Cervical abscess caused by Mycobacterium tilburgii in a patient carrying anti-interferon gamma autoantibody: A case report and literature review.

Mycobacterium tilburgii, a nonculturable mycobacterium, is an important nontuberculous mycobacterium that occasionally causes serious infections in patients with cellular immune deficiencies. Due to its nonculturable nature, information about its drug susceptibility is not available, and data about its clinical response to antimycobacterial treatment remains insufficient. Here, we report a case of a patient who presented with neck swelling and was finally diagnosed with cervical abscess caused by M. tilburgii carrying anti-interferon gamma autoantibodies using a molecular method. The relevant literature was reviewed in the context of epidemiological and clinical data on M. tilburgii infections. In this report, 15 patients were reported to be infected with M. tilburgii. Almost all patients had a cellular immune deficiency and presented with disseminated infections. Multiple refractory or relapse cases that often required prolonged antimycobacterial treatment have been reported, although a few fatal cases have also been reported. In conclusion, M. tilburgii is an important pathogen in patients with cellular immune deficiency. Physicians should thoroughly investigate cellular immune deficiency, including adult-onset immune deficiency with anti-interferon gamma autoantibodies, in patients with M. tilburgii infection.

Serum Anti-interferon-γ Autoantibody Titer as a Potential Biomarker of Disseminated Non-tuberculous Mycobacterial Infection.

PURPOSE: In the past decade, the relationship between naturally occurring interferon-γ-neutralizing autoantibodies (IFNγ-Ab) and disseminated non-tuberculous mycobacteria (NTM) infection has been established. Furthermore, immune suppressive therapy aimed at the suppression of antibody production has shown efficacy as a supportive treatment. However, the nature of antibody behavior and antibody titer during the course of this disease, as well as the pathophysiological significance of IFNγ-Ab, has not yet been fully elucidated. METHODS: Thirteen Japanese subjects suffering from disseminated NTM (dNTM) infection with IFNγ-Ab were evaluated. The fluctuation of IFNγ-Ab titer and the neutralizing capacity against IFN-γ during the course of the disease were retrospectively analyzed. IFNγ-Ab titers in the sera were quantified using an enzyme-linked immunosorbent assay; neutralizing capacity was evaluated via flow cytometry. RESULTS: Serum antibody titers were not constant during the treatment period and varied over the course of the disease. The antibody titer decreased when the disease was improved by anti-mycobacterial treatment (p < 0.01) and increased as the disease progressed (p < 0.05). Even after the antibody titer decreased, the neutralizing capacity against IFN-γ was maintained by individual sera. CONCLUSIONS: Despite the improvement in the pathological condition via treatment, the patients' sera maintained neutralizing capacity against IFN-γ. Antibody titer fluctuated over the course of the disease and exhibited potential as a biomarker for judgment of the disease state.

Disseminated Mycobacterium abscessus subsp. massiliense infection in a Good's syndrome patient negative for human immunodeficiency virus and anti-interferon-γ autoantibody: a case report.

BACKGROUND: Good's syndrome (GS) is characterized by immunodeficiency, and can lead to severe infection, which is the most significant complication. Although Mycobacterium rarely causes infection in patients with GS, disseminated nontuberculous mycobacterial (NTM) infection frequently occurs in GS patients that are also positive for the human immunodeficiency virus (HIV) or anti-interferon (IFN)-γ autoantibodies. Here, we report a rare case of GS with NTM without HIV or IFN-γ autoantibodies. CASE PRESENTATION: A 57-year-old Japanese male with GS and myasthenia gravis (treated with prednisolone and tacrolimus) was diagnosed with disseminated NTM infection caused by Mycobacterium abscessus subsp. massiliense. He presented with fever and back pain. Blood, lumbar tissue, urine, stool, and sputum cultures tested positive for M. abscessus. Bacteremia, spondylitis, intestinal lumber abscess, and lung infection were confirmed by bacteriological examination and diagnostic imaging; urinary and intestinal tract infections were suspected by bacteriological examination but not confirmed by imaging. Despite multidrug combination therapy, including azithromycin, imipenem/cilastatin, levofloxacin, minocycline, linezolid, and sitafloxacin, the patient ultimately died of the infection. The patient tested negative for HIV and anti-IFN-γ autoantibodies. CONCLUSIONS: Since myasthenia gravis symptoms interfere with therapy, patients with GS and their physicians should carefully consider the antibacterial treatment options against disseminated NTM.

