Non-infectious Inflammatory Diseases Research Articles

Inflammatory ascending aortic disease: Perspectives from pathology

Inflammatory diseases of the aorta comprise a spectrum of disease with diverse clinical and histopathologic presentations. Broadly, they may be dichotomized into infectious and noninfectious varieties. Although uncommon, infectious forms, caused by bacteria, fungi, or mycobacteria, may result from hematogenous seeding of the aorta or direct spread from a contiguous infectious source. The noninfectious forms include a number of entities, the most common of which is atherosclerosis, a disease that primarily affects the aortic intima but has important secondary effects on the media and adventitia that may result in aneurysm formation. Other important noninfectious inflammatory diseases include giant cell arteritis, Takayasu arteritis, granulomatosis with polyangiitis (Wegener granulomatosis), sarcoidosis, and lymphoplasmacytic aortitis. Importantly, there is increasing recognition that there is a subset of cases of lymphoplasmacytic aortitis perhaps better classified under the spectrum of so-called IgG4-related sclerosing disease, with important clinical and therapeutic ramifications. This review focuses on the variable and defining characteristics of the inflammatory aortopathies, specifically those affectingthe ascending aorta, and discusses areas of important clinical and pathological distinction between them.

Diagnostic Utility of 18F-FDG PET/CT in Inflammation of Unknown Origin

The goal of this multicenter retrospective study was to evaluate the contribution of F-FDG PET/CT in the diagnosis of patients with inflammation of unknown origin (IUO). In addition, C-reactive protein (CRP) level and erythrocyte sedimentation rate were assessed as possible predictors for the outcome of F-FDG PET/CT. Inflammation of unknown origin was defined as prolonged and perplexing inflammation, with repeated CRP levels more than 20 mg/L or erythrocyte sedimentation rate more than 20 mm/h, body temperature of less than 38.3°C, and without a diagnosis after a variety of conventional diagnostic procedures.A total of 140 patients with IUO (67 men, 73 women; mean age, 64.2 years; age range, 18-87 years) underwent F-FDG PET/CT. F-FDG PET/CT was considered helpful when the imaging findings led to a diagnosis, either confirmed by histopathology, microbiological assays, clinical and imaging follow-up, or response to treatment. In 104 patients (73%), a final diagnosis could be established as follows: infection in 35 patients, malignancy in 18 patients, noninfectious inflammatory disease in 44 patients, and a variety of uncommon conditions in 7 patients. F-FDG PET/CT was true positive in 95 patients, true negative in 30 patients (ie, self-limiting conditions), false positive in 6 patients, and false negative in 9 patients (predominantly systemic diseases). In this population, the positive predictive value, negative predictive value, and diagnostic accuracy of F-FDG PET/CT were 94%, 77%, and 89%, respectively. In a multivariate analysis, CRP was the only independent predictor for the outcome of F-FDG PET/CT. F-FDG PET/CT correctly identified or excluded a causal explanation in approximately 90% of patients with IUO. However, a negative F-FDG PET/CT is indicative for a self-limiting condition only after systemic diseases are excluded by other diagnostic tests.

Analysis of 256 cases of classic fever of unknown origin.

The causes of fever of unknown origin (FUO) vary depending on the region and time period. We herein present a study of patients with classic FUO where we investigated differences based on patient background factors, such as age and causative diseases, and changes that have occurred over time. We extracted and analyzed data from the medical records of 256 patients ≥18 years old who met the criteria for classic FUO and were hospitalized between August, 1994 and December, 2012. The median age of the patients was 55 years (range: 18-94 years). The cause of FUO was infection in 27.7% of the patients (n=71), non-infectious inflammatory disease (NIID) in 18.4% (47), malignancy in 10.2% (26), other in 14.8% (38), and unknown in 28.9% (74). The most common single cause was human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) (n=17). NIID and malignancy were more common in patients ≥65 years old than in patients <65 years old. During 2004-2012, compared to 1994-2003, infections and "other" causes were decreased, whereas NIID, malignancy, and unknown causes were increased. FUO associated with HIV/AIDS is increasing in Japan. In addition, as in previous studies in Japan and overseas, our study showed that the number of patients in whom the cause of FUO remains unknown is increasing and exceeds 20% of all cases. The present study identified diseases that should be considered in the differential diagnosis of FUO, providing useful information for the future diagnosis and treatment of FUO.

