Neurofibromatosis type 1-associated interstitial lung disease misdiagnosed as asthma: a case report and literature review

Neurofibromatosis type 1-associated interstitial lung disease misdiagnosed as asthma: a case report and literature review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Neurofibromatosis type 1-associated interstitial lung disease misdiagnosed as asthma: a case report and literature review Yanyan Li, Mengjing SunHuang, Hongyi Zhu, Zijie Zhan, Ge Li, Xianglin Liu, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9149150/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background: Neurofibromatosis type 1 (NF1)-associated interstitial lung disease (NF-ILD) represents an uncommon pulmonary manifestation frequently misdiagnosed as asthma, largely due to insufficient clinical recognition. This report describes a case of NF-ILD that remained misdiagnosed over an extended period, with the aim of improving diagnostic awareness among clinicians. Case presentation: A 51-year-old male with a long-standing history of neurofibromatosis type 1 (NF1) underwent evaluation in February 2023 for chronic cough. Initial high-resolution computed tomography (HRCT) of the chest revealed bilateral thin-walled cysts, predominantly distributed in the upper lobes with scattered involvement of the lower lobes. The cysts exhibited thin walls without associated nodules. Pulmonary function tests (PFTs) demonstrated mild obstructive ventilatory impairment and a positive bronchial provocation test, consistent with the diagnosis of cough-variant asthma. Partial symptomatic improvement was achieved with inhaled corticosteroids combined with a long-acting β₂-agonist (ICS/LABA); however, symptoms subsequently recurred. In December 2025, the patient underwent re-evaluation due to a persistent cough. Given the atypical radiographic presentation of cystic lesions on high-resolution computed tomography (HRCT) in the context of asthma, interstitial lung disease was suspected. Subsequent pulmonary function testing revealed a mild reduction in the diffusing capacity for carbon monoxide (DLCO), (measured at 55% of the predicted value. An extensive diagnostic workup was conducted, which excluded allergic bronchopulmonary aspergillosis (ABPA), eosinophilic granulomatosis with polyangiitis (EGPA), smoking-related pulmonary pathology, and connective tissue disorder-associated interstitial lung diseases. Based on the presence of characteristic extrapulmonary features of neurofibromatosis type 1 (NF1)—including multiple cutaneous neurofibromas and café-au-lait macules—coupled with the comprehensive exclusion of other cystic lung diseases, a clinical diagnosis of NF1-associated interstitial lung disease (NF-ILD) was established. Conclusions: Non-specific interstitial lung disease (NS-ILD) is frequently misdiagnosed as asthma over extended periods due to symptomatological overlap and a partial response to therapeutic interventions such as inhaled corticosteroids and long-acting beta-agonists (ICS/LABA). In patients with neurofibromatosis type 1 (NF1) who present with respiratory symptoms and demonstrate a suboptimal therapeutic response to conventional asthma management, prompt evaluation via high-resolution computed tomography (HRCT) and assessment of diffusion capacity for carbon monoxide (DLCO) is recommended. A comprehensive differential diagnostic workup is imperative in cases exhibiting atypical presentations of asthma, and abnormal HRCT findings should prompt further investigation to elucidate potential underlying etiologies and preclude diagnostic oversight. Neurofibromatosis type 1 Interstitial lung disease Asthma Misdiagnosis Immunoglobulin E High-resolution computed tomography Figures Figure 1 Figure 2 Introduction Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder resulting from mutations in the NF1 gene, with an estimated incidence of approximately 1 in 3000 individuals, and the NF1 gene encodes neurofibromin, a negative regulator of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway [ 1 , 2 ] ; loss of neurofibromin function consequently leads to uncontrolled cellular proliferation.Its typical clinical manifestations include multiple café-au-lait macules, axillary and inguinal freckling, cutaneous neurofibromas, and iris Lisch nodules, with some patients exhibiting tumor predisposition [ 3 – 5 ]. NF1 can involve multiple organ systems; although pulmonary complications are relatively uncommon, they significantly impair quality of life. NF1-associated interstitial lung disease (NF-ILD) represents the most characteristic pulmonary manifestation. High-resolution computed tomography (HRCT) typically demonstrates thin-walled cystic lesions, predominantly located in the upper lobes with a subpleural distribution, occasionally accompanied by ground-glass opacities or reticulation; the lower lobes may also be affected. The pathogenesis may involve aberrant fibroblast proliferation related to dysregulation of the RAS pathway. Non-specific interstitial lung disease (NF-ILD) is exceedingly rare and manifests with non-specific respiratory symptoms, such as cough and chest tightness, which frequently lead to its erroneous diagnosis as more common respiratory conditions, including asthma or chronic obstructive pulmonary disease. Furthermore, its characteristic cystic lesions are often misinterpreted on conventional imaging studies as bullae or smoking-related parenchymal changes, resulting in their frequent oversight during initial assessment [ 6 ]. Additionally, pulmonary diffusing capacity testing is frequently omitted during the diagnostic workup of suspected asthma, further contributing to delays in accurate diagnosis. This report presents a case of NF-ILD that was misdiagnosed and managed as asthma for an extended period. We provide a three-year longitudinal imaging surveillance and a comprehensive differential diagnosis based on extrapulmonary manifestations. We further elucidate the diagnostic pitfalls and clinical implications of this condition to enhance awareness of this uncommon pulmonary complication. Case Presentation Patient Information A 51-year-old male (height: 164 cm, weight: 55 kg) presented with a long-standing medical history of neurofibromatosis type 1, characterized by multiple cutaneous neurofibromas and café-au-lait spots. The patient reported no personal smoking history but had prolonged exposure to environmental tobacco smoke. No significant occupational hazards were documented. Clinical trial registration number: Not application. Clinical Course Initial Presentation (February 10, 2023) The patient was evaluated at our respiratory medicine clinic for a three-year history of recurrent cough and chest tightness, with exacerbation of symptoms over the preceding month. Physical examination revealed multiple soft, sessile cutaneous nodules (neurofibromas) of various sizes and several café-au-lait spots distributed across the trunk and limbs. The largest café-au-lait spot measured approximately 5×3 cm with well-demarcated borders. Lung auscultation was clear, with no adventitious sounds such as crackles or wheezes. Pulmonary function tests (PFTs) indicated mild obstructive ventilatory impairment, and a bronchial provocation test was positive (Table 1 ). Chest computed tomography (CT) revealed multiple cystic lesions bilaterally, initially interpreted as “emphysema.” A diagnosis of