A study of factors related to asthma exacerbation using a questionnaire survey in Niigata Prefecture, Japan.

BACKGROUND: As indices of asthma control, exacerbations are equally important with symptoms and respiratory function. Thus, it is critical to recognize the risk factors of exacerbation. OBJECTIVE: We conducted a questionnaire survey of asthma patients in Niigata Prefecture to clarify the factors involved in asthma exacerbation. METHODS: The questionnaire survey was carried out in patients and their physicians from September to October 2014. In 2015, the same sample population also received a questionnaire about current asthma control and exacerbation. RESULTS: One hundred patients experienced asthma exacerbation during the 1-year period. There were significant differences in age, sex, history of hospitalization due to asthma, smoking history, Asthma Control Test, treatment step, and transient steroid treatment history in the previous year between the exacerbation group and non-exacerbation group. On multivariate analysis, there was a significant difference in history of transient steroid therapy, history of hospitalization associated with asthma attacks, and nonsmoking history. Cluster analysis of cases with exacerbation was classified into three clusters. Cluster 1 comprised slightly older cases with smoking history, Cluster 2 had more females, non-smoking and nonatopic cases with uncontrolled symptoms, and Cluster 3 had more females, non-smoking and mild atopic cases. CONCLUSIONS: Our findings suggest that patients with asthma exacerbation in the previous year and nonsmoking females are important targets for the study of asthma exacerbation. The adequate treatment of women patients might be important for the prevention of asthma exacerbation.

Characterization of low adherence population in asthma patients from Japan using Adherence Starts with Knowledge-12.

BACKGROUND: Adherence Starts with Knowledge-12 (ASK-12) is a useful indicator of drug adherence. In this study, we analyzed patient background including social and psychological factors in a low-adherence group of patients with asthma defined using ASK-12. METHODS: From a questionnaire survey for patients with asthma from the Niigata Prefecture, Japan, conducted in the fall of 2016, we enrolled patients who answered all ASK-12 items and underwent a measured respiratory function test within 1 year. The low-adherence group (ASK-12 ≥ 28) was compared with the control group (ASK-12 < 28), and we conducted a cluster analysis of the low-adherence group. RESULTS: There were 170 patients in the low-adherence group and 402 patients in the control group. There was a significant difference between age, gender, working status, smoking history, the percentage of forced expiratory volume in one second (%FEV1), asthma control test (ACT), and Patient Health Questionnaire-9 (PHQ-9) score between the two groups. Logistic analysis revealed that working status (working), % FEV1 (<90%), and PHQ-9 score (>5) were independent factors for the low-adherence group. The cluster analysis identified three clusters in the low-adherence group. Among these, one cluster was characterized by elderly males with chronic obstructive pulmonary disease and another by middle-aged nonsmoking females with a depression tendency, had problems with asthma control. CONCLUSIONS: Several factors were considered to be attributed to low drug-adherence. There were several phenotypes in the low-adherence population correlated with incomplete asthma control. Intervention with drug adherence should be a future goal for asthma treatment.

Clinical Significance of Interferon-γ Neutralizing Autoantibodies Against Disseminated Nontuberculous Mycobacterial Disease.

