Clinical Characteristics and Outcomes in Adults with Anti-IFN-γ Autoantibody-Associated Immunodeficiency and Skeletal Involvement: A 10-Year Retrospective Cohort Study

Clinical Characteristics and Outcomes in Adults with Anti-IFN-γ Autoantibody-Associated Immunodeficiency and Skeletal Involvement: A 10-Year Retrospective Cohort Study | 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 Research Article Clinical Characteristics and Outcomes in Adults with Anti-IFN-γ Autoantibody-Associated Immunodeficiency and Skeletal Involvement: A 10-Year Retrospective Cohort Study Xuemei Huang, Haiyan Pang, JiaQi Qin, Siqiao Liang, Xiaona Liang, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8542097/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Purpose Anti-interferon-γ autoantibodies (AIGAs)-associated immunodeficiency is a rare, adult-onset disorder characterized by multi-system infections with geographic variability. However, the clinical features and prognosis related to skeletal involvement remain unclear. Methods A 10-year retrospective study of AIGAs-positive skeletal involvement with HIV-negative patients from Guangxi, China. Results A total of 103 patients (median onset age: 55 years; median follow-up: 28.40 months), hypertension (29.13%) and HBV carriage (10.68%) were prevalent underlying diseases. Cough/sputum (66.99%) was the predominant initial symptom, while bone pain (21.36%) was less common. Among those with bone involvement, peripheral lymphadenopathy (86.41%) and cough/sputum (85.44%) were highly prevalent, unlike bone/joint pain (37.86%) and myalgia (14.56%). Most patients exhibited elevated levels of white blood cells, neutrophils, C-reactive protein, procalcitonin, erythrocyte sedimentation rate, globulin, immunoglobulin (Ig) G, and IgE. The predominant types of infection were disseminated Talaromyces marneffei (TM) (63.11%) and non-tuberculous mycobacteria (NTM) (55.34%), with an increasing trend of co-infection observed. Chest CT revealed lung involvement in all patients, with 63.11% exhibiting bone lesions. Bone emission computed tomography (ECT) showed abnormal uptake in the thoracic (75.73%) and lumbar vertebrae (56.31%); 63.11% of patients had bone destruction, of which 13.59% were osteolytic. All patients received full-course anti-infective therapy, some received individualized immunotherapy, and 19.41% required surgical intervention. Conclusion Skeletal involvement in AIGAs syndrome is common yet occult, presenting as disseminated infection, with TM and NTM co-infection complicating the course. The axial skeleton is frequently involved, with early detection by skeletal ECT enabling comprehensive treatment and precise management to improve prognosis. AIGAs Skeletal Involvement Clinical Characteristics Infection Figures Figure 1 Figure 2 Figure 3 Introduction Anti-interferon (IFN)-γ autoantibodies (AIGAs) syndrome is a rare form of adult-onset immunodeficiency (AOID) that has been increasingly recognized in recent years( 1 , 2 ). The core mechanism of the disease involves the production of neutralizing AIGAs that target and neutralize IFN-γ, thereby disrupting the IL-12/IFN-γ axis signaling pathway and impairing IFN-γ-dependent antimicrobial cell-mediated immune responses( 1 – 4 ). Consequently, patients show heightened susceptibility to intracellular pathogens, particularly opportunistic infections like non-tuberculous mycobacteria (NTM) and Talaromyces marneffei (TM)( 5 , 6 ), and typically present with refractory, recurrent, and disseminated multisystem infections ( 7 , 8 ). AIGAs were first detected in 2004 in two patients with complex infections( 9 , 10 ). The disease is endemic in Southeast Asia, with high prevalence reported in Guangxi, Guangdong, and Taiwan regions of China( 7 ). Multi-system involvement is common in AIGAs syndrome, including the lymph nodes, lungs, skin, and skeletal system ( 7 , 8 ). However, the frequency of involvement varies considerably across geographic regions. For example, in a Thai cohort (n = 74), lymph node lesions were most common, followed by skin involvement; in a US. cohort (n = 23), bone involvement was predominant, with lymph nodes being the next most frequent( 8 ). In contrast, our recent study indicated that pulmonary involvement is most prominent in patients from Guangxi, China, followed by lymph node lesions( 7 ). These differences may be associated with genetic background, environmental exposures, and other factors. It is particularly noteworthy that the reported frequency of bone involvement varies across cohorts. When the skeletal system is affected, severe complications such as bone destruction, fractures, and osteomyelitis may occur( 11 – 13 ), significantly impacting patients' quality of life. While numerous studies have centered on the overall features of AIGAs syndrome ( 1 , 7 ), investigation into specific organ systems, such as the skeleton, is still insufficient. As a key target of disseminated infections, the clinical patterns, imaging features, and long-term prognosis of skeletal involvement have not yet been clearly defined. Skeletal involvement often manifests as bone pain, fractures, or imaging abnormalities. A deeper understanding of its clinical phenotypes, pathogen profiles, and disease progression is essential for improving diagnosis and treatment. This study employs a large-sample retrospective analysis to systematically summarize the demographic, immunological, clinical, therapeutic, and prognostic characteristics of AIGAs-positive patients with skeletal involvement, aiming to provide a basis for early identification and intervention. Patients and Methods Study Population A retrospective analysis was conducted on follow-up data from 103 HIV-negative adult patients with AIGAs and skeletal system involvement, who were identified at the First Affiliated Hospital of Guangxi Medical University between May 2015 and May 2025. The follow-up data included demographic information (gender, age, and occupation), medical history (comorbidities and past history), auxiliary examination results (routine laboratory tests, HIV antibody screening, lymphocyte subset analysis, immunological status, imaging studies, as well as pathological and microbiological detection), treatment regimens, and clinical outcomes, which were summarized and analyzed. This study was approved by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University (IRB Protocol Number: 2022-KT-Guike-127). Written informed consent was obtained from all participants. AIGAs Assay Anti-interferon-γ autoantibody (AIGAs) titers were measured using enzyme-linked immunosorbent assay (ELISA). Recombinant human IFN-γ was coated onto microtiter plates, followed by incubation with patient serum and subsequent detection of antibody levels. Both the operational procedures and the positive threshold were consistent with previously established protocols( 7 ). Western blot was employed to evaluate the inhibitory effect of AIGAs on the IFN-γ/STAT1 signaling axis( 7 ). Briefly, THP-1 monocytes were first induced by PMA to adhere and differentiate into macrophages, which were then co-incubated with patient serum and IFN-γ. AIGAs in positive serum samples neutralized IFN-γ, thereby suppressing STAT1 phosphorylation, which was reflected by a noticeably weakened p-STAT1 band on the PVDF membrane. In contrast, normal or negative serum did not interfere with IFN-γ activity, allowing full activation of the STAT1 pathway and a marked increase in p-STAT1 expression. Flow Cytometry: The entire assay was performed by physicians in the hospital's clinical laboratory following standardized operating procedures. The main steps included sample preparation, antibody labeling and incubation, machine detection, and data analysis. Pathogen Identification: Clinical specimens, including sputum, blood, bronchoalveolar lavage fluid (BALF), pus from skin lesions, bone marrow, and tissue biopsies, were subjected to pathogen identification by culture, histopathological examination, or next-generation sequencing (NGS) performed. Skeletal system involvement is defined as the affection of bones during the disease process, encompassing structural damage (such as bone destruction), pain, functional limitations, and distinct abnormalities observed through medical imaging and pathological assessment. Disseminated infection is the presence of infectious foci in two or