cough-variant asthma was established, and the patient was initiated on regular inhaled budesonide/formoterol (ICS/LABA). Symptoms partially improved but subsequently recurred. Follow-Up Visit (June 18, 2024) The patient returned with persistent recurrent cough. High-resolution computed tomography (HRCT) of the chest showed no significant interval change from the previous scan in 2023, with cystic lung lesions remaining stable (Fig. 1 B). PFTs demonstrated an FEV 1 of 90.9% predicted and an FEV 1 /FVC of 71.9% (Table 1 ). Management for asthma was continued. Re-evaluation (December 27, 2025) The patient presented again with a one-month history of cough that responded poorly to asthma therapy, prompting a comprehensive reassessment. Repeat HRCT showed stable pulmonary findings (Fig. 1 C). Detailed HRCT and chest radiographic findings are presented in Fig. 2 . PFTs revealed an FEV 1 of 87.9% predicted, FEV 1 /FVC of 65.8%, and DLCO was measured for the first time at 61.1% predicted, indicating mild reduction. Laboratory investigations yielded the following results: C-reactive protein (CRP) 75.53 mg/L, erythrocyte sedimentation rate (ESR) 63 mm/h; total serum IgE markedly elevated at 3040 IU/mL; eosinophil count within normal range at 0.2×10⁹/L; autoantibodies (ANA, anti-CCP, ANCA) were negative; Aspergillus-specific IgE and IgG were also negative. Imaging Features Serial high-resolution computed tomography (HRCT) examinations conducted over a three-year period demonstrated bilateral thin-walled cystic lesions, predominantly located in the upper lobes, with scattered involvement in the lower lobes. The cysts exhibited thin walls (< 2 mm), absence of significant nodules or consolidation, a subpleural distribution, and areas of confluence. Their morphology remained stable throughout the observation period (Fig. 1 A–C). Mediastinal window settings revealed soft tissue masses in the left axilla and right lateral chest wall, (consistent with neurofibromas, along with enlarged mediastinal and left axillary lymph nodes, and multiple subcutaneous nodules on the anterior chest wall (Fig. 2 ). Thoracic scoliosis was also observed. Pulmonary Function Dynamics Review of prior pulmonary function tests (PFTs) indicated that diffusing capacity for carbon monoxide (DLCO) had not been assessed in earlier evaluations. This omission contributed significantly to the delayed recognition of interstitial lung disease. DLCO was initially measured in December 2025, revealing a mild reduction (55% of predicted value). Ventilatory parameters remained stable over the three-year follow-up period (Table 1 ). Table 1 Serial Assessments of Pulmonary Function Date FEV1 (% predicted) FEV1/FVC(%) DLCO (% predicted) Bronchial provocation test 2023-05-13 90.8 68.8 — Positive 2023-06-17 92.5 70.5 — Negative 2023-07-17 95.1 69.6 — Positive 2023-08-17 95.3 70.7 — Positive 2024-06-18 90.9 71.9 — - 2025-12-27 87.9 65.8 61.1 Positive Data are expressed as percent predicted. A dash (—) denotes values that were not obtained. A bronchial provocation test was considered positive when a decline in FEV₁ of 20% or more was observed. post-BD: post-bronchodilator. Differential Diagnosis Based on the high-resolution computed tomography (HRCT) features—including (upper lobe-predominant cystic changes with lower lobe involvement, thin-walled cysts, and absence of nodules—in conjunction with characteristic extrapulmonary manifestations of neurofibromatosis type 1 (NF1), a systematic differential diagnosis was conducted. Condition Imaging characteristics Clinical features Our patient Conclusion Allergic bronchopulmonary aspergillosis Central bronchiectasis, mucoid impaction, fleeting infiltrates Asthma, high IgE, Aspergillus sensitization No central bronchiectasis, no mucoid impaction, negative Aspergillus antibodies Excluded Eosinophilic granulomatosis with polyangiitis Fleeting infiltrates, nodules (may cavitate) Asthma, eosinophilia, ANCA-positive Eosinophils normal, ANCA-negative Excluded Langerhans cell histiocytosis Upper lobe cysts + nodules, nodules may precede cysts Young smokers, possible diabetes insipidus, bone lesions Age 51, non-smoker, no nodules Excluded Lymphangioleiomyomatosis Diffuse thin-walled cysts, uniform distribution Women of childbearing age, pneumothorax, chylothorax Male Excluded Birt-Hogg-Dubé syndrome Lower lobe-predominant, subpleural cysts, various shapes Family history, fibrofolliculomas, renal cancer risk No family history, no typical skin lesions Excluded Emphysema Imperceptible or very thin walls, irregular distribution Smoking history Non-smoker, imaging not typical Excluded Lymphocytic interstitial pneumonia Cysts + ground-glass + nodules Immunological abnormalities (Sjögren's, HIV, etc.) No relevant history, autoantibodies negative Excluded Connective tissue disease-ILD Various patterns (NSIP, UIP, LIP, etc.) Corresponding systemic manifestations and autoantibodies No symptoms, autoantibodies negative Excluded After systematic exclusion, combined with the background of NF1 and typical extrapulmonary manifestations, a unifying diagnosis of NF-ILD was made. Definitive Diagnosis The diagnosis of neurofibromatosis type 1-associated interstitial lung disease (NF-ILD) was established based on the following criteria: Documented history of neurofibromatosis type 1 (NF1) with classic extrapulmonary manifestations, including cutaneous neurofibromas and café-au-lait spots; Characteristic high-resolution computed tomography (HRCT) findings revealing bilateral thin-walled cysts, predominantly in the upper lobes with lower lobe involvement, demonstrating stability over a three-year period; Pulmonary function tests demonstrating a mixed ventilatory defect, with initial assessment of diffusing capacity for carbon monoxide (DLCO) indicating mild reduction (61.1% predicted); Systematic exclusion of alternative cystic lung diseases and associated rheumatologic disorders; Elevated serum IgE levels and transient systemic symptoms, suggestive of an immune-mediated component of the disease. (Note: Although histological confirmation via lung biopsy was not performed, the presented clinical and radiological evidence was deemed adequate for establishing a definitive diagnosis.) Treatment and Follow-up ICS/LABA therapy was maintained for ongoing control of airway symptoms. The patient was advised to avoid exposure to secondhand smoke and to undergo annual pulmonary function tests (PFTs), along with high-resolution computed tomography (HRCT) every 1–2 years. At the most recent follow-up (February 2026), the cough remained stable with no sputum production or dyspnea. Discussion This case exemplifies a prolonged misdiagnosis of neurofibromatosis type 1–associated interstitial lung disease (NF-ILD) as asthma and yields significant clinical implications. The diagnostic clarification was achieved through: ① identification of characteristic high-resolution computed tomography (HRCT) features, including upper lobe–predominant cystic lesions with concomitant lower lobe involvement [ 7 , 8 ]; ② confirmation of radiographic stability over a three-year imaging surveillance period; ③ integration of extrapulmonary manifestations typical of neurofibromatosis type 1 (NF1) to establish a unifying diagnosis; and ④ detection of persistently reduced diffusing capacity for carbon monoxide (DLCO) upon eventual assessment. 