Evidence Of Granuloma Formation Research Articles

Establishing a Diagnosis of Pulmonary Sarcoidosis.

Pulmonary sarcoidosis is the most prevalent manifestation of sarcoidosis and the commonest diagnosis in clinics for ILD. Due to the lack of a simple and reliable test, making the diagnosis is often challenging. There are three criteria that must always be considered: (1) compatible clinical presentation; (2) evidence of granuloma formation (usually non-caseating); and (3) exclusion of alternative causes of granulomatous disease. There are various tools available for diagnosis, amongst which serum biomarkers like sACE and sIL-2R, HRCT, BAL, EBUS/EUS and sometimes bronchoscopic or surgical lung biopsy are most contributive. However, the degree of invasiveness of the applied test and associated risk to the patient must be weighed against management consequences. In specific situations (e.g., presentation as Löfgren's syndrome) or when there is high suspicion based on HRCT in the context of supportive clinical findings, it might be justifiable to decide on a "working diagnosis of sarcoidosis" and to refrain from further invasive procedures for the patient. This should, however, preferably be agreed upon after discussion in an experienced multidisciplinary team and requires close follow-up of the patient. In general, it is advisable to always maintain a healthy dose of skepticism when making the diagnosis of sarcoidosis, especially when the clinical course of disease gives rise to this.

P055 Granulomatosis with polyangiitis presenting as compressive cervico-thoracic myelopathy

Abstract Background/Aims Granulomatosis with polyangiitis (GPA), a subgroup of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), is a small vessel vasculitis, characteristically associated with granulomatous inflammation. It demonstrates an increased propensity for pulmonary and renal involvement, in addition to ear, nose and throat disease. Central nervous system involvement is rare. Methods We present the case of a 64-year-old male who presented with a 6-week history of upper back pain and gradual deterioration in his gait, with associated lower limb paraesthesia and leg weakness. Results His background medical history is significant for a right sided mastoidectomy, in addition to recurrent episodes of sinusitis, with nasal crusting. He also had a history of frequent epistaxis requiring cauterisation. Neurological examination was significant for a spastic paraparesis, with MRC grade 3/5 weakness in lower limb flexors bilaterally, bilateral lower limb hypertonia, sustained clonus, hyperreflexia, and extensor plantar responses. Sensory examination revealed a mid-thoracic sensory level. Other systems examination were normal. Routine blood tests revealed normal full blood count, renal and liver indices. Inflammatory markers were elevated: C-reactive protein 43 mg/L (0-5 mg/L) and erythrocyte sedimentation rate 80 mm/hr (0-15 mm/hr). Gadolinium enhanced MRI spine and brain revealed a circumferential enhancing mass-like lesion extending from C5 to T9 with compression of the spinal cord at T2 and T3 levels, with normal brain parenchyma. There was evidence of mild sinusitis in the maxillary sinuses. CT of the thorax, abdomen and pelvis was normal. Urinalysis was normal, as was his urinary protein creatinine ratio, and there was no evidence of red cell casts. ANCA revealed a strongly positive perinuclear pattern (p-ANCA) with a markedly elevated myeloperoxidase (MPO) autoantibody, 117 (0-10 units/mL). Proteinase-3 (PR3) was negative. On identification of spinal cord compromise, the patient underwent urgent neurosurgical evaluation, and surgical exploration. During surgery, direct visualisation revealed the lesion to be solid and mass-like and samples of the tissue excised were sent for pathological analysis. Histopathological studies revealed a dense lymphocytic infiltrate, with fibrinoid necrosis of blood vessel wall consistent with vasculitis. There was no evidence of granuloma formation. A diagnosis of MPO positive GPA causing compressive myelopathy was made. He was commenced on high dose glucocorticoids which were tapered as per PEXIVAS reduced dose regimen. In tandem, he was commenced on pulsed intravenous cyclophosphamide. Within days of treatment initiation his neurological status improved, and he is currently engaging in rehabilitation. At his most recent review he was walking independently with crutches. Conclusion Our case highlights a rare cause of myelopathy but one that should enter the differential diagnosis when assessing a patient presenting with myelopathy, particularly with a mass-like lesion on neuroimaging. It should be treated aggressively and as part of the life-threatening organ involvement algorithm. Disclosure P. Harkins: None. R. Field: None. S. Hutchinson: None. R. Conway: None.