Diagnosis of Periprosthetic Joint Infection

Diagnosis of Periprosthetic Joint Infection

Fever of Unknown Origin: A Retrospective Study of 95 Children in an Iranian Referral Hospital

Fever of unknown origin (FUO) is a common manifestation in paediatrics and is a diagnostic problem especially in primary care. The present study aims to revue the causes of FUO in an Iranian referral tertiary care hospital. Information on 95 patients referred to the Children’s Medical Center Hospital, Tehran, between 2004 and 2006 with a primary diagnosis of FUO was evaluated retrospectively. Infectious diseases were diagnosed in 26.3% (n=25) of the cases, while malignant and non-infectious inflammatory diseases constituted 7.4% (n=7) and 14.7% (n = 14), respectively. Urinary tract infections, acute lymphoid leukaemia and Kawasaki disease were the most commonly diagnosed conditions. Urinary tract infection accounted for approximately half of the infectious cases (n=14). Conclusive diagnostic factors included history and examination in 21 cases, analysis of different specimens (i.e., urine analysis, urine culture, serology, peripheral blood and cerebrospinal fluid [CSF] examination) in 12 cases, culture in nine cases and serological tests in four cases. Infection and malignancy in patients aged under three years, and inflammatory diseases in patients aged over three years were more common. In patients aged under three years urine culture, bone marrow aspiration and peripheral blood smear proved more helpful in arriving at a final diagnosis of FUO, while in patients aged over three years, history and physical examination also contributed to the final diagnosis.

Diagnostic workup for fever of unknown origin: a multicenter collaborative retrospective study

ObjectiveFever of unknown origin (FUO) can be caused by many diseases, and varies depending on region and time period. Research on FUO in Japan has been limited to single medical...

Non-infectious inflammatory diseases of the central nervous system in dogs

Inflammatory diseases of the central nervous system (CNS) present as progressive diseases, often with a collection of neurological deficits reflecting multifocal involvement of the CNS. The most common signalment (middle-aged small-breed dogs, more commonly females) can provide a high index of suspicion, combined with neurological findings, CSF analysis and imaging studies. The prognosis is guarded, and some dogs will deteriorate rapidly despite therapy, while others can live for years with or without medication, which reflects currently our lack of understanding of this group of diseases.

Necrotizing Meningoencephalitis in Atypical Dog Breeds: A Case Series and Literature Review

BackgroundCanine necrotizing meningoencephalitis (NME) is a fatal, noninfectious inflammatory disease of unknown etiology. NME has been reported only in a small number of dog breeds, which has led to the presumption that it is a breed‐restricted disorder.Hypothesis/ObjectivesOur objective was to describe histopathologically confirmed NME in dog breeds in which the condition has not been reported previously and to provide preliminary evidence that NME affects a wider spectrum of dog breeds than previously reported.AnimalsFour dogs with NME.MethodsArchives from 3 institutions and from 1 author's (BS) collection were reviewed to identify histopathologically confirmed cases of NME in breeds in which the disease has not been reported previously. Age, sex, breed, survival from onset of clinical signs, and histopathologic findings were evaluated.ResultsNecrotizing meningoencephalitis was identified in 4 small dog breeds (Papillon, Shih Tzu, Coton de Tulear, and Brussels Griffon). Median age at clinical evaluation was 2.5 years. Histopathologic abnormalities included 2 or more of the following: lymphoplasmacytic or histiocytic meningoencephalitis or encephalitis, moderate‐to‐severe cerebrocortical necrosis, variable involvement of other anatomic locations within the brain (cerebellum, brainstem), and absence of detectable infectious agents.Conclusions and Clinical ImportanceUntil now, NME has only been described in 5 small dog breeds. We document an additional 4 small breeds previously not shown to develop NME. Our cases further illustrate that NME is not a breed‐restricted disorder and should be considered in the differential diagnosis for dogs with signalment and clinical signs consistent with inflammatory brain disease.