1. Reasons for Misdiagnosis Symptom overlap NF-ILD can induce a restrictive ventilatory defect and airway distortion due to traction, resulting in clinical manifestations that mimic asthma. Intermittently positive bronchial provocation tests further reinforced the erroneous asthma diagnosis. False treatment response Inhalation therapy with corticosteroids and long-acting beta-agonists (ICS/LABA) may modestly ameliorate airway inflammation and bronchial hyperresponsiveness in NF-ILD, generating a false impression of partial therapeutic response and thereby delaying further diagnostic evaluation. Neglect of underlying disease In patients with NF1 presenting with respiratory complaints, clinicians frequently prioritize common respiratory disorders over potential NF1-related pulmonary complications. In this instance, the association was not recognized until December 2025. Systematic misinterpretation of imaging Although cystic lesions were evident on initial CT imaging, they were erroneously attributed to emphysema or smoking-induced parenchymal changes [ 6 ]. The involvement of the lower lobes was overlooked, lobes further mimicked diffuse emphysema. Omission of DLCO testing Over a three-year follow-up period, DLCO—a critical parameter for the detection of interstitial lung disease—was not assessed until the concluding evaluation. This critical omission substantially contributed to the delay in diagnosis. 2. A Framework for Differential Diagnosis When cystic lung lesions are detected on high-resolution computed tomography (HRCT), a systematic diagnostic approach—incorporating lesion distribution, wall characteristics, the presence of nodules or ground-glass opacities, and extrapulmonary manifestations—is essential. Key differential diagnostic considerations include: - Upper lobe-predominant cysts : neurofibromatosis type 1–associated interstitial lung disease (NF-ILD; (characterized by thin-walled cysts and stigmata of NF1), pulmonary Langerhans cell histiocytosis (cysts with nodules, typically in young smokers), and emphysema (lacking visible walls, with a history of smoking). - Lower lobe-predominant cysts : Birt-Hogg-Dubé syndrome (often familial with cutaneous manifestations) and lymphocytic interstitial pneumonia (in patients with underlying immunological abnormalities). - Diffuse cysts : lymphangioleiomyomatosis (predominantly affecting women of reproductive age) and emphysema (associated with smoking). In the present case, imaging findings—upper lobe-predominant cystic changes with lower lobe involvement, thin-walled cysts, and absence of nodules—in conjunction with classic neurofibromatosis type 1 (NF1) features, strongly support NF-ILD as the unifying diagnosis. 3. Significance of Elevated IgE and Systemic Inflammation The markedly elevated serum IgE level (3040 IU/mL), accompanied by transient facial swelling and arthritis, suggests an immune-activated subtype of NF-ILD. Dysregulation of the RAS pathway in NF1 may influence immune cell function, promoting a polarization toward T-helper 2 (Th2) dominance and subsequent excessive IgE production. This immunologic aberration may account for the systemic inflammatory manifestations observed and further corroborates the diagnosis of NF-ILD. 4. Treatment and Future Directions No targeted therapies are currently available for NF-ILD; clinical management remains supportive. In this patient, maintenance therapy with an inhaled corticosteroid/long-acting beta-agonist (ICS/LABA) combination was associated with stable lung function, though it is unclear whether this stability reflects treatment efficacy or the inherently indolent natural history of the disease. For patients exhibiting significant systemic inflammation or rapid progression, corticosteroids or immunosuppressants may be considered, albeit without robust supporting evidence. Future studies should investigate targeted agents, such as MEK inhibitors, that modulate the RAS/MAPK pathway. Additionally, smoking cessation in patients may delay disease progression [ 9 , 10 ]. 5. Limitations This report has several limitations. First, a lung biopsy—the diagnostic gold standard for interstitial lung disease—was not performed. Nevertheless, in clinical practice, a confident diagnosis can often be established based on characteristic imaging findings and exclusion of alternative diagnoses. Second, as a single-case report, the generalizability of these findings is constrained. However, the three-year longitudinal imaging surveillance and comprehensive pulmonary function testing provide strong supportive evidence for the diagnosis and illustrate the characteristically stable clinical course of NF-ILD. Conclusion This case demonstrates that interstitial lung disease associated with neurofibromatosis type 1 (NF-ILD) is susceptible to prolonged misdiagnosis as asthma. Key diagnostic challenges include: (1) the misinterpretation of cystic lesions as bullae or smoking-related parenchymal changes, and (2) the omission of diffusing capacity for carbon monoxide (DLCO) measurement, which overlooks critical physiological evidence indicative of interstitial lung involvement. The stability of imaging findings over a three-year period represents a significant feature that helps distinguish NF-ILD from progressive cystic lung diseases. Furthermore, this case underscores the necessity for clinicians to rigorously apply diagnostic criteria for asthma and to consider differential diagnoses in cases exhibiting atypical features. In NF1 patients with respiratory symptoms that respond poorly to standard asthma treatment, early high-resolution computed tomography (HRCT) and comprehensive pulmonary function tests—including DLCO—are recommended. Additionally, extrapulmonary manifestations should be incorporated to achieve a comprehensive diagnostic assessment. Enhancing clinician awareness of NF-ILD is imperative to reduce misdiagnosis and improve patient outcomes. Declarations Ethics approval and consent to participate: This study strictly complies with the principles outlined in the Declaration of Helsinki. It has received approval from the Medical Ethics Committee of Changde Hospital, Xiangya School of Medicine, Central South University, China (Approval No. 2026 - 114 - 01), and informed consent has been waived. Consent for publication: Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the consent form is available for review by the Editor of this journal. Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests: The authors declare that they have no competing interests. Funding: This study was support by The Science Foundation Of The First People’s Hospital Of Changde City (2025ZC01). Authors' contributions: All authors contributed to the clinical management, data collection, and writing of the manuscript. All authors read and approved the final manuscript. Acknowledgements: Not applicable. References National Multi-Center Treatment Collaboration Group For, Neurofibromatosis T, National Multi-Center Research Platform, For P, Reconstructive S. [Expert consensus on diagnosis and management of neurofibromatosis type 1 (2021 edition)]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2021;35(11):1384–95. PubMed PMID: 34779163; PubMed Central PMCID: PMCPMC8586770. Wang MX, Dillman JR, Guccione J, Habiba A, Maher M, Kamel S, et al. Neurofibromatosis from Head to Toe: What the Radiologist Needs to Know. Radiographics. 