Secondary Aspergillus candidus Infection in a Lung Cancer Patient with a Heavy Smoking History: A Case Report

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Patients with hematologic or solid tumor malignancies—especially those with concomitant structural lung damage, such as results from long-term heavy smoking—are at heightened risk. Case presentation： We describe a case of invasive aspergillosis caused by A. candidus in a 66-year-old man with untreated lung cancer. The patient had a 40-year history of heavy smoking, with known chronic bronchitis and emphysema. Bilateral pulmonary nodules had been identified two years prior, for which he had declined intervention. He presented with complaints of cough, productive sputum, and worsening dyspnea. Chest imaging revealed progression of his underlying malignancy, accompanied by inflammatory changes. Bronchoalveolar lavage fluid was obtained and cultured; mycological analysis yielded colonies morphologically consistent with A. candidus , an identification subsequently confirmed through internal transcribed spacer (ITS) sequencing—the current gold standard for fungal speciation. Conclusions： To our knowledge, this represents the first reported case of A. candidus infection in a treatment-naïve lung cancer patient with an extensive smoking history. It underscores the importance of considering this pathogen in heavily smoking-related lung cancer cases and highlights diagnostic and therapeutic challenges in this high-risk population. Aspergillus candidus untreated lung cancer heavy smoking history ITS sequencing bronchoalveolar lavage fluid Figures Figure 1 Figure 2 Figure 3 Figure 4 1. Introduction Invasive aspergillosis (IA) represents a life-threatening fungal infection that predominantly occurs in individuals with severely weakened immune systems—such as those with hematologic malignancies, recipients of hematopoietic stem cell transplants, or patients under long-term, high-dose immunosuppressive regimens.[ 1 ] Aspergillus fumigatus ( A. fumigatus ) remains the most frequently identified species, accounting for approximately 60% to 90% of all IA cases.[ 2 ] Interestingly, emerging clinical evidence indicates that IA is increasingly recognized in patients with chronic pulmonary conditions—including COPD, pulmonary fibrosis, and active tuberculosis—even in the absence of classic immunosuppression.[ 3 ] In addition, lung cancer patients constitute another high-risk group, owing to mechanisms such as bronchial obstruction, tissue necrosis, and dysregulation of the local immune microenvironment. [ 4 ] It is noteworthy, however, that most documented cases of IA in lung cancer have been reported among those receiving chemotherapy, radiation, or corticosteroids.[ 3 ] Evidence supporting untreated lung cancer itself as an independent risk factor for IA remains limited.[ 5 ] There is strong evidence that tobacco smoke plays a central role in driving lung carcinogenesis, while also acting as a potent inducer of broad immune dysfunction.[ 6 , 7 ] This immunosuppression manifests in multiple ways. To begin with, chronic exposure to cigarette smoke erodes the structural integrity of the respiratory epithelium, undermining its dual role as both a physical barrier and an immunological defense.[ 8 ] At the same time, innate immunity becomes dysregulated: the phagocytic and microbicidal activity of alveolar macrophages is dulled, and the capacity of neutrophils to recruit effectively and clear pathogens is weakened.[ 9 ] Furthermore, the impact of smoking extends to adaptive immunity, where it can suppress T-cell receptor signaling and skew T-helper cell differentiation, ultimately impairing antigen-specific immune responses.[ 10 , 11 ] Together, these defects across innate and adaptive immunity markedly increase the vulnerability of immunocompromised individuals, including lung cancer patients, to severe pulmonary infections such as invasive aspergillosis.[ 12 , 13 ] Notably, studies have shown that heavy smokers exhibit higher rates of Aspergillus colonization within their respiratory tracts compared to non-smokers,[ 14 ] indicating that smoking itself might be a direct risk factor for fungal establishment in the lung.[ 15 ] A. candidus , a relatively uncommon pathogenic species within the genus, is predominantly environmental—typically isolated from soil and decomposing plant matter.[ 16 ] The literature supports that invasive pulmonary disease due to uncommon environmental fungi such as A. candidus is extremely rare, with fewer than 20 cases reported worldwide, while superficial infections like keratitis and skin involvement are more commonly observed.[ 17 ] Importantly, A. candidus differs biologically from A. fumigatus —for example, in its cell wall composition and optimal growth temperature—which can lead to false-negative results in standard galactomannan assays.[ 18 , 19 ] These limitations underscore the risk of underdiagnosis and highlight the value of molecular tools such as ITS sequencing for accurate species identification.[ 20 ] In this report, we present a case of invasive aspergillosis caused by A. candidus in a treatment-naive patient with advanced lung cancer and a four-decade history of heavy smoking. This case suggests that A. candidus is capable of causing serious infection even in individuals without classic immunocompromise, and implicates chronic heavy smoking as a key predisposing condition. It also reinforces the essential role of molecular diagnostics in the identification of non-fumigatus Aspergillus species. 2. Case Presentation 2.1 Clinical Features The patient is a 66-year-old man with a 40-pack-year smoking history, having consumed approximately 40 to 60 cigarettes daily for four decades. His medical history includes chronic bronchitis and emphysema. During a routine physical exam two years ago at a local clinic, a chest CT scan identified nodular lesions in the right lower lobe and left upper lobe. Bronchoalveolar lavage fluid (BALF) analysis at that time demonstrated a marked increase in inflammatory cells and occasional clusters of atypical cells, raising concern for possible malignancy. Nonetheless, the patient did not pursue additional diagnostic assessment or intervention at that time. He was admitted on this occasion due to a three-week history of persistent productive cough and progressively worsening dyspnea. No hemoptysis or chest pain was reported. On physical examination, the patient was alert and oriented without cyanosis. Vital signs were within normal limits: blood pressure 148/97 mmHg, heart rate 79 beats per minute, respiratory rate 20 breaths per minute, and body temperature 36.2℃. Lung auscultation revealed coarse breath sounds with scattered dry and moist rales bilaterally. Examination of other organ systems showed no notable abnormalities. To determine the nature of the pulmonary lesion, the patient underwent contrast-enhanced chest CT (Fig. 1 ). Figure 1 A showed the right lower lobe CT image, where a large irregular shadow with “spiky margins” (Figure Legend 1: Spiky margins referred to fine, irregular linear structures along the lesion's edge, a typical radiographic feature of lung cancer cells infiltrating the surrounding lung tissue) was visible in the area indicated by the red arrow. Figure 1 B showed the CT image of the left upper lobe. The nodule indicated by the yellow arrow was considered a metastatic lesion from lung cancer. Additionally, scattered patchy and fluffy high-density shadows were observed in both lung fields, suggesting concurrent pulmonary inflammatory exudation. Laboratory findings included a white blood cell count of 8.19 × 10⁹/L, with neutrophils accounting for 72.4% of the total. Elevated inflammatory markers were observed, including a C-reactive protein (CRP) level of 27.6 mg/L, suggestive of an ongoing infectious process. Tumor marker assays also returned abnormal values: carbohydrate antigen 125 (CA125) was notably increased at 89.4 U/mL, and cytokeratin fragment 19 (CYFRA 21 − 1) measured 13.0 ng/mL—both elevating clinical