The management and the diagnosis of fever of unknown origin

Prolonged fever presents a challenge for the patient and the physician. Fever with a temperature higher than 38.3°C on several occasions that lasts for at least 3 weeks and lacks a clear diagnosis after 1 week of study in the hospital is called a fever of unknown origin (FUO). More than 200 diseases can cause FUO, and the information gathered from history taking, physical examination, laboratory and imaging studies should be evaluated with care. History taking and physical examination may provide some localizing signs and symptoms pointing toward a diagnosis. Infection, cancers, noninfectious inflammatory diseases and some miscellaneous diseases are the main etiologies, and some patients remain undiagnosed despite investigations. Tuberculosis, lymphoma and adult-onset Still’s disease are the main diseases. Fluorodeoxyglucose PET is a promising imaging modality in FUO. Establishing a uniform algorithm for FUO management is difficult. Every patient should be carefully evaluated individually considering the previous FUO management experience.

Noninfectious Inflammatory Lung Disease: Imaging Considerations and Clues to Differential Diagnosis

Noninfectious inflammatory lung diseases represent a spectrum of idiopathic and secondary conditions that may involve the airspaces, vasculature, or interstitium. The most important clinical and pathologic characteristics are reviewed, emphasizing CT findings and potential clues to differential diagnosis. Noninfectious inflammatory lung diseases translate into various CT appearances that are important in making the correct diagnosis.

FDG-PET in Fever of Unknown Origin

Fever of unknown origin (FUO) is commonly defined as fever higher than 38.3°C on several occasions during at least 3 weeks with uncertain diagnosis after a number of obligatory tests. FUO remains a clinical challenge as no diagnosis is reached in up to 50% of cases. In general, infection accounts for one-fourth of cases of FUO, followed by neoplasm and noninfectious inflammatory diseases. FDG-PET is a sensitive diagnostic technique for the evaluation of FUO. Especially integrated imaging combining PET and CT facilitates anatomical localization of focally increased FDG uptake, thereby guiding further diagnostic tests to achieve a final diagnosis. FDG-PET/CT appears to be a more sensitive diagnostic tool in FUO than stand-alone FDG-PET, because of the precise anatomical localization of small lesions and better differentiation between physiological and pathologic metabolic foci. With FDG-PET/CT becoming widely available, FDG-PET/CT should be a routine procedure in the workup of FUO.

Circulating galectin-3 in infections and non-infectious inflammatory diseases

Recent studies point to a dual role for galectin-3 as both a circulating damage-associated molecular pattern and a cell membrane-associated pattern recognition receptor. The aim of this study was to assess the potential of circulating galectin-3 for discriminating between infections and non-infectious inflammatory disorders on the one hand, and between fungal and bacterial infections on the other. Galectin-3 and C-reactive protein (CRP) were measured in the plasma of 127 patients with either non-infectious inflammatory disorders (gout, autoinflammatory syndrome or pancreatitis) or an infection (viral lower respiratory tract infection, bacterial sepsis or candidaemia). Circulating galectin-3 concentrations were increased in patients with infections when compared with healthy volunteers or patients with non-infectious inflammatory diseases. At cut-off values with a specificity of 95%, the sensitivity of galectin-3 (>20.6 ng/ml) to discriminate between an infection and non-infectious inflammation was higher than that of CRP (>156 mg/l): 43% [95% confidence interval (CI) 33-53%] versus 27% (95% CI 19-37%), p = 0.03. After exclusion of patients with CRP <156 mg/l, galectin-3 concentration >20.6 ng/ml could identify 41 % (95% CI 29-53%) of the patients with an infection at the cost of one false-positive with non-infectious inflammation. Using this sequential approach, 57% of the patients with an infection could be selected. Galectin-3 concentrations were similar in patients with bacterial and Candida sepsis, while being lower in viral respiratory infections. Although galectin-3 does not discriminate between bacterial and Candida sepsis, the sequential use of CRP and galectin-3 in distinguishing infectious diseases from non-infectious inflammation may be superior to CRP alone.

OP0012 Chronic recurrent non-bacterial osteomyelitis in danish children

BackgroundChronic recurrent multifocal osteomyelitis (CRMO) is a non-infectious inflammatory bone disease of unknown etiology that predominantly affects children and young adults. It is characterized by multifocal inflammatory bone lesions with...