more non-adjacent organ systems. Results During the 10-year study period, 263 patients were diagnosed with AIGAs syndrome, including 217 with disseminated infection and 46 with localized infection. Among them, 103 patients (all with disseminated infection) presented with skeletal system involvement and were included in this study. The median age of onset was 55 (18–78) years, with males accounting for 55.34%. Underlying diseases included hypertension (29.13%), hepatitis B virus carriage (10.67%), and diabetes (9.71%). The most common initial symptoms were cough/sputum production (66.99%), followed by fever (52.43%), bone pain (21.36%), and peripheral lymphadenopathy (19.42%). At the time of medical consultation, antibody titers of 1:2,500 and 1:500 were observed in 86.41% and 12.62% of patients, respectively. A total of 21.36% of patients had been misdiagnosed with tuberculosis, and 12.62% had a prior culture-confirmed history of tuberculosis (Table 1). Table 2 summarized the clinical and laboratory characteristics of 103 adult patients with AIGAs syndrome and skeletal involvement. The most common features were peripheral lymphadenopathy (86.41%), cough or sputum (85.44%) and fever (79.61%). Other frequent findings were weight loss (63.11%), chills (60.19%), anemia (43.69%), rash or subcutaneous nodules (42.72%), bone or joint pain (37.86%) and myalgia (14.56%). All patients had elevated procalcitonin and erythrocyte sedimentation rate. Leukocytosis (92.23%), neutrophilia (91.26%) and monocytosis (73.79%) were common, as were increased levels of C-reactive protein (95.15%), serum ferritin (86.41%), globulin (72.82%), immunoglobulin (Ig) G (77.67%) and IgE (66.02%). Conversely, hemoglobin and albumin concentrations were reduced in 90.29% and 96.12% of patients, respectively. Lymphocyte counts remained within the normal range in 69.90% of subjects. Flow cytometry demonstrated normal distributions of total T cells (57.28%), CD4 + T cells (60.19%), CD8 + T cells (66.99%), NK cells (66.99%) and B cells (48.54%) in the majority of individuals (Supplementary Fig. 1). As shown in Fig. 1A, pathogen identification was attempted in 103 patients using NGS (81.55%), culture confirmation (43.69%), or pathological examination (10.68%). For NGS, BALF was the predominant specimen (66.67%), followed by lymph-node (21.43%) and blood (14.29%) samples. Culture-based identification most frequently used BALF and blood (each 24.44%), followed by lymph-node samples (20.00%). Pathological examination was carried out mainly on lymph-node (54.55%), bone-tissue (18.18%), and soft-tissue (18.18%) specimens. Figure 1B depicts the distribution of pathogens. Among bacteria, NTM (55.34%) and Streptococcus pneumoniae (16.50%) predominated; among fungi, TM (63.11%) and Candida (15.53%) were most frequent; and among viruses, cytomegalovirus (CMV, 44.66%) and Epstein–Barr virus (EBV, 34.95%) accounted for the majority of cases. Chest CT of all 103 patients showed pulmonary involvement. The dominant pattern was bilateral diffuse disease (87.38%), whereas unilateral multifocal opacities were seen in 13.59%; abnormalities involved every lung segment. The most frequent imaging features were mediastinal lymphadenopathy (84.47%), patchy opacities (77.67%), linear opacities (68.93%), nodules (59.22%), nodular opacities (47.57%) and pleural effusion (44.66%) (Supplementary Fig. 2). All 103 patients underwent bone emission computed tomography (ECT) scans upon admission. The involved sites primarily showed abnormal radiotracer concentration, commonly found in the thoracic spine (75.73%), lumbar spine (56.31%), ribs (49.51%), skull (47.57%), hip bone (46.60%), and cervical spine (45.63%) (Fig. 2). Bone ECT indicated bone destruction in 65 cases, which included lytic destruction (14 cases), compressive destruction (3 cases), and osteoblastic destruction (2 cases). Additionally, chest computed tomography (CT) scans suggested bone involvement in 66 cases (64.08%), and positron emission tomography - computed tomography (PET-CT) scans performed on another 14 patients also indicated bone involvement. (Supplementary Table) All 103 patients underwent whole-body bone emission computed tomography (ECT) at admission. Abnormal radiotracer accumulation was most frequently observed in the thoracic spine (75.73%), lumbar spine (56.31%), ribs (49.51%), skull (47.57%), hip bone (46.60%) and cervical spine (45.63%) (Fig. 2). Bone ECT revealed bone destruction in 65 cases: lytic in 14, compressive in 3 and osteoblastic in 2. In addition, chest CT suggested osseous involvement in 66 (64.08%) cases, and PET-CT performed in an additional 14 patients also demonstrated bone lesions (Supplementary Table 1) The annual enrolment over the 10-year study period is summarized in Supplementary Fig. 3. The median follow-up for the 103 patients was 28.40 months (range 0.27–119.73). Thirteen patients died; none of the deaths were directly attributable to bone disease, and all were caused by recurrent severe infections. Of the 103 patients with disseminated infection, 100 were infected with TM and/or NTM. At baseline, 22 (21.34%) of those with bone involvement already had microbiologically all of whom also had bone lesions. In addition, 29 patients (28.16%) were sequentially diagnosed with TM and NTM infection after a median interval of 10 months (IQR 6–14.5) (Fig. 3). All patients received guideline-based antimicrobial therapy, with regimens adjusted according to follow-up results, and underwent individualized immunomodulatory treatment (e.g., glucocorticoids and cyclophosphamide). Bone involvement was controlled and symptoms relieved in the majority. Twenty patients required surgery: 13 underwent debridement with internal fixation, lumbar vertebroplasty, or bone grafting under general or spinal anesthesia, and 7 had bone-marrow aspiration or biopsy for diagnostic purposes. Antimicrobial therapy was continued postoperatively, yet two patients still succumbed to severe infection (Supplementary Table 2). Discussion This study conducted a relatively large retrospective analysis of AIGAs-positive adult patients without HIV infection who had bone involvement, summarizing their clinical characteristics and long-term outcomes. The results indicated that patients with bone involvement exhibited higher levels of inflammatory responses and immune markers, with disseminated TM and NTM infections being more common. Additionally, 36.89% of these patients had TM and NTM co-infections. All patients with bone involvement also had pulmonary involvement, and the skeletal lesions primarily affected the axial bones (such as the thoracic and lumbar vertebrae). Bone ECT was helpful in identifying potential bone involvement. The findings of this study can assist clinicians in early identification and standardized management of bone involvement complications, reducing the need for surgical intervention and improving patients' quality of life. Skeletal involvement is a significant comorbidity in patients with AIGAs-positive. Previous data indicated a skeletal involvement rate of 23.6% among AIGA-positive patients with TM infections in Guangxi, China( 14 ). while diffuse NTM infections associated with osteolytic lesions have primarily been documented in case reports or small series( 15 – 17 ). Our earlier study reported a skeletal involvement rate of 49.6% in patients with AIGAs syndrome( 7 ). Consistent with these findings, the current retrospective study revealed skeletal involvement in 39.16% (103/263) of all AIGAs-positive patients. Notably, among the subgroup with disseminated infection (n = 217), the proportion increased to 47.47%. These results collectively demonstrate that skeletal involvement is highly prevalent in this patient population. However, its manifestation during the progression of AIGAs syndrome is often insidious. At the initial diagnosis of AIGAs positivity, patients mainly presented with respiratory symptoms (cough and sputum), while bone pain accounted for only 21.36%. Compared with previously reported AIGAs-positive patients( 18 ), those with bone involvement in this study exhibited a more intense systemic inflammatory response. Nearly all patients (100%) showed elevated procalcitonin and erythrocyte sedimentation rates, and over 90% had increased leukocyte and neutrophil counts, suggesting that skeletal system involvement may exacerbate a systemic