P33 A female with a drooping eyelid and positive autoantibodies: mystery solved?

Case report - IntroductionThe presence of autoantibodies in IgG4-related disease (IgG4-RD) can lead to confusion and we present a case to highlight the diagnostic difficulty in this condition.Case report - Case descriptionA 63-year-old Indian female presented with progressive ptosis and swelling of the left eyelid for 2 months. She was referred to the stroke clinic where she was found to have left ptosis with associated swelling. An MRI of the orbit revealed an enlarged left lacrimal gland and mucosal thickening in paranasal sinuses. Her ESR was 20, CRP 2, 15% peripheral eosinophils and IgG 17.55 g/L (6-16). A referral was made to rheumatology due to an abnormal immunological profile: cANCA +, MPO ANCA positive 32 IU/ml (0-3.5) and a strongly positive anti-Ro antibody >600 U/ml (0-10). Differential diagnosis considered: ANCA associated vasculitis (AAV), Primary Sjögren’s syndrome (SS), and IgG4-related orbital disease. She was assessed by the ENT surgeon and there was no sinusitis or evidence of vasculitis. Chest X-ray and CT scan of chest were normal.A left lacrimal gland biopsy revealed reactive lymphoid hyperplasia with numerous plasma cells and eosinophils. Immunohistochemistry revealed over 50% of plasma cells to be IgG4-positive (approximately 100/HPF) suggestive of IgG4-RD. There was no evidence of granuloma formation or malignancy. Serum IgG4 was raised 6.82 g/l (<1.3). A review by ophthalmology revealed no objective evidence of dry eyes. She was treated as IgG4-RD and demonstrated a marked improvement following treatment with oral steroids and azathioprine.Case report - DiscussionIgG4-RD is an immune-mediated systemic fibro inflammatory disease characterised by tumefactive lesions with abundant IgG4-positive plasma cells infiltrating into multiple organs. Isolated IgG4-related ophthalmic disease is present in 23% of patients with IgG4-RD, in whom the lacrimal gland is the most commonly involved structure, followed by orbital fat and extraocular muscles. IgG4-related ophthalmic disease is rare and we need to exclude commoner causes of orbital inflammation (such as thyroid ophthalmopathy, granulomatosis with poly-angiitis, sarcoidosis, and tuberculosis) or malignancy.Case report - Key learning pointsThe diagnosis of IgG4-RD is often challenging. It is well recognised that small vessel vasculitis can increase the number of IgG4-positive plasma cells in tissue biopsies. Additionally, literature reveals biopsy-proven IgG4-RD can have ANCA positivity with and without concomitant presence of ANCA-associated vasculitis and there are case reports of patients who fulfil criteria for both Sjogren’s syndrome and IgG4-RD. As such, diagnosis requires careful correlation of clinical, radiologic and histological features due to the overlapping features in differential diagnoses.

