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PURPOSE: Anti-granulocyte-macrophage colony-stimulating factor autoantibodies (anti-GM-CSF Abs) are implicated in the pathogenesis of Cryptococcus gattii (C. gattii) infection and pulmonary alveolar proteinosis (PAP). Their presence has also been noted in nocardiosis cases, particularly those with disseminated disease. This study delineates a case series characterizing clinical features and specificity of anti-GM-CSF Abs in nocardiosis patients. METHODS: In this study, eight patients were recruited to determine the presence or absence of anti-GM-CSF Abs. In addition to the detailed description of the clinical course, we thoroughly investigated the autoantibodies regarding the characteristics, isotypes, subclasses, titers, and neutralizing capacities by utilizing the plasma samples from patients. RESULTS: Of eight patients, five tested positive for anti-GM-CSF Abs, all with central nervous system (CNS) involvement; patients negative for these antibodies did not develop CNS nocardiosis. Distinct from previously documented cases, none of our patients with anti-GM-CSF Abs exhibited PAP symptoms. The titer and neutralizing activity of anti-GM-CSF Abs in our cohort did not significantly deviate from those found in C. gattii cryptococcosis and PAP patients. Uniquely, one individual (Patient 3) showed a minimal titer and neutralizing action of anti-GM-CSF Abs, with no relation to disease severity. Moreover, IgM autoantibodies were notably present in all CNS nocardiosis cases investigated. CONCLUSION: The presence of anti-GM-CSF Abs suggests an intrinsic immunodeficiency predisposing individuals toward CNS nocardiosis. The presence of anti-GM-CSF Abs helps to elucidate vulnerability to CNS nocardiosis, even with low titer of autoantibodies. Consequently, systematic screening for anti-GM-CSF Abs should be considered a crucial diagnostic step for nocardiosis patients.
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Autoanticuerpos , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Nocardiosis , Humanos , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Nocardiosis/inmunología , Nocardiosis/diagnóstico , Femenino , Masculino , Persona de Mediana Edad , Anciano , Adulto , Proteinosis Alveolar Pulmonar/inmunología , Proteinosis Alveolar Pulmonar/diagnóstico , Cryptococcus gattii/inmunologíaRESUMEN
Background: Nocardiosis, a bacterial opportunistic infection caused by Nocardia spp, has recently been reported in patients with anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies, but insufficient data are available about disease presentation, outcomes, and occurrence of autoimmune pulmonary alveolar proteinosis (aPAP) in this population. Methods: We performed a prospective, multicenter, nationwide study in France and included patients with a Nocardia infection who had anti-GM-CSF autoantibodies. We describe their clinical, microbiological, and radiological characteristics, and their outcome at 1 year of follow-up. Results: Twenty patients (18 [90%] male) were included, with a median age of 69 (interquartile range, 44-75) years. The organs most frequently involved were the brain (14/20 [70%]) and the lung (12/20 [60%]). Half of the infections were disseminated (10/20 [50%]). Nocardia identification was predominantly made in abscess fluid (17/20 [85%]), among which 10 (59%) were brain abscesses. The 1-year all-cause mortality was 5% (1/20), and only 1 case of aPAP (1/20 [5%]) occurred during the follow-up period. Conclusions: Nocardiosis with anti-GM-CSF autoantibodies is associated with a low mortality rate despite a high incidence of brain involvement. Although the occurrence of aPAP was infrequent during the 1-year follow-up period, long-term clinical data are needed to fully understand the potential relationship between nocardiosis, anti-GM-CSF autoantibodies, and aPAP.