inflammatory cascade. Despite severe infections, flow cytometry indicated that 50%-70% of patients had roughly normal proportions of lymphocyte subsets (including CD4 + and CD8 + T cells, B cells, and NK cells), consistent with previous reports( 1 , 14 , 19 ). This may imply that neutralizing AIGAs lead to a functional immunodeficiency rather than a numerical loss of cells. By blocking the IFN-γ signaling pathway, AIGAs paralyze immune cells such as macrophages, rendering them unable to effectively clear intracellular pathogens, without broadly disrupting lymphocyte homeostasis( 1 , 2 , 4 , 14 ). In terms of etiology, the findings of this study are consistent with previous reports( 2 , 7 ), indicating that the most common pathogens in patients with AIGAs syndrome are TM and NTM. The novelty of this study lies in revealing the high frequency of TM and NTM co-infections in such patients with bone involvement. Data show that the co-infection rate in patients with bone involvement was 21.34% at baseline and increased to 36.89% during follow-up, suggesting that the skeletal system is a significant target for TM/NTM infections. It is particularly noteworthy that 28.16% of patients were successively diagnosed with TM and NTM infections, with an average interval of 10 months. Our earlier case report also described an AIGAs-positive patient with skeletal involvement who, during follow-up, sequentially developed TM and NTM infections and displayed recurrent, highly variable clinical manifestations( 12 ). For AIGAs-positive patients with disseminated TM or NTM infection (especially those with bone involvement), clinicians should maintain a high index of suspicion for the risk of TM and NTM co-infection. This phenomenon suggests that the initial infection may create a favorable microenvironment for subsequent infections or reflects an extremely high susceptibility to intracellular bacteria in the context of persistent immunodeficiency. Furthermore, the high frequencies of CMV (44.66%) and EBV (34.95%) infections further corroborate the impairment of cellular immune function in these patients. It is recommended that in cases of suboptimal treatment response or disease recurrence, repeated and comprehensive etiological assessments should be actively conducted using techniques such as molecular diagnostics to achieve early and accurate diagnosis, and to develop targeted combination therapy regimens, thereby improving patient outcomes. All 103 patients in this cohort had pulmonary involvement. Chest CT findings primarily showed diffuse lesions in both lungs (87.38%), accompanied by a high prevalence of mediastinal lymphadenopathy (84.47%) and pleural effusion (44.66%). Additionally, chest CT indicated bone destruction in 63.11% of the patients. The chest imaging findings in AIGAs-positive patients need to be differentiated from pulmonary tumors, especially when CT suggests lung occupying space( 18 ). Bone ECT scans revealed multifocal abnormal radiotracer uptake in all patients, primarily involving the axial skeleton (thoracic spine 75.73%, lumbar spine 56.31%), followed by flat bones (skull 47.57%). Among them, 65 patients exhibited significant bony destruction. Additionally, chest CT also indicated bony destruction in the thoracic vertebrae and ribs. The sites of bone involvement on PET-CT corresponded with the findings on bone ECT. These imaging characteristics are consistent with previous reports( 20 – 22 ), suggesting that the pathogens tend to colonize highly vascularized bone regions, leading to destructive lesions. Taken together, the findings suggest that the lung likely serves as the primary portal of entry and initial site of infection, with subsequent hematogenous spread to multiple systems, including the skeletal system. The fact that chest CT indicated bone destruction in 63.11% of the 103 AIGAs-positive patients with bone involvement, coupled with the generally inconspicuous nature of patient-reported skeletal symptoms, underscores the insidious presentation of bone involvement in AIGAs-positive patients. Therefore, it is recommended to perform a detailed physical examination of the skeletal system in AIGAs-positive patients and conduct early bone ECT evaluations in high-risk individuals to achieve early identification and diagnosis of bone involvement complications. All patients in this study received personalized antibiotic therapy. Due to the absence of unified clinical guidelines for AIGAs syndrome, treatment strategies were determined based on identified pathogens. AIGAs-positive patients with TM infection received antifungal therapy following guidelines for HIV-positive individuals with TM( 23 ), supplemented by individualized immunosuppression to reduce the risk of relapse after discontinuation( 1 , 24 ). Those with NTM infection received anti-NTM therapy per relevant guidelines( 25 ), while patients with co-infection were managed with combination therapy targeting pathogens. Due to factors such as poor patient compliance, COVID-19 control measures, or health insurance policies, many patients did not undergo regular bone ECT monitoring after skeletal involvement. Most only received a repeat bone ECT during rehospitalization for acute episodes, with new lesions often detected. During follow-up, 19.4% of patients required surgical intervention (e.g., debridement, spinal fixation, or bone biopsy) for diagnostic or therapeutic purposes, highlighting the challenges posed by skeletal lesions. Overall, aggressive anti-infective therapy combined with immunomodulation controlled skeletal symptoms in most patients. During follow-up, thirteen deaths were attributed to severe systemic infections, reflecting the difficulty in controlling disseminated infections in an immunocompromised state. Although skeletal lesions themselves were not direct causes of death, their presence indicated a greater disease burden and more complex treatment challenges. This was a single-center retrospective study, which may be subject to selection bias. The incomplete inclusion of certain laboratory tests (such as levels of specific bone immune cytokines and metabolic markers) and detailed treatment regimen data may limit deeper exploration of efficacy assessment and pathological mechanisms. Future prospective, multicenter studies are warranted to further validate our findings. Conclusions In summary, this study systematically delineates the comprehensive clinical profile of AIGAs-positive patients with skeletal involvement. Bone involvement represents a common yet clinically subtle manifestation of disease dissemination in this syndrome, characterized by a marked systemic inflammatory response, abnormal immune parameters, a high prevalence of pathogens such as TM and NTM with frequent co-infections, and multi-site involvement predominantly affecting the axial skeleton. As skeletal lesions serve as indicators of disease dissemination and severity, clinicians should maintain a high index of suspicion for skeletal system involvement in AIGAs-positive patients, particularly those with disseminated infection, and promptly conduct systematic evaluations such as radionuclide bone scanning. Early recognition, aggressive antimicrobial therapy, and individualized immunomodulation are crucial for improving outcomes in this patient population. Declarations Author contributions Study conceptualization and design were led by ZYH and SQL. On-site study execution and data collection were carried out by XMH, HYP, JQQ, LMH, SYW, XNL, JHH and TTQ. Samples were collected and classified by XMH, HYP, JQQ, YN, and SYW. XMH and HYP curated the data; ZYH, SQL, XNL, QYC, XW and HYW oversaw the analysis and interpretation of results. Sample analysis, data interpretation, and the first draft of the manuscript were performed by XMH, HYP, and JQQ. All authors critically reviewed the manuscript and approved the final version for submission. Transparency declaration All authors report no potential conflicts of interest. Data availability The original contributions presented in the study are included in the article/supplementary materials. Further inquiries can be directed to the corresponding author. Acknowledgements Not appliable. 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Chinese Journal of Tuberculosis and Respiratory Diseases. 