Abstract
Concurrent Session
2:00 PM
Friday, February 19, 1999
Diagnostic Criteria For Sarcoidosis Of The Sinuses.
Although newer technologies facilitate its diagnosis and treatment, little is known about sarcoid of the sinuses. We established case finding criteria for sarcoid of the sinuses and identified nine patients in the published literature of some 50 reports and an additional six patients from our clinics fulfilling these criteria. An analysis of associated clinical, laboratory, histopathologic, radiologic and laboratory findings was undertaken. Nasal obstruction and chronic sinusitis were the usual presenting complaints. Five of our six patients had nasal mucosal abnormalities which included crusting, studding, plaque-like changes or polyps. Similar lesions were present within the sinuses in four of these six individuals. Lupus pernio was not noted in either series and, more often than not, patients had extrapulmonary sarcoidosis involving multiple organs. Radiologic studies showed extensive and often complete opacification of the sinuses and nose similar to that seen in diffuse polyposis. Biopsies of the sinus mucosa showed granulomas of various patterns and there were inconsistent accumulations of eosinophils, plasma cells, mononuclear cells and giant cells in some specimens. Fibrinoid necrosis, non-polarizable foreign material and Langhan's cells were present in about half of the specimens. However, there were no distinctive histopathologic findings in the sinus mucosa which distinguished sinus from reported pulmonary histopathology. Angiotensin-inhibiting enzyme levels were elevated in about half of our patients. Laryngeal involvement was present in two case reports and caused apparent asphyxiation of one of our patients. Three of the patients in our series had apparent responses to nasal or oral corticosteroid therapy and three others had ongoing symptoms.
On the basis of this experience, we propose diagnostic criteria for sarcoidosis of the sinuses. These include (1) radiologic evidence of sinusitis, (2) histopathologic confirmation of non-caseating granuloma in sinus tissue supported by special stains, (3) negative serologic testing for syphilis and ANCA, and (4) no clinical evidence of other disease processes associated with granulomatous nasal and sinus inflammation. In concert with recently proposed staging recommendations, these criteria will provide the basis for assessing both the natural history and the effectiveness of treatment in sarcoidosis of the sinuses.
Late Onset Generalized Urticaria And Arthralgias After Hepatitis B Vaccine:
The adverse reactions after the use of recombinant Hepatitis B Vaccine are uncommon. For example in one study an overall rate of one adverse effect per 15,500 doses was reported. The generalized urticarial reactions are rare, may occur within 12-24 hours and have been attributed to the sensitivity to the components of the vaccine.
We are reporting two patients who presented with generalized urticaria and arthralgias 10-12 days after the second dose of Hepatitis B vaccine. A 21 year old male and a 41 year old female with negative Hepatitis B Serology received the first dose of Hepatitis B vaccine without any local or systemic adverse reactions. Four weeks later both received second doses of Hepatitis B vaccine without any immediate local or systemic reactions. Both patients reported severe generalized urticaria and arthralgias involving knee joints, ankle joints, and joints of both hands. Laboratory studies revealed normal complete blood count (CBC), serum complement C3, C4, urine analysis and renal function and negative ANA.
Treatment with Hydroxyzine and Loratidine failed to alleviate symptoms. Three days later patient one received 60 mg of Prednisone and patient 2 received 24 mg of Methylprednisolone which was tapered over a two week period, and resulted in complete resolution of symptoms.
Case I was negative for Hepatitis surface antibody at the time of symptoms but became positive three months later. Case 2 was positive for Hepatitis B surface antibody at the time she developed generalized Urticaria.
We suggest that generalized urticaria and arthralgia after 2nd dose of Hepatitis B vaccine were most likely due to serum sickness type reaction due to Hepatitis B vaccine. This conclusion is based on the facts that a) The symptoms developed 10-12 days after the second dose of vaccine, b) The urticarial lesions lasted more than 72 hours, c) Failure to respond to HI antihistamine d) Resolution of symptoms after the use of corticosteroids.
Anti-Cd20 Monoclonal Antibody For The Treatment Of Post-Transplant Lymphoproliferative Disease In A Pediatric Heart Transplant Recipient.
Post-transplant lymphoproliferative disease (PTLD) is a morphologically heterogeneous group of Epstein-Barr virus (EBV) driven B cell lymphoid proliferations of varying clonal composition. It is seen most frequently after heart or heart-lung transplantation and in children who are EBV negative prior to transplant. While some cases of PTLD regress with a reduction in immunosuppressive therapy, others progress despite all measures to a frankly malignant phenotype that carries a high mortality rate.