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BACKGROUND: Pulmonary alveolar proteinosis (PAP) is characterized by an abnormal accumulation of surfactants in the alveoli. Most cases are classified as autoimmune PAP (APAP) because they are associated with autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF). However, GM-CSF autoantibody levels are unlikely to correlate with the disease severity or prognosis of APAP. METHODS: We collected clinical records and measured 38 serum cytokine concentrations for consecutive patients with APAP. After exclusion of 21 cytokines because of undetectable levels, 17 cytokine levels were compared between low and high disease severity scores (DSSs). We also compared whole lung lavage (WLL)-free survival with cut-off values defined by receiver operating characteristic (ROC) curves of cytokine levels and WLL administration at 11 months. RESULTS: Nineteen patients with APAP were enrolled in the study. Five were classified as DSS 1 or 2, while the others were classified as DSS 4 or 5. Comparison between DSS 1-2 and 4-5 revealed that the concentrations of IP-10 and GRO increased in the latter groups (p < 0.05). Fifteen patients underwent WLL. Comparison between those who underwent WLL within 11 months and the others showed that IP-10 and TNF-α were tended to be elevated in the former group (p = 0.082 and 0.057, respectively). The cut-off values of IP-10, 308.8 pg/mL and TNF-α, 19.1 pg/mL, defined by the ROC curves, significantly separated WLL-free survivals with log-rank analyses (p = 0.005). CONCLUSIONS: The concentrations of IP-10 and GRO may reflect the DSSs of APAP. A combination of IP-10 and TNF-α levels could be a biomarker to predict WLL-free survival.
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Enfermedades Autoinmunes , Citocinas , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Proteinosis Alveolar Pulmonar , Índice de Severidad de la Enfermedad , Humanos , Proteinosis Alveolar Pulmonar/inmunología , Proteinosis Alveolar Pulmonar/diagnóstico , Proteinosis Alveolar Pulmonar/sangre , Proteinosis Alveolar Pulmonar/terapia , Pronóstico , Citocinas/sangre , Masculino , Femenino , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/diagnóstico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/sangre , Persona de Mediana Edad , Adulto , Autoanticuerpos/sangre , Quimiocina CXCL10/sangre , Anciano , Factor de Necrosis Tumoral alfa/sangre , Biomarcadores/sangre , Lavado Broncoalveolar , Adulto JovenRESUMEN
Pulmonary alveolar proteinosis (PAP) is a rare disease which involves the accumulation of insoluble lipoproteinaceous material in the alveoli leading to impaired gas exchange and even respiratory failure. Autoimmune PAP is the most common type and is characterized by the presence of anti-granulocyte-monocyte colony stimulating factor (anti GM-CSF) antibody. Whole lung lavage has been traditionally used as first-line management of PAP but there is a lack of clarity especially in the treatment of relapsing cases of PAP. Rituximab is an anti Cluster of Differentiate 20 (CD 20) monoclonal antibody that has been tried as salvage therapy for relapsing cases of PAP. We present a case of 35 years old female patient who was diagnosed as a case of relapsing PAP who was managed initially with neoadjuvant rituximab. This is a retrospective observational report showing novel use of neoadjuvant rituximab in a difficult case of relapsing PAP.
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Although pulmonary alveolar proteinosis (PAP) showed various shadows, its shadows are usually distributed predominantly in the central lung area. We report a case of autoimmune PAP with localized subpleural ground-glass shadows in the bilateral upper lobes, which was diagnosed based on transbronchial lung biopsy (TBLB) specimen findings and anti-granulocyte macrophage colony PAP stimulating factor antibody positivity. PAP should be listed as a differential diagnosis for subpleural shadows. If subpleural shadows are observed, TBLB should be performed aggressively, and anti-granulocyte macrophage colony-stimulating factor (anti-GM-CSF) antibodies should be submitted.