2020: https://rs.yiigle.com/cmaid/1256319 Tables Table 1 Baseline characteristics at skeletal involvement in 103 adult patients with AIGAs syndrome Characteristic n （ % ） Demographic Median age at disease onset, years (range) 55（18-78） Male gender 57(55.34) Underlying disease Hypertension 30(29.13) Hepatitis B virus carrier 11(10.68) Diabetes mellitus 10(9.71) Cardiovascular disease 6(5.83) Chronic lung disease 3(2.91) Malignancy 1(0.97) Top 4 Symptoms at First Visit Cough/Expectoration 69(66.99) Fever 54(52.43) Bone pain 22(21.36) Peripheral lymph node enlargement 20(19.42) Antibody titer at this visit 1:2500 89(86.41) 1:500 13(12.62) 1:100 1(0.97) Misdiagnosed as tuberculosis 22(21.36) Prior culture-proven tuberculosis 13(12.62) Table 2 Presentations and laboratory data at skeletal involvement in 103 adult patients with AIGAs syndrome Characteristic n (%) Clinical manifestation Peripheral lymph node enlargement 89(86.41) Cough/Expectoration 88(85.44) Fever 82(79.61) Wasting Syndrome 65(63.11) chills 62(60.19) anemic 45(43.69) Skin Rash/Subcutaneous Mass 44(42.72) Bone pain/arthralgia 39(37.86) Myalgia 15(14.56) Laboratory finding Leukocytosis (WBC >9.5 x10 9 /L) 95(92.23) Neutrophilia (Neu >6.3 x10 9 /L) 94(91.26) Normal lymphocyte (x10 9 /L) 72(69.90) Monocytosis (Mon >0.6 x10 9 /L) 76(73.79) Thrombocytosis (PLT >360 K/mL) 72(69.90) Decreased HB (Male <130/Female0.05 ng/mL) 103(100) Elevated ESR (>20 mm/h) 103(100) Elevated CRP (>10 mg/L) 98(95.15) Elevated D-dimer (>450 mg/L) 59(57.28) Elevated SF (>274.66 ng/ml) 89(86.41) Decreased ALB (>40 g/L) 99(96.12) Elevated GLB, g/L (17.4 g/L) 80(77.67) Elevated IgE (>100 g/L) 68(66.02) Elevated IgG4 (>2 g/L) 25(24.27) Elevated IgM (>2.8 g/L) 12(11.65) Elevated IgA (>4.2 g/L) 8(7.77) WBC: White blood cell count; Neu: Neutrophil; Mon: monocytes; PLT: platelet; HB: hemoglobin; PCT: procalcitonin; ESR: Erythrocyte sedimentation rate; CRP: C-reactive protein; SF: Serum Ferritin; ALB: Albumin; GLB: globulin; Ig: immunoglobulin. Additional Declarations No competing interests reported. Supplementary Files SupplementaryFigure1.jpg SupplementaryFigure2.jpg SupplementaryFigure3.jpg SupplementaryTable1.docx SupplementaryTable2.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 02 Feb, 2026 Editor assigned by journal 07 Jan, 2026 Submission checks completed at journal 07 Jan, 2026 First submitted to journal 07 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-8542097","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":584643912,"identity":"9e49aeba-6f9d-484c-b4af-0c933def597a","order_by":0,"name":"Xuemei Huang","email":"","orcid":"","institution":"First Affiliated Hospital of GuangXi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xuemei","middleName":"","lastName":"Huang","suffix":""},{"id":584643913,"identity":"66cbf39a-0247-4b7c-846c-337cbff16216","order_by":1,"name":"Haiyan Pang","email":"","orcid":"","institution":"First Affiliated Hospital of GuangXi 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09:13:17","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":17629,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8542097/v1/992d2a0eff78095a63e086ae.docx"},{"id":101940189,"identity":"56f2d950-c734-4304-bcef-cf89effbbd55","added_by":"auto","created_at":"2026-02-05 09:13:16","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":25131,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable2.docx","url":"https://assets-eu.researchsquare.com/files/rs-8542097/v1/2b97fe55b83d429a585e0189.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical Characteristics and Outcomes in Adults with Anti-IFN-γ Autoantibody-Associated Immunodeficiency and Skeletal Involvement: A 10-Year Retrospective Cohort Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAnti-interferon (IFN)-γ autoantibodies (AIGAs) syndrome is a rare form of adult-onset immunodeficiency (AOID) that has been increasingly recognized in recent years(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The core mechanism of the disease involves the production of neutralizing AIGAs that target and neutralize IFN-γ, thereby disrupting the IL-12/IFN-γ axis signaling pathway and impairing IFN-γ-dependent antimicrobial cell-mediated immune responses(\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Consequently, patients show heightened susceptibility to intracellular pathogens, particularly opportunistic infections like \u003cem\u003enon-tuberculous mycobacteria\u003c/em\u003e (NTM) and \u003cem\u003eTalaromyces marneffei\u003c/em\u003e(TM)(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), and typically present with refractory, recurrent, and disseminated multisystem infections (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAIGAs were first detected in 2004 in two patients with complex infections(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). The disease is endemic in Southeast Asia, with high prevalence reported in Guangxi, Guangdong, and Taiwan regions of China(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Multi-system involvement is common in AIGAs syndrome, including the lymph nodes, lungs, skin, and skeletal system (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). However, the frequency of involvement varies considerably across geographic regions. For example, in a Thai cohort (n\u0026thinsp;=\u0026thinsp;74), lymph node lesions were most common, followed by skin involvement; in a US. cohort (n\u0026thinsp;=\u0026thinsp;23), bone involvement was predominant, with lymph nodes being the next most frequent(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). In contrast, our recent study indicated that pulmonary involvement is most prominent in patients from Guangxi, China, followed by lymph node lesions(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). These differences may be associated with genetic background, environmental exposures, and other factors. It is particularly noteworthy that the reported frequency of bone involvement varies across cohorts. When the skeletal system is affected, severe complications such as bone destruction, fractures, and osteomyelitis may occur(\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), significantly impacting patients' quality of life.\u003c/p\u003e \u003cp\u003eWhile numerous studies have centered on the overall features of AIGAs syndrome (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), investigation into specific organ systems, such as the skeleton, is still insufficient. As a key target of disseminated infections, the clinical patterns, imaging features, and long-term prognosis of skeletal involvement have not yet been clearly defined. Skeletal involvement often manifests as bone pain, fractures, or imaging abnormalities. A deeper understanding of its clinical phenotypes, pathogen profiles, and disease progression is essential for improving diagnosis and treatment. This study employs a large-sample retrospective analysis to systematically summarize the demographic, immunological, clinical, therapeutic, and prognostic characteristics of AIGAs-positive patients with skeletal involvement, aiming to provide a basis for early identification and intervention.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cp\u003eStudy Population\u003c/p\u003e \u003cp\u003eA retrospective analysis was conducted on follow-up data from 103 HIV-negative adult patients with AIGAs and skeletal system involvement, who were identified at the First Affiliated Hospital of Guangxi Medical University between May 2015 and May 2025. The follow-up data included demographic information (gender, age, and occupation), medical history (comorbidities and past history), auxiliary examination results (routine laboratory tests, HIV antibody screening, lymphocyte subset analysis, immunological status, imaging studies, as well as pathological and microbiological detection), treatment regimens, and clinical outcomes, which were summarized and analyzed.\u003c/p\u003e \u003cp\u003e This study was approved by the Ethics Committee of the First Affiliated Hospital of Guangxi Medical University (IRB Protocol Number: 2022-KT-Guike-127). Written informed consent was obtained from all participants.