002 Aug;88(2):183\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eBowers TK, Eckert E. Leukopenia in anorexia nervosa. Lack of increased risk of infection. Arch Intern Med. 1978 Oct;138(10):1520\u0026ndash;3. \u003c/li\u003e\n\u003cli\u003eNova E, Samart\u0026iacute;n S, G\u0026oacute;mez S, Morand\u0026eacute; G, Marcos A. The adaptive response of the immune system to the particular malnutrition of eating disorders. Eur J Clin Nutr. 2002 Aug;56(3):S34\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eHotta M, Nagashima E, Takagi S, Itoda I, Numata T, Kobayashi N, et al. Two young female patients with anorexia nervosa complicated by Mycobacterium tuberculosis infection. Intern Med Tokyo Jpn. 2004 May;43(5):440\u0026ndash;4. \u003c/li\u003e\n\u003cli\u003eFg G, E V, F B, A L, V N, C DD, et al. Paucisymptomatic pulmonary and right ear tuberculosis in young woman suffering from anorexia and bulimia nervosa. Radiol Case Rep [Internet]. 2019 Jan 29 [cited 2023 Nov 22];14(3). Available from: https://pubmed.ncbi.nlm.nih.gov/30766647/\u003c/li\u003e\n\u003cli\u003eHotta M, Minami Y, Itoda I, Yoshimori K, Takano K. A young female patient with anorexia nervosa complicated by Mycobacterium szulgai pulmonary infection. Int J Eat Disord. 2004 Jan;35(1):115\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eShah K, Siglin J, Patel DM. Mycobacterium szulgai pulmonary infection in a woman with anorexia nervosa. IDCases. 2020;21:e00883. \u003c/li\u003e\n\u003cli\u003eK O, Y N, H S, H B, H K, T A, et al. Pulmonary infection caused by Mycobacterium marinum in a patient with anorexia nervosa. ERJ Open Res [Internet]. 2021 Mar 15 [cited 2023 Nov 22];7(1). Available from: https://pubmed.ncbi.nlm.nih.gov/33748256/\u003c/li\u003e\n\u003cli\u003eYoshinouchi T, Yamamoto K, Migita M, Yokoyama T, Nakamura T, Matsuoka M. Diagnosis and clinical management of Exophiala dermatitidis pneumonia in a patient with anorexia nervosa: A case report. Med Mycol Case Rep. 2023 Dec;42:100617. \u003c/li\u003e\n\u003cli\u003eLatg\u0026eacute; JP, Chamilos G. Aspergillus fumigatus and Aspergillosis in 2019. Clin Microbiol Rev. 2019 Dec 18;33(1):e00140-18. \u003c/li\u003e\n\u003cli\u003eTashiro M, Takazono T, Izumikawa K. Chronic pulmonary aspergillosis: comprehensive insights into epidemiology, treatment, and unresolved challenges. Ther Adv Infect Dis. 2024;11:20499361241253751. \u003c/li\u003e\n\u003cli\u003eTakushima M, Haraguchi S, Hioki M, Endou N, Kawamura J, Yamashita Y, et al. Video-assisted thoracic surgery for pulmonary aspergilloma in patients with anorexia nervosa. J Nippon Med Sch Nippon Ika Daigaku Zasshi. 2004 Oct;71(5):333\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eNoter SL, Hendriks ER, Steup WH, Pahlplatz PVM, Beverdam FH. Aspergilloma of the lung due to aspiration during nasal tube feeding. Gen Thorac Cardiovasc Surg. 2009 Mar;57(3):169\u0026ndash;70. \u003c/li\u003e\n\u003cli\u003eMogi A, Kosaka T, Yamaki E, Kuwano H. Pulmonary aspergilloma in patient with anorexia nervosa: case report. Ann Thorac Cardiovasc Surg Off J Assoc Thorac Cardiovasc Surg Asia. 2012;18(5):465\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003ePejčić TA, Stanković I, Djordjević I, Pavlović D, Petković TR, Stoimenov TJ, et al. Necrotizing pulmonary aspergillosis caused by anorexic syndrome \u0026mdash; a case report. Cent Eur J Med. 2012 Feb 1;7(1):108\u0026ndash;11. \u003c/li\u003e\n\u003cli\u003eEnriquez-Estrada VM, Tapia-de la Barrera L, Rubio-Fuentes OJ, Brito-Citalan S, Corlay-Noriega I. Comorbid pulmonary aspergillosis as a justifier for weight loss in anorexia nervosa. Actas Esp Psiquiatr. 2019 July;47(4):165\u0026ndash;70. \u003c/li\u003e\n\u003cli\u003eShimoni Z, Goldenberg A, Niven M. Fatal invasive pulmonary aspergillosis presenting as profound hypoglycemia in a patient with anorexia nervosa. Eur J Intern Med. 2006 July;17(4):295\u0026ndash;7. \u003c/li\u003e\n\u003cli\u003eShirahata T, Akimoto M, Minegishi K, Endo S, Nakamura H, Nagata M. Video‐assisted thoracic surgery for a case of chronic progressive pulmonary aspergillosis undergoing haemodialysis complicated by anorexia nervosa: a case report. Respirol Case Rep. 2021 Feb 22;9(4):e00727. \u003c/li\u003e\n\u003cli\u003eTreasure J, Zipfel S, Micali N, Wade T, Stice E, Claudino A, et al. Anorexia nervosa. Nat Rev Dis Primer. 2015 Nov 26;1(1):1\u0026ndash;21. \u003c/li\u003e\n\u003cli\u003eSinghal V, Misra M, Klibanski A. Endocrinology of anorexia nervosa in young people: recent insights. Curr Opin Endocrinol Diabetes Obes. 2014 Feb;21(1):64\u0026ndash;70. \u003c/li\u003e\n\u003cli\u003eHarding AT, Heaton NS. The Impact of Estrogens and Their Receptors on Immunity and Inflammation during Infection. Cancers. 2022 Feb 12;14(4):909. \u003c/li\u003e\n\u003cli\u003ePag\u0026egrave;s PB, Grima R, Mordant P, Grand B, Badia A, Le Pimpec-Barthes F, et al. [Does antifungal therapy influence postoperative morbidity or long-term survival after surgical resection for pulmonary aspergilloma?]. Rev Pneumol Clin. 2014 Dec;70(6):322\u0026ndash;8. \u003c/li\u003e\n\u003cli\u003eUllmann AJ, Aguado JM, Arikan-Akdagli S, Denning DW, Groll AH, Lagrou K, et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2018 May;24 Suppl 1:e1\u0026ndash;38. \u003c/li\u003e\n\u003cli\u003eLevine MT, Chandrasekar PH. Adverse effects of voriconazole: Over a decade of use. Clin Transplant. 