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In a 6-month, double-blind multicenter trial conducted over the winter, the effects of daily administration of ambroxol retard (75 mg) were compared with those of placebo in preventing exacerbations and improving symptoms and clinical signs in chronic bronchitis patients. The trial was completed by 110 patients in the ambroxol group and by 104 in the placebo group. Initially, there were no significant differences between the groups. By the end of the 2nd month of treatment, 67.2% of the ambroxol group had had no exacerbations compared to 50.4% in the placebo group. At the end of the 6-month trial, 45.5% of the treatment group had had no exacerbations, compared to only 14.4% of the control group. These differences were statistically significant. Patients in the treatment group lost significantly fewer days through illness (442) and had fewer days when they needed antibiotic therapy (371) compared to the placebo group patients (837 and 781). Ambroxol also produced statistically significant symptomatic improvement, measured as difficulty in expectoration, coughing, presence of dyspnea and the auscultatory signs as compared to controls. Since ambroxol was well tolerated and compliance was good, it appears like a drug of choice for pharmacological prophylaxis of chronic bronchitis.
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Systolic blood pressure (SBP), diastolic blood pressure (DBP), and plasma norepinephrine (NE), cortisol (CRT), growth hormone (GH) and prolactin (PRL) were studied before and after clonidine (2.5 micrograms/kg i.m.) administration in 193 chronic severely ill patients and 193 normal subjects matched by age and sex. During exacerbation periods (positive manifestations of impairment and progressive disease), the patients showed higher NE, CRT and DBP than the normals or when they were investigated during non-exacerbation periods (92 of the 193). Clonidine induced sharp, marked reductions of NE, CRT and DBP, plus a sudden increase of GH, in all the patients during exacerbation periods. Non-significant reductions of NE, CRT and DBP were observed