\u003c/p\u003e \u003cp\u003eAIGAs Assay\u003c/p\u003e \u003cp\u003eAnti-interferon-γ autoantibody (AIGAs) titers were measured using enzyme-linked immunosorbent assay (ELISA). Recombinant human IFN-γ was coated onto microtiter plates, followed by incubation with patient serum and subsequent detection of antibody levels. Both the operational procedures and the positive threshold were consistent with previously established protocols(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Western blot was employed to evaluate the inhibitory effect of AIGAs on the IFN-γ/STAT1 signaling axis(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Briefly, THP-1 monocytes were first induced by PMA to adhere and differentiate into macrophages, which were then co-incubated with patient serum and IFN-γ. AIGAs in positive serum samples neutralized IFN-γ, thereby suppressing STAT1 phosphorylation, which was reflected by a noticeably weakened p-STAT1 band on the PVDF membrane. In contrast, normal or negative serum did not interfere with IFN-γ activity, allowing full activation of the STAT1 pathway and a marked increase in p-STAT1 expression.\u003c/p\u003e \u003cp\u003eFlow Cytometry: The entire assay was performed by physicians in the hospital's clinical laboratory following standardized operating procedures. The main steps included sample preparation, antibody labeling and incubation, machine detection, and data analysis. Pathogen Identification: Clinical specimens, including sputum, blood, bronchoalveolar lavage fluid (BALF), pus from skin lesions, bone marrow, and tissue biopsies, were subjected to pathogen identification by culture, histopathological examination, or next-generation sequencing (NGS) performed.\u003c/p\u003e \u003cp\u003eSkeletal system involvement is defined as the affection of bones during the disease process, encompassing structural damage (such as bone destruction), pain, functional limitations, and distinct abnormalities observed through medical imaging and pathological assessment. Disseminated infection is the presence of infectious foci in two or more non-adjacent organ systems.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eDuring the 10-year study period, 263 patients were diagnosed with AIGAs syndrome, including 217 with disseminated infection and 46 with localized infection. Among them, 103 patients (all with disseminated infection) presented with skeletal system involvement and were included in this study. The median age of onset was 55 (18\u0026ndash;78) years, with males accounting for 55.34%. Underlying diseases included hypertension (29.13%), hepatitis B virus carriage (10.67%), and diabetes (9.71%). The most common initial symptoms were cough/sputum production (66.99%), followed by fever (52.43%), bone pain (21.36%), and peripheral lymphadenopathy (19.42%). At the time of medical consultation, antibody titers of 1:2,500 and 1:500 were observed in 86.41% and 12.62% of patients, respectively. A total of 21.36% of patients had been misdiagnosed with tuberculosis, and 12.62% had a prior culture-confirmed history of tuberculosis (Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;2 summarized the clinical and laboratory characteristics of 103 adult patients with AIGAs syndrome and skeletal involvement. The most common features were peripheral lymphadenopathy (86.41%), cough or sputum (85.44%) and fever (79.61%). Other frequent findings were weight loss (63.11%), chills (60.19%), anemia (43.69%), rash or subcutaneous nodules (42.72%), bone or joint pain (37.86%) and myalgia (14.56%). All patients had elevated procalcitonin and erythrocyte sedimentation rate. Leukocytosis (92.23%), neutrophilia (91.26%) and monocytosis (73.79%) were common, as were increased levels of C-reactive protein (95.15%), serum ferritin (86.41%), globulin (72.82%), immunoglobulin (Ig) G (77.67%) and IgE (66.02%). Conversely, hemoglobin and albumin concentrations were reduced in 90.29% and 96.12% of patients, respectively. Lymphocyte counts remained within the normal range in 69.90% of subjects. Flow cytometry demonstrated normal distributions of total T cells (57.28%), CD4\u0026thinsp;+\u0026thinsp;T cells (60.19%), CD8\u0026thinsp;+\u0026thinsp;T cells (66.99%), NK cells (66.99%) and B cells (48.54%) in the majority of individuals (Supplementary Fig.\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eAs shown in Fig.\u0026nbsp;1A, pathogen identification was attempted in 103 patients using NGS (81.55%), culture confirmation (43.69%), or pathological examination (10.68%). For NGS, BALF was the predominant specimen (66.67%), followed by lymph-node (21.43%) and blood (14.29%) samples. Culture-based identification most frequently used BALF and blood (each 24.44%), followed by lymph-node samples (20.00%). Pathological examination was carried out mainly on lymph-node (54.55%), bone-tissue (18.18%), and soft-tissue (18.18%) specimens. Figure\u0026nbsp;1B depicts the distribution of pathogens. Among bacteria, NTM (55.34%) and \u003cem\u003eStreptococcus pneumoniae\u003c/em\u003e (16.50%) predominated; among fungi, TM (63.11%) and \u003cem\u003eCandida\u003c/em\u003e (15.53%) were most frequent; and among viruses, \u003cem\u003ecytomegalovirus\u003c/em\u003e (CMV, 44.66%) and \u003cem\u003eEpstein\u0026ndash;Barr virus\u003c/em\u003e (EBV, 34.95%) accounted for the majority of cases.\u003c/p\u003e \u003cp\u003eChest CT of all 103 patients showed pulmonary involvement. The dominant pattern was bilateral diffuse disease (87.38%), whereas unilateral multifocal opacities were seen in 13.59%; abnormalities involved every lung segment. The most frequent imaging features were mediastinal lymphadenopathy (84.47%), patchy opacities (77.67%), linear opacities (68.93%), nodules (59.22%), nodular opacities (47.57%) and pleural effusion (44.66%) (Supplementary Fig.\u0026nbsp;2).\u003c/p\u003e \u003cp\u003eAll 103 patients underwent bone emission computed tomography (ECT) scans upon admission. The involved sites primarily showed abnormal radiotracer concentration, commonly found in the thoracic spine (75.73%), lumbar spine (56.31%), ribs (49.51%), skull (47.57%), hip bone (46.60%), and cervical spine (45.63%) (Fig.\u0026nbsp;2). Bone ECT indicated bone destruction in 65 cases, which included lytic destruction (14 cases), compressive destruction (3 cases), and osteoblastic destruction (2 cases). Additionally, chest computed tomography (CT) scans suggested bone involvement in 66 cases (64.08%), and positron emission tomography - computed tomography (PET-CT) scans performed on another 14 patients also indicated bone involvement. (Supplementary Table)\u003c/p\u003e \u003cp\u003eAll 103 patients underwent whole-body bone emission computed tomography (ECT) at admission. Abnormal radiotracer accumulation was most frequently observed in the thoracic spine (75.73%), lumbar spine (56.31%), ribs (49.51%), skull (47.57%), hip bone (46.60%) and cervical spine (45.63%) (Fig.\u0026nbsp;2). Bone ECT revealed bone destruction in 65 cases: lytic in 14, compressive in 3 and osteoblastic in 2. In addition, chest CT suggested osseous involvement in 66 (64.08%) cases, and PET-CT performed in an additional 14 patients also demonstrated bone lesions (Supplementary Table\u0026nbsp;1)\u003c/p\u003e \u003cp\u003eThe annual enrolment over the 10-year study period is summarized in Supplementary Fig.\u0026nbsp;3. The median follow-up for the 103 patients was 28.40 months (range 0.27\u0026ndash;119.73). Thirteen patients died; none of the deaths were directly attributable to bone disease, and all were caused by recurrent severe infections. Of the 103 patients with disseminated infection, 100 were infected with TM and/or NTM. At baseline, 22 (21.34%) of those with bone involvement already had microbiologically all of whom also had bone lesions. In addition, 29 patients (28.16%) were sequentially diagnosed with TM and NTM infection after a median interval of 10 months (IQR 6\u0026ndash;14.5) (Fig.\u0026nbsp;3). All patients received guideline-based antimicrobial therapy, with regimens adjusted according to follow-up results, and underwent individualized immunomodulatory treatment (e.g., glucocorticoids and cyclophosphamide). Bone involvement was controlled and symptoms relieved in the majority. Twenty patients required surgery: 13 underwent debridement with internal fixation, lumbar vertebroplasty, or bone grafting under general or spinal anesthesia, and 7 had bone-marrow aspiration or biopsy for diagnostic purposes. Antimicrobial therapy was continued postoperatively, yet two patients still succumbed to severe infection (Supplementary Table\u0026nbsp;2).