Study of ocular manifestations in tuberculosis and its association with HIV AIDS in a tertiary care hospital.

OBJECTIVE: To assess and understand the prevalence and clinical presentation of ocular morbidity in patients suffering from tuberculosis and compare it with ocular involvement in patients coinfected with tuberculosis and HIV AIDS. MATERIALS AND METHODS: This was a non-comparative, observational, cross sectional study done on 580 patients, who were diagnosed cases of tuberculosis, pulmonary or extrapulmonary, on or off treatment, visiting the Ophthalmology OPD, Tuberculosis OPD and ART Centre of the institute in the period from March 2015 to March 2018, screened for ocular morbidity. RESULTS: Out of 580, 408 patients had only tuberculosis and 172 had tuberculosis with HIV AIDS. 108 patients were found to have ocular involvement (18.6%) out of which 63 were males and 45 were females. The prevalence of ocular morbidity in patients with only tuberculosis was found to be 16.4% and in those having both tuberculosis and HIV AIDS was found to be 23.8%. CONCLUSION: Our study concludes that posterior uveitis, pan uveitis, periphlebitis and vitritis are the most common ocular manifestations in tuberculosis. In patients with both tuberculosis and HIV most common ocular findings included vitritis and herpes zoster ophthalmicus. Our study also concludes that lower CD4 counts (less than 200) in HIV AIDS patient is significantly associated with ocular involvement.

Acute polyarthritis in a young patient caused by meningococcal and parvovirus B19 infections: a case report and review of the literature.

BACKGROUND: Meningococcal infection is a multifaceted disease including acute polyarthritis. This presentation should be known by clinicians in order to prevent delay in treatment. We report what we believe to be the first case of an association of parvovirus B19 and meningococcal polyarthritis in a young adult. CASE PRESENTATION: A 19-year-old Caucasian woman presented to our hospital with fever, intense leg pain, and a transient rash. A physical examination showed asymmetric polyarthritis and no neurological abnormalities. A parvovirus B19 polymerase chain reaction performed using a blood sample and knee fluid aspirate came back positive, but serology was negative for immunoglobulin M and positive for immunoglobulin G. A blood culture was positive for serotype C meningococcus; a polymerase chain reaction performed for Neisseria meningitidis was positive in joint fluid but negative in blood samples (performed after antibiotic treatment had begun). Our patient was treated with ceftriaxone for 15 days, associated with analgesic therapy. Hydroxychloroquine treatment was introduced 5 months after the onset of polyarthritis because of persisting inflammatory arthralgia. CONCLUSIONS: To the best of our knowledge, this is the first case report of polyarthritis caused by concomitant meningococcal and parvovirus B19 infections. This unusual presentation of meningococcal disease may have resulted from the persistent parvovirus B19 infection. Our experience with this case illustrates the need for a systematic approach to the diagnosis of febrile acute polyarthritis. Only long-term follow-up will reveal if this infectious polyarthritis will evolve towards an autoimmune rheumatism.

Detection of serum IgG4 levels in patients with IgG4-related disease and other disorders.

OBJECTIVE: Elevated serum IgG4 levels are an important hallmark for diagnosing IgG4-related disease (IgG4-RD), but can also be observed in other diseases. This study aimed to compare two different testing methods for IgG4: ELISA and nephelometric assay. Both assays were used to measure serum IgG4 concentrations, and to assess the prevalence of high serum IgG4 levels in both IgG4-RD and non-IgG4-RD diseases. METHODS: A total of 80 serum samples were tested using the nephelometric assay and ELISA method that we established. Serum IgG4 concentrations were determined by ELISA for 957 patients with distinct diseases, including 12 cases of IgG4-RD and 945 cases of non-IgG4-RD. RESULTS: IgG4 levels from 80 selected serum samples examined by ELISA were in agreement with those detected using the nephelometry assay. Meanwhile, the serum IgG4 concentrations measured by ELISA were also consistent with the clinical diagnoses of patients with IgG4-RD during the course of disease. The Elevated levels of serum IgG4 (>1.35 g/L) were detected in all IgG4-RD (12/12) patients, and the prevalence of high IgG4 serum levels was 3.39% in non-IgG4-RD cases. Among them, the positive rates of serum IgG4 were 2.06% in patients with carcinoma and 6.3% in patients with other non-IgG4 autoimmune diseases. CONCLUSION: Our established ELISA method is a reliable and convenient technique, which could be extensively used in the clinic to measure serum IgG4 levels. High levels of IgG4 were observed in IgG4-RD. However, this phenomenon could also be observed in other diseases, such as carcinomas and other autoimmune diseases. Thus, a diagnosis of IgG4 disease cannot only be dependent on the detection of elevated serum IgG4 levels.