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Infections that are unusually severe or caused by opportunistic pathogens are a hallmark of primary immunodeficiency (PID). Anti-cytokine autoantibodies (ACA) are an emerging cause of acquired immunodeficiency mimicking PID. Nocardia spp. are Gram-positive bacteria generally inducing disseminated infections in immunocompromised patients, but seldom also occurring in apparently immunocompetent hosts. Anti-GM-CSF autoantibodies are associated with autoimmune pulmonary alveolar proteinosis (PAP). In those patients, an increased incidence of disseminated nocardiosis and cryptococcosis has been observed. It is unclear whether the PAP or the autoantibodies predispose to the infection. We report an apparently immunocompetent woman presenting with disseminated nocardiosis without any evidence of PAP. Clinical data and radiological images were retrospectively collected. Lymphocyte populations were analyzed by flow cytometry. Anti-GM-CSF autoantibodies were measured by ELISA. A 55-year-old otherwise healthy woman presented with cerebral and pulmonary abscesses. Personal and familial history of infections or autoimmunity were negative. After extensive examinations, a final diagnosis of disseminated nocardiosis was made. Immunologic investigations including neutrophilic function and IFN-γ/IL-12 circuitry failed to identify a PID. Whole-exome sequencing did not find pathogenic variants associated with immunodeficiency. Serum anti-GM-CSF autoantibodies were positive. There were no clinical or instrumental signs of PAP. Trimethoprim-sulfamethoxazole and imipenem were administered, with progressive improvement and recovery of the infectious complication. We identified anti-GM-CSF autoantibodies as the cause of disseminated nocardiosis in a previously healthy and apparently immunocompetent adult. This case emphasizes the importance of including ACA in the differential diagnosis of PID, especially in previously healthy adults. Importantly, anti-GM-CSF autoantibodies can present with disseminated nocardiosis without PAP.
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Autoanticuerpos , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Nocardiosis , Nocardia , Humanos , Nocardiosis/diagnóstico , Nocardiosis/inmunología , Nocardiosis/microbiología , Nocardiosis/tratamiento farmacológico , Femenino , Persona de Mediana Edad , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Nocardia/inmunologíaRESUMEN
OBJECTIVES: To explore the seroprevalence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies in non-HIV cryptococcal meningitis (CM) and assess its predictive value for survival. METHODS: This is a retrospective study of 12 years of non-HIV CM. We detected serum anti-GM-CSF autoantibodies, and evaluated the clinical features and outcomes, together with the exploration of prognostic factors for 2-week and 1-year survival. RESULTS: A total of 584 non-HIV CM cases were included. 301 of 584 patients (51.5%) were phenotypically healthy. 264 Cryptococcus isolates were obtained from cerebrospinal fluid (CSF) culture, of which 251 were identified as C. neoformans species complex and 13 as C. gattii species complex. Thirty-seven of 455 patients (8.1%) tested positive for serum anti-GM-CSF autoantibodies. Patients with anti-GM-CSF autoantibodies were more susceptible to C. gattii species complex infection (66.7% vs. 6.3%; p < 0.001) and more likely to develop pulmonary mass lesions with a diameter >3 centimetres (42.9% vs. 6.5%; p 0.001). Of 584 patients 16 (2.7%) died within 2 weeks, 77 of 563 patients (13.7%) died at 1 year, and 93 of 486 patients (19.1%) lived with disabilities at 1 year. Univariant Cox regression analysis found that anti-GM-CSF autoantibodies were associated with lower 1-year survival (HR, 2.66; 95% CI, 1.34-5.27; p 0.005). Multivariable Cox proportional hazards modelling revealed that CSF cryptococcal antigen titres ≥1:1280 were associated with both, reduced 2-week and 1-year survival rates (HR, 5.44; 95% CI, 1.23-24.10; p 0.026 and HR, 5.09; 95% CI, 1.95-13.26; p 0.001). DISCUSSION: Presence of serum anti-GM-CSF autoantibodies is predictive of poor outcomes, regardless of host immune status and the causative Cryptococcus species complex.
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Autoanticuerpos , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Meningitis Criptocócica , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Autoanticuerpos/sangre , Autoanticuerpos/líquido cefalorraquídeo , Cryptococcus gattii/inmunología , Cryptococcus neoformans/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Meningitis Criptocócica/mortalidad , Meningitis Criptocócica/inmunología , Meningitis Criptocócica/diagnóstico , Pronóstico , Estudios Retrospectivos , Estudios SeroepidemiológicosRESUMEN
Anticytokine autoantibodies (ACAAs) can cause adult onset immunodeficiencies which mimic primary immunodeficiencies and can present as refractory and severe fungal infections. This paper provides an overview of the role of innate immunity, including key cytokines, in fungal infections and then describes four clinical scenarios where ACAAs are associated with severe presentations of a fungal infection: (1) Talaromyces marneffei infection and anti-interferon-γ, (2) histoplasmosis and anti-interferon-γ, (3) Cryptococcus gattii infection and anti-GM-CSF, and (4) mucocutaneous candidiasis and anti-IL-17A/F (IL-22). Testing for ACAAs and potential therapeutic options are discussed.