concern for an underlying malignant process. Lymphocyte subset analysis revealed mild dysregulation, consistent with altered immune activity. Full reference intervals for these parameters are summarized in Table 1 . Table 1 Patient laboratory test results Test Category Test Item Result Reference Range Routine Blood Test WBC 8.19×10⁹/L 3.5–9.5×10⁹/L Hemoglobin 125g/L 130–175g/L (male) Neutrophil Percentage 72.4% 40%–75% Inflammatory Markers CRP 27.6mg/L 0–10mg/L Tumor Markers CA125 89.4U/ml 0–35U/ml CYFRA 21 − 1 13.0ng/ml 0–3.3ng/ml Lymphocyte subsets absolute CD4⁺ T cell count 589.9 537–1282 CD4⁺/CD8⁺ ratio 0.89 1.2–2.5 absolute NK cell count 232.9 44–436 absolute total B cell count 129 173–447 WBC, white blood cell count; CRP, C-reactive protein 2.2 Pathological Examination To confirm the nature of the pulmonary mass, the patient underwent bronchoscopy with brush sampling and biopsy of the lesion. The specimens were sent to the pathology department for HE staining and immunohistochemical testing. Pathological morphological examination revealed (Fig. 2 ). A bronchoscopic brush smear obtained from the right lower basal bronchus revealed malignant cells exhibiting morphological features consistent with non-small cell carcinoma (NSCLC) (Fig. 2 A). Subsequent biopsy and histopathological examination confirmed the presence of a poorly differentiated carcinoma displaying characteristic patterns of NSCLC (Fig. 2 B). To further refine the tumor classification, additional immunohistochemical staining was carried out. The tumor cells exhibited the following profile: CK(Pan)(+), P40 (focally positive), CK5/6(+), P63 (partial+), TTF-1(+), CK7(+), NapsinA(-), and EGFR(+). Integrating the morphological and immunohistochemical findings, the final diagnosis was established as lung adenocarcinoma. 2.3 Etiological Examination To identify the pathogen responsible for the pulmonary infection, BALF was collected from the inflammatory lesion in the right lower lobe during bronchoscopy. The sample was subjected to Gram staining and microscopic examination, bacterial and fungal cultures, as well as molecular biology testing. The bacterial culture of the BALF showed normal flora, and tests for Mycobacterium tuberculosis , Cryptococcus antigen, and Pneumocystis jirovecii staining were all negative, effectively ruling out common bacterial, Cryptococcal, and Pneumocystis infections. Upon examination of the Giemsa-stained BALF smear, mycelial fragments were identified (Fig. 3A). The smear also contained cancer cells, which corroborated the lung cancer diagnosis (Fig. 3B). After inoculation onto Sabouraud Dextrose Agar (SDA), the BALF sample yielded white, powdery fungal colonies that developed on the agar surface (Figs. 3C and 3D). Gentian violet staining was used to further characterize the colonial morphology (Fig. 3E). The pathogen was identified as A. candidus . via matrix-assisted laser desorption ionization–time of flight mass spectrometry(bioMerieux, France)(Fig. 3F). Notably, galactomannan (GM) testing of the BALF returned a negative result. This finding may reflect the relatively lower galactomannan content in the cell wall of A. candidus compared to other Aspergillus species, potentially reducing the sensitivity of GM assays. Thus, molecular confirmation through sequencing proved essential for a definitive diagnosis. Based on the patient’s clinical presentation—untreated lung cancer accompanied by cough, sputum, and dyspnea—microbiological testing was conducted on bronchoalveolar lavage fluid (BALF) to evaluate possible fungal infection. Giemsa-stained BALF smears (Fig. 3A) showed hyphal fragments morphologically suggestive of A. candidus (indicated by black arrows). The observation of hyphae—as opposed to conidia—was considered indicative of invasive aspergillosis, aligning with initial clinical suspicion. Accompanying inflammatory activity was evidenced by the presence of vacuolated macrophages and neutrophils within the same sample. Malignant cells were also identified (Fig. 3B), consistent with the patient’s known lung cancer diagnosis. To isolate and characterize the fungal agent, BALF was cultured on Sabouraud dextrose agar (SDA), which produced white, powdery colonies typical of A. candidus . Subsequent microscopic examination using gentian violet staining (Fig. 3E) revealed conidial structures consistent with this species, lending further support to the phenotypic identification. For microbial identification, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis was performed, and the resulting characteristic mass spectrum (Fig. 3F), which reflects the unique protein profile of the isolate, showed a high-confidence match with the reference spectrum of A. candidus , enabling unambiguous species-level confirmation. To rule out morphologically or genetically similar species and reinforce taxonomic assignment, a phylogenetic tree was constructed based on the ITS sequence using MEGA11 software (Fig. 4 ). The clinical isolate clustered with high support among reference sequences of A. candidus EF669594 from GenBank, conclusively verifying its phylogenetic identity. 2.4 Treatment and prognosis Given the patient’s complex presentation, the treatment strategy adhered to the principle of first addressing the A. candidus infection before initiating palliative care for lung cancer. Antifungal therapy with voriconazole was chosen based on in vitro susceptibility testing of the isolated A. candidus strain (Table 2 ). The regimen started with an intravenous loading dose of 400 mg every 12 hours on day one, followed by a maintenance dose of 200 mg intravenously every 12 hours from day two onward. For palliative management of lung cancer-related symptoms, the patient received compound methoxamine capsules (25 mg three times daily) and ambroxol hydrochloride tablets (30 mg three times daily) to alleviate cough and facilitate expectoration. Supplemental oxygen was also provided via nasal cannula at 2 L/min to relieve dyspnea. Following symptomatic improvement, the patient was referred back to the local hospital for continued follow-up. Table 2 A. candidus antimicrobial susceptibility Antifungal Drug Method Result Breakpoint Unit Interpretation Voriconazole MIC 0.125 - ug/mL Sensitive (S) Itraconazole MIC 0.1 0.125-1 ug/mL Sensitive (S) Caspofungin MIC 0.25 1–2 ug/mL Sensitive (S) Amphotericin B MIC 0.5 1–2 ug/mL Sensitive (S) Fluconazole MIC 2 2–8 ug/mL Sensitive (S) At the last follow-up, which occurred 6 months after treatment, the patient showed no signs of infection recurrence, no significant progression of lung cancer, and maintained a good quality of life. No adverse reactions related to voriconazole (such as hepatotoxicity or visual disturbances) were observed during the treatments. 3. Discussion This study reported the case of a 66-year-old man with untreated lung cancer and a four-decade history of heavy smoking (40–60 cigarettes per day) who developed a concurrent infection with A. candidus . The diagnosis was established through BALF culture and confirmed by ITS gene sequencing. This case highlights a complex clinical interplay between long-term smoking, untreated malignancy, and infection by a rare fungal pathogen, offering valuable insights for the management of similar patients. The patient’s 40-year smoking history represents a major risk factor underlying both his lung cancer and A. candidus infection. Long-term smoking is a well-established primary cause of lung cancer, promoting tumor development through persistent DNA damage and chronic inflammation in the airways.[ 21 ] Beyond its carcinogenic role, smoking significantly compromises innate pulmonary defenses—it disrupts ciliary function, impairs mucociliary clearance, and induces structural lung damage such as emphysema, which was also evident on this patient’s chest CT.[ 22 ] These alterations foster a microenvironment that facilitates fungal colonization and invasion.[ 23 ] Moreover, cigarette use has been associated with an elevated risk of invasive aspergillosis (IA), including among non-neutropenic individuals.