CRYPTOGENIC ORGANIZING PNEUMONIA DISGUISING AS A LUNG MASS

SESSION TITLE: Diffuse Lung Disease 2 SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/09/2018 01:15 pm - 02:15 pm INTRODUCTION: The most characteristic presentation of Cryptogenic organizing pneumonia(COP) is multifocal,migratory,relapsing,highly corticosensitive pneumonic opacities.Here we report the case of COP presenting as a solitary lung mass. CASE PRESENTATION: A 76 years old male,smoker with a 40 pack years history of smoking,presented with a 2 month history of breathlessness with fever and productive cough 2 weeks back.The patient reported a 5 kg weight loss.Examination revealed bilateral wheeze.Lab tests were normal.Chest X-ray showed a prominent left hilum.CT chest revealed a soft tissue density mass with irregular margins, measuring 28 x 29 mm in the lingular segment of the left upper lobe, abutting the anterior chest wall.Core biopsy of the left lung mass on pathological examination revealed nodules and plugs containing spindle fibroblasts arranged in myxoid matrix within the alveolar spaces and bronchioles. Lung parenchyma showed evidence of acute on chronic inflammation with mild interstitial widening of the alveolar walls. There was no evidence of granuloma formation or malignancy.Findings were suggestive of COP.The patient was started on oral prednisolone(1 mg/kg/day) which was tapered and stopped.Follow-up chest X-ray and CT scan showed resolution of the soft tissue density previously noted. COP results from incomplete resolution of inflammation in the alveoli, alveolar ducts and terminal and respiratory bronchioles.The diagnosis requires a combination of clinical, radiologic and histopathological(1)expertise. DISCUSSION: COP can at times simulate lung cancer(2)or even coexist with lung cancer(1)due to its sub-acute course and a wide range of clinical presentation.A bilateral non-segmental and patchy sub-pleural distribution is the most common radiologic finding (3).On the contrary lung cancer presents as irregular nodules and masses with evidence of lobulation, speculation, pleural invasion and lymph node metastasis(3).Multiple large(>1 cm)nodules or masses are an uncommon manifestation of COP and are rarely reported.COP with multiple large nodules must be differentiated from other conditions,e.g metastatic lung tumors. This distinction is all the more important as cases of OP due to the direct influence of the tumor on the surrounding lung parenchyma or as direct consequence of chemotherapy and radiotherapy have been well reported in literature. Radiologic similarity at times makes distinction a dilemma based upon radiologic findings alone. Lung biopsy is often required to make a definitive diagnosis.At present the most common treatment options for COP are systemic corticosteroids or surgical resection followed by a period of observation to ensure a sustained treatment response. CONCLUSIONS: COP can present with a variety of radiologic appearance’s making distinction from lung tumors difficult. Clinicians must be aware of this possibility to avoid traumatic and unnecessary procedures. Reference #1: Nakahara Y,Oonishi Y,Takiguchi J,Morimoto A,Matsuokak,Imanishi N,Higashino T,Mimura R, Kamamura T,Mochiduki Y. Nontuberculous mycobacterial lung disease accompanied by organizing pneumonia.Internal Medicine. 2015;54(8):945-51. Reference #2: Zhao F,Yan SX,Wang GF,Wang J,Lu PX,Chen B,Yuan J,Zhang SZ,Wang YX.CT features of focal organizing pneumonia: an analysis of consecutive histopathologically confirmed 45 cases.European journal of radiology. 2014 Jan 1; 83 (1) : 73-8. Reference #3: Lee KS,Kullnig P,Hartman TE,Muller NL.Cryptogenic organizing pneumonia: CT findings in 43 patients AJR.American journal of roentgenology.1994 mar; 162(3): 543-6. DISCLOSURES: No relevant relationships by Yasmin Rahim, source=Web Response

Proteinase 3-antineutrophil cytoplasmic antibody positive necrotizing vasculitis induced by ciprofloxacin