2022;42(4):1123–44. Epub 20220624. doi: 10.1148/rg.210235. PubMed PMID: 35749292. Friedman JM. Neurofibromatosis 1. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®). Seattle (WA): University of Washington, Seattle Copyright © 1993–2026, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 1993. Bui A, Jiang C, McKay RM, Klesse LJ, Le LQ. Insights into the Pathogenesis of NF1-Associated Neoplasms. JID Innov. 2021;1(3). Epub 20210820. 10.1016/j.xjidi.2021.100044 . 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Shino MY, Rabbani S, Belperio JA, Lynch JP 3rd, Weigt SS. Neurofibromatosis-associated diffuse lung disease: case report. Semin Respir Crit Care Med. 2012;33(5):572–5. 10.1055/s-0032-1325165 . Epub 20120921. Miyamoto K. Pulmonary manifestations in von Recklinghausen's disease. Intern Med. 1997;36(6):381. 10.2169/internalmedicine.36.381 . PubMed PMID: 9213180. Additional Declarations No competing interests reported. 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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-9149150","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":625941808,"identity":"6dd44935-254b-4997-917e-018519ab40b8","order_by":0,"name":"Yanyan Li","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"Yanyan","middleName":"","lastName":"Li","suffix":""},{"id":625941809,"identity":"28e09c5d-dbd6-4907-8e42-55c7d42cafdd","order_by":1,"name":"Mengjing SunHuang","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"Mengjing","middleName":"","lastName":"SunHuang","suffix":""},{"id":625941810,"identity":"af00c1c6-6e0f-47a9-993f-4eb4a5be17d8","order_by":2,"name":"Hongyi Zhu","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"Hongyi","middleName":"","lastName":"Zhu","suffix":""},{"id":625941815,"identity":"996198c4-deeb-476d-b5c1-ee0bf6bf5946","order_by":3,"name":"Zijie Zhan","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"Zijie","middleName":"","lastName":"Zhan","suffix":""},{"id":625941821,"identity":"87c0b27b-79da-4719-b668-8aa36b31a061","order_by":4,"name":"Ge Li","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"Ge","middleName":"","lastName":"Li","suffix":""},{"id":625941822,"identity":"4c6974c0-ac91-43c6-8262-b741b281b15a","order_by":5,"name":"Xianglin Liu","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"Xianglin","middleName":"","lastName":"Liu","suffix":""},{"id":625941823,"identity":"793547ef-04ab-49e5-8ffa-63286c4346c8","order_by":6,"name":"Changhui Xiao","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"Changhui","middleName":"","lastName":"Xiao","suffix":""},{"id":625941824,"identity":"0ba7f31b-1fd0-4cc4-ae72-02588144c5a7","order_by":7,"name":"Ying Li","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Li","suffix":""},{"id":625941825,"identity":"5abe64b0-3d6d-447a-8bec-d925d4f867c4","order_by":8,"name":"Chao Zheng","email":"","orcid":"","institution":"Central South University","correspondingAuthor":false,"prefix":"","firstName":"Chao","middleName":"","lastName":"Zheng","suffix":""},{"id":625941829,"identity":"57f88c56-7ecf-425f-9542-b094c6a5925b","order_by":9,"name":"Fan Huang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxUlEQVRIiWNgGAWjYBACA+YDDAwfDGzk+JmZDz8gTgtbAgPjjIo0Y8l2tjQDorUw85w5nGhwnkdBgigt5mzMzx7wtjEnGB/mYTBgqLGJJqjFso3N3ECyjS3P7DDvgQcMx9JyGwg67H6DmYRhG0+x2WG+BAPGhsNEaDnG/k0isU0icXMzj4EEkVp4zCQOnDFI3MBMgpYyyYaKBGOJw8BATiDKL8fYt0n/Mfgvx99/+PCDDzU2hLWgggTSlI+CUTAKRsEowAUAtY09e3uMge4AAAAASUVORK5CYII=","orcid":"","institution":"Central South University","correspondingAuthor":true,"prefix":"","firstName":"Fan","middleName":"","lastName":"Huang","suffix":""}],"badges":[],"createdAt":"2026-03-17 13:08:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9149150/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9149150/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107617188,"identity":"95fe7498-ad30-4a66-9fd2-b051296c7316","added_by":"auto","created_at":"2026-04-23 09:17:40","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":251548,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSerial chest HRCT over three years.\u003c/strong\u003e(A) February 10, 2023 (initial visit): bilateral thin-walled cysts predominantly in the upper lobes with scattered distribution in the lower lobes, subpleural, some confluent, resembling honeycombing. (B) March 9, 2024: no significant interval change compared to 2023. (C) December 27, 2025: stable findings, with similar extent and morphology.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9149150/v1/c582db888560e8f31d09d8cf.jpg"},{"id":107617189,"identity":"9b3bda53-a038-4b0f-91b9-9aa0e54cef61","added_by":"auto","created_at":"2026-04-23 09:17:40","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":208231,"visible":true,"origin":"","legend":"\u003cp\u003eSerial chest HRCT and Chest X-ray over three years.\u003cbr\u003e\n(A) :Chest HRCT axial (lung window,From top to bottom: Lung apices, mid-to-lower lungs, lower lungs) and \u0026nbsp;(B):Chest HRCT axial (lung window, From top to bottom: Coronal view, Sagittal view, Coronal view of lower lungs) shows diffuse thin-walled cystic lucencies in both lungs, with distinct cyst walls, predominantly in the upper lobes, and also distributed in the lower lobes. (Window width 1500 HU, window level -600 HU, slice thickness 1 mm)\u003cbr\u003e\n (C):Axial chest CT(soft tissue window):shows multiple subcutaneous nodules in the anterior chest wall, some protruding from the skin surface, consistent with the manifestations of cutaneous neurofibromas. \u0026nbsp;\u003cbr\u003e\n(D):Axial chest CT(mediastinal window):shows soft tissue masses in the left axilla and right lateral chest wall (neurofibroma), as well as enlargement of mediastinal and left axillary lymph nodes. (Window Width 350 HU, Window Level 40 HU).\u003cbr\u003e\n(E):Chest X-ray: Bronchitis, mild pulmonary inflammation, scoliosis deformity.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9149150/v1/55a5a85e23be17c75a429421.jpg"},{"id":107705941,"identity":"778f897f-da46-466f-bc67-c57b3f18a3d9","added_by":"auto","created_at":"2026-04-24 09:15:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":700323,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9149150/v1/86c58109-32ee-4392-b177-a90a9c475e98.pdf"},{"id":107617187,"identity":"87e6bcc3-4d8a-417c-9ab4-a037d3886815","added_by":"auto","created_at":"2026-04-23 09:17:40","extension":"wps","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":91680,"visible":true,"origin":"","legend":"","description":"","filename":"MicrosoftWordCAREchecklistEnglish.wps","url":"https://assets-eu.researchsquare.com/files/rs-9149150/v1/19335404b81ddc3dbf7f7d05.wps"}],"financialInterests":"No competing interests reported.","formattedTitle":"Neurofibromatosis type 1-associated interstitial lung disease misdiagnosed as asthma: a case report and literature review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNeurofibromatosis type 1 (NF1) is an autosomal dominant disorder resulting from mutations in the \u003cem\u003eNF1\u003c/em\u003e gene, with an estimated incidence of approximately 1 in 3000 individuals, and the NF1 gene encodes neurofibromin, a negative regulator of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] ; loss of neurofibromin function consequently leads to uncontrolled cellular proliferation.Its typical clinical manifestations include multiple caf\u0026eacute;-au-lait macules, axillary and inguinal freckling, cutaneous neurofibromas, and iris Lisch nodules, with some patients exhibiting tumor predisposition [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNF1 can involve multiple organ systems; although pulmonary complications are relatively uncommon, they significantly impair quality of life. NF1-associated interstitial lung disease (NF-ILD) represents the most characteristic pulmonary manifestation. High-resolution computed tomography (HRCT) typically demonstrates thin-walled cystic lesions, predominantly located in the upper lobes with a subpleural distribution, occasionally accompanied by ground-glass opacities or reticulation; the lower lobes may also be affected. The pathogenesis may involve aberrant fibroblast proliferation related to dysregulation of the RAS pathway.