[ 24 ] A retrospective multicenter cohort study found that smoking independently predicts IA in critically ill patients, with an odds ratio comparable to that of immunosuppressive treatment.[ 25 ] In this case, given that the patient had not received chemotherapy or radiotherapy, smoking likely served as the principal contributor to both malignant transformation and fungal susceptibility. These findings highlight the need to carefully evaluate smoking history when assessing fungal infection risks in lung cancer patients—even in the absence of conventional immunosuppressive therapies. Diagnosing A. candidus infection in this patient with untreated lung cancer presented multiple clinical difficulties, arising from both the distinctive biological features of the fungus and the complexity of the patient’s medical background. Initially, symptoms such as cough, sputum production, and dyspnea closely mirrored those commonly seen in advanced lung cancer, creating diagnostic ambiguity between malignant progression and superimposed fungal disease. Although imaging findings—including ground-glass opacities and the "halo sign"—hinted at fungal involvement, these features are nonspecific and can also occur in other pulmonary disorders, such as tumor-related inflammation or bacterial pneumonia.[ 26 ] Furthermore, the negative galactomannan (GM) test highlighted the limitations of traditional fungal biomarkers in detecting rare Aspergillus species. Although GM testing is highly sensitive for Aspergillus fumigatus (the most common cause of invasive aspergillosis), its sensitivity is lower for rare species like A. candidus .[ 27 ] The definitive diagnosis in this case was made through BALF culture (which grew Aspergillus colonies) and subsequent ITS gene sequencing, which identified the pathogen as A. candidus . This approach aligns with the latest clinical guidelines, which emphasize the importance of culture and molecular sequencing in identifying non-A. fumigatus Aspergillus species.[ 28 , 29 ] Additionally, the presence of both tumor cells and inflammatory infiltrates in the patient's BALF highlighted the need for a multimodal diagnostic approach. Initially, atypical cells raised suspicion for malignancy, while the concurrent detection of fungal elements (confirmed by sequencing) revealed dual pathology. This supports the recommendation to prioritize fungal diagnostics in lung cancer patients with progressive respiratory symptoms, even in the absence of overt immunosuppression (e.g., neutropenia, long-term corticosteroid use).[ 30 ] Notably, this patient had only chronic airway damage from smoking and normal lymphocyte counts and CD4⁺ T-cell ratios, suggesting that A. candidus may have unique pathogenic mechanisms that enable it to infect hosts with mild immune impairment, such as those with smoking-related epithelial barrier damage.[ 31 , 32 ] From a therapeutic standpoint, managing this case involved a delicate balance between controlling the fungal infection and addressing the complicating factor of untreated lung cancer. Unlike the more common A. fumigatus , A. candidus displays a markedly different susceptibility pattern to azole antifungals, typically showing higher minimum inhibitory concentrations (MICs) to fluconazole and itraconazole.[ 33 ] Nevertheless, voriconazole continues to serve as the first-line agent for A. candidus- related invasive aspergillosis, supported by in vitro evidence confirming its activity against most clinical isolates of this species. [ 33 , 34 ] Considering the high mortality associated with untreated invasive aspergillosis in cancer patients, the treatment strategy emphasized controlling the fungal infection as the immediate priority, aiming to stabilize respiratory function before introducing any antitumor interventions.[ 35 , 36 ] Looking ahead, longer-term management will require reassessing tumor progression once the infection is adequately controlled—weighing the potential benefits of anticancer treatments against the possible risk of fungal recurrence. This case highlights that even in advanced, untreated lung cancer, appropriately targeted antifungal therapy may not only help alleviate symptoms but also enhance the patient’s overall quality of life. 4. Conclusion This case highlights the need to maintain a high index of suspicion for rare fungal pathogens such as A. candidus in lung cancer patients—especially those with extensive smoking histories who have not undergone antitumor treatment. Smoking not only promotes lung carcinogenesis but also heightens susceptibility to fungal infections by compromising respiratory defenses. Due to the diagnostic difficulties inherent in such infections, clinicians should carefully correlate clinical presentation with imaging findings and employ a multifaceted diagnostic approach, including BALF culture and molecular sequencing, to achieve a definitive diagnosis. For confirmed A. candidus infections, voriconazole remains the first-line antifungal agent. Management should incorporate a balanced strategy that addresses both infection control and cancer-related complications. Further investigations are warranted to elucidate the pathogenic mechanisms and refine diagnostic and therapeutic protocols for such complex clinical scenarios. Declarations Acknowledgements Not applicable. Authors’ contributions J.Y. collected clinical data and imaging materials, reviewed literature, drafted the original manuscript, prepared figures, and summarized the case. X.Z. provided clinical diagnosis consultation and supervised case authenticity verification. J.Ye. designed the case report framework, acquired funding if applicable, supervised manuscript quality control, reviewed and edited the manuscript, and validated clinical conclusion rationality. P.N. organized case records and conducted patient follow-up. Y.Ge. provided guidance on case report writing norms and validated literature citation accuracy. All authors read and approved the final manuscript. Funding No funding. Data availability The sequencing data reported in this study was archived in the Sequnece Read Archive (SRA) with the accession number EF669594, with web link https://www.ncbi.nlm.nih.gov/nuccore/EF669594.1/. Ethics approval and consent to participate This study was approved by the Ethics Committee of Zhejiang People's Hospital (Approval No.: 2022JS008) and was conducted in accordance with the ethical standards of the Declaration of Helsinki. Consent for publication Written informed consent was obtained from the patient to publish this study. Competing interests The authors declare no competing interests. References Schauwvlieghe, A.; Rijnders, B.; Philips, N.; Verwijs, R.; Vanderbeke, L.; Van Tienen, C.; Lagrou, K.; Verweij, P.E.; Van de Veerdonk, F.L.; Gommers, D., et al. Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study. Lancet Resp Med 2018 , 6, 782-792, doi:10.1016/S2213-2600(18)30274-1. 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Current status of antifungal resistance and its impact on clinical practice. Brit J Haematol 2014 , 166, 471-484, doi:10.1111/bjh.12896. Arendrup, M.C. Update on antifungal resistance in Aspergillus and Candida. Clin Microbiol Infec 2014 , 20 Suppl 6, 42-48, doi:10.1111/1469-0691.12513. Ullmann, A.J.; Aguado, J.M.; Arikan-Akdagli, S.; Denning, D.W.; Groll, A.H.; Lagrou, K.; Lass-Florl, C.; Lewis, R.E.; Munoz, P.; Verweij, P.E., et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infec 2018 , 24 Suppl 1, e1-e38, doi:10.1016/j.cmi.2018.01.002. Lamoth, F.; Calandra, T. Pulmonary aspergillosis: diagnosis and treatment. Eur Respir Rev 2022 , 31, doi:10.1183/16000617.0114-2022. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 06 Jan, 2026 Read the published version in BMC Infectious Diseases → Version 1 posted Editorial decision: Revision requested 12 Nov, 2025 Reviews received at journal 10 Nov, 2025 Reviewers agreed at journal 02 Nov, 2025 Reviews received at journal 01 Nov, 2025 Reviewers agreed at journal 01 Nov, 2025 Reviewers agreed at journal 31 Oct, 2025 Reviewers invited by journal 30 Oct, 2025 Editor invited by journal 29 Oct, 2025 Editor assigned by journal 28 Oct, 2025 Submission checks completed at journal 28 Oct, 2025 First submitted to journal 24 Oct, 2025 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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of Zhejiang Chinese Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xinyu","middleName":"","lastName":"Zhu","suffix":""},{"id":542191417,"identity":"99130815-e5e4-4e69-831e-c940eecd1541","order_by":2,"name":"Jiaming Ye","email":"","orcid":"","institution":"Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)","correspondingAuthor":false,"prefix":"","firstName":"Jiaming","middleName":"","lastName":"Ye","suffix":""},{"id":542191419,"identity":"5b1d793d-89bd-4faa-8442-f6f8b8bab9eb","order_by":3,"name":"Youqi Ji","email":"","orcid":"","institution":"The Second Affiliated Hospital of Zhejiang University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Youqi","middleName":"","lastName":"Ji","suffix":""},{"id":542191420,"identity":"41ccc4b4-50f3-4685-affa-9908f75be64a","order_by":4,"name":"Peng Nan","email":"","orcid":"","institution":"Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)","correspondingAuthor":false,"prefix":"","firstName":"Peng","middleName":"","lastName":"Nan","suffix":""},{"id":542191421,"identity":"7a0c5e3e-5bd1-4420-8a3a-de4e3a73a983","order_by":5,"name":"Yumei Ge","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3ElEQVRIie3RsYoCMRCA4ZFAthlv21i4vkJgG8GXySBoc1hbWASEtNvqcyxYz7JwVQ7bewLrFXvPaGXl5roD83cD8xGSAKRS/zApBHOnfzEHMGEW/eQjk9Ts1qIY2VhS5Fi26EWp+TFHEClAN3snqT7yScF6Rjb75j5i+OyQDswLBX5JFlemj3A4RdGhsQs1cC1ZhbqHDGw7dJrqLQRyjSICwvVNqeWd2CgiITwyF8rDfGq+lqXDz9dkUh0vXacZ88rTT7eZjavMvyZPoXl8pozdD2X8h+VUKpV6p24eekT9utSZEQAAAABJRU5ErkJggg==","orcid":"","institution":"The Second Clinical Medical College of Zhejiang Chinese Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yumei","middleName":"","lastName":"Ge","suffix":""}],"badges":[],"createdAt":"2025-10-25 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16:38:27","extension":"html","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":120536,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7942255/v1/d2d921dda58a8dbf05c6a37b.html"},{"id":95663277,"identity":"82e98e5a-e629-4db9-87ad-b2242a6a339d","added_by":"auto","created_at":"2025-11-11 16:38:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":238079,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCT images of the patient's lungs. (A)\u003c/strong\u003eIrregular patchy and nodular shadows in the right lower lobe. \u003cstrong\u003e(B)\u003c/strong\u003eNodular lesions in the left upper lobe.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7942255/v1/18e21bfc9b2b7dfd83864bdd.png"},{"id":95663259,"identity":"486df47b-cb49-47e7-bd6c-f0c493317bee","added_by":"auto","created_at":"2025-11-11 16:38:38","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":413959,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePatient's pathological images. (A)\u003c/strong\u003eBronchoscopic brush smear from the right lower basal bronchus: The morphological features of the cells are consistent with NSCLC, with black arrows indicating cancer cells.\u003cstrong\u003e(B)\u003c/strong\u003eBiopsy of the neoplasm in the right lower basal bronchus: Histopathological examination reveals poorly differentiated carcinoma, which is morphologically consistent with NSCLC; red arrows denote the area of inflammatory infiltration.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7942255/v1/542476464668b3e9e690dc9f.png"},{"id":95797990,"identity":"d2e42029-e7fc-4589-8bb6-b219c6de16b3","added_by":"auto","created_at":"2025-11-13 08:13:31","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":537301,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePathogenic identification. (A)\u003c/strong\u003e Microscopic examination of Giemsa-stained BALF smears reveals fragments of hyphae (black arrows), macrophages containing vacuolar structures (yellow arrows), and neutrophils (blue arrows). \u003cstrong\u003e(B) \u003c/strong\u003eCancer cells are observed in the alveolar lavage fluid. \u003cstrong\u003e(C)\u003c/strong\u003e and\u003cstrong\u003e (D) \u003c/strong\u003eThe BALF was inoculated onto Sabouraud dextrose agar (SDA) and incubated at 35°C for 72 hours, leading to the development of white, powdery colonies on the agar surface (Figures 3C and 3D show dorsal and ventral views, respectively).\u003cstrong\u003e (E) \u003c/strong\u003eThe colony was stained with lactophenol cotton blue and examined under the microscope. \u003cstrong\u003e(F) \u003c/strong\u003eMatrix-assisted laser desorption ionization–time of flight mass spectrometry confirmed the presence of \u003cem\u003eA. candidus\u003c/em\u003e.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7942255/v1/8be2e1c56112ad90cb6db696.png"},{"id":95663280,"identity":"c4dcb628-c328-4089-bc1f-4e2f27e121a1","added_by":"auto","created_at":"2025-11-11 16:38:40","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":89480,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePhylogenetic tree of the clinical isolate \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eA. candidus EF669594.\u003c/strong\u003e\u003c/em\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7942255/v1/ae7d9c3751a26c64622a5c9d.png"},{"id":100069600,"identity":"b9067f19-210d-412e-b713-d54e294fa0e6","added_by":"auto","created_at":"2026-01-12 16:14:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2280927,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7942255/v1/1ffb06ee-afcd-4efa-9f40-6f92fc16ccad.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Secondary Aspergillus candidus Infection in a Lung Cancer Patient with a Heavy Smoking History: A Case Report","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eInvasive aspergillosis (IA) represents a life-threatening fungal infection that predominantly occurs in individuals with severely weakened immune systems\u0026mdash;such as those with hematologic malignancies, recipients of hematopoietic stem cell transplants, or patients under long-term, high-dose immunosuppressive regimens.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] \u003cem\u003eAspergillus fumigatus\u003c/em\u003e (\u003cem\u003eA. fumigatus\u003c/em\u003e) remains the most frequently identified species, accounting for approximately 60% to 90% of all IA cases.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] Interestingly, emerging clinical evidence indicates that IA is increasingly recognized in patients with chronic pulmonary conditions\u0026mdash;including COPD, pulmonary fibrosis, and active tuberculosis\u0026mdash;even in the absence of classic immunosuppression.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] In addition, lung cancer patients constitute another high-risk group, owing to mechanisms such as bronchial obstruction, tissue necrosis, and dysregulation of the local immune microenvironment. [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] It is noteworthy, however, that most documented cases of IA in lung cancer have been reported among those receiving chemotherapy, radiation, or corticosteroids.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] Evidence supporting untreated lung cancer itself as an independent risk factor for IA remains limited.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eThere is strong evidence that tobacco smoke plays a central role in driving lung carcinogenesis, while also acting as a potent inducer of broad immune dysfunction.[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] This immunosuppression manifests in multiple ways. To begin with, chronic exposure to cigarette smoke erodes the structural integrity of the respiratory epithelium, undermining its dual role as both a physical barrier and an immunological defense.[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] At the same time, innate immunity becomes dysregulated: the phagocytic and microbicidal activity of alveolar macrophages is dulled, and the capacity of neutrophils to recruit effectively and clear pathogens is weakened.