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study conducted a relatively large retrospective analysis of AIGAs-positive adult patients without HIV infection who had bone involvement, summarizing their clinical characteristics and long-term outcomes. The results indicated that patients with bone involvement exhibited higher levels of inflammatory responses and immune markers, with disseminated TM and NTM infections being more common. Additionally, 36.89% of these patients had TM and NTM co-infections. All patients with bone involvement also had pulmonary involvement, and the skeletal lesions primarily affected the axial bones (such as the thoracic and lumbar vertebrae). Bone ECT was helpful in identifying potential bone involvement. The findings of this study can assist clinicians in early identification and standardized management of bone involvement complications, reducing the need for surgical intervention and improving patients' quality of life.\u003c/p\u003e \u003cp\u003eSkeletal involvement is a significant comorbidity in patients with AIGAs-positive. Previous data indicated a skeletal involvement rate of 23.6% among AIGA-positive patients with TM infections in Guangxi, China(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). while diffuse NTM infections associated with osteolytic lesions have primarily been documented in case reports or small series(\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Our earlier study reported a skeletal involvement rate of 49.6% in patients with AIGAs syndrome(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Consistent with these findings, the current retrospective study revealed skeletal involvement in 39.16% (103/263) of all AIGAs-positive patients. Notably, among the subgroup with disseminated infection (n\u0026thinsp;=\u0026thinsp;217), the proportion increased to 47.47%. These results collectively demonstrate that skeletal involvement is highly prevalent in this patient population. However, its manifestation during the progression of AIGAs syndrome is often insidious. At the initial diagnosis of AIGAs positivity, patients mainly presented with respiratory symptoms (cough and sputum), while bone pain accounted for only 21.36%. Compared with previously reported AIGAs-positive patients(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), those with bone involvement in this study exhibited a more intense systemic inflammatory response. Nearly all patients (100%) showed elevated procalcitonin and erythrocyte sedimentation rates, and over 90% had increased leukocyte and neutrophil counts, suggesting that skeletal system involvement may exacerbate a systemic inflammatory cascade. Despite severe infections, flow cytometry indicated that 50%-70% of patients had roughly normal proportions of lymphocyte subsets (including CD4\u0026thinsp;+\u0026thinsp;and CD8\u0026thinsp;+\u0026thinsp;T cells, B cells, and NK cells), consistent with previous reports(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). This may imply that neutralizing AIGAs lead to a functional immunodeficiency rather than a numerical loss of cells. By blocking the IFN-γ signaling pathway, AIGAs paralyze immune cells such as macrophages, rendering them unable to effectively clear intracellular pathogens, without broadly disrupting lymphocyte homeostasis(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn terms of etiology, the findings of this study are consistent with previous reports(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e), indicating that the most common pathogens in patients with AIGAs syndrome are TM and NTM. The novelty of this study lies in revealing the high frequency of TM and NTM co-infections in such patients with bone involvement. Data show that the co-infection rate in patients with bone involvement was 21.34% at baseline and increased to 36.89% during follow-up, suggesting that the skeletal system is a significant target for TM/NTM infections. It is particularly noteworthy that 28.16% of patients were successively diagnosed with TM and NTM infections, with an average interval of 10 months. Our earlier case report also described an AIGAs-positive patient with skeletal involvement who, during follow-up, sequentially developed TM and NTM infections and displayed recurrent, highly variable clinical manifestations(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). For AIGAs-positive patients with disseminated TM or NTM infection (especially those with bone involvement), clinicians should maintain a high index of suspicion for the risk of TM and NTM co-infection. This phenomenon suggests that the initial infection may create a favorable microenvironment for subsequent infections or reflects an extremely high susceptibility to intracellular bacteria in the context of persistent immunodeficiency. Furthermore, the high frequencies of CMV (44.66%) and EBV (34.95%) infections further corroborate the impairment of cellular immune function in these patients. It is recommended that in cases of suboptimal treatment response or disease recurrence, repeated and comprehensive etiological assessments should be actively conducted using techniques such as molecular diagnostics to achieve early and accurate diagnosis, and to develop targeted combination therapy regimens, thereby improving patient outcomes.\u003c/p\u003e \u003cp\u003eAll 103 patients in this cohort had pulmonary involvement. Chest CT findings primarily showed diffuse lesions in both lungs (87.38%), accompanied by a high prevalence of mediastinal lymphadenopathy (84.47%) and pleural effusion (44.66%). Additionally, chest CT indicated bone destruction in 63.11% of the patients. The chest imaging findings in AIGAs-positive patients need to be differentiated from pulmonary tumors, especially when CT suggests lung occupying space(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Bone ECT scans revealed multifocal abnormal radiotracer uptake in all patients, primarily involving the axial skeleton (thoracic spine 75.73%, lumbar spine 56.31%), followed by flat bones (skull 47.57%). Among them, 65 patients exhibited significant bony destruction. Additionally, chest CT also indicated bony destruction in the thoracic vertebrae and ribs. The sites of bone involvement on PET-CT corresponded with the findings on bone ECT. These imaging characteristics are consistent with previous reports(\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), suggesting that the pathogens tend to colonize highly vascularized bone regions, leading to destructive lesions. Taken together, the findings suggest that the lung likely serves as the primary portal of entry and initial site of infection, with subsequent hematogenous spread to multiple systems, including the skeletal system. The fact that chest CT indicated bone destruction in 63.11% of the 103 AIGAs-positive patients with bone involvement, coupled with the generally inconspicuous nature of patient-reported skeletal symptoms, underscores the insidious presentation of bone involvement in AIGAs-positive patients. Therefore, it is recommended to perform a detailed physical examination of the skeletal system in AIGAs-positive patients and conduct early bone ECT evaluations in high-risk individuals to achieve early identification and diagnosis of bone involvement complications.\u003c/p\u003e \u003cp\u003eAll patients in this study received personalized antibiotic therapy. Due to the absence of unified clinical guidelines for AIGAs syndrome, treatment strategies were determined based on identified pathogens. AIGAs-positive patients with TM infection received antifungal therapy following guidelines for HIV-positive individuals with TM(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e), supplemented by individualized immunosuppression to reduce the risk of relapse after discontinuation(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Those with NTM infection received anti-NTM therapy per relevant guidelines(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e), while patients with co-infection were managed with combination therapy targeting pathogens. Due to factors such as poor patient compliance, COVID-19 control measures, or health insurance policies, many patients did not undergo regular bone ECT monitoring after skeletal involvement. Most only received a repeat bone ECT during rehospitalization for acute episodes, with new lesions often detected. During follow-up, 19.4% of patients required surgical intervention (e.g., debridement, spinal fixation, or bone biopsy) for diagnostic or therapeutic purposes, highlighting the challenges posed by skeletal lesions. Overall, aggressive anti-infective therapy combined with immunomodulation controlled skeletal symptoms in most patients. During follow-up, thirteen deaths were attributed to severe systemic infections, reflecting the difficulty in controlling disseminated infections in an immunocompromised state. Although skeletal lesions themselves were not direct causes of death, their presence indicated a greater disease burden and more complex treatment challenges.