Previous investigators have used engineered B cell monoclonal antibodies to successfully treat PTLD in transplant recipients. We report the first use of a commercially available anti-CD20 monoclonal antibody (Rituxan) in a pediatric transplant patient with progressive PTLD.
LF underwent cardiac transplantation at the age of eight years for dilated cardiomyopathy. She had an uneventful post-transplant course and was maintained on triple drug immunosuppression. At the age of fifteen, she developed an acute infectious mononucleosis-like syndrome with progressive cervical lymphadenopathy. A lymph node biopsy revealed EBV-associated polymorphous, polyclonal lymphoproliferative disease. Her lymphadenopathy regressed with an initial reduction in immunosuppression, nodal excision and ganciclovir therapy. However, eight months later her cervical lymphadenopathy returned. A lymph node biopsy showed recurrent polymorphous PTLD with evidence of a clonal B cell population.
Rituxan therapy was started at a dose of 375 mg/m2 weekly for four weeks. The patient experienced no side effects with the infusions, and within two months there was a dramatic reduction in her lymphadenopathy. A follow-up CAT scan showed a greater than 75 percent reduction in her cervical lymph nodes. She remains well four months post therapy with no recurrence of lymphadenopathy.
Anti-CD20 monoclonal antibody holds promise as a treatment for PTLD in patients who do not respond to an initial reduction in immunosuppression, surgical excision, and anti-viral therapy.
Mucosal Versus Non-Mucosal Iga Anticardiolipin And Anti-β2 Glycoprotein 1.
IgA anticardiolipin (IgA-aCL) and anti-β2 glycoprotien I(IgA-anti-β2GP1) have recently been reported to be the most prevalent isotype in some groups of patients with SLE and HTLV-1 related myelopathy (HAM). To investigate whether these antibodies are mainly of mucosal origin we tested 65 serum samples, all positive for IgA-aCL from 15 HAM, 23 Jamaican (J-SLE) and 27 African-American (AA-SLE) SLE patients and also 68 sera, all positive for IgA-anti-β2GP1, from the same groups (10, 28 and 30, respectively) for J-chain (of dimeric mucosal IgA) and IgA subisotypes IgAl (central immune system) and IgA2 (mucosal) by ELISA. The number of sera a positive for J-chain is shown below:
Chi-Square test *) p=0.01; **) p=0.02, aCL versus anti-β2GP1 Linear regression analysis of the OD values for IgAl and IgA2 subisotypes of aCL and anti-β2GP1 revealed a strong and significant correlation between IgAl and IgA2 aCL in all groups of subjects (r=0.60 to r =0.93) and between IgAl and IgA2 anti-β2GP1 in all groups (r =0.75 to r =0.98). The results are consistent with a close relationship between mucosal and non-mucosal IgA aCL and anti-β2GP1 levels in serum and with greater mucosal production of IgA anti-β2GP1 than IgA ACL.
Ige-Binding Epitopes Of Pen A 1 (Shrimp Tropomyosin): Localization Of Antigenic Regions Using Overlapping Peptides.
Although the amino acid sequences and epitopes of numerous allergens have been determined over the last years, the molecular basis of allergenicity still remains unclear. Even though tropomyosins are highly homologous muscle proteins present in different animal species, only some of them are allergenic. While tropomyosin is the major allergen in brown shrimp, Penaeus aztecus, beef, pork and chicken tropomyosins are not allergenic; thus, analysis of this family of proteins can help our understanding of the relationship between protein structure and allergenicity. In order to characterize Pen a 1 epitopes, 46 overlapping peptides (15 amino acids long, with an offset of 6) comprising the 284 amino acids of Pen a 1 were synthesized (SPOTs system, Genosys), and tested for IgE antibody binding with sera from 18 shrimp-allergic subjects. Based on frequency and intensity of the IgE binding, five main allergenic regions were identified: Pen a 1 (43-57), Pen a 1 (85-105), Pen a 1 (133-159), Pen a 1 (187-201), Pen a 1 (247-284). Pen a 1 (133-159) and Pen a 1 (247-284) overlap with two IgE-binding peptides, Pen a 1 (136-148) and (262-282), previously identified by our group using a recombinant peptide library. Also Pen a 1 (133-159) and Pen a 1 (43-57) partially overlap with Pen i 1 (153-161) and Pen i 1 (50-66) respectively, the two IgE-reactive peptides previously identified in the tropomyosin of Indian shrimp Penaeus indicus. IgE-binding sequences identified in Pan a 1 appear to occur at regular intervals in the molecule (approximately every 42 amino acids), suggesting some relation with the coiled-coil structure of tropomyosin. Further studies will provide a better understanding of the relationship of protein structure and allergenicity.