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] Furthermore, the impact of smoking extends to adaptive immunity, where it can suppress T-cell receptor signaling and skew T-helper cell differentiation, ultimately impairing antigen-specific immune responses.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] Together, these defects across innate and adaptive immunity markedly increase the vulnerability of immunocompromised individuals, including lung cancer patients, to severe pulmonary infections such as invasive aspergillosis.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] Notably, studies have shown that heavy smokers exhibit higher rates of \u003cem\u003eAspergillus\u003c/em\u003e colonization within their respiratory tracts compared to non-smokers,[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] indicating that smoking itself might be a direct risk factor for fungal establishment in the lung.[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/p\u003e\u003cp\u003e\u003cem\u003eA. candidus\u003c/em\u003e, a relatively uncommon pathogenic species within the genus, is predominantly environmental\u0026mdash;typically isolated from soil and decomposing plant matter.[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] The literature supports that invasive pulmonary disease due to uncommon environmental fungi such as \u003cem\u003eA. candidus\u003c/em\u003e is extremely rare, with fewer than 20 cases reported worldwide, while superficial infections like keratitis and skin involvement are more commonly observed.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] Importantly, \u003cem\u003eA. candidus\u003c/em\u003e differs biologically from \u003cem\u003eA. fumigatus\u003c/em\u003e\u0026mdash;for example, in its cell wall composition and optimal growth temperature\u0026mdash;which can lead to false-negative results in standard galactomannan assays.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] These limitations underscore the risk of underdiagnosis and highlight the value of molecular tools such as ITS sequencing for accurate species identification.[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eIn this report, we present a case of invasive aspergillosis caused by \u003cem\u003eA. candidus\u003c/em\u003e in a treatment-naive patient with advanced lung cancer and a four-decade history of heavy smoking. This case suggests that \u003cem\u003eA. candidus\u003c/em\u003e is capable of causing serious infection even in individuals without classic immunocompromise, and implicates chronic heavy smoking as a key predisposing condition. It also reinforces the essential role of molecular diagnostics in the identification of non-fumigatus \u003cem\u003eAspergillus\u003c/em\u003e species.\u003c/p\u003e"},{"header":"2. Case Presentation","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Clinical Features\u003c/h2\u003e\u003cp\u003eThe patient is a 66-year-old man with a 40-pack-year smoking history, having consumed approximately 40 to 60 cigarettes daily for four decades. His medical history includes chronic bronchitis and emphysema. During a routine physical exam two years ago at a local clinic, a chest CT scan identified nodular lesions in the right lower lobe and left upper lobe. Bronchoalveolar lavage fluid (BALF) analysis at that time demonstrated a marked increase in inflammatory cells and occasional clusters of atypical cells, raising concern for possible malignancy. Nonetheless, the patient did not pursue additional diagnostic assessment or intervention at that time.\u003c/p\u003e\u003cp\u003eHe was admitted on this occasion due to a three-week history of persistent productive cough and progressively worsening dyspnea. No hemoptysis or chest pain was reported. On physical examination, the patient was alert and oriented without cyanosis. Vital signs were within normal limits: blood pressure 148/97 mmHg, heart rate 79 beats per minute, respiratory rate 20 breaths per minute, and body temperature 36.2℃. Lung auscultation revealed coarse breath sounds with scattered dry and moist rales bilaterally. Examination of other organ systems showed no notable abnormalities.\u003c/p\u003e\u003cp\u003eTo determine the nature of the pulmonary lesion, the patient underwent contrast-enhanced chest CT (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA showed the right lower lobe CT image, where a large irregular shadow with \u0026ldquo;spiky margins\u0026rdquo; (Figure Legend 1: Spiky margins referred to fine, irregular linear structures along the lesion's edge, a typical radiographic feature of lung cancer cells infiltrating the surrounding lung tissue) was visible in the area indicated by the red arrow. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB showed the CT image of the left upper lobe. The nodule indicated by the yellow arrow was considered a metastatic lesion from lung cancer. Additionally, scattered patchy and fluffy high-density shadows were observed in both lung fields, suggesting concurrent pulmonary inflammatory exudation.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eLaboratory findings included a white blood cell count of 8.19 \u0026times; 10⁹/L, with neutrophils accounting for 72.4% of the total. Elevated inflammatory markers were observed, including a C-reactive protein (CRP) level of 27.6 mg/L, suggestive of an ongoing infectious process. Tumor marker assays also returned abnormal values: carbohydrate antigen 125 (CA125) was notably increased at 89.4 U/mL, and cytokeratin fragment 19 (CYFRA 21\u0026thinsp;\u0026minus;\u0026thinsp;1) measured 13.0 ng/mL\u0026mdash;both elevating clinical concern for an underlying malignant process. Lymphocyte subset analysis revealed mild dysregulation, consistent with altered immune activity. Full reference intervals for these parameters are summarized in 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\u003ePatient laboratory test results\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTest Category\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTest Item\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eResult\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eReference Range\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e\u003cb\u003eRoutine Blood Test\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWBC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8.19\u0026times;10⁹/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.5\u0026ndash;9.5\u0026times;10⁹/L\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHemoglobin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e125g/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e130\u0026ndash;175g/L (male)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNeutrophil Percentage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e72.4%\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e40%\u0026ndash;75%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eInflammatory Markers\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCRP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27.6mg/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u0026ndash;10mg/L\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eTumor Markers\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCA125\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e89.4U/ml\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u0026ndash;35U/ml\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCYFRA 21\u0026thinsp;\u0026minus;\u0026thinsp;1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13.0ng/ml\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u0026ndash;3.3ng/ml\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003e\u003cb\u003eLymphocyte subsets\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eabsolute CD4⁺ T cell count\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e589.