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Introduction: Pulmonary alveolar proteinosis (PAP) is a disease characterized by the accumulation of lipoprotein-aceous material in the alveoli as a consequence of deficient processing of pulmonary surfactant. It is classified into primary, secondary, and congenital forms. Primary PAP (autoimmune origin) is characterized by the presence of antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), while secondary PAP is due to multiple causes such as exposure to certain environmental substances. We present a case of a patient with probable mixed PAP, primary and secondary, due to exposure at the patient's workplace. Case presentation: A 35-year-old male patient attends the outpatient clinic of pulmonology due to symptoms of exertional dyspnea for one year. Pulmonary function tests are performed, and the chest X-ray reveals diffuse bilateral lung involvement with a ground-glass pattern. Incision and excision lung biopsy show findings compatible with predominant PAP in the left lower lobe (LLL). Additionally, a positive anti-GM-CSF antibody result is obtained. The patient is treated with bronchoalveolar lavage (BAL) and nebulized sargramostim. The patient shows satisfactory progress. Discussion: The clinical, analytical, radiological, and histological manifestations were compatible with the diagnosis of autoimmune PAP, and there was suspicion of secondary PAP due to exposure to rock wool. The role of the laboratory, in this case, was essential for the diagnostic confirmation of PAP by performing the determination of anti-GM-CSF antibodies.
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Herein, we report the case of a 73-year-old woman with an occupational history of plaster grinding who developed autoimmune pulmonary alveolar proteinosis (PAP) during the treatment of fibrotic hypersensitivity pneumonitis with steroids and immunosuppressive drugs. Based on the changes in computed tomography imaging findings, poor response to steroid therapy, and markedly elevated KL-6 levels, PAP was suspected and diagnosed by bronchoscopy. Repeated segmental bronchoalveolar lavage under high-flow nasal cannula oxygen therapy resulted in slight improvement. Steroids and immunosuppressive treatments for other interstitial lung diseases may cause PAP or exacerbate latent PAP.
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Anti-cytokine autoantibodies (ACAA) have been reported to be an important cause of secondary immunodeficiencies. High titers of neutralizing autoantibodies may cause susceptibility to different life-threatening infectious diseases. For example, neutralizing autoantibodies against IFNg have been reported to be correlated with susceptibility to mycobacterial infections and intracellular fungal pathogens. Autoantibodies against IL-6 were detected in patients with subcutaneous abscesses and recurrent staphylococcal cellulitis; on the other hand, patients with cryptococcosis, nocardiosis, and pulmonary alveolar proteinosis were positive for autoantibodies to GM-CSF. A relationship has also been established between autoantibodies against IL-17 and IL-22 and chronic mucosal Candida infections, which have been identified in patients with APECED or thymoma. Autoantibodies against type-I IFN have been recently reported during the onset of acute COVID-19. These ACAAs resemble genetic defects in cytokines or their signaling pathways. Therefore, they may be considered to be primary immunodeficiencies phenocopies. Consequently, the detection of ACAA could be important in the diagnosis of patients, particularly in the case of late-onset diseases, in order to decide appropriate treatments. This review presents an overview of current understanding of ACAA-associated secondary immunodeficiencies.