Background: Interferon-γ neutralizing autoantibodies (nIFNγ-autoAbs) are reported in patients with disseminated nontuberculous mycobacteria (NTM) infection and may function by increasing the infection risk. Notwithstanding, the prevalence of nIFNγ-autoAbs as well as the clinical presentation, diagnosis, and natural history of disseminated NTM infection in these patients is poorly understood. Methods: In this retrospective observational study, data and sera for 331 Japanese subjects with mycobacterial infection were collected and analyzed. IFNγ-autoAb titers in sera were quantified using an enzyme-linked immunosorbent assay; neutralizing capacity was evaluated via flow cytometry. Results: Disseminated NTM was identified in 50 human immunodeficiency virus-uninfected patients. Of these, 30 of 37 (81%) immunocompetent patients had an increased nIFNγ-autoAb titer whereas only 1 of 13 (7.7%) immunodeficient patients had an increased nIFNγ-autoAb titer (P < .0001, χ2 test). Presenting symptoms were nonspecific and NTM infection was not included in the differential diagnosis in most cases. All patients with disseminated NTM and an increased serum nIFNγ-autoAb level received prolonged antimicrobial therapy. In 6 cases when antibiotic treatment was discontinued, NTM infection recurred and required resumption of antibiotic therapy for infection control. The mortality rate was 3.2% in disseminated NTM patients with nIFNγ-autoAbs and 21% in those without. Conclusions: nIFNγ-autoAbs were present in most patients with disseminated NTM infection without a diagnosis of clinical immunodeficiency. Diagnosis of disseminated NTM requires a high degree of suspicion and can be improved by measuring serum nIFNγ-autoAb titer. Long-term antibiotic therapy helps prevent recrudescent NTM infection.

Mycobacterial lymphadenitis without granuloma formation in a patient with anti-interferon-gamma antibodies.

A previously healthy 49-year-old Japanese woman presented with cervical lymph node swelling and tenderness. Lymph node biopsy revealed reactive lymphadenitis without granulomas. No malignant cells were found, and no acid-fast positive bacilli were identified by Ziehl-Neelsen staining. She was treated unsuccessfully with various antibiotics, and it was very challenging to reach a diagnosis. 18F-Fluorodeoxyglucose (18F-FDG) uptake in bones was evaluated using positron emission tomography-computed tomography (PET-CT), and disseminated mycobacterial infection was suspected. The interferon-gamma (IFN-γ) release assays QuantiFERON (QFT) and T-SPOT were used to diagnose tuberculosis infection. On testing, a difference in mitogen response was found between these assays. The response was low for QFT but adequate for T-SPOT, suggesting the presence of anti-IFN-γ antibodies. This difference depended on whether the patient's plasma (including anti-IFN-γ antibodies) was used within the assay system. Mycobacterium abscessus was isolated from lymph node cultures, and plasma anti-IFN-γ antibodies were confirmed. The patient was diagnosed with disseminated M. abscessus infection with underlying adult-onset immunodeficiency caused by anti-IFN-γ antibodies. Granulomas are a pathological hallmark of mycobacterial infection, but may not fully form in immunodeficient patients. Clinicians should be aware of the possibility of mycobacterial infection without granuloma formation due to anti-IFN-γ antibodies.

Comparison of cytokine profiles between anti-ARS antibody-positive interstitial lung diseases and those with anti-MDA-5 antibodies.