\u003c/p\u003e \u003cp\u003eNon-specific interstitial lung disease (NF-ILD) is exceedingly rare and manifests with non-specific respiratory symptoms, such as cough and chest tightness, which frequently lead to its erroneous diagnosis as more common respiratory conditions, including asthma or chronic obstructive pulmonary disease. Furthermore, its characteristic cystic lesions are often misinterpreted on conventional imaging studies as bullae or smoking-related parenchymal changes, resulting in their frequent oversight during initial assessment [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Additionally, pulmonary diffusing capacity testing is frequently omitted during the diagnostic workup of suspected asthma, further contributing to delays in accurate diagnosis.\u003c/p\u003e \u003cp\u003eThis report presents a case of NF-ILD that was misdiagnosed and managed as asthma for an extended period. We provide a three-year longitudinal imaging surveillance and a comprehensive differential diagnosis based on extrapulmonary manifestations. We further elucidate the diagnostic pitfalls and clinical implications of this condition to enhance awareness of this uncommon pulmonary complication.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient Information\u003c/h2\u003e \u003cp\u003eA 51-year-old male (height: 164 cm, weight: 55 kg) presented with a long-standing medical history of neurofibromatosis type 1, characterized by multiple cutaneous neurofibromas and caf\u0026eacute;-au-lait spots. The patient reported no personal smoking history but had prolonged exposure to environmental tobacco smoke. No significant occupational hazards were documented. \u003cb\u003eClinical trial registration number: Not application.\u003c/b\u003e\u003c/p\u003e \u003cp\u003eClinical Course\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eInitial Presentation (February 10, 2023)\u003c/h3\u003e\n\u003cp\u003eThe patient was evaluated at our respiratory medicine clinic for a three-year history of recurrent cough and chest tightness, with exacerbation of symptoms over the preceding month. Physical examination revealed multiple soft, sessile cutaneous nodules (neurofibromas) of various sizes and several caf\u0026eacute;-au-lait spots distributed across the trunk and limbs. The largest caf\u0026eacute;-au-lait spot measured approximately 5\u0026times;3 cm with well-demarcated borders. Lung auscultation was clear, with no adventitious sounds such as crackles or wheezes. Pulmonary function tests (PFTs) indicated mild obstructive ventilatory impairment, and a bronchial provocation test was positive (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Chest computed tomography (CT) revealed multiple cystic lesions bilaterally, initially interpreted as \u0026ldquo;emphysema.\u0026rdquo; A diagnosis of cough-variant asthma was established, and the patient was initiated on regular inhaled budesonide/formoterol (ICS/LABA). Symptoms partially improved but subsequently recurred.\u003c/p\u003e\n\u003ch3\u003eFollow-Up Visit (June 18, 2024)\u003c/h3\u003e\n\u003cp\u003eThe patient returned with persistent recurrent cough. High-resolution computed tomography (HRCT) of the chest showed no significant interval change from the previous scan in 2023, with cystic lung lesions remaining stable (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). PFTs demonstrated an FEV\u003csub\u003e1\u003c/sub\u003e of 90.9% predicted and an FEV\u003csub\u003e1\u003c/sub\u003e/FVC of 71.9% (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Management for asthma was continued.\u003c/p\u003e\n\u003ch3\u003eRe-evaluation (December 27, 2025)\u003c/h3\u003e\n\u003cp\u003eThe patient presented again with a one-month history of cough that responded poorly to asthma therapy, prompting a comprehensive reassessment. Repeat HRCT showed stable pulmonary findings (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). Detailed HRCT and chest radiographic findings are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. PFTs revealed an FEV\u003csub\u003e1\u003c/sub\u003e of 87.9% predicted, FEV\u003csub\u003e1\u003c/sub\u003e/FVC of 65.8%, and DLCO was measured for the first time at 61.1% predicted, indicating mild reduction. Laboratory investigations yielded the following results: C-reactive protein (CRP) 75.53 mg/L, erythrocyte sedimentation rate (ESR) 63 mm/h; total serum IgE markedly elevated at 3040 IU/mL; eosinophil count within normal range at 0.2\u0026times;10⁹/L; autoantibodies (ANA, anti-CCP, ANCA) were negative; Aspergillus-specific IgE and IgG were also negative.\u003c/p\u003e\n\u003ch3\u003eImaging Features\u003c/h3\u003e\n\u003cp\u003eSerial high-resolution computed tomography (HRCT) examinations conducted over a three-year period demonstrated bilateral thin-walled cystic lesions, predominantly located in the upper lobes, with scattered involvement in the lower lobes. The cysts exhibited thin walls (\u0026lt;\u0026thinsp;2 mm), absence of significant nodules or consolidation, a subpleural distribution, and areas of confluence. Their morphology remained stable throughout the observation period (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA\u0026ndash;C). Mediastinal window settings revealed soft tissue masses in the left axilla and right lateral chest wall, (consistent with neurofibromas, along with enlarged mediastinal and left axillary lymph nodes, and multiple subcutaneous nodules on the anterior chest wall (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Thoracic scoliosis was also observed.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePulmonary Function Dynamics\u003c/h2\u003e \u003cp\u003eReview of prior pulmonary function tests (PFTs) indicated that diffusing capacity for carbon monoxide (DLCO) had not been assessed in earlier evaluations. This omission contributed significantly to the delayed recognition of interstitial lung disease. DLCO was initially measured in December 2025, revealing a mild reduction (55% of predicted value). Ventilatory parameters remained stable over the three-year follow-up period (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSerial Assessments of Pulmonary Function\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFEV1 (% predicted)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFEV1/FVC(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDLCO (% predicted)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBronchial provocation test\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023-05-13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e90.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e68.