The Retrovirus Htlv-1 Is Associated With Anticardiolipin But Not Anti-β2Glycoprotein 1 Antibodies In Tropical Spastic Paraparesis.
HTLV-1-associated myelopathy (HAM) also termed Tropical Spastic Paraparesis (TSP) is a neurologic disease that is endemic in the Caribbean, Japan and elsewhere. IgA anticardiolipin (aCL) antibodies have been associated with biologic false positive treponemal serology in HAM-TSP. To assess whether a) anti-β2GP1 antibodies also occur in HAM-TSP and b) the role of HTLV-1 in the presence of aCL and/or anti-β2GP1 in HAM-TSP we studied sera from: 50 TSP (all HTLV-1-positive) 128 SLE and 69 blood donors (34 healthy carriers of HTLV-1 and 35 HTLV-1-negative controls) in Kingston, Jamaica. All the samples were tested by ELISA for both aCL and anti-β2GP1 of IgG, IgM and IgA isotypes. Comparison between the mean OD values was made by the r-test and showed that the IgA-aCL and IgA-anti-β2GP1 levels were significantly higher in TSP patients as compared to HTLV-1-positive controls (0.173 vs 0.101; p=0.0004 and 0.191 vs 0.02, respectively) and HTLV-1-negative controls (0.173 vs 0.068 and 0.191 vs 0.139, respectively; p<0.0001). When HTLV-1-positive were compared with HTLV-1-negative controls, IgA aCL was significantly increased (0.101 vs 0.068; p=0.01) but not IgA anti-β2GP1 (0.0150 vs 0.139; p=0.48). Mean levels of aCL and anti-β2GP1 were similar in TSP and SLE patients with the exception of IgM-aCL (0.105 vs 0.061; p=0.004) and IgM-anti-β2GP1 (0.105 vs 0.077; p=0.008) which were higher in TSP patients. The results suggest that HTLV-1 infection is associated with presence of aCL but not with anti-β2GP1 in TSP. Further studies are needed to define this association and its clinical significance.
Fragrances And Respiratory Reactions.
Asthma/rhinitis patients frequently complain of symptoms following exposure to fragrances. This study assessed respiratory symptoms in subjects who report sensitivity to fragrance. A preliminary questionnaire was administered to 145 allergic/asthmatic adults to assess asthma status, fragrance-induced symptoms, and identification of fragrance brands which elicit symptoms. 125/145 (86%) individuals were asthmatic (81% female and 19% male); 87% reported symptoms upon fragrance exposure. Upper respiratory symptoms were the most frequently reported (81%), followed by shortness of breath with wheezing (77%), conjunctivitis (62%), eczema (30%), and hives (22%). Fifty-eight percent indicated they were allergic to fragrance; the top eight reported fragrances by asthmatics were White Diamonds, Red, Giorgio, Old Spice, Charlie, Poison, Navy and Red Door. Fifteen asthmatics (14 females and 1 male) were challenged in an inhalation chamber with White Diamonds (0.1x-5000x odor threshold atmosphere) for up to 120 minutes. The % change in FEV1 at maximal fragrance concentration ranged from +3.3 to 11.5. The mean decrease in FEV1 was 2.3% (from baseline). No subject had a positive challenge (20% or greater decline in FEV1). During challenge, subjective symptoms were scored every 30 minutes from none to severe by the subject. The highest score during the last 30 minutes of exposure was: (% reporting, fragrance/control): odor (severe, 20/0), nasal (moderate, 20/7), ocular (moderate, 27/13), throat (severe, 7/7), chest (moderate, 27/13), annoyance (moderate, 40/0), and overall acceptability (moderate, 27/0). Results suggest that symptoms reported by asthmatics following exposure to fragrances are more likely due to their effect on the upper airways.