INTRODUCTION/OBJECTIVES: Interstitial lung disease (ILD) is a significant cause of mortality among patients with dermatomyositis (DM) or polymyositis (PM). There are two subtypes of PM and DM often complicated with ILD: those with anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies and those with anti-MDA-5-associated amyopathic DM (ADM). Our aim is to clarify the inflammatory and immunological differences between the disorders. METHODS: We retrospectively collected consecutive patients with anti-ARS-ILD and those with anti-MDA-5 antibody-positive ADM-ILD. The serum concentration of 38 cytokines was measured using a cytokine panel. The relative risks for anti-MDA-5 antibody-positive ADM-ILD were examined with univariate and multivariate logistic regression models. Spearman's rank correlation coefficient was calculated between cytokine levels and clinical parameters in the disease. Levels of cytokines were compared between anti-ARS-ILD and anti-MDA-5-positive ADM-ILD patients (alive or dead) using Dunnett's test. RESULTS: Twenty-three patients with anti-ARS-ILD and the same number of patients with anti-MDA-5-positive ADM-ILD were enrolled. The anti-MDA-5 group had poor survival (p = 0.025). Univariate logistic regression models showed that eotaxin, IL-10, IP-10, and MCP-1 were associated with the diagnosis of anti-MDA-5-positive ADM-ILD. Multivariate logistic regression models revealed that IP-10 was the most significantly associated (p = 0.001). Relationship analyses showed that IL-10 had significant positive correlations with CK (r = 0.5267, p = 0.009) and ferritin (r = 0.4528, p = 0.045). A comparison of the cytokine levels found that IP-10 was elevated in both patients who were alive and patients who had died with ADM-ILD compared with the levels in those with ARS-ILD (p = 0.003 and p = 0.001, respectively). CONCLUSIONS: Anti-MDA-5-positive ADM-ILD had poorer survival than anti-ARS-ILD. IP-10 seems to be most deeply involved in the pathophysiology of anti-MDA-5-associated ADM-ILD.Key Points• To clarify differences in the inflammatory and immunological features of anti-MDA-5-positive ADM-ILD and anti-ARS-ILD, we performed an observational study to measure serum cytokine concentrations before treatment using a multiplex immunoassay system.• Multivariate logistic regression models revealed that IP-10 was associated with the most significant relative risk for ADM-ILD with anti-MDA-5 antibodies.• Levels of IP-10 were elevated considerably in anti-MDA-5-positive survivors and nonsurvivors compared with the levels in anti-ARS patients.• These results suggest that IP-10 is the most deeply involved in the pathophysiology of anti-MDA-5-positive ADM-ILD.

Validation of a new serum granulocyte-macrophage colony-stimulating factor autoantibody testing kit.

Very recently, a modest but significant efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation therapy for the treatment of mild to moderate autoimmune pulmonary alveolar proteinosis (aPAP) has been reported. As the ability to measure the level of GM-CSF autoantibody (GMAb) in the serum is required to decide the indication for this therapy, we developed a high-performance GMAb testing kit for clinical use. As the kit succeeded in reducing nonspecific IgG binding to the ELISA plate, the predictive performance shown in the training study to discriminate aPAP patients from healthy subjects was perfect, providing a cut-off value of 1.65 U·mL-1 in 78 patients with aPAP and 90 healthy subjects in an operator-blinded manner using logistic regression analysis. As in the validation study, serum samples from another 213 patients with aPAP were also blinded and evaluated in an operator-blinded manner against external 207 samples from patients with other types of PAP and patients exhibiting various ground-glass opacities on chest high-resolution computed tomography that require discrimination from PAP. The logistic regression analysis of these validation data sets revealed values of 97.6% and 100% for specificity and sensitivity, respectively. Thus, this new GMAb testing kit is reliable for the diagnosis of aPAP and differential diagnosis of other lung diseases.

Crowned Dens Syndrome as an Initial Manifestation of Crystalline Deposition Disease.

An 88-year-old woman presented with fever and acute posterior neck pain. A CT scan revealed calcification of the transverse ligament and crown-like calcification around the odontoid process. According to the clinical and radiological findings, she was diagnosed with crowned dens syndrome (CDS). Her symptoms drastically improved following treatment with oral nonsteroidal anti-inflammatory medication. An X-ray of her wrist, elbow, shoulder and knee joints showed asymptomatic calcium deposits, suggesting underlying crystalline deposition disease. CDS may occur as the initial presentation of crystalline deposition disease. The measurement of procalcitonin and an X-ray survey of the major joints may be helpful for the diagnosis of CDS.