2016;30(11):1377\u0026ndash;86. \u003c/li\u003e\n\u003cli\u003eMaertens JA, Raad II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet Lond Engl. 2016 Feb 20;387(10020):760\u0026ndash;9. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"anorexia nervosa, malnutrition, aspergillosis, cavities, invasive pulmonary aspergillosis, chronic pulmonary aspergillosis, diagnosis, treatment, outcomes","lastPublishedDoi":"10.21203/rs.3.rs-8657208/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8657208/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003eAnorexia nervosa (AN) is an eating disorder that mainly affects adolescents and young women. The disorder is characterised by dietary restriction or purges leading to malnutrition with subsequent metabolic anomalies, changes in immune function and increased mortality for the most severe forms of the disease. The changes in immune function may lead to increased susceptibility to bacterial infections or, more rarely, fungal infections, where only seven cases of chronic pulmonary aspergillosis (CPA) and one case of invasive pulmonary aspergillosis (IPA) have been described in the literature.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Presentation\u003c/strong\u003e Two cases of CPA occurring in the context of extreme AN according to the DSM5 classification are described. These two cases are compared to eight cases described in the literature. Clinical, biological and radiological data were collected. The majority of the patients (9/10) were female. AN was considered to be extreme in seven patients, severe in one patient and undetermined in 2 patients (BMI missing). Preexisting lesions were mentioned in four patients and in our two cases. Computed tomography scans demonstrated the presence of endocavitary material in two cases in the literature. The presence of anti-\u003cem\u003eAspergillus\u003c/em\u003e antibodies (IgG and IgE) was reported in 6/10 patients. Galactomannan was detected in serum and bronchoalveolar lavage fluid in respectively 1 and 3 patients. An \u003cem\u003eAspergillus\u003c/em\u003espp. was recovered from fungal culture in six cases including: \u003cem\u003eAspergillus niger \u003c/em\u003e(n=1), \u003cem\u003eAspergillus fumigatus\u003c/em\u003e (n=3). Four patients underwent surgical removal of the mass and two of these were also treated with voriconazole (VCZ). Four patients received antifungal treatment alone, including VCZ monotherapy (n=1), or a combination of antibiotic and antifungal with either VCZ (n=2) or amphotericin B (n=1). One patient received liposomal amphotericin B then oral voriconazole and another one received voriconazole before micafungin due to panazole-resistant \u003cem\u003eAspergillus\u003c/em\u003e strain associated with treatment for nontuberculous mycobacteria. Regression of the lesions was confirmed radiologically in two patients. The evolution was favourable for 8/10 cases. One death occurred in the context of IPA and the second after the patient left hospital against medical advice.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions \u003c/strong\u003eThese observations illustrate the possibility of CPA, or more rarely IPA, in patients with extreme AN. Evolution is usually favourable and rarely fatal. This complication should be considered in a patient with extreme AN in the presence of a preexisting cavity. Management should be multidisciplinary, involving personalised refeeding, medical treatment of aspergillosis associated with surgical treatment depending on the clinical context.\u003c/p\u003e","manuscriptTitle":"Aspergillosis in anorexia nervosa: a report of two cases and review of the literature","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-19 09:14:34","doi":"10.21203/rs.3.rs-8657208/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-30T08:52:37+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-30T01:16:33+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-29T07:15:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"195747206540630670713752185279746328008","date":"2026-03-27T07:30:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"205519142682097716576194811590564171933","date":"2026-03-27T07:28:31+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-13T08:45:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-13T08:42:44+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-11T06:06:47+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-10T15:31:57+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2026-02-10T14:19:49+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"eb4002eb-e216-4696-a2a7-9f346b06b523","owner":[],"postedDate":"February 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-27T05:25:19+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-19 09:14:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8657208","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8657208","identity":"rs-8657208","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}