The Production Of Monoclonal Antibodies For The Differentiation Of Penicillium And Aspergillus Species.
Cause and effect relationships between exposure to fungi and health problems are still very difficult to establish and hence guidelines for mold exposure levels are currently not available. This is primarily due to the lack of accurate and precise means of objectively identifying and quantifying levels of fungi in air or settled dust samples. The purpose of the study was to produce monoclonal antibodies (Mabs) for the identification and quantification of Penicillium and Aspergillus species. P. expansum previously identified as one of the most cross-reactive fungi among Penicillium and Aspergillus species was used as model fungus. Five Mabs were raised which detected 5 ng/ml of mycelial extract (5B11), 10 ng/ml (2E6), 25 ng/ml (7F10) and 100 ng/ml (1D8, 2F8) in ELISA, respectively. Mabs 1D8, 2E6 and 2F8 recognize 10 out of 10 Penicillium species but do not react with any of 10 Aspergillus species investigated. Mabs 5B11 and 7F10 react with 7 Penicillium and 10 of the Aspergillus species tested. Thus, reactivity of Mabs 5B11 or 7F10 in the absence of reactivity of any Penicillium-specific Mabs would indicate the presence of an Aspergillus species in the sample. Inhibition tests with spores showed that Mabs 5B11 and 7F10 react with 7 Penicillium and 9 Aspergillus species indicating that mycelium and spores share common epitopes. None of the Mabs, however, showed any cross-reactivity with other common inhalant allergens such as birch, ragweed and grass pollen or mite, cat and dog antigens. Other fungi commonly found in indoor environments such as Alternaria alternata, Aureobasidium pullulans, Botrytis cinerea, Cladosporium cladosporioides, C. herbarum, C. sphaerosporium, Curvularia trifolii, Stachybotrys chartarum and Ulocladium consortiale were not recognized by any Mab. In conclusion, genus-specific Mabs against Penicillium and Aspergillus species have been produced and their potential for indoor air monitoring will be further investigated.
Interleukin-1β And Transforming Growth Factor-β Are Associated With Increased Pathology In γ-Interferon Gene Knockout Mice Infected With Chlamydiae.
The components of the host response to chlamydial genital tract infection that cause tissue damage remain to be determined. Normal female C57 mice resolve chlamydial genital tract infection in 3 to 4 weeks, whereas C57 mice deficient in the interferon-γ gene (IFNγKO) develop a low grade persistent infection. Upon sacrifice, IFNγKO mice exhibit gross purulence in the uterine horns and severe fibrinous peritoneal disease likened to Fitz-Hugh-Curtis syndrome. Histopathological scoring of mesosalpingeal tissues from mice sacrificed on day 35 of infection reveal significantly increased inflammation and fibrosis in the IFNγKO mice compared to normal C57 mice (neutrophils:4+ vs. 1+; lymphocytes:3+ vs. 1+; fibrosis: 1+ vs. none). Endocervical secretions collected on interval days over the course of infection in the two groups reveal significant differences in levels of IL-1β and TGF-β determined by ELISA. IL-1β increases rapidly in both the normal and IFNγKO mice during the first week of infection, and then begins to decline in both groups. However, on days 14 through 35, IL-1β levels are significantly increased in the IFNγKO mice compared to normals with p= 0.04 by 2-way analysis of variance. Thus, IL-1β is present in increased amounts in the C57 IFNγKO mice compared to normals during the later days of infection, at a time when exudative neutrophils are noted to be significantly increased in the genital tract tissues. Assay for active TGF-β1 revealed a peak on day 7 in the normal C57 mice and then a fall to baseline by day 21. In the C57 IFNγKO mice, significant increases over baseline occurred on days 7, 21, and 28, and continued as late as day 40. Significantly higher amounts of active TGFβ1 were detected in the IFNγKO mice on days 28, and 40 (day 28 = 0.80 ± 0.08 vs. 0.09 ± 0.02 ng/mL; day 40 = 0.43 + 0.07 vs. 0.05 ± 0.01 ng/mL). The late increase in TGFβ seen in the IFNγKO mice is likely in response to the continued presence of IL-1β and other proinflammatory mediators released in the face of a low grade persistent infection. But, despite the fact that TGFβ works to down-regulate the inflammatory response, its continued presence in excess may promote fibrosis and scarring as seen in the mesosalpingeal tissues of the IFNγKO mice.