Enterocolic lymphocytic phlebitis as a newly recognized manifestation of IgG4-related disease.

Herein we present a case of a 65-year-old woman with enterocolic lymphocytic phlebitis (ELP) who presented with anemic syndrome and in whom severe stenosis of the right flexure of large bowel was detected. The microscopic examination revealed fibrosis of the submucosa and lymphoplasmacytic phlebitis of small veins and venules, whereas arteries were spared. There were 110 IgG4-positive and 160 IgG-positive plasma cells in 1 high-power field, respectively, with corresponding IgG4/IgG ratio of 0.69. The IgG4 serum level was 2.42 g/L. According to the currently proposed criteria, this ELP case is the first that may be diagnosed as definite IgG4-related disease (IgG4-RD). Although based on the sole case description, taken together with a recent review and a case report, we presume that a subset of ELPs is a manifestation of IgG4-RD.

Enterocolic lymphocytic phlebitis of the cecal pole and appendix vermiformis with increase of IgG4-positive plasma cells.

Here we describe the clinicopathological course of a 20-year-old female patient with enterocolic lymphocytic phlebitis (ELP) of the appendix vermiformis and cecal pole with increase of IgG4-positive plasma cells. The patient presented with acute abdomen, suspicious of acute appendicitis. Diagnostic laparoscopy showed tumefaction of the cecal pole and appendix vermiformis. Histologic examination revealed mural thickening and a dense lymphoplasmocytic, partly obliterative infiltrate of the veins with sparing of the arteries, diagnostic of ELP. In addition, we found an elevated number of IgG4-positive plasma cells blended in with the lymphocytes. The IgG4-to-IgG ratio accounted for >40 %. This case meets the histopathological criteria requested for IgG4-related disease (IgG4-RD) and thus opens the possibility that ELP might be part of the IgG4-RD spectrum.

IgG4-related sclerosing disease: an emerging entity frequently misdiagnosed.

IgG4-related sclerosing disease, a multiorgan system disease that has been identified in the last 10 years, is a fibroinflammatory condition with a marked propensity to manifest itself as mass forming lesions characterized by three main histological features (sclerosis, obliterative phlebitis and lymphoplasmacytic infiltrate) and by the presence of abundant IgG4+ plasma cells, frequent elevation of serum IgG4 and a dramatic initial response to steroid therapy. The aim of this mini-review is to increase the capacity to identify the characteristic features of IgG4-related sclerosing disease in specific organs and in two newly proposed entities (urethral caruncle and paratesticular fibrous pseudotumor) using biopsy specimens and methods of counting IgG4. In addition we examine the relationship between IgG4-related sclerosing disease and malignancy. In fact, an increased ability to recognize the characteristic features of IgG4-related sclerosing disease would play an extremely important role in avoiding unnecessary surgery in favor of initiating corticosteroid therapy.

Idiopathic vs. secondary retroperitoneal fibrosis: a clinicopathological study of 12 cases, with emphasis to possible relationship to IgG4-related disease.