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e537\u0026ndash;1282\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCD4⁺/CD8⁺ ratio\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.2\u0026ndash;2.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eabsolute NK cell count\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e232.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e44\u0026ndash;436\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eabsolute total B cell count\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e129\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e173\u0026ndash;447\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\u003cb\u003eWBC, white blood cell count; CRP, C-reactive protein\u003c/b\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Pathological Examination\u003c/h2\u003e\u003cp\u003eTo confirm the nature of the pulmonary mass, the patient underwent bronchoscopy with brush sampling and biopsy of the lesion. The specimens were sent to the pathology department for HE staining and immunohistochemical testing. Pathological morphological examination revealed (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eA bronchoscopic brush smear obtained from the right lower basal bronchus revealed malignant cells exhibiting morphological features consistent with non-small cell carcinoma (NSCLC) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Subsequent biopsy and histopathological examination confirmed the presence of a poorly differentiated carcinoma displaying characteristic patterns of NSCLC (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e\u003cp\u003eTo further refine the tumor classification, additional immunohistochemical staining was carried out. The tumor cells exhibited the following profile: CK(Pan)(+), P40 (focally positive), CK5/6(+), P63 (partial+), TTF-1(+), CK7(+), NapsinA(-), and EGFR(+). Integrating the morphological and immunohistochemical findings, the final diagnosis was established as lung adenocarcinoma.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Etiological Examination\u003c/h2\u003e\u003cp\u003eTo identify the pathogen responsible for the pulmonary infection, BALF was collected from the inflammatory lesion in the right lower lobe during bronchoscopy. The sample was subjected to Gram staining and microscopic examination, bacterial and fungal cultures, as well as molecular biology testing. The bacterial culture of the BALF showed normal flora, and tests for \u003cem\u003eMycobacterium tuberculosis\u003c/em\u003e, \u003cem\u003eCryptococcus\u003c/em\u003e antigen, and \u003cem\u003ePneumocystis jirovecii\u003c/em\u003e staining were all negative, effectively ruling out common bacterial, Cryptococcal, and Pneumocystis infections.\u003c/p\u003e\u003cp\u003eUpon examination of the Giemsa-stained BALF smear, mycelial fragments were identified (Fig.\u0026nbsp;3A). The smear also contained cancer cells, which corroborated the lung cancer diagnosis (Fig.\u0026nbsp;3B). After inoculation onto Sabouraud Dextrose Agar (SDA), the BALF sample yielded white, powdery fungal colonies that developed on the agar surface (Figs.\u0026nbsp;3C and 3D). Gentian violet staining was used to further characterize the colonial morphology (Fig.\u0026nbsp;3E).\u003c/p\u003e\u003cp\u003eThe pathogen was identified as \u003cem\u003eA. candidus\u003c/em\u003e. via matrix-assisted laser desorption ionization\u0026ndash;time of flight mass spectrometry(bioMerieux, France)(Fig.\u0026nbsp;3F). Notably, galactomannan (GM) testing of the BALF returned a negative result. This finding may reflect the relatively lower galactomannan content in the cell wall of \u003cem\u003eA. candidus\u003c/em\u003e compared to other \u003cem\u003eAspergillus\u003c/em\u003e species, potentially reducing the sensitivity of GM assays. Thus, molecular confirmation through sequencing proved essential for a definitive diagnosis.\u003c/p\u003e\u003cp\u003eBased on the patient\u0026rsquo;s clinical presentation\u0026mdash;untreated lung cancer accompanied by cough, sputum, and dyspnea\u0026mdash;microbiological testing was conducted on bronchoalveolar lavage fluid (BALF) to evaluate possible fungal infection. Giemsa-stained BALF smears (Fig.\u0026nbsp;3A) showed hyphal fragments morphologically suggestive of \u003cem\u003eA. candidus\u003c/em\u003e (indicated by black arrows). The observation of hyphae\u0026mdash;as opposed to conidia\u0026mdash;was considered indicative of invasive aspergillosis, aligning with initial clinical suspicion. Accompanying inflammatory activity was evidenced by the presence of vacuolated macrophages and neutrophils within the same sample. Malignant cells were also identified (Fig.\u0026nbsp;3B), consistent with the patient\u0026rsquo;s known lung cancer diagnosis.\u003c/p\u003e\u003cp\u003eTo isolate and characterize the fungal agent, BALF was cultured on Sabouraud dextrose agar (SDA), which produced white, powdery colonies typical of \u003cem\u003eA. candidus\u003c/em\u003e. Subsequent microscopic examination using gentian violet staining (Fig.\u0026nbsp;3E) revealed conidial structures consistent with this species, lending further support to the phenotypic identification. For microbial identification, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis was performed, and the resulting characteristic mass spectrum (Fig.\u0026nbsp;3F), which reflects the unique protein profile of the isolate, showed a high-confidence match with the reference spectrum of \u003cem\u003eA. candidus\u003c/em\u003e, enabling unambiguous species-level confirmation.\u003c/p\u003e\u003cp\u003eTo rule out morphologically or genetically similar species and reinforce taxonomic assignment, a phylogenetic tree was constructed based on the ITS sequence using MEGA11 software (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The clinical isolate clustered with high support among reference sequences of \u003cem\u003eA. candidus EF669594\u003c/em\u003e from GenBank, conclusively verifying its phylogenetic identity.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Treatment and prognosis\u003c/h2\u003e\u003cp\u003eGiven the patient\u0026rsquo;s complex presentation, the treatment strategy adhered to the principle of first addressing the \u003cem\u003eA. candidus\u003c/em\u003e infection before initiating palliative care for lung cancer. Antifungal therapy with voriconazole was chosen based on in vitro susceptibility testing of the isolated \u003cem\u003eA. candidus\u003c/em\u003e strain (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The regimen started with an intravenous loading dose of 400 mg every 12 hours on day one, followed by a maintenance dose of 200 mg intravenously every 12 hours from day two onward.\u003c/p\u003e\u003cp\u003eFor palliative management of lung cancer-related symptoms, the patient received compound methoxamine capsules (25 mg three times daily) and ambroxol hydrochloride tablets (30 mg three times daily) to alleviate cough and facilitate expectoration. Supplemental oxygen was also provided via nasal cannula at 2 L/min to relieve dyspnea. Following symptomatic improvement, the patient was referred back to the local hospital for continued follow-up.