Los autoanticuerpos anticitocinas (ACAA) han sido reportados como causa importante de inmunodeficiencias secundarias. Altos títulos de autoanticuerpos neutralizantes pueden causar susceptibilidad a diferentes enfermedades infecciosas potencialmente mortales. Por ejemplo, se ha informado que autoanticuerpos neutralizantes contra IFNg se correlacionan con susceptibilidad a infecciones micobacterianas y patógenos fúngicos intracelulares. Autoanticuerpos contra IL-6 se detectaron en pacientes con abscesos subcutáneos y celulitis estafilocócica recurrente; asimismo, pacientes con criptococosis, nocardiosis y proteinosis alveolar pulmonar fueron positivos a autoanticuerpos contra GM-CSF. También se ha establecido una relación entre los autoanticuerpos contra IL-17 e IL-22 y las infecciones crónicas por Candida en mucosas, que se han identificado en pacientes con poliendocrinopatía autoinmune tipo 1 o timoma. Recientemente se han reportado autoanticuerpos contra interferón tipo I durante el inicio de COVID-19 aguda. Estos ACAA se asemejan a defectos genéticos en citocinas o en sus rutas de señalización. Por ello, pueden considerarse fenocopias de inmunodeficiencias primarias. De esta forma, la detección de ACAA podría ser importante en el diagnóstico, particularmente en pacientes con enfermedades de aparición tardía, para decidir los tratamientos apropiados. Esta revisión presenta una descripción general de la comprensión actual de las inmunodeficiencias secundarias asociadas a ACAA.
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COVID-19 , Criptococosis , Síndromes de Inmunodeficiencia , Humanos , Citocinas , AutoanticuerposRESUMEN
Resumen Los autoanticuerpos anticitocinas (ACAA) han sido reportados como causa importante de inmunodeficiencias secundarias. Altos títulos de autoanticuerpos neutralizantes pueden causar susceptibilidad a diferentes enfermedades infecciosas potencialmente mortales. Por ejemplo, se ha informado que autoanticuerpos neutralizantes contra IFNγ se correlacionan con susceptibilidad a infecciones micobacterianas y patógenos fúngicos intracelulares. Autoanticuerpos contra IL-6 se detectaron en pacientes con abscesos subcutáneos y celulitis estafilocócica recurrente; asimismo, pacientes con criptococosis, nocardiosis y proteinosis alveolar pulmonar fueron positivos a autoanticuerpos contra GM-CSF. También se ha establecido una relación entre los autoanticuerpos contra IL-17 e IL-22 y las infecciones crónicas por Candida en mucosas, que se han identificado en pacientes con poliendocrinopatía autoinmune tipo 1 o timoma. Recientemente se han reportado autoanticuerpos contra interferón tipo I durante el inicio de COVID-19 aguda. Estos ACAA se asemejan a defectos genéticos en citocinas o en sus rutas de señalización. Por ello, pueden considerarse fenocopias de inmunodeficiencias primarias. De esta forma, la detección de ACAA podría ser importante en el diagnóstico, particularmente en pacientes con enfermedades de aparición tardía, para decidir los tratamientos apropiados. Esta revisión presenta una descripción general de la comprensión actual de las inmunodeficiencias secundarias asociadas a ACAA.
Abstract Anti-cytokine autoantibodies (ACAA) have been reported to be an important cause of secondary immunodeficiencies. High titers of neutralizing autoantibodies may cause susceptibility to different life-threatening infectious diseases. For example, neutralizing autoantibodies against IFNγ have been reported to be correlated with susceptibility to mycobacterial infections and intracellular fungal pathogens. Autoantibodies against IL-6 were detected in patients with subcutaneous abscesses and recurrent staphylococcal cellulitis; on the other hand, patients with cryptococcosis, nocardiosis, and pulmonary alveolar proteinosis were positive for autoantibodies to GM-CSF. A relationship has also been established between autoantibodies against IL-17 and IL-22 and chronic mucosal Candida infections, which have been identified in patients with APECED or thymoma. Autoantibodies against type-I IFN have been recently reported during the onset of acute COVID-19. These ACAAs resemble genetic defects in cytokines or their signaling pathways. Therefore, they may be considered to be primary immunodeficiencies phenocopies. Consequently, the detection of ACAA could be important in the diagnosis of patients, particularly in the case of late-onset diseases, in order to decide appropriate treatments. This review presents an overview of current understanding of ACAA-associated secondary immunodeficiencies.