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023-06-17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e92.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e70.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023-07-17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e95.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e69.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2023-08-17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e95.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e70.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2024-06-18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e90.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e71.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2025-12-27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e87.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e65.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eData are expressed as percent predicted. A dash (\u0026mdash;) denotes values that were not obtained. A bronchial provocation test was considered positive when a decline in FEV₁ of 20% or more was observed. post-BD: post-bronchodilator.\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDifferential Diagnosis\u003c/h3\u003e\n\u003cp\u003eBased on the high-resolution computed tomography (HRCT) features\u0026mdash;including (upper lobe-predominant cystic changes with lower lobe involvement, thin-walled cysts, and absence of nodules\u0026mdash;in conjunction with characteristic extrapulmonary manifestations of neurofibromatosis type 1 (NF1), a systematic differential diagnosis was conducted.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCondition\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eImaging characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eClinical features\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eOur patient\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eConclusion\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAllergic bronchopulmonary aspergillosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCentral bronchiectasis, mucoid impaction, fleeting infiltrates\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAsthma, high IgE, Aspergillus sensitization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo central bronchiectasis, no mucoid impaction, negative Aspergillus antibodies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eExcluded\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEosinophilic granulomatosis with polyangiitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFleeting infiltrates, nodules (may cavitate)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAsthma, eosinophilia, ANCA-positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEosinophils normal, ANCA-negative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eExcluded\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLangerhans cell histiocytosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUpper lobe cysts\u0026thinsp;+\u0026thinsp;nodules, nodules may precede cysts\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYoung smokers, possible diabetes insipidus, bone lesions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAge 51, non-smoker, no nodules\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eExcluded\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphangioleiomyomatosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiffuse thin-walled cysts, uniform distribution\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWomen of childbearing age, pneumothorax, chylothorax\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eExcluded\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirt-Hogg-Dub\u0026eacute; syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLower lobe-predominant, subpleural cysts, various shapes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFamily history, fibrofolliculomas, renal cancer risk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo family history, no typical skin lesions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eExcluded\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEmphysema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eImperceptible or very thin walls, irregular distribution\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSmoking history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNon-smoker, imaging not typical\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eExcluded\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphocytic interstitial pneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCysts\u0026thinsp;+\u0026thinsp;ground-glass\u0026thinsp;+\u0026thinsp;nodules\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eImmunological abnormalities (Sj\u0026ouml;gren's, HIV, etc.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo relevant history, autoantibodies negative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eExcluded\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConnective tissue disease-ILD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVarious patterns (NSIP, UIP, LIP, etc.)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCorresponding systemic manifestations and autoantibodies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNo symptoms, autoantibodies negative\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eExcluded\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAfter systematic exclusion, combined with the background of NF1 and typical extrapulmonary manifestations, a unifying diagnosis of NF-ILD was made.\u003c/p\u003e\n\u003ch3\u003eDefinitive Diagnosis\u003c/h3\u003e\n\u003cp\u003eThe diagnosis of \u003cb\u003eneurofibromatosis type 1-associated interstitial lung disease (NF-ILD)\u003c/b\u003e was established based on the following criteria:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eDocumented history of neurofibromatosis type 1 (NF1) with classic extrapulmonary manifestations, including cutaneous neurofibromas and caf\u0026eacute;-au-lait spots;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eCharacteristic high-resolution computed tomography (HRCT) findings revealing bilateral thin-walled cysts, predominantly in the upper lobes with lower lobe involvement, demonstrating stability over a three-year period;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003ePulmonary function tests demonstrating a mixed ventilatory defect, with initial assessment of diffusing capacity for carbon monoxide (DLCO) indicating mild reduction (61.1% predicted);\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSystematic exclusion of alternative cystic lung diseases and associated rheumatologic disorders;\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eElevated serum IgE levels and transient systemic symptoms, suggestive of an immune-mediated component of the disease.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003e(Note: Although histological confirmation via lung biopsy was not performed, the presented clinical and radiological evidence was deemed adequate for establishing a definitive diagnosis.)