Thymic stromal lymphopoietin controls prostaglandin D2 generation in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: Prostaglandin (PG) D2 is the dominant COX product of mast cells and is an effector of aspirin-induced respiratory reactions in patients with aspirin-exacerbated respiratory disease (AERD). OBJECTIVE: We evaluated the role of the innate cytokine thymic stromal lymphopoietin (TSLP) acting on mast cells to generate PGD2 and facilitate tissue eosinophilia and nasal polyposis in patients with AERD. METHODS: Urinary eicosanoid levels were measured in aspirin-tolerant control subjects and patients with AERD. Nasal polyp specimens from patients with AERD and chronic rhinosinusitis were analyzed by using quantitative PCR, Western blotting, and immunohistochemistry. Human cord blood-and peripheral blood-derived mast cells were stimulated with TSLP in vitro to assess PGD2 generation. RESULTS: Urinary levels of a stable PGD2 metabolite (uPGD-M) were 2-fold higher in patients with AERD relative to those in control subjects and increased further during aspirin-induced reactions. Peak uPGD-M levels during aspirin reactions correlated with reductions in blood eosinophil counts and lung function and increases in nasal congestion. Mast cells sorted from nasal polyps expressed PGD2 synthase (hematopoietic PGD2 synthase) mRNA at higher levels than did eosinophils from the same tissue. Whole nasal polyp TSLP mRNA expression correlated strongly with mRNA encoding hematopoietic PGD2 synthase (r = .75), the mast cell-specific marker carboxypeptidase A3 (r = .74), and uPGD-M (r = 0.74). Levels of the cleaved active form of TSLP were increased in nasal polyps from patients with AERD relative to those in aspirin-tolerant control subjects. Recombinant TSLP induced PGD2 generation by cultured human mast cells. CONCLUSIONS: Our study demonstrates that mast cell-derived PGD2 is a major effector of type 2 immune responses driven by TSLP and suggests that dysregulation of this innate system contributes significantly to the pathophysiology of AERD.

Leukotriene E(4) in urine in patients with asthma and COPD--the effect of smoking habit.

Leukotriene E(4) (LTE(4)) is implicated in asthma pathophysiology and possibly in chronic obstructive pulmonary disease (COPD) as one of the causes of persistent bronchoconstriction and mucus hypersecretion. Cigarette smoking stimulates cysteinyl leukotrienes (CysLTs) production. We investigated whether LTE(4) is equally increased in asthma and COPD and whether smoking significantly affects LTE(4) levels. Secondary outcomes involved correlations with inflammatory and functional parameters. We studied 40 patients with COPD [20 smokers], 40 asthmatics [20 smokers] and 30 healthy subjects [15 smokers]. Spirometry (FEV(1)% pred., FEV(1)/FVC) was performed, urine was collected for measurement of LTE(4) and creatinine, induced sputum was collected for differential cell counts and serum for ECP. LTE(4)/creatinine levels (pg/mg) [mean (sd)] were increased in asthmatic patients compared to COPD and controls, [125.6(54.5) vs. 54.5(19) vs. 55.9(18.9)pg/mg, respectively, P<0.0001 for asthma]. Smoking significantly affects LTE(4) levels only in asthmatic patients [164 (48) vs. 87 (26.3), P<0.0001 for smokers]. The only significant correlation was between eosinophils in induced sputum and LTE(4)/creatinine levels in asthmatics. In conclusion, patients with asthma presented higher LTE(4) values compared to normals and patients with COPD. Smoking significantly affects LTE(4) values only in asthmatics indicating a different underlying CysLTs inflammatory process in this condition.

Urinary eosinophils.

The sensitivity of the presence of urinary eosinophils for the diagnosis of acute interstitial nephritis is 60%. Of those with interstitial nephritis without urinary eosinophils, in most cases, few eosinophils are present in the renal interstitial inflammatory infiltrate. The specificity of urinary eosinophils for acute interstitial nephritis has not been determined but urinary eosinophils have been reported with eosinophilic cystitis, urinary tract infections, and various renal diseases. However, the incidence of eosinophiluria in any of these conditions has not been investigated.