Retroperitoneal fibrosis (RF) is a rare disease characterized by inflammation and fibrosis of retroperitoneal soft tissues. It is classified into two types: idiopathic (iRF) and secondary (sRF). The aim of the study was to investigate the relationship between iRF and IgG4-related disease (IgG4-RD) and to eventually extend the clinicopathological features of this condition by analysis of the sample comprising six iRF and six sRF patients. The iRF patients included four males and two females, aged 12-62 years (median 55 years). Two lesions were periaortic, one was periureteral, and three cases showed both periaortic and periureteral localization. Two patients had increased serum levels of IgG4. None of the patients developed any manifestation of IgG4-RD during the follow-up period ranging for 15-133 months (median 43 months). Microscopically, in two iRF cases, fibrosis was highly cellular encircling the vessels, nerves, and paraganglia. Phlebitis was found in all cases and being obliterative in four. Lymphocytic inflammation with formation of follicles and plasma cell infiltration were scored as severe in five iRF cases. The numbers of IgG-positive plasma cells ranged 0-373 per 1 HPF (high power field; median 132) and of IgG4-positive plasma cells 0-238 per 1 HPF (median 91). The IgG4/IgG ratio values ranged 0.38-0.74 (median 0.68). Two of the iRF cases were diagnosed as definite and three cases as probable IgG4-RD. To the contrary, none of the sRF cases met the diagnostic criteria for either definite, probable, or possible IgG4-related disease. Our results indicate that a substantial portion of iRF cases, including some of very rare pediatric cases, is a manifestation of IgG4-RD.

IgG4-related disease: a systemic condition with characteristic microscopic features.

During the first decade of the 21st century, IgG4-related disease (IgG4-RD), a fibroinflammatory condition occurring at multiple sites of the body, has been newly recognized. As indicated by its name, elevation of IgG4 in the serum and tissue is a common denominator of IgG4-RD. Since the observation that many patients suffering from autoimmune pancreatitis (AIP), a specific type of chronic pancreatitis, had elevated serum levels of IgG4, it was reported that these patients also had increased numbers of IgG4-positive cells in the inflamed pancreatic tissue. In 2003, it was noted that a significant proportion of the AIP patients had a variety of extrapancreatic fibroinflammatory lesions, and that AIP therefore was the pancreatic manifestation of a systemic disease. Among these extrapancreatic manifestations, the extrahepatic bile ducts, salivary glands, thyroid, lymph nodes and retroperitoneum were most frequently reported, and infiltration of the tissue with IgG4-positive cells was also noted at these sites. During the following years, a multitude of other conditions have been added to the spectrum of IgG4-RD. While some of these organ manifestations were once believed to represent diseases on their own, others have been included under the umbrella of "multifocal fibrosclerosis". Biopsies or resection specimens from affected organs in IgG4-RD reveal several common microscopic features irrespective of the site of the lesion. Cellular and storiform fibrosis, lymphoplasmacytic infiltration, increased numbers of IgG4-positive cells and obliterative phlebitis are among the most characteristic histological changes in IgG4-RD. The detailed etiology, pathophysiology, epidemiology and clinical long-term outcome have at present yet to be fully elucidated. This paper focuses on the microscopic features, diagnosis and differential diagnosis of the different organ manifestations of IgG4-RD, and the current concepts of its pathogenesis will also be addressed.

Autoimmune pancreatitis: a guide for the histopathologist.

Autoimmune pancreatitis (AIP) is a distinct form of pancreatitis with a characteristic histological appearance. Clinically and radiologically, many of these patients show enlargement of pancreas and pancreatic duct/bile duct strictures, thus mimicking pancreatic carcinoma. There are 2 forms of the disease: (1) type 1 AIP characterized by storiform type fibrosis, obliterative phlebitis, and elevated numbers of immunoglobulin G4 (IgG4) positive plasma cells, typically >50 per high-power field, and, (2) type 2 AIP characterized by granulocytic epithelial lesions and only occasional IgG4-bearing plasma cells, typically <10 per high-power field. The type 1 variant of AIP is the pancreatic manifestation of IgG4-related disease, thus both pancreatic and extrapancreatic recurrences are common. The type 2 variant is unrelated to IgG4-related disease, and disease recurrence is uncommon. Both forms of the disease show a swift response to immunosuppressive therapy. This review highlights the clinical and pathological differences between the 2 forms of AIP. We also review guidelines that assist in distinguishing AIP from its closest mimic, pancreatic adenocarcinoma.

Orbital inflammation in IgG4-related sclerosing disease.

IgG4-related sclerosing disease is a recently described systemic inflammatory disease that should be considered when evaluating patients with nonspecific orbital inflammation (pseudotumor). Orbital biopsy is necessary to establish a diagnosis and demonstrates lymphoplasmacytic infiltration, fibrosis, obliterative phlebitis of medium and small veins, and variable degrees of eosinophilia. We report the clinical and histopathological findings of 2 patients who developed chronic orbital inflammation as a manifestation of IgG4-related sclerosing disease. The 2 cases illustrate the widely varying clinical characteristics of this elusive disease.