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Anticytokine autoantibodies (ACAAs) are a fascinating group of antibodies that have gained more and more attention in the field of autoimmunity and secondary immunodeficiencies over the years. Some of these antibodies are characterized by their ability to target and neutralize specific cytokines. ACAAs can play a role in the susceptibility to several infectious diseases, and their infectious manifestations depending on which specific immunological pathway is affected. In this review, we will give an outline per infection in which ACAAs might play a role and whether additional immunomodulatory treatment next to antimicrobial treatment can be considered. Finally, we describe the areas for future research on ACAAs.
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Autoanticuerpos , Enfermedades Transmisibles , Humanos , Autoinmunidad , Citocinas , InmunomodulaciónRESUMEN
PURPOSE: Anti-granulocyte-macrophage colony-stimulating factor autoantibodies (anti-GM-CSF Abs) are a predisposing factor for pulmonary alveolar proteinosis (PAP) and Cryptococcus gattii cryptococcosis. This study aimed to investigate clinical manifestations in anti-GM-CSF Ab-positive patients with C. gattii cryptococcosis and analyze the properties of anti-GM-CSF Abs derived from these patients and patients with PAP. METHODS: Thirty-nine patients diagnosed with cryptococcosis (caused by C. neoformans or C. gattii) and 6 with PAP were enrolled in the present study. Clinical information was obtained from medical records. Blood samples were collected for analysis of autoantibody properties. We also explored the National Health Insurance Research Database (NHIRD) of Taiwan to investigate the epidemiology of cryptococcosis and PAP. RESULTS: High titers of neutralizing anti-GM-CSF Abs were identified in 15 patients with cryptococcosis (15/39, 38.5%). Most anti-GM-CSF Ab-positive cryptococcosis cases had central nervous system (CNS) involvement (14/15, 93.3%). Eleven out of 14 (78.6%) anti-GM-CSF Ab-positive CNS cryptococcosis patients were confirmed to be infected with C. gattii, and PAP did not occur synchronously or metachronously in a single patient from our cohort. Exploration of an association between HLA and anti-GM-CSF Ab positivity or differential properties of autoantibodies from cryptococcosis patients and PAP yielded no significant results. CONCLUSION: Anti-GM-CSF Abs can cause two diseases, C. gattii cryptococcosis and PAP, which seldom occur in the same subject. Current biological evidence regarding the properties of anti-GM-CSF Abs cannot provide clues regarding decisive mechanisms. Further analysis, including more extensive cohort studies and investigations into detailed properties, is mandatory to better understand the pathogenesis of anti-GM-CSF Abs.
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Criptococosis , Proteinosis Alveolar Pulmonar , Humanos , Autoanticuerpos , Criptococosis/diagnóstico , Criptococosis/epidemiología , Proteinosis Alveolar Pulmonar/diagnóstico , Proteinosis Alveolar Pulmonar/etiología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunologíaRESUMEN
A 58-year-old woman with cough and dyspnea who was suspected of having idiopathic interstitial pneumonia had been treated with corticosteroids and cyclosporine, but the symptoms had worsened. There were no findings to suspect pulmonary alveolar proteinosis (PAP) in the bronchoalveolar lavage fluid, 17 months after the start of treatment. The transbronchial lung biopsy specimens showed eosinophilic bodies that strongly stained with periodic acid-Schiff staining. Anti-granulocyte macrophage colony-stimulating factor (anti-GM-CSF) antibodies were detected in her serum. We diagnosed the patient with autoimmune PAP. Thus, we present a rare case of PAP presenting atypical radiological images and bronchoalveolar lavage fluid findings.