Granulomatosis with polyangiitis (Wegener’s), microscopic polyangitis, and eosinophilic granulomatosis with polyangiitis are commonly grouped together as antineutrophil cytoplasmic antibody (ANCA)-positive vasculitides. Many drugs and infections can induce serologic positivity for ANCA, while a few can precipitate overt ANCA-positive vasculitis. Although fluoroquinolones have been reported to cause ANCA-negative leukocytoclastic vasculitis (LCV), fluoroquinolones are not known to induce proteinase 3-ANCA (PR3-ANCA)-positive vasculitis. Here, we present the case of a middle-aged man who developed severe headache, purpura on legs and numbness in hands and feet after taking ofloxacin for 5 days. Subsequently, he was diagnosed with ANCA-negative LCV and treated with steroids and immunosuppressants. Thirteen years later, he inadvertently received intravenous ciprofloxacin and developed severe headache and epistaxis. Serologic testing at that time revealed elevated titers of PR3-ANCA. Biopsy of nasal septum revealed a mixed mononuclear and polymorphonuclear infiltrate without evidence of granuloma formation. He was treated with steroids and immunosuppressive therapy. Over the next several years, he remained stable with residual hearing loss and nasal septal deformity. This case provides the first evidence for a PR3-ANCA-positive necrotizing vasculitis induced by ciprofloxacin.

Characteristics and significance of colorectal cancer associated lymphoid reaction

A subset of colorectal cancers (CRCs) exhibits so-called Crohn's like lymphoid reaction (CLR), an inflammatory reaction pattern that consists of numerous transmural lymphoid aggregates. However, the composition of these aggregates, their biological mechanisms and their prognostic significance are not well-defined. We analyzed two CRC cohorts (418 and 149 patients) and determined clinicopathological features including survival. A new method for evaluating CLR based on counting the areal density of the lymphoid follicles (CLR density) was adopted. Immune cell densities at intratumoral and peritumoral regions, as well as the composition of the lymphoid follicles, were studied by immunohistochemistry. We found that CLR comprised of lymphoid aggregates with no evidence of granuloma formation. High CLR density associated with lower tumor stage, lack of preoperative radiotherapy or chemoradiotherapy and deficient mismatch repair enzyme expression. CLR density had positive correlations with peritumoral and intratumoral densities of CD83(+) mature dendritic cells and T cells. High CLR density associated with better survival and had prognostic value that was independent of stage, Klintrup-Mäkinen score for peritumoral inflammation and the numbers of tumor infiltrating T cells. CLR density evaluation had excellent intraobserver and interobserver agreement. In conclusion, the results suggest that CLR contributes to the adaptive antitumor immunity. Quantitative evaluation of CLR density is a relevant prognostic indicator in CRC.

Facial ulcer treated with olanzapine

A 69-year-old woman presented with a nonhealing ulcer on her right cheek. On histological examination of a biopsy, no evidence of granuloma formation or malignancy was found, and the overall picture was felt to be consistent with dermatitis artefacta (DA). The patient was referred to a joint psychodermatology clinic, where treatment with risperidone was started. However, at follow-up the ulcer remained unchanged, and treatment was changed to olanzapine 2.5 mg twice daily. Within 10 months, the large facial ulcer, which had been refractory to treatment for several years, had completely healed. Anxiolytics, antidepressants and low-dose antipsychotics have been shown to be helpful in the management of DA. Successful treatment with olanzapine has been described. The good clinical response to olanzapine may be attributed to its anti-impulsive effect, antihistaminic properties and low risk of parkinsonian side-effects.

Fat repositioning via supraperiosteal dissection with internal fixation for tear trough deformity in an Asian population

To investigate the efficacy and complications of fat repositioning via supraperiosteal dissection with internal fat-flap fixation for tear trough deformity in an Asian population. This study is a retrospective chart review. From June 2005 to May 2010, 212 patients with lower eyelid fat prolapse and tear trough deformity underwent fat repositioning via supraperiosteal dissection with internal fat-flap fixation. Postoperative complications were recorded, and the degree of outcome satisfaction was obtained at the 6-month postoperative follow-up. In total, 142 patients underwent transconjunctival fat repositioning, and 70 received the transcutaneous approach for redundant lower lid skin and tear trough deformity. The level of satisfaction 6 months after the operation was high: 152 patients rated their experience as very satisfied (71.7%), 54 as satisfied (25.5%) and six as acceptable (2.8%). None reported being dissatisfied or unhappy. No diplopia or evidence of granuloma formation in the lower eyelid or check area was noted. Four patients who suffered from significant ecchymosis and conjunctival chemosis with corneal exposure were managed with lubricants and resolved spontaneously. Three patients who underwent the transcutaneous approach and excess skin excision had the complication of lower lid ectropion; they received lateral tarsal strip procedures with good results. Three patients required revision to remove the residual lateral fat pad because of inadequate lateral orbital fat excision during the initial procedure. Fat repositioning via supraperiosteal dissection with internal fat-flap fixation is a safe and effective method to create a youthful midface appearance for Asians with tear trough deformity.