\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eTreatment and Follow-up\u003c/h2\u003e \u003cp\u003eICS/LABA therapy was maintained for ongoing control of airway symptoms. The patient was advised to avoid exposure to secondhand smoke and to undergo annual pulmonary function tests (PFTs), along with high-resolution computed tomography (HRCT) every 1\u0026ndash;2 years. At the most recent follow-up (February 2026), the cough remained stable with no sputum production or dyspnea.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis case exemplifies a prolonged misdiagnosis of neurofibromatosis type 1\u0026ndash;associated interstitial lung disease (NF-ILD) as asthma and yields significant clinical implications. The diagnostic clarification was achieved through: ① identification of characteristic high-resolution computed tomography (HRCT) features, including upper lobe\u0026ndash;predominant cystic lesions with concomitant lower lobe involvement [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]; ② confirmation of radiographic stability over a three-year imaging surveillance period; ③ integration of extrapulmonary manifestations typical of neurofibromatosis type 1 (NF1) to establish a unifying diagnosis; and ④ detection of persistently reduced diffusing capacity for carbon monoxide (DLCO) upon eventual assessment.\u003c/p\u003e \u003cp\u003e \u003cb\u003e1. Reasons for Misdiagnosis\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eSymptom overlap\u003c/strong\u003e \u003cp\u003eNF-ILD can induce a restrictive ventilatory defect and airway distortion due to traction, resulting in clinical manifestations that mimic asthma. Intermittently positive bronchial provocation tests further reinforced the erroneous asthma diagnosis.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eFalse treatment response\u003c/strong\u003e \u003cp\u003eInhalation therapy with corticosteroids and long-acting beta-agonists (ICS/LABA) may modestly ameliorate airway inflammation and bronchial hyperresponsiveness in NF-ILD, generating a false impression of partial therapeutic response and thereby delaying further diagnostic evaluation.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eNeglect of underlying disease\u003c/strong\u003e \u003cp\u003eIn patients with NF1 presenting with respiratory complaints, clinicians frequently prioritize common respiratory disorders over potential NF1-related pulmonary complications. In this instance, the association was not recognized until December 2025.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eSystematic misinterpretation of imaging\u003c/strong\u003e \u003cp\u003eAlthough cystic lesions were evident on initial CT imaging, they were erroneously attributed to emphysema or smoking-induced parenchymal changes [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The involvement of the lower lobes was overlooked, lobes further mimicked diffuse emphysema.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eOmission of DLCO testing\u003c/strong\u003e \u003cp\u003eOver a three-year follow-up period, DLCO\u0026mdash;a critical parameter for the detection of interstitial lung disease\u0026mdash;was not assessed until the concluding evaluation. This critical omission substantially contributed to the delay in diagnosis.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003e2. A Framework for Differential Diagnosis\u003c/b\u003e \u003c/p\u003e \u003cp\u003eWhen cystic lung lesions are detected on high-resolution computed tomography (HRCT), a systematic diagnostic approach\u0026mdash;incorporating lesion distribution, wall characteristics, the presence of nodules or ground-glass opacities, and extrapulmonary manifestations\u0026mdash;is essential. Key differential diagnostic considerations include:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003e- \u003cb\u003eUpper lobe-predominant cysts\u003c/b\u003e: neurofibromatosis type 1\u0026ndash;associated interstitial lung disease (NF-ILD; (characterized by thin-walled cysts and stigmata of NF1), pulmonary Langerhans cell histiocytosis (cysts with nodules, typically in young smokers), and emphysema (lacking visible walls, with a history of smoking).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003e- Lower lobe-predominant cysts\u003c/b\u003e: Birt-Hogg-Dub\u0026eacute; syndrome (often familial with cutaneous manifestations) and lymphocytic interstitial pneumonia (in patients with underlying immunological abnormalities).\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003e \u003cb\u003e- Diffuse cysts\u003c/b\u003e: lymphangioleiomyomatosis (predominantly affecting women of reproductive age) and emphysema (associated with smoking).\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eIn the present case, imaging findings\u0026mdash;upper lobe-predominant cystic changes with lower lobe involvement, thin-walled cysts, and absence of nodules\u0026mdash;in conjunction with classic neurofibromatosis type 1 (NF1) features, strongly support NF-ILD as the unifying diagnosis.\u003c/p\u003e \u003cp\u003e \u003cb\u003e3. Significance of Elevated IgE and Systemic Inflammation\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe markedly elevated serum IgE level (3040 IU/mL), accompanied by transient facial swelling and arthritis, suggests an immune-activated subtype of NF-ILD. Dysregulation of the RAS pathway in NF1 may influence immune cell function, promoting a polarization toward T-helper 2 (Th2) dominance and subsequent excessive IgE production. This immunologic aberration may account for the systemic inflammatory manifestations observed and further corroborates the diagnosis of NF-ILD.\u003c/p\u003e \u003cp\u003e \u003cb\u003e4. Treatment and Future Directions\u003c/b\u003e \u003c/p\u003e \u003cp\u003eNo targeted therapies are currently available for NF-ILD; clinical management remains supportive. In this patient, maintenance therapy with an inhaled corticosteroid/long-acting beta-agonist (ICS/LABA) combination was associated with stable lung function, though it is unclear whether this stability reflects treatment efficacy or the inherently indolent natural history of the disease. For patients exhibiting significant systemic inflammation or rapid progression, corticosteroids or immunosuppressants may be considered, albeit without robust supporting evidence. Future studies should investigate targeted agents, such as MEK inhibitors, that modulate the RAS/MAPK pathway. Additionally, smoking cessation in patients may delay disease progression [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cb\u003e5. Limitations\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThis report has several limitations. First, a lung biopsy\u0026mdash;the diagnostic gold standard for interstitial lung disease\u0026mdash;was not performed. Nevertheless, in clinical practice, a confident diagnosis can often be established based on characteristic imaging findings and exclusion of alternative diagnoses. Second, as a single-case report, the generalizability of these findings is constrained. However, the three-year longitudinal imaging surveillance and comprehensive pulmonary function testing provide strong supportive evidence for the diagnosis and illustrate the characteristically stable clinical course of NF-ILD.