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Introduction: Cryptococcus spp. infection of the central nervous system (CINS) is a devastating opportunistic infection that was historically described in patients with acquired immunodeficiency syndrome (AIDS). Cryptococcus spp. infections are also associated with sarcoidosis; the impairment of cell-mediated immunity and long-term corticosteroid therapy being evoked to explain this association. Nevertheless, this assertion is debated and the underlying pathophysiological mechanisms are still unknown. The aims of this study were (i) to describe the clinical and biological presentation, treatments, and outcomes of CINS patients with and without sarcoidosis and (ii) to review the pathophysiological evidence underlying this clinical association. Patients and Methods: Every patient with positive cerebrospinal fluid (CSF) cryptococcal antigen testing, India ink preparation, and/or culture from January 2015 to December 2020 at a tertiary university hospital were included, and patients with sarcoidosis were compared with non-sarcoidosis patients. Quantitative variables are presented as mean ± SD and are compared using the Mann-Whitney Wilcoxon rank-sum test. Categorical variables are expressed as the number of patients (percentage) and compared using the χ2 or Fisher's tests. Results: During the study period, 16 patients experienced CINS, of whom 5 (31%) were associated with sarcoidosis. CINS symptoms, biological, and CSF features were similar between CINS patients with and without sarcoidosis except regarding CD4 cells percentages and CD4/CD8 ratio that was higher in those with sarcoidosis (47 ± 12 vs. 22 ± 18, p = 0.02 and 2.24 ± 1.42 vs. 0.83 ± 1.10, p = 0.03, respectively). CINS patients with sarcoidosis had less often positive blood antigen testing than those without sarcoidosis (2/5 vs. 11/11, p = 0.02). CINS patients with and without sarcoidosis were treated with similar drugs, but patients with sarcoidosis had a shorter length of treatment. CD4 cell levels do not seem to explain the association between sarcoidosis and cryptococcosis. Conclusion: Sarcoidosis was the most frequently associated condition with CINS in this study. CINS patients associated with sarcoidosis had overall similar clinical and biological presentation than CINS patients associated with other conditions but exhibited a lower rate of positive blood cryptococcal antigen testing and higher CD4/CD8 T cells ratio. Pathophysiological mechanisms underlying this association remain poorly understood but B-1 cell deficiency or lack of IgM could be a part of the explanation. Another plausible mechanism is the presence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in a subset of patients with sarcoidosis, which could impair macrophage phagocytic function. Further studies are strongly needed to better understand those mechanisms and to identify at-risk patients.
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BACKGROUND: Neutralizing anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies (AAbs) have been increasingly recognized to predispose healthy individuals to disseminated cryptococcosis. However, studies have only considered patients with central nervous system (CNS) infection. No longitudinal study has captured the disease spectrum and clinical course. METHODS: We prospectively enrolled adults without human immunodeficiency virus infection who had disseminated or unusual cryptococcosis. We compared the demographics, clinical features, kinetics of serum cryptococcal antigen (CrAg) titers, anti-GM-CSF AAb concentrations, and treatment outcomes between patients with (case patients) and without (control patients) anti-GM-CSF AAbs. Additional reports from the literature were also reviewed. RESULTS: Twenty-three patients were enrolled, of whom 6 tested positive for anti-GM-CSF AAbs. All case patients with positive fungal cultures (5/5 [100%]) were infected with Cryptococcus gattii VGII. Among them, 3 had exclusively pulmonary involvement, and 1 had only musculoskeletal lesions. Patients with CNS cryptococcosis exhibited a higher serum concentration of anti-GM-CSF AAbs than those with extraneural cryptococcosis. Case patients had higher initial and peak levels of serum CrAg and longer duration of antigenemia compared with the control patients. All case patients who had completed antifungal therapy had favorable outcomes without recurrence. CONCLUSIONS: Testing for anti-GM-CSF AAbs should be considered for not only previously healthy patients with disseminated cryptococcosis but also those with unexplained, localized cryptococcosis. Recurrence after completion of antifungal therapy was rare despite the persistence of anti-GM-CSF AAbs.