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003e\u003cem\u003eA. candidus\u003c/em\u003e antimicrobial susceptibility\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\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\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAntifungal Drug\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMethod\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eResult\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eBreakpoint\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnit\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eInterpretation\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVoriconazole\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.125\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eug/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSensitive (S)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eItraconazole\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.125-1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eug/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSensitive (S)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCaspofungin\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u0026ndash;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eug/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSensitive (S)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAmphotericin B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u0026ndash;2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eug/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSensitive (S)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFluconazole\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMIC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2\u0026ndash;8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eug/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSensitive (S)\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\u003eAt the last follow-up, which occurred 6 months after treatment, the patient showed no signs of infection recurrence, no significant progression of lung cancer, and maintained a good quality of life. No adverse reactions related to voriconazole (such as hepatotoxicity or visual disturbances) were observed during the treatments.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eThis study reported the case of a 66-year-old man with untreated lung cancer and a four-decade history of heavy smoking (40\u0026ndash;60 cigarettes per day) who developed a concurrent infection with \u003cem\u003eA. candidus\u003c/em\u003e. The diagnosis was established through BALF culture and confirmed by ITS gene sequencing. This case highlights a complex clinical interplay between long-term smoking, untreated malignancy, and infection by a rare fungal pathogen, offering valuable insights for the management of similar patients.\u003c/p\u003e\u003cp\u003eThe patient\u0026rsquo;s 40-year smoking history represents a major risk factor underlying both his lung cancer and \u003cem\u003eA. candidus\u003c/em\u003e infection. Long-term smoking is a well-established primary cause of lung cancer, promoting tumor development through persistent DNA damage and chronic inflammation in the airways.[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] Beyond its carcinogenic role, smoking significantly compromises innate pulmonary defenses\u0026mdash;it disrupts ciliary function, impairs mucociliary clearance, and induces structural lung damage such as emphysema, which was also evident on this patient\u0026rsquo;s chest CT.[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] These alterations foster a microenvironment that facilitates fungal colonization and invasion.[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eMoreover, cigarette use has been associated with an elevated risk of invasive aspergillosis (IA), including among non-neutropenic individuals.[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] A retrospective multicenter cohort study found that smoking independently predicts IA in critically ill patients, with an odds ratio comparable to that of immunosuppressive treatment.[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] In this case, given that the patient had not received chemotherapy or radiotherapy, smoking likely served as the principal contributor to both malignant transformation and fungal susceptibility. These findings highlight the need to carefully evaluate smoking history when assessing fungal infection risks in lung cancer patients\u0026mdash;even in the absence of conventional immunosuppressive therapies.\u003c/p\u003e\u003cp\u003eDiagnosing \u003cem\u003eA. candidus\u003c/em\u003e infection in this patient with untreated lung cancer presented multiple clinical difficulties, arising from both the distinctive biological features of the fungus and the complexity of the patient\u0026rsquo;s medical background. Initially, symptoms such as cough, sputum production, and dyspnea closely mirrored those commonly seen in advanced lung cancer, creating diagnostic ambiguity between malignant progression and superimposed fungal disease. Although imaging findings\u0026mdash;including ground-glass opacities and the \"halo sign\"\u0026mdash;hinted at fungal involvement, these features are nonspecific and can also occur in other pulmonary disorders, such as tumor-related inflammation or bacterial pneumonia.[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eFurthermore, the negative galactomannan (GM) test highlighted the limitations of traditional fungal biomarkers in detecting rare \u003cem\u003eAspergillus\u003c/em\u003e species. Although GM testing is highly sensitive for \u003cem\u003eAspergillus\u003c/em\u003e fumigatus (the most common cause of invasive aspergillosis), its sensitivity is lower for rare species like \u003cem\u003eA. candidus\u003c/em\u003e.[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] The definitive diagnosis in this case was made through BALF culture (which grew \u003cem\u003eAspergillus\u003c/em\u003e colonies) and subsequent ITS gene sequencing, which identified the pathogen as \u003cem\u003eA. candidus\u003c/em\u003e. This approach aligns with the latest clinical guidelines, which emphasize the importance of culture and molecular sequencing in identifying \u003cem\u003enon-A. fumigatus Aspergillus\u003c/em\u003e species.[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eAdditionally, the presence of both tumor cells and inflammatory infiltrates in the patient's BALF highlighted the need for a multimodal diagnostic approach. Initially, atypical cells raised suspicion for malignancy, while the concurrent detection of fungal elements (confirmed by sequencing) revealed dual pathology. This supports the recommendation to prioritize fungal diagnostics in lung cancer patients with progressive respiratory symptoms, even in the absence of overt immunosuppression (e.g., neutropenia, long-term corticosteroid use).[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] Notably, this patient had only chronic airway damage from smoking and normal lymphocyte counts and CD4⁺ T-cell ratios, suggesting that \u003cem\u003eA. candidus\u003c/em\u003e may have unique pathogenic mechanisms that enable it to infect hosts with mild immune impairment, such as those with smoking-related epithelial barrier damage.[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eFrom a therapeutic standpoint, managing this case involved a delicate balance between controlling the fungal infection and addressing the complicating factor of untreated lung cancer. Unlike the more common \u003cem\u003eA. fumigatus\u003c/em\u003e, \u003cem\u003eA. candidus\u003c/em\u003e displays a markedly different susceptibility pattern to azole antifungals, typically showing higher minimum inhibitory concentrations (MICs) to fluconazole and itraconazole.[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] Nevertheless, voriconazole continues to serve as the first-line agent for \u003cem\u003eA. candidus-\u003c/em\u003erelated invasive aspergillosis, supported by in vitro evidence confirming its activity against most clinical isolates of this species. [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eConsidering the high mortality associated with untreated invasive aspergillosis in cancer patients, the treatment strategy emphasized controlling the fungal infection as the immediate priority, aiming to stabilize respiratory function before introducing any antitumor interventions.[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] Looking ahead, longer-term management will require reassessing tumor progression once the infection is adequately controlled\u0026mdash;weighing the potential benefits of anticancer treatments against the possible risk of fungal recurrence. This case highlights that even in advanced, untreated lung cancer, appropriately targeted antifungal therapy may not only help alleviate symptoms but also enhance the patient\u0026rsquo;s overall quality of life.