Analysis of a Novel Protocol of Pulsed Intravenous Cyclophosphamide for Recalcitrant or Severe Ocular Inflammatory Disease

To analyze the success rate of pulsed intravenous (IV) cyclophosphamide (CyP) for noninfectious ocular inflammatory disease and to identify risk factors for failure of therapy. Retrospective, interventional, noncomparative cohort study. One hundred ten eyes of 65 patients. Through a computer search of the Massachusetts Eye Research and Surgery Institution's database, we identified patients who were treated with IV CyP between May 2005 and April 2012. We obtained demographic and clinical information through review of the electronic health record of each patient. Clinical response, corticosteroid-sparing effect, recurrence rate, calculated "risk factors" for failure, visual acuity, and adverse reactions. Pulsed IV CyP achieved complete remission of inflammation (for ≥ 2 visits) in 54 patients (84.4%). Sustained remission of inflammation occurred in 70% of patients within 3 months, 86.6% of patients within 6 months, and 91.7% within 9 months. The mean time to achieving quiescence was 3.5 months. The success rate in reducing corticosteroid to prednisone ≤ 10 mg/d within 6 months, while maintaining control of ocular inflammation, was 89.7% (95% confidence interval [CI], 81.1-93.5%). The mean duration of clinical remission for those patients who had a positive response to CyP was 32.67 months (95% CI, 25.91-39.43). Relapse of vasculitis was observed in 1 patient (1.5%) after completing the course of therapy. Early initiation of therapy during the course of the disease was correlated with a lesser rate of recurrence (P = 0.028). The most common adverse effects were nausea (29%) and transient lymphopenia (26%). The mean best-corrected visual acuity (BCVA) improved from 0.59 ± 0.66 at baseline to 0.30 ± 0.54 at 6 months of follow-up (P<0.001). The mean follow-up period was 31.61 ± 20.47 months. Pulsed IV CyP employing our protocol results in an extremely high rate of sustained complete remission in patients with recalcitrant and fulminant, vision-threatening ocular inflammatory disorders, with an excellent safety profile in the hands of physicians trained and skilled in the art of this therapy. It also allows tapering and discontinuing corticosteroids in most patients. Early initiation of therapy may decrease the risk of relapses. The authors have no proprietary or commercial interest in any materials discussed in this article.

Fieber ungeklärter Ursache

Fever of unknown origin (FUO) is defined as sustained unexplained fever despite intensive diagnostic evaluation and represents a particular diagnostic challenge. It can be classified into different categories, e.g. classical, nosocomial, neutropenic and HIV-associated FUO, which is based on the patient-specific clinical and immunological situation. Infections, malignant diseases and non-infectious inflammatory diseases have to be considered as the most important causes of FUO; however, no definitive diagnosis can be established in a substantial number of FUO patients despite an extensive diagnostic work-up. The present review focuses on the important diagnostic aspects as well as therapeutic options in FUO patients.