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Autoanticuerpos , Criptococosis , Adulto , Antifúngicos/uso terapéutico , Antígenos Fúngicos , Sistema Nervioso Central , Criptococosis/diagnóstico , Criptococosis/tratamiento farmacológico , Estudios de Seguimiento , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Humanos , Factor Estimulante de Colonias de Macrófagos/uso terapéuticoRESUMEN
The Cryptococcus gattii species complex has often been referred to as a primary pathogen due to its high infection frequency among apparently immunocompetent patients. In order to scrutinize the immune status of patients and the lineages of etiologic agents, we analyzed patient histories and the molecular types of etiologic agents from 135 global C. gattii cases. Eighty-six of 135 patients had been diagnosed as immunocompetent, although some of them had underlying medical issues, and 49 were diagnosed as immunocompromised with risk factors similar to those seen in Cryptococcus neoformans infection. We focused on the 86 apparently immunocompetent patients and were able to obtain plasma from 32 (37%) to analyze for the presence of autoantibodies against the granulocyte-macrophage colony-stimulating factor (GM-CSF) since these antibodies have been reported as a hidden risk factor for C. gattii infection. Among the 32 patients, 25 were free from any known other health issues, and 7 had various medical conditions at the time of diagnosis for cryptococcosis. Importantly, plasma from 19 (76%) of 25 patients with no recognized underlying medical condition showed the presence of GM-CSF autoantibodies, supporting this antibody as a major hidden risk factor for C. gattii infection. These data indicate that seemingly immunocompetent people with C. gattii infection warrant detailed evaluation for unrecognized immunologic risks. There was no relationship between molecular type and underlying conditions of patients. Frequency of each molecular type was related to its geographic origin exemplified by the overrepresentation of VGIV in HIV-positive (HIV+) patients due to its prevalence in Africa. IMPORTANCE The C. neoformans and C. gattii species complex causes cryptococcosis. The C. neoformans species complex is known as an opportunistic pathogen since it primarily infects immunocompromised patients. C. gattii species complex has been referred to as a primary pathogen due to its high infection frequency in apparently immunocompetent people. We analyzed 135 global cases of C. gattii infection with documented patient history. Eighty-six of 135 patients were originally diagnosed as immunocompetent and 49 as immunosuppressed with similar underlying conditions reported for C. neoformans infection. A significant number of C. gattii patients without known underlying conditions possessed autoantibodies against granulocytes-macrophage colony-stimulating factor (GM-CSF) in their plasma, supporting the presence of GM-CSF antibodies as a hidden risk factor for C. gattii infection. No relationship was found between C. gattii lineages and the underlying conditions except for overrepresentation of the molecular type VGIV among HIV+ patients due to the prevalence of VGIV in Africa.
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Criptococosis/etiología , Cryptococcus gattii/patogenicidad , Infecciones Oportunistas/etiología , Infecciones Oportunistas/microbiología , África/epidemiología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Criptococosis/inmunología , Criptococosis/microbiología , Cryptococcus gattii/clasificación , Cryptococcus gattii/genética , Cryptococcus gattii/inmunología , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , Humanos , Inmunocompetencia , Huésped Inmunocomprometido , Infecciones Oportunistas/inmunología , Factores de RiesgoRESUMEN
In this study, we report the history of a 40-year-old man with a primary cerebral abscess caused by Nocardia abscessus that led to the discovery of autoimmune pulmonary alveolar lipoproteinosis (anti-granulocyte-macrophage colony-stimulating factor [GM-CSF] autoantibodies). Anti-GM-CSF autoantibodies promote immunodeficiency and should be monitored to prevent opportunistic and disseminated infections and to diagnose asymptomatic pulmonary alveolar lipoproteinosis.
RESUMEN
Diagnosis by biopsy is difficult in the ovary since it is located deep in the abdomen. As a result, ovarian cancer is mostly found insidiously during exploratory laparotomy. Consequently, the early diagnosis of ovarian cancer is often difficult. The likelihood of peritoneal dissemination increases with the progress of ovarian cancer. With further progression, ovarian cancer metastasizes to the momentum, retroperitoneal lymph nodes, large intestine, small intestine, diaphragm, spleen, and other organs. Ovarian cancer has been considered a tumor that has a favorable response to chemotherapy, but more effective treatments are still being explored. Tumors use their own immune escape mechanism to evade host immunity. The immune checkpoint (IC) mechanism, one of the immune escape mechanisms, is established by programmed cell death-1 (PD-1)/PD-ligand-1 (PD-L1) communication. It has been shown that inhibiting PD-1/PD-L1 communication in various malignancies produces antitumor effects. However, the antitumor effect of ICI monotherapy on ovarian cancer is limited in actual clinical practice. In this review, we describe a novel cancer immunotherapeutic agent that targets myeloid-derived suppressor cells (MDSCs).