\u003c/p\u003e \u003cp\u003eThis was a single-center retrospective study, which may be subject to selection bias. The incomplete inclusion of certain laboratory tests (such as levels of specific bone immune cytokines and metabolic markers) and detailed treatment regimen data may limit deeper exploration of efficacy assessment and pathological mechanisms. Future prospective, multicenter studies are warranted to further validate our findings.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn summary, this study systematically delineates the comprehensive clinical profile of AIGAs-positive patients with skeletal involvement. Bone involvement represents a common yet clinically subtle manifestation of disease dissemination in this syndrome, characterized by a marked systemic inflammatory response, abnormal immune parameters, a high prevalence of pathogens such as TM and NTM with frequent co-infections, and multi-site involvement predominantly affecting the axial skeleton. As skeletal lesions serve as indicators of disease dissemination and severity, clinicians should maintain a high index of suspicion for skeletal system involvement in AIGAs-positive patients, particularly those with disseminated infection, and promptly conduct systematic evaluations such as radionuclide bone scanning. Early recognition, aggressive antimicrobial therapy, and individualized immunomodulation are crucial for improving outcomes in this patient population.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy conceptualization and design were led by ZYH and SQL. On-site study execution and data collection were carried out by XMH, HYP, JQQ, LMH, SYW, XNL, JHH and TTQ. Samples were collected and classified by XMH, HYP, JQQ, YN, and SYW. XMH and HYP curated the data; ZYH, SQL, XNL, QYC, XW and HYW oversaw the analysis and interpretation of results. Sample analysis, data interpretation, and the first draft of the manuscript were performed by XMH, HYP, and JQQ. All authors critically reviewed the manuscript and approved the final version for submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTransparency declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors report no potential conflicts of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the article/supplementary materials. Further inquiries can be directed to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot appliable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe work was supported by Guangxi Science and Technology Program (2023AB22055), Central Leading Local Science and Technology Development Fund Project (2023ZYZX1021) and National Key R\u0026amp;D Program of China (2024YFC2309600).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBrowne SK, Burbelo PD, Chetchotisakd P, Suputtamongkol Y, Kiertiburanakul S, Shaw PA, et al. Adult-onset immunodeficiency in Thailand and Taiwan. 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Chinese Journal of Tuberculosis and Respiratory Diseases. 2020:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://rs.yiigle.com/cmaid/1256319\u003c/span\u003e\u003cspan address=\"https://rs.yiigle.com/cmaid/1256319\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"567\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"bottom\" style=\"width: 98.7654%;\"\u003e\n \u003cp\u003eTable 1 Baseline characteristics\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eat skeletal involvement in 103 adult patients with AIGAs syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47.0899%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003cstrong\u003e（\u003c/strong\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003cstrong\u003e）\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47.0899%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDemographic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47.0899%;\"\u003e\n \u003cp\u003eMedian age at disease onset, years (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e55（18-78）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47.0899%;\"\u003e\n \u003cp\u003eMale gender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e57(55.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47.0899%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnderlying disease\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47.0899%;\"\u003e\n \u003cp\u003eHypertension\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e30(29.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47.0899%;\"\u003e\n \u003cp\u003eHepatitis B virus carrier\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e11(10.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47.0899%;\"\u003e\n \u003cp\u003eDiabetes mellitus\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e10(9.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47.0899%;\"\u003e\n \u003cp\u003eCardiovascular disease\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e6(5.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47.0899%;\"\u003e\n \u003cp\u003eChronic lung disease\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e3(2.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47.0899%;\"\u003e\n \u003cp\u003eMalignancy\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e1(0.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47.0899%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTop 4 Symptoms at First Visit\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47.0899%;\"\u003e\n \u003cp\u003eCough/Expectoration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e69(66.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47.0899%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e54(52.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47.0899%;\"\u003e\n \u003cp\u003eBone pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e22(21.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47.0899%;\"\u003e\n \u003cp\u003ePeripheral lymph node enlargement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e20(19.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47.0899%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAntibody titer at this visit\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47.0899%;\"\u003e\n \u003cp\u003e1:2500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e89(86.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47.0899%;\"\u003e\n \u003cp\u003e1:500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e13(12.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 1.23457%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 47.0899%;\"\u003e\n \u003cp\u003e1:100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e1(0.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 48.3245%;\"\u003e\n \u003cp\u003eMisdiagnosed as tuberculosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e22(21.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\" style=\"width: 48.3245%;\"\u003e\n \u003cp\u003ePrior culture-proven tuberculosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 18.3422%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 33.3333%;\"\u003e\n \u003cp\u003e13(12.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"600\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"bottom\" style=\"width: 600px;\"\u003e\n \u003cp\u003eTable 2 Presentations and laboratory data at skeletal involvement in 103 adult patients with AIGAs syndrome\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eCharacteristic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eClinical manifestation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003ePeripheral lymph node enlargement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e89(86.