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case demonstrates that interstitial lung disease associated with neurofibromatosis type 1 (NF-ILD) is susceptible to prolonged misdiagnosis as asthma. Key diagnostic challenges include: (1) the misinterpretation of cystic lesions as bullae or smoking-related parenchymal changes, and (2) the omission of diffusing capacity for carbon monoxide (DLCO) measurement, which overlooks critical physiological evidence indicative of interstitial lung involvement. The stability of imaging findings over a three-year period represents a significant feature that helps distinguish NF-ILD from progressive cystic lung diseases. Furthermore, this case underscores the necessity for clinicians to rigorously apply diagnostic criteria for asthma and to consider differential diagnoses in cases exhibiting atypical features. In NF1 patients with respiratory symptoms that respond poorly to standard asthma treatment, early high-resolution computed tomography (HRCT) and comprehensive pulmonary function tests\u0026mdash;including DLCO\u0026mdash;are recommended. Additionally, extrapulmonary manifestations should be incorporated to achieve a comprehensive diagnostic assessment. Enhancing clinician awareness of NF-ILD is imperative to reduce misdiagnosis and improve patient outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e This study strictly complies with the principles outlined in the Declaration of Helsinki. It has received approval from the Medical Ethics Committee of Changde Hospital, Xiangya School of Medicine, Central South University, China (Approval No. 2026 - 114 - 01), and informed consent has been waived.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the consent form is available for review by the Editor of this journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This study was support by The Science Foundation Of The First People\u0026rsquo;s Hospital Of Changde City (2025ZC01).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions:\u003c/strong\u003e\u0026nbsp; All authors contributed to the clinical management, data collection, and writing of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e Not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNational Multi-Center Treatment Collaboration Group For, Neurofibromatosis T, National Multi-Center Research Platform, For P, Reconstructive S. [Expert consensus on diagnosis and management of neurofibromatosis type 1 (2021 edition)]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2021;35(11):1384\u0026ndash;95. PubMed PMID: 34779163; PubMed Central PMCID: PMCPMC8586770.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang MX, Dillman JR, Guccione J, Habiba A, Maher M, Kamel S, et al. Neurofibromatosis from Head to Toe: What the Radiologist Needs to Know. Radiographics. 2022;42(4):1123\u0026ndash;44. Epub 20220624. doi: 10.1148/rg.210235. PubMed PMID: 35749292.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFriedman JM. 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PubMed PMID: 9213180.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Neurofibromatosis type 1, Interstitial lung disease, Asthma, Misdiagnosis, Immunoglobulin E, High-resolution computed tomography","lastPublishedDoi":"10.21203/rs.3.rs-9149150/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9149150/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003eNeurofibromatosis type 1 (NF1)-associated interstitial lung disease (NF-ILD) represents an uncommon pulmonary manifestation frequently misdiagnosed as asthma, largely due to insufficient clinical recognition. This report describes a case of NF-ILD that remained misdiagnosed over an extended period, with the aim of improving diagnostic awareness among clinicians.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation:\u003c/strong\u003e A 51-year-old male with a long-standing history of neurofibromatosis type 1 (NF1) underwent evaluation in February 2023 for chronic cough. Initial high-resolution computed tomography (HRCT) of the chest revealed bilateral thin-walled cysts, predominantly distributed in the upper lobes with scattered involvement of the lower lobes. The cysts exhibited thin walls without associated nodules. Pulmonary function tests (PFTs) demonstrated mild obstructive ventilatory impairment and a positive bronchial provocation test, consistent with the diagnosis of cough-variant asthma. Partial symptomatic improvement was achieved with inhaled corticosteroids combined with a long-acting β₂-agonist (ICS/LABA); however, symptoms subsequently recurred.\u003c/p\u003e\n\u003cp\u003eIn December 2025, the patient underwent re-evaluation due to a persistent cough. Given the atypical radiographic presentation of cystic lesions on high-resolution computed tomography (HRCT) in the context of asthma, interstitial lung disease was suspected. Subsequent pulmonary function testing revealed a mild reduction in the diffusing capacity for carbon monoxide (DLCO), (measured at 55% of the predicted value. An extensive diagnostic workup was conducted, which excluded allergic bronchopulmonary aspergillosis (ABPA), eosinophilic granulomatosis with polyangiitis (EGPA), smoking-related pulmonary pathology, and connective tissue disorder-associated interstitial lung diseases. Based on the presence of characteristic extrapulmonary features of neurofibromatosis type 1 (NF1)—including multiple cutaneous neurofibromas and café-au-lait macules—coupled with the comprehensive exclusion of other cystic lung diseases, a clinical diagnosis of NF1-associated interstitial lung disease (NF-ILD) was established.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Non-specific interstitial lung disease (NS-ILD) is frequently misdiagnosed as asthma over extended periods due to symptomatological overlap and a partial response to therapeutic interventions such as inhaled corticosteroids and long-acting beta-agonists (ICS/LABA). In patients with neurofibromatosis type 1 (NF1) who present with respiratory symptoms and demonstrate a suboptimal therapeutic response to conventional asthma management, prompt evaluation via high-resolution computed tomography (HRCT) and assessment of diffusion capacity for carbon monoxide (DLCO) is recommended. A comprehensive differential diagnostic workup is imperative in cases exhibiting atypical presentations of asthma, and abnormal HRCT findings should prompt further investigation to elucidate potential underlying etiologies and preclude diagnostic oversight.\u003c/p\u003e","manuscriptTitle":"Neurofibromatosis type 1-associated interstitial lung disease misdiagnosed as asthma: a case report and literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-23 09:17:36","doi":"10.21203/rs.3.rs-9149150/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-04-25T11:37:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"315222121668179191709697943044498926889","date":"2026-04-15T04:24:39+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-15T03:34:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-13T14:47:33+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-26T11:45:44+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-26T11:13:51+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pulmonary Medicine","date":"2026-03-26T11:09:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2ef55eef-dbb2-465b-b551-8145ac38d757","owner":[],"postedDate":"April 23rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-23T09:17:36+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-23 09:17:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9149150","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9149150","identity":"rs-9149150","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}