\u003c/p\u003e"},{"header":"4. Conclusion","content":"\u003cp\u003eThis case highlights the need to maintain a high index of suspicion for rare fungal pathogens such as \u003cem\u003eA. candidus\u003c/em\u003e in lung cancer patients\u0026mdash;especially those with extensive smoking histories who have not undergone antitumor treatment. Smoking not only promotes lung carcinogenesis but also heightens susceptibility to fungal infections by compromising respiratory defenses. Due to the diagnostic difficulties inherent in such infections, clinicians should carefully correlate clinical presentation with imaging findings and employ a multifaceted diagnostic approach, including BALF culture and molecular sequencing, to achieve a definitive diagnosis. For confirmed \u003cem\u003eA. candidus\u003c/em\u003e infections, voriconazole remains the first-line antifungal agent. Management should incorporate a balanced strategy that addresses both infection control and cancer-related complications. Further investigations are warranted to elucidate the pathogenic mechanisms and refine diagnostic and therapeutic protocols for such complex clinical scenarios.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJ.Y. collected clinical data and imaging materials, reviewed literature, drafted the original manuscript, prepared figures, and summarized the case. X.Z. provided clinical diagnosis consultation and supervised case authenticity verification. J.Ye. designed the case report framework, acquired funding if applicable, supervised manuscript quality control, reviewed and edited the manuscript, and validated clinical conclusion rationality. P.N. organized case records and conducted patient follow-up. Y.Ge. provided guidance on case report writing norms and validated literature citation accuracy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe sequencing data reported in this study was archived in the Sequnece Read Archive (SRA) with the accession number EF669594, with web link https://www.ncbi.nlm.nih.gov/nuccore/EF669594.1/.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Zhejiang People\u0026apos;s Hospital (Approval No.: 2022JS008) and was conducted in accordance with the ethical standards of the Declaration of Helsinki.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient to publish this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSchauwvlieghe, A.; Rijnders, B.; Philips, N.; Verwijs, R.; Vanderbeke, L.; Van Tienen, C.; Lagrou, K.; Verweij, P.E.; Van de Veerdonk, F.L.; Gommers, D., et al. 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The impact of the Fungus-Host-Microbiota interplay upon Candida albicans infections: current knowledge and new perspectives. \u003cem\u003eFems Microbiol Rev\u003c/em\u003e \u003cstrong\u003e2021\u003c/strong\u003e, 45, doi:10.1093/femsre/fuaa060.\u003c/li\u003e\n\u003cli\u003eAlcazar-Fuoli, L.; Mellado, E. Current status of antifungal resistance and its impact on clinical practice. \u003cem\u003eBrit J Haematol\u003c/em\u003e \u003cstrong\u003e2014\u003c/strong\u003e, 166, 471-484, doi:10.1111/bjh.12896.\u003c/li\u003e\n\u003cli\u003eArendrup, M.C. Update on antifungal resistance in Aspergillus and Candida. \u003cem\u003eClin Microbiol Infec\u003c/em\u003e \u003cstrong\u003e2014\u003c/strong\u003e, 20 Suppl 6, 42-48, doi:10.1111/1469-0691.12513.\u003c/li\u003e\n\u003cli\u003eUllmann, A.J.; Aguado, J.M.; Arikan-Akdagli, S.; Denning, D.W.; Groll, A.H.; Lagrou, K.; Lass-Florl, C.; Lewis, R.E.; Munoz, P.; Verweij, P.E., et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. \u003cem\u003eClin Microbiol Infec\u003c/em\u003e \u003cstrong\u003e2018\u003c/strong\u003e, 24 Suppl 1, e1-e38, doi:10.1016/j.cmi.2018.01.002.\u003c/li\u003e\n\u003cli\u003eLamoth, F.; Calandra, T. Pulmonary aspergillosis: diagnosis and treatment. \u003cem\u003eEur Respir Rev\u003c/em\u003e \u003cstrong\u003e2022\u003c/strong\u003e, 31, doi:10.1183/16000617.0114-2022.\u003c/li\u003e\n\u003c/ol\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":"Aspergillus candidus, untreated lung cancer, heavy smoking history, ITS sequencing, bronchoalveolar lavage fluid","lastPublishedDoi":"10.21203/rs.3.rs-7942255/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7942255/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground：\u003c/strong\u003e\u003cem\u003eAspergillus candidus \u003c/em\u003e(\u003cem\u003eA. candidus\u003c/em\u003e), while an uncommon clinical isolate, represents an emerging cause of severe invasive fungal disease, particularly among individuals with compromised immunity. Patients with hematologic or solid tumor malignancies—especially those with concomitant structural lung damage, such as results from long-term heavy smoking—are at heightened risk.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation：\u003c/strong\u003eWe describe a case of invasive aspergillosis caused by \u003cem\u003eA. candidus\u003c/em\u003e in a 66-year-old man with untreated lung cancer. The patient had a 40-year history of heavy smoking, with known chronic bronchitis and emphysema. Bilateral pulmonary nodules had been identified two years prior, for which he had declined intervention. He presented with complaints of cough, productive sputum, and worsening dyspnea. Chest imaging revealed progression of his underlying malignancy, accompanied by inflammatory changes. Bronchoalveolar lavage fluid was obtained and cultured; mycological analysis yielded colonies morphologically consistent with \u003cem\u003eA. candidus\u003c/em\u003e, an identification subsequently confirmed through internal transcribed spacer (ITS) sequencing—the current gold standard for fungal speciation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions：\u003c/strong\u003eTo our knowledge, this represents the first reported case of \u003cem\u003eA. candidus\u003c/em\u003e infection in a treatment-naïve lung cancer patient with an extensive smoking history. It underscores the importance of considering this pathogen in heavily smoking-related lung cancer cases and highlights diagnostic and therapeutic challenges in this high-risk population.\u003c/p\u003e","manuscriptTitle":"Secondary Aspergillus candidus Infection in a Lung Cancer Patient with a Heavy Smoking History: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-11 16:28:57","doi":"10.21203/rs.3.rs-7942255/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-12T14:32:06+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-10T20:53:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"612972983409447541873608602645709745","date":"2025-11-02T14:09:18+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-01T17:52:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"1239432051209983846654900780113607676","date":"2025-11-01T17:10:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"67138871026907669578810378263137385692","date":"2025-10-31T04:01:59+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-30T13:52:34+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-29T14:37:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-29T01:16:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-29T01:16:15+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2025-10-24T16:19:17+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":"15c36fab-148f-4ce2-b381-8f6dcbffcb7a","owner":[],"postedDate":"November 11th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-12T16:07:47+00:00","versionOfRecord":{"articleIdentity":"rs-7942255","link":"https://doi.org/10.1186/s12879-025-12339-7","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2026-01-06 15:58:05","publishedOnDateReadable":"January 6th, 2026"},"versionCreatedAt":"2025-11-11 16:28:57","video":"","vorDoi":"10.1186/s12879-025-12339-7","vorDoiUrl":"https://doi.org/10.1186/s12879-025-12339-7","workflowStages":[]},"version":"v1","identity":"rs-7942255","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7942255","identity":"rs-7942255","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}