Clinical correlates of eosinophiluria.

We assessed the clinical correlates of eosinophils in the urine in 65 patients. In 16% of 470 patients whose urine was specifically examined, eosinophils were noted in the urine sediment. Review of the 65 patients with eosinophiluria demonstrated that when eosinophils were expressed as a percentage of total urine white blood cells, 85% (55/65 patients) had less than 5% urine eosinophils and 45% (29/65 patients) had less than 1%. Infection of the upper and lower urinary tract accounted for 45% of the clinical conditions associated with eosinophiluria. In nine (14%) of the 65 patients a diagnosis of acute interstitial nephritis could be made by clinical criteria or from renal biopsy specimens. We conclude that the finding of urine eosinophils is associated with a variety of clinical conditions and may be most useful when expressed as a percentage of total white blood cells in the urine. At a low-percentage positive (less than 5%), it may not be a good predictor of acute interstitial nephritis, but at a higher level (greater than 5%) it may be a more valuable predictor.

Eosinophiluria in atheroembolic renal disease.

PURPOSE AND PATIENTS: Eosinophiluria has been reported in acute interstitial nephritis and other renal diseases, but its presence in atheroembolic renal disease (AERD) has not been previously established. AERD has been identified as a cause of acute and chronic renal failure, particularly in elderly patients with advanced atherosclerosis and in those patients who have undergone manipulation or intervention of the abdominal aorta, renal artery, or coronary artery. The definitive diagnosis is made by renal biopsy. However, many patients are too acutely ill to tolerate renal biopsy and, in recent years, peripheral eosinophilia, hypocomplementemia, and thrombocytopenia have been recognized in association with AERD. Previous studies have reported that AERD is associated with an inactive renal sediment and an absence of urine eosinophils. We reviewed our experience over a 4-year period with 24 patients with renal biopsy-proven AERD. RESULTS: Urine eosinophils were evaluated in nine patients to help determine the cause of their renal deterioration. Seven of these patients presented with evidence of vascular disease. Three patients had procedures involving manipulation of the abdominal aorta. Physical examination revealed findings of atheroembolism in three of nine patients. Overall, eight of nine patients had a positive Hansel's stain for eosinophiluria. Six of eight patients had more than 5% of their urinary white cell count as eosinophils. The reason for failure of previous studies to detect eosinophiluria in AERD is unclear but may have been related to the use of Wright's stain instead of Hansel's stain. CONCLUSION: In the evaluation of acute renal insufficiency, eosinophiluria may indicate AERD in addition to the other known causes for this finding.

Acute interstitial nephritis: immunologic and clinical aspects.

Acute interstitial nephritis is a common renal syndrome that may be associated with a variety of infections and drug therapies or may develop without an identified cause. Three cases are presented to illustrate the three types of acute interstitial nephritis--drug related, infection related, and idiopathic. Cell-mediated immune mechanisms seem to be more important than humorally mediated mechanisms in the pathogenesis of acute interstitial nephritis. Frequently, eosinophils are identified as a component of the interstitial cellular infiltrate, and eosinophiluria and eosinophilia have been claimed to be helpful in the diagnosis of acute interstitial nephritis, especially the drug-induced type. Neither eosinophiluria nor the presence of increased urinary levels of eosinophil major basic protein, however, is specific for the diagnosis of acute interstitial nephritis. Patients with drug-induced interstitial nephritis frequently have symptoms and signs suggestive of a hypersensitivity syndrome and rarely have more dramatic anaphylactic manifestations. Systemic glucocorticoids have been shown to be beneficial in this type of acute interstitial nephritis.

Eosinophilic fasciitis associated with tryptophan ingestion. A manifestation of eosinophilia-myalgia syndrome.