The Clinical and Pathological Features of IgG(4)-Related Disease.

The rapidly emerging disorder now known as IgG(4)-related disease (IgG(4)-RD) includes a variety of clinical entities once regarded as being entirely separate diseases. Manifestations of IgG(4)-RD have now been reported in essentially all organ systems. Regardless of which organ is involved, tissue biopsies reveal striking histopathological similarities. The hallmark pathology findings are diffuse lymphoplasmacytic infiltrates, abundant IgG(4)-positive plasma cells, modest tissue eosinophilia, and extensive fibrosis. Tumorous swelling and obliterative phlebitis are other frequently observed features. Polyclonal elevations of serum IgG(4) are found in approximately 70% of patients. Many questions pertaining to the etiology, pathophysiology, epidemiology, clinical features, therapy, disease monitoring, and long-term outcomes remain to be addressed. This paper focuses on the clinical and pathological features of IgG(4)-RD.

Cancer-associated retinopathy with retinal periphlebitis in a patient with ovarian cancer.

PURPOSE: To describe a case of cancer-associated retinopathy (CAR) due to ovarian cancer presenting with retinal periphlebitis and a negative-type pattern electroretinogram (ERG). DESIGN: Case report. METHODS: Retrospective chart review. RESULTS: A negative-type ERG in the setting of progressive vision loss and retinal periphlebitis led to the discovery of metastatic ovarian cancer and ultimately the diagnosis of CAR. CONCLUSIONS: CAR can present with periphlebitis and a negative-type ERG. Greater awareness of these associations may allow for earlier detection of future cases.

Retroperitoneal fibrosis: a clinicopathologic study with respect to immunoglobulin G4.

The possible involvement of immunoglobulin G4 (IgG4) in the pathogenesis of idiopathic sclerosing lesions has been suggested. In this study, a clinicopathologic analysis was performed to reveal characteristics of retroperitoneal fibrosis relating to IgG4. The study involved 17 patients with retroperitoneal fibrosis. Immunohistochemistry revealed numerous IgG4-positive plasma cell infiltrates in 10 cases (IgG4-related), but only a few positive cells in 7 cases (non-IgG4-related). All patients with IgG4-related retroperitoneal fibrosis were male, whereas all except 1 with unrelated lesions were female. Histologically, eosinophilic infiltration (>5 cells per high-power field) and obliterative phlebitis were commonly observed in IgG4-related lesions. Serologically, serum IgG and IgG4 concentrations were significantly higher in the IgG4-related cases, with the IgG4 concentrations all over 135 mg/dL (the upper limit of the normal range). Steroid therapy was performed in 13 cases, and was effective irrespective of IgG4. Three patients had recurrence during the follow up. Five of 10 IgG4-related cases had sclerosing lesions at other sites. The only tests that reliably distinguish the 2 groups were serum IgG4 levels or IgG4/IgG ratio in the plasma cells in a tissue biopsy. The only major clinical difference was the striking male predominance in IgG4-related cases. In conclusion, this study revealed that retroperitoneal fibrosis could be classified as IgG4-related or not. This distinction seems important to help better characterize the biology/pathogenesis of both groups and better predict the possibility of other IgG4-related processes at other anatomic sites.

Inflammatory myofibroblastic tumor versus IgG4-related sclerosing disease and inflammatory pseudotumor: a comparative clinicopathologic study.