Vision‐related quality of life in patients with birdshot chorioretinopathy

Dear Editor, Birdshot chorioretinopathy (BSCR) is a potentially blinding chronic form of bilateral posterior uveitis. Despite intensive anti-inflammatory therapies, patients may exhibit a slow decline in visual functioning including the central visual acuity and contrast sensitivity (Shah et al. 2005). Here, we ascertain the vision-specific quality of life (QOL) in patients with BSCR and study the associations between QOL and treatment modalities. The study was performed in accordance with the Declaration of Helsinki and with the approval of the local institutional review board. We included 127 consecutive patients with BSCR from the department of ophthalmology of the University Medical Centre Utrecht and the Eye Hospital Rotterdam, the Netherlands. Diagnosis was based on research criteria established by an international consensus conference (Levinson et al. 2006) and included fluorescein angiography. All included patients were HLA-A29 positive. The Dutch translation of the NEI Visual Function Questionnaire (VFQ)-25 was sent to all subjects (Mangione et al. 2001). A total of 105 (83%) patients (median age 59.5; range 28–83 years) completed questionnaires, which were returned after obtaining informed consent. The reasons for not responding included death (n = 4) or no interest in participation (n = 18). Gender, age, duration of uveitis, previous treatment and best-corrected visual acuity (BCVA) were registered for all subjects (mean binocular visual acuity; LogMAR 0.82 ± 0.24; range 0.05–1.0). Previous treatment was divided into three groups: (i) no systemic treatment (26 patients, 25%), (ii) systemic corticosteroids, but no other immunosuppressive drugs (15 patients, 14%), and (iii) immunosuppressive drugs occasionally in combination with systemic corticosteroids (64 patients, 61%). A p-value of 0.0045 or less was accepted as indicating statistical significance, using Bonferroni correction. The median NEI VFQ-25 composite score for patients with BSCR was 75.9, and median subscale scores ranged from 60 for general health to 91.7 for social functioning and dependency (Table 1). There was no difference in NEI VFQ-25 composite or subscales scores between the various treatment categories (Kruskal–Wallis test, p = 0.473). The composite scores were related to BCVA (Spearman correlation, p = 0.003), but not related to age (p = 0.6) or duration of uveitis (p = 0.8). The BCVA was not different between the treatment categories (p = 0.289). All correlations between the NEI VFQ-25 subscale scores and BCVA were significant, except for ocular pain (p = 0.878). BSCR has a high impact on vision-related QOL. VFQ-25 scores were associated with visual acuity, but no difference in VFQ-25 scores or BCVA was observed among the different treatment regimens and between treated and not treated patients. Our NEI VFQ-25 subscale score results are in the same range of those found in a previous cohort of BSCR (Levinson et al. 2009) and a recent study of vision-related QOL in noninfectious ocular inflammatory disease (Qian et al. 2012). The authors of the latter study stated that low composite VFQ-25 score was a predictor of depression, which they found was associated with the use of corticosteroids and antimetabolites. In this study, we did not assess depression specifically; however, the median composite and mental health scores were lower in the group of patients treated with systemic corticosteroids compared with the other groups (Table 1). The design of our study does not allow the evaluation of specific treatment efficacy because the treatment regimens were not random. Future randomized studies on the effect of different immunosuppressive treatment regimes and visual outcomes in BSCR are warranted.

Diagnostic Use of Serum Ferritin Levels to Differentiate Infectious and Noninfectious Diseases in Patients with Fever of Unknown Origin

INTRODUCTION: In this study, we determined whether serum ferritin levels could be used to differentiate between fever of unknown origin (FUO) caused by infectious and noninfectious diseases.METHODS: FUO patients were hospitalized at Chonnam National University Hospital between January, 2005 and December, 2011. According to the final diagnoses, five causes were identified, including infectious diseases, hematologic diseases, noninfectious inflammatory diseases, miscellaneous and undiagnosed.RESULTS: Of the 77 patients, 11 were caused by infectious diseases, 13 by hematologic diseases, 20 by noninfectious inflammatory diseases, 8 by miscellaneous diseases, and 25 were undiagnosed. The median serum ferritin levels in infectious diseases was lower than those in hematologic diseases and (median (interquartile range) of 282.4 (149.0–951.8) ng/mL for the infectious disease group, 1818.2 (485.4–4789.5) ng/mL for the hematologic disease group, and 563.7 (399.6–1927.2) ng/mL for the noninfectious inflammatory disease group,p= 0.048, Kruskal–Wallis test). By comparison using the Mann–Whitney test, statistically significant differences were found only between the infectious disease and hematologic disease groups (p= 0.049) and between the infectious disease and groups (p= 0.04).CONCLUSION: An optimal cutoff value of serum ferritin levels to predict FUO caused by a noninfectious disease (hematologic diseases, noninfectious inflammatory diseases) was established as 561 ng/mL.

Diagnostic use of serum ferritin levels to differentiate infectious and noninfectious diseases in patients with fever of unknown origin.

INTRODUCTION: In this study, we determined whether serum ferritin levels could be used to differentiate between fever of unknown origin (FUO) caused by infectious and noninfectious diseases.METHODS: FUO patients were hospitalized at Chonnam National University Hospital between January, 2005 and December, 2011. According to the final diagnoses, five causes were identified, including infectious diseases, hematologic diseases, noninfectious inflammatory diseases, miscellaneous and undiagnosed.RESULTS: Of the 77 patients, 11 were caused by infectious diseases, 13 by hematologic diseases, 20 by noninfectious inflammatory diseases, 8 by miscellaneous diseases, and 25 were undiagnosed. The median serum ferritin levels in infectious diseases was lower than those in hematologic diseases and (median (interquartile range) of 282.4 (149.0–951.8) ng/mL for the infectious disease group, 1818.2 (485.4–4789.5) ng/mL for the hematologic disease group, and 563.7 (399.6–1927.2) ng/mL for the noninfectious inflammatory disease group, p = 0.048, Kruskal–Wallis test). By comparison using the Mann–Whitney test, statistically significant differences were found only between the infectious disease and hematologic disease groups (p = 0.049) and between the infectious disease and groups (p = 0.04).CONCLUSION: An optimal cutoff value of serum ferritin levels to predict FUO caused by a noninfectious disease (hematologic diseases, noninfectious inflammatory diseases) was established as 561 ng/mL.

Differential Diagnosis of Non-Segmental Consolidations

Consolidation and Ground-Glass Opacities (GGO) are common findings on chest Computed Tomographic (CT) scans. Consolidation and GGO can be divided into segmental, non-segmental and interstitial pneumonia types based upon distribution pattern. The aim of this review is to highlight the importance of the non-segmental distribution pattern, and to explain its relevancy in various conditions. Non-segmental distribution pattern presents as lobar pneumonia histologically, whereas segmental distribution appears as bronchopneumonia. The different diagnoses that can be derived from non-segmental distribution consist of infectious pneumonias caused by S. pneumoniae, K. pneumoniae and L. pneumophila, Chlamydophila psittaci, M. pneumoniae, measles, viral pneumonia and tuberculosis, as well as non-infectious inflammatory diseases including Cryptogenic Organizing Pneumonia (COP), Chronic Eosinophilic Pneumonia (CEP) and Pulmonary Alveolar Proteinosis (PAP), and other conditions including Anti-Neutrophil Cytoplasmic Antibody (ANCA) related pulmonary hemorrhage and Bronchoalveolar Carcinoma (BAC). A detailed analysis and correlation of non-segmental distribution with other CT findings (e.g., ground-glass opacity, interlobular septal thickening, fibrosis, pleural effusion, air trapping, nodular lesions, and air bronchiologram and air bronchogram) can facilitate the accurate diagnosis of these respiratory diseases. Specifically of interest is L. pneumophila infection, which first presents as bronchopneumonia but later converts into lobar pneumonia. The mechanism behind this conversion involves inflammatory exudates that can pass through Kohn’s pores and Lambert’s channel during L. pneumophila infection. Therefore, L. pneumophila pneumonia pattern first presents as segmental at the start of infection and after 2 weeks or more converts into non-segmental type. Overall, this review demonstrates that the nonsegmental distribution pattern can be very valuable in making respiratory disease diagnosis.

Identification of Orch3, a Locus Controlling Dominant Resistance to Autoimmune Orchitis, as Kinesin Family Member 1C

Experimental autoimmune orchitis (EAO), the principal model of non-infectious testicular inflammatory disease, can be induced in susceptible mouse strains by immunization with autologous testicular homogenate and appropriate adjuvants. As previously established, the genome of DBA/2J mice encodes genes that are capable of conferring dominant resistance to EAO, while the genome of BALB/cByJ mice does not and they are therefore susceptible to EAO. In a genome scan, we previously identified Orch3 as the major quantitative trait locus controlling dominant resistance to EAO and mapped it to chromosome 11. Here, by utilizing a forward genetic approach, we identified kinesin family member 1C (Kif1c) as a positional candidate for Orch3 and, using a transgenic approach, demonstrated that Kif1c is Orch3. Mechanistically, we showed that the resistant Kif1cD2 allele leads to a reduced antigen-specific T cell proliferative response as a consequence of decreased MHC class II expression by antigen presenting cells, and that the L578→P578 and S1027→P1027 polymorphisms distinguishing the BALB/cByJ and DBA/2J alleles, respectively, can play a role in transcriptional regulation. These findings may provide mechanistic insight into how polymorphism in other kinesins such as KIF21B and KIF5A influence susceptibility and resistance to human autoimmune diseases.