Recently, the ingestion of tryptophan has been associated with eosinophilia-myalgia syndrome, which is characterized by eosinophilia, myalgias, and several less consistently reported findings. We treated 13 patients who exhibited clinical features of eosinophilic fasciitis who were taking high-dose tryptophan before the onset of clinical symptoms. Twelve patients exhibited eosinophilia, with eosinophil counts ranging from 0.13 to 0.88. The remaining patient was taking oral corticosteroids when her eosinophil count was determined. Eight patients complained of myalgias. Other symptoms included arthralgias, pruritus, cutaneous burning, weakness, fever, rashes, malaise, edema, muscle spasms, and alopecia. 5-Hydroxyindoleacetic acid levels were elevated in four of the eight urine specimens that were tested. Our findings suggest that previously diagnosed cases of eosinophilic fasciitis may represent variants of tryptophan-associated eosinophilia-myalgia syndrome. Derangements in the metabolism of tryptophan may play a role in sclerotic diseases.

[Clinical study of eosinophilic cystitis (2). Clinical observation on 5 cases of eosinophilic cystitis].

Clinical observations were performed on 5 cases of eosinophilic cystitis that had been diagnosed by our criteria. In all 5 cases some kind of allergic diseases was found. General urinalysis did not show any definite tendency, but eosinophils in urine were found in 4 cases. Cystoscopy revealed only chronic inflammation and submucosal hemorrhage in 4 cases, and the other case showed ulcerative changes. A positive to immediate skin reaction was seen in 2 of the 4 cases. IgE RAST was positive for mite, house dust and mugwort in 1 of these 2 cases. In this case immediate allergic reaction was suspected as part of the cause of the cystitis.

Eosinophilia: clinical significance in HIV-infected individuals.

This study was conducted to determine the relationship between eosinophilia and parasitic infection in HIV-infected individuals. HIV-positive patients attending an HIV clinic in Birmingham were recruited and classified as either eosinophilic (>400 eosinophils/mm(3)) or non-eosinophilic. A demographic and parasitic risk history was taken and clinical examination was performed. Urine and stool were examined for parasites, and blood samples taken for parasite serology. A total of 266 patients (96 eosinophilic and 170 non-eosinophilic) were recruited. Of 64 eosinophilic patients who had a stool examination, one (1.6%) was positive for both Strongyloides larvae and schistosomal eggs. Urine microscopy was negative in the 245 patients (88 eosinophilic, 157 non-eosinophilic) from whom a sample was available. Two hundred and sixty-three patients underwent serological investigation (96 eosinophilic and 167 non-eosinophilic): 13 (4.9%) were positive for schistosomiasis and three (1.1%) positive for Strongyloides. A significant association between eosinophilia and positive schistosomal serology was found (P = 0.003): 11 (10.5%) were eosinophilic patients, while only four (2.3%) were non-eosinophilic patients. Eosinophilia was associated with a low nadir CD4 count (P = 0.021) and prior AIDS-defining illness (P = 0.041). In all, 7.8% of patients from a developing country and 5.3% of patients from a developed country with a travel history had positive parasitic serology. Eosinophilia in HIV-infected patients was significantly associated with positive serology for schistosomiasis, low nadir CD4 count and prior AIDS-defining illness. Geographical exposure is also an important determinant of positive parasitic serology.

Urinary Charcot-Leyden crystals in the hypereosinophilic syndrome with acute renal failure.