Inflammatory pseudotumor (IPT) is a heterogeneous group of lesions occurring in various organs, which is histologically characterized by fibroblastic and myofibroblastic proliferation with inflammatory infiltrate. Inflammatory myofibroblastic tumor (IMT) is a neoplastic counterpart of IPT, which shows aberrant expression of ALK and its gene translocation. In contrast, the concept "immunoglobulin (Ig)G4-related IPT" in the lung, liver, and pancreas has recently been proposed as a member of IgG4-related sclerosing disease. In this study, we compared the histopathologic features with an emphasis on IgG4 expression between 22 cases of IMT and 16 cases of IgG4-related sclerosing disease, including chronic sclerosing sialadenitis (n=8), mass-forming autoimmune pancreatitis (n=3), sclerosing cholangitis (n=1), retroperitoneal fibrosis (n=2), and chronic sclerosing dacryoadenitis (n=2). Bland-looking spindle cell proliferation with fibrosis and inflammatory infiltrate of lymphocytes and plasma cells was the common morphologic feature in both lesions. Obstructive phlebitis was observed in all of the IgG4-related sclerosing lesions, but in only 1/22 (4.5%) of IMT. The immunohistochemical expression of ALK was observed in 15/22 (68.2%) of IMT and 0/16 (0%) of IgG4-related sclerosing disease. The number of IgG4-positive plasma cells and the ratio of IgG4+/ IgG+ plasma cells were each significantly lower in IMT than in IgG4-related sclerosing disease [mean 6.4/HPF vs. 178.3/HPF (P<0.0001), 3.0% vs. 67.5% (P<0.0001), respectively]. The results suggest that IgG4 does not play an important role in the pathogenesis of IMT. In addition, the evaluation of IgG4+ plasma cells and the ratio of IgG4+/IgG+ plasma cells and the presence of obstructive phlebitis may be useful for the differential diagnosis between IMT and IgG4-related sclerosing disease.

Are tumefactive lesions classified as sclerosing mesenteritis a subset of IgG4-related sclerosing disorders?

BACKGROUND: The relationship between tumefactive lesions classified as sclerosing mesenteritis and IgG4-related sclerosing disorders (eg, lymphoplasmacytic sclerosing pancreatitis/autoimmune pancreatitis) remains uncertain. AIMS: To review lesions coded as "sclerosing mesenteritis" for findings in keeping with IgG4-related sclerosing disorders. METHODS: Inclusion in the study required available paraffin blocks for IgG4 staining and documentation of a mass lesion. RESULTS: A total of nine mesenteric lesions (3-14 cm) were identified in 6 male and 3 female patients. On H&E-stained sections, all were characterised as loosely marginated fibroinflammatory processes with variable amounts of fat necrosis. Lymphocytic venulitis/phlebitis was identified in 8 of 9 cases. IgG and IgG4 expression in lesional plasma cells was assessed by immunohistochemistry. IgG4-positive plasma cells were counted in the areas of greatest density in >or=3 high power fields (HPFs). The highest number per HPF was recorded and a score assigned based on the following scale: <5/HPF, none/minimal; 5-10/HPF, mild; 11-30/HPF, moderate; >30/HPF, marked. The relative proportion of IgG4-reactive plasma cells to total IgG-positive plasma cells was assessed. IgG4-reactive plasma cells ranged from 0 to >100 in the most dense zones (3 cases, none/minimal; 4 cases, moderate; 2 cases, marked). CONCLUSIONS: Although this study is limited by small numbers, findings suggest that some tumefactive lesions regarded as sclerosing mesenteritis may be a subset of IgG4-related sclerosing disorders.

Inflammatory abdominal aortic aneurysm: close relationship to IgG4-related periaortitis.

Inflammatory abdominal aortic aneurysm (AAA) is a member of a family of disorders referred to as "chronic periaortitis" together with retroperitoneal fibrosis. Retroperitoneal fibrosis is included in IgG4-related disease, which is characterized by numerous infiltrating IgG4-positive plasma cells and high serum IgG4 concentrations. However, the relationship between IgG4-related disease and inflammatory AAA has not been documented. In this study, we examined the clinicopathologic characteristics of inflammatory (10 cases) and atherosclerotic (22 cases) AAAs, based on the hypothesis that inflammatory AAA might be related to IgG4-related disease. Cases of inflammatory AAA could be classified into 2 groups based on immunostaining of IgG4. Four patients showed diffuse infiltration of abundant IgG4-positive plasma cells (IgG4-related cases), whereas the remaining 6 cases of inflammatory AAA and all cases of atherosclerotic AAA had only a few IgG4-positive plasma cells (non-IgG4-related cases). IgG4-related inflammatory AAA was pathologically characterized by the frequent infiltration of eosinophils, lymph follicle formation, perineural inflammatory extension, and inconspicuous infiltration of neutrophils compared with non-IgG4-related inflammatory AAA. Obliterative phlebitis, which is venous occlusion with inflammatory cell infiltration, is observed in all IgG4-related cases. In addition, serum IgG4 concentrations were significantly higher in IgG4-related inflammatory AAA (109 to 559 mg/dL, normal range: 4 to 110 mg/dL) than non-IgG4-related inflammatory AAA (32 to 59 mg/dL) and all atherosclerotic AAA (12 to 83 mg/dL). In conclusion, inflammatory AAAs might be classified into 2 groups: IgG4-related or nonrelated. The former might be one of the IgG4-related diseases, and could be included in IgG4-related periaortitis together with retroperitoneal fibrosis.