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eCough/Expectoration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e88(85.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e82(79.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eWasting Syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e65(63.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003echills\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e62(60.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eanemic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e45(43.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eSkin Rash/Subcutaneous Mass\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e44(42.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eBone pain/arthralgia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e39(37.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eMyalgia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e15(14.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eLaboratory finding\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eLeukocytosis (WBC \u0026gt;9.5\u0026nbsp;x10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e95(92.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eNeutrophilia (Neu \u0026gt;6.3 x10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e94(91.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eNormal lymphocyte (x10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e72(69.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eMonocytosis (Mon \u0026gt;0.6 x10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e76(73.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eThrombocytosis (PLT \u0026gt;360 K/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e72(69.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eDecreased HB (Male \u0026lt;130/Female\u0026lt;115 g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e93(90.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eElevated PCT (\u0026gt;0.05 ng/mL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e103(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eElevated ESR (\u0026gt;20\u0026nbsp;mm/h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e103(100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eElevated CRP (\u0026gt;10\u0026nbsp;mg/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e98(95.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eElevated D-dimer (\u0026gt;450 mg/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e59(57.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eElevated SF (\u0026gt;274.66\u0026nbsp;ng/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e89(86.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eDecreased\u0026nbsp;ALB (\u0026gt;40 g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e99(96.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 309px;\"\u003e\n \u003cp\u003eElevated GLB, g/L (\u0026lt;40 g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e75(72.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 309px;\"\u003e\n \u003cp\u003eElevated\u0026nbsp;IgG (\u0026gt;17.4 g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e80(77.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 309px;\"\u003e\n \u003cp\u003eElevated\u0026nbsp;IgE (\u0026gt;100 g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e68(66.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 309px;\"\u003e\n \u003cp\u003eElevated\u0026nbsp;IgG4 (\u0026gt;2 g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e25(24.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 309px;\"\u003e\n \u003cp\u003eElevated\u0026nbsp;IgM (\u0026gt;2.8 g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e12(11.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 309px;\"\u003e\n \u003cp\u003eElevated\u0026nbsp;IgA (\u0026gt;4.2 g/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 145px;\"\u003e\n \u003cp\u003e8(7.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eWBC: White blood cell count; Neu: Neutrophil; Mon: monocytes; PLT: platelet; HB: hemoglobin; PCT: procalcitonin; ESR: Erythrocyte sedimentation rate; CRP: C-reactive protein; SF: Serum Ferritin; ALB: Albumin; GLB: globulin; Ig: immunoglobulin.\u003c/p\u003e\n"}],"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":"journal-of-clinical-immunology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"joci","sideBox":"Learn more about [Journal of Clinical Immunology](https://www.springer.com/journal/10875)","snPcode":"10875","submissionUrl":"https://submission.nature.com/new-submission/10875/3","title":"Journal of Clinical Immunology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"AIGAs, Skeletal Involvement, Clinical Characteristics, Infection","lastPublishedDoi":"10.21203/rs.3.rs-8542097/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8542097/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eAnti-interferon-γ autoantibodies (AIGAs)-associated immunodeficiency is a rare, adult-onset disorder characterized by multi-system infections with geographic variability. However, the clinical features and prognosis related to skeletal involvement remain unclear.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA 10-year retrospective study of AIGAs-positive skeletal involvement with HIV-negative patients from Guangxi, China.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 103 patients (median onset age: 55 years; median follow-up: 28.40 months), hypertension (29.13%) and HBV carriage (10.68%) were prevalent underlying diseases. Cough/sputum (66.99%) was the predominant initial symptom, while bone pain (21.36%) was less common. Among those with bone involvement, peripheral lymphadenopathy (86.41%) and cough/sputum (85.44%) were highly prevalent, unlike bone/joint pain (37.86%) and myalgia (14.56%). Most patients exhibited elevated levels of white blood cells, neutrophils, C-reactive protein, procalcitonin, erythrocyte sedimentation rate, globulin, immunoglobulin (Ig) G, and IgE. The predominant types of infection were disseminated \u003cem\u003eTalaromyces marneffei\u003c/em\u003e (TM) (63.11%) and \u003cem\u003enon-tuberculous mycobacteria\u003c/em\u003e (NTM) (55.34%), with an increasing trend of co-infection observed. Chest CT revealed lung involvement in all patients, with 63.11% exhibiting bone lesions. Bone emission computed tomography (ECT) showed abnormal uptake in the thoracic (75.73%) and lumbar vertebrae (56.31%); 63.11% of patients had bone destruction, of which 13.59% were osteolytic. All patients received full-course anti-infective therapy, some received individualized immunotherapy, and 19.41% required surgical intervention.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eSkeletal involvement in AIGAs syndrome is common yet occult, presenting as disseminated infection, with TM and NTM co-infection complicating the course. The axial skeleton is frequently involved, with early detection by skeletal ECT enabling comprehensive treatment and precise management to improve prognosis.\u003c/p\u003e","manuscriptTitle":"Clinical Characteristics and Outcomes in Adults with Anti-IFN-γ Autoantibody-Associated Immunodeficiency and Skeletal Involvement: A 10-Year Retrospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-05 09:10:55","doi":"10.21203/rs.3.rs-8542097/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-02-02T23:17:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-07T23:28:32+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-07T23:27:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Clinical Immunology","date":"2026-01-07T13:14:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-clinical-immunology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"joci","sideBox":"Learn more about [Journal of Clinical Immunology](https://www.springer.com/journal/10875)","snPcode":"10875","submissionUrl":"https://submission.nature.com/new-submission/10875/3","title":"Journal of Clinical Immunology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"08a698ba-d6b1-4a86-84e0-a3b63e6b16e7","owner":[],"postedDate":"February 5th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-05T09:10:55+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-05 09:10:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8542097","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8542097","identity":"rs-8542097","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}