Fallopian tube carcinoma associated with schistosomiasis

The identification of Schistosoma ova in the upper genital tract is well documented, but the extent to which this is related to morbidity and mortality is unknown. We describe a case of right fallopian tube carcinoma associated with evidence of granuloma formation and Schistosoma ova of the left fallopian tube. To our knowledge this is the first documented case of such an association.

Nonclinical Safety of Ziconotide: An Intrathecal Analgesic of a New Pharmaceutical Class

Ziconotide, a potent, selective, reversible blocker of neuronal N-type voltage-sensitive calcium channels, is approved in the United States for the management of severe chronic pain in patients for whom intrathecal therapy is warranted, and who are intolerant or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. In the European Union, ziconotide is indicated for the treatment of severe chronic pain in patients who require intrathecal analgesia. Nonclinical investigations of ziconotide included a comprehensive characterization of its toxicology, incorporating acute and subchronic toxicity studies in rats, dogs, and monkeys; reproductive toxicity assessments in rats and rabbits; and mutagenic, carcinogenic evaluations performed in vivo and in vitro. Additional investigations assessed the potential for cardiotoxicity (rats) and immunogenicity (mice, rats, and guinea pigs), and the presence or absence of intraspinal granuloma formation and local cell proliferation and apoptosis (dogs). The resulting nonclinical toxicology profile was predictive of human adverse events reported in clinical trials and consistent with ziconotide's pharmacological activity. Frequently observed nonclinical behavioral effects included tremoring, shaking, ataxia, and hyperreactivity. Occurrences were generally transient and reversible upon cessation of treatment, and intolerable effects occurred at doses more than 45 times the maximum recommended clinical dose. Ziconotide was not associated with target organ toxicity, teratogenicity, or treatment-related gross or histopathological changes; it displayed no mutagenic or carcinogenic potential and no propensity to induce local cell proliferation or apoptosis. Although guinea pigs developed systemic anaphylaxis, antibodies to ziconotide were not detected in mice, rats, or guinea pigs, indicating low immunogenic potential. No evidence of granuloma formation was observed with intrathecal ziconotide treatment. In summary, the results from these nonclinical safety assessments revealed no significant toxicological risk to humans treated with ziconotide as recommended.

Wegener granulomatosis: a case report with primary oral manifestation

<h3>Background</h3> Wegener's granulomatosis (WG) is a form of systemic leukocytoclastic vasculitis of small and medium vessels leading to granuloma formation. Oral manifestations are uncommon and may include palatal and lingual ulceration, aphthae, and nonhealing extraction sockets. <h3>Case report</h3> A 45-year-old white female presented with an 8-month history of an exophytic and hemorrhagic mulberry-like growth, with granular surface involving the gingiva from the mandibular lateral incisor to the first molar on the left side. The teeth involved showed significant mobility. Periapical and panoramic x-rays presented bone destruction with imprecise limits. Extraoral examination showed no pecularities. Hematologic and serologic tests, including complete blood cell counts, antinuclear antibodies, p-ANCA and c-ANCA, renal functions, and erythrocyte sedimentation rate, were all within normal range. Chest x-ray showed no abnormality, and urinanalysis was unremarkable. Incisional biopsy revealed acute proliferative gingivitis with pseudoepitheliomatous hyperplasia, focal epithelial degeneration, and presence of microabscesses. The inflammatory infiltrate in the lamina propria consisted of a histiocytic component admixed with plasmocytes, neutrophils, numerous eosinophils, and scattered multinucleate cells. There was no evidence of granuloma formation. Focal necrosis, hemhorrage, and vascular dilation were observed. Vascular wall necrosis and inflammation were lacking. No fungi or bacilli were seen with special stains. These features are compatible with oral manifestation WG. <h3>Conclusion</h3> Gingival lesions are extremely rare in WG, but when present they are pathognomonic of the early stages of the disease, preceding any other systemic signs. In these cases ANCA might be negative. Case discussion with literature review is presented.

The expandable metal stent for tracheal obstruction.

A 10 month old boy with stridor persisting from birth was found to have tracheal narrowing secondary to myofibromatosis of the tracheal wall. An expandable metal stent was positioned across the tracheal stenosis with immediate clinical improvement. There were no complications relating to stent insertion. The child remained clinically asymptomatic and repeat bronchoscopy at nine months' follow up showed that the stent had become completely endothelialised with no evidence of granuloma formation.

Bone Formation in the Presence of Phagocytosable Hydroxyapatite Particles

Small particles of biomaterials used in orthopaedic surgery have been shown to induce the resorption of bone. The purpose of this study was to determine whether phagocytosable particles of hydroxyapatite had an adverse effect on bone ingrowth. Bone harvest chambers were implanted bilaterally in the proximal tibial metaphyses of 13 mature rabbits. The bone harvest chamber has a transverse 1-mm wide pore, providing a continuous canal through the chamber for tissue ingrowth. After an initial 6-week period for osseointegration of the bone harvest chambers, the contents of the canal were harvested at 3-or 6-week intervals. Hydroxyapatite particles (diameter, 5 mu) were mixed with a carrier solution, 1% sodium hyaluronate, and implanted in the canal of one chamber in each animal. The contralateral chamber was implanted with the carrier only and served as a control. Histological sections from the tissue harvested from the chambers were evaluated by light microscopy and histomorphometry, and the area of bone ingrowth was measured as a percentage of total area in each section. At 3 weeks there was more bone in the hydroxyapatite sections than in controls; at 6 weeks there was no difference. Hydroxyapatite particles were incorporated within the matrix of new ingrown bone at both time periods. There was no evidence of granuloma formation or inflammation. Previous studies have shown that particles of high density polyethylene and bone cement adversely affect bone ingrowth in this model. The present results suggest that hydroxyapatite particles, small enough to be phagocytosed by macrophages, did not have such effects.

Dynamics and Mechanism of the Sarcoidal Granuloma

Punch biopsies of K-S test sites were studied by the use of monoclonal antibodies for the presence of T cells, T cell subsets, B cells, IgG, IgM, IgA, and kappa and lambda chains by an indirect and direct immunoperoxidase technique. A total of 10 biopsies were performed at intervals ranging from 6 hr to 34 days. Results revealed that at 6 hr there was an influx of T cells, predominantly helper cells, at the injection site, followed by an infiltration of monocytes, an infiltration that was maximal at 48 hr. By day 7 there was a marked increase in the number of T lymphocytes, predominantly helper cells, and a few persistent monocytes were seen. By day 12 there was evidence of granuloma formation with the appearance of some epithelioid cells and a few giant cells. These cells, along with helper T cells, were seen to have progressively increased in number when the confluent granulomas on the day 34 biopsies were studied. Epithelioid cells, however, did not show any reactivity with Leu-M3 monoclonal antibody, which stained the majority of peripheral blood monocytes. B cells were rarely present; immunoglobulins were absent in all biopsies. It was concluded that the evolution of the sarcoidal granuloma in response to K-S antigen is a purely cell-mediated phenomenon. Helper-inducer T cells appear to play a dominant role in its evolution and maintenance. Lack of reactivity of epithelioid and giant cells with Leu-M3 monoclonal antibody indicates either a different lineage from monocytes or a change in their phenotype.