Fasudil, a Rho-kinase inhibitor, inhibits leukocyte adhesion in inflamed large blood vessels in vivo.

OBJECTIVE AND DESIGN: Emerging data suggest that Rho-kinase signaling may regulate numerous aspects of inflammatory reactions. Herein, we investigated the role of Rho-kinase in inflammatory interactions between leukocytes and the endothelium in femoral arteries and veins in vivo. MATERIAL AND METHODS: Mice were injected with lipopolysaccharide (LPS) and Rho-kinase was inhibited by pre-treatment with fasudil, which is a highly selective inhibitor of Rho-kinase. Six hours after LPS challenge, intravital fluorescence microscopy of the femoral vessels was performed and leukocyte-endothelium interactions were visualized after in vivo staining with rhodamine 6G. RESULTS: LPS increased leukocyte rolling and adhesion in femoral arteries and veins. Pre-treatment with fasudil had no effect on leukocyte rolling but significantly decreased venular leukocyte adhesion by 85% and completely abrogated leukocyte adhesion in femoral arteries in endotoxin-treated mice. CONCLUSIONS: We conclude that Rho-kinase signaling regulates LPS-induced leukocyte adhesion in femoral arteries and veins in vivo and that inhibition of Rho-kinase may be useful in the treatment of pathological inflammation in large blood vessels of the vascular system.

The in vitro effects of quinupristin/dalfopristin, erythromycin and levofloxacin at low concentrations on the expression of different cell adhesion molecules on the surface of endothelial cells (Eahy926).

OBJECTIVES: Infusion phlebitis is a common clinical problem associated with some antimicrobial agents. The pathomechanism of infusion phlebitis has not yet been elucidated, however, it has been proposed that chemical irritation of the endothelium leads to subsequent sterile inflammation with recruitment and migration of leukocytes. In the present study, cultured endothelial cells were exposed to antibiotics at clinically relevant concentrations to detect changes in various cell surface markers. METHODS: Cells from the endothelial hybrid cell line Eahy926 were exposed to quinupristin/dalfopristin, erythromycin and levofloxacin at increasing concentrations (3, 10, 30 and 100 mg/l) for 24 h. After washing, the cells were marked with monoclonal antibodies against different cell surface antigens (intercellular cell adhesion molecule-1 [ICAM-1], platelet-endothelial cell adhesion molecule-1 [PECAM-1], vascular cell adhesion molecule-1 [VCAM-1], E-selectin, L-selectin, CD34, alpha(2), alpha(5), beta(1) and beta(4) integrin chains and analysed by flow cytometry. For comparison, cells were either untreated or incubated with tumor necrosis factor alpha (TNF-alpha) at a concentration of 10 ng/ml and analysed for ICAM-1, VCAM-1 and E-selectin expression. RESULTS: There was an increase in ICAM-1 expression on endothelial cells with increasing concentrations of quinupristin/dalfopristin. VCAM-1, E-selectin, L-selectin and CD34 showed an excursive upregulation at the concentration of 100 mg/l only, while no consistent changes were observed for PECAM-1 and the integrins. Markedly less prominent changes in the expression of these adhesion molecules were seen with erythromycin while no relevant changes at all occurred with levofloxacin. The absolute change in ICAM-1 activation with quinupristin/dalfopristin at 100 mg/l (34.4%) was less pronounced than that observed after stimulation with TNF-alpha (>80%). CONCLUSIONS: The results of this study indicate that antibiotics with a high potential for local cytotoxicity may cause an inflammatory response by endothelial cells even at rather low concentrations. The increase in expression of cell surface markers involved in cell-cell interaction could be an important mechanism in the development of infusion phlebitis.