A 48-year-old man with idiopathic hypereosinophilic syndrome (IHS) developed blast crisis along with a fulminant autoimmune hemolytic anemia. Hemoglobinuria and anuric acute renal failure (ARF) ensued. Urinalysis revealed countless Charcot-Leyden crysals (CLC). This is the only known report of Charcot-Leyden crystalluria. The CLC protein (lysophospholipase) should normally undergo glomerular filtration and catabolism by the tubules during reabsorption. Its abundant presence in the urine of our patient may reflect impairment of tubular reabsorption, saturation of the tubular reabsorptive process by excessive CLC load through residual functioning glomeruli, or a combination thereof. The extreme degree of hypereosinophilia suggests a massive load of CLC protein and acute tubular necrosis implies impaired tubular function, so both mechanisms should have been operative. At the autopsy, no eosinophilic infiltrates were present in the kidneys, which points against a local spillage of CLC protein into the tubules.

[Eosinophilic cystitis]. / Cistitis eosinofílica.

We report two cases of eosinophilic cystitis in children of 11 months and 11 and a half year of age respectively. The presenting symptoms were the emision of mucosanguinolent filaments in the urine in one case and with lower urinary tract symptoms and macroscopic hematuria in the other. Physical examination revealed in one of them a round, tough and painful mass in the hypogastric area. In one case we found peripheral blood eosinophilia. They both showed in the Urinalysis albuminuria, pyuria and hematuria, with the presence of eosinophils in one of them. Macroscopic examination presented in the two cases a tumoral, mamelonne mass in the wall of the bladded. The diagnosis was anatomopathologic due to the demonstration of an inflammatory infiltration, primarily of eosinophils. The clinical course was unfavourable in the case an hemicystectomy was practicated and self-limited in the one only symptomatic treatment was used.

Tubulointerstitial nephritis in a patient with eosinophilic fasciitis and IgA nephropathy.

We report a tubulointerstitial nephritis in a patient with eosinophilic fasciitis and IgA nephropathy. Urinalysis revealed mild proteinuria and microscopic hematuria, and renal biopsy disclosed diffuse interstitial infiltrations of lymphocytes and plasma cells with few eosinophils in spite of mild mesangial proliferation with IgA deposits, indistinguishable from those of primary tubulointerstitial nephritis. Immunohistochemical examination showed a predominance of helper/inducer T cells infiltrating the renal interstitium and the fascia. Corticosteroid treatment led to a decrease of infiltrating cells in both tissues. Therefore, eosinophilic fasciitis and tubulointerstitial nephritis in our patient seemed to be interdependent phenomena.

Eotaxin contributes to renal interstitial eosinophilia.

BACKGROUND: A potent eosinophil chemotactic cytokine, human eotaxin, is directly chemotactic for eosinophils. Therefore, the specific expression of eotaxin in tissue might play a crucial role in tissue eosinophilia. However, the precise molecular mechanism of the recruitment and activation of eosinophils in human renal diseases remains to be investigated. We evaluated the role of eotaxin in the pathogenesis of human diffuse interstitial nephritis with marked infiltration of eosinophils. METHODS: In this study, we examined 20 healthy volunteers. 56 patients with primary or secondary glomerular diseases and two hypereosinophilic syndrome patients without renal involvement. Urinary and serum eotaxin levels were determined by an enzyme-linked immunosorbent assay. We also detected the presence of eotaxin protein immunohistochemically. RESULTS: On the one hand, urinary levels of eotaxin were significantly higher before the initiation of glucocorticoid administration in the patient with interstitial nephritis with marked infiltration of eosinophils. On the other hand, urinary eotaxin levels were not detected in any patients with nephrotic syndrome, interstitial nephritis without eosinophils, hypereosinophilic syndrome without renal involvement or other renal diseases. Serum eotaxin levels were not detected in any of the patients. Therefore, the detection of eotaxin in the urine was specific for renal interstitial eosinophilia. Moreover, endothelial cells, infiltrating mononuclear cells and renal epithelial cells in the tubulointerstitial lesions were immunostained with specific anti-eotaxin antibodies. Furthermore, the elevated urinary levels of eotaxin decreased dramatically during glucocorticoid-induced convalescence. HYPOTHESIS: We hypothesize that in situ expression of eotaxin may provide a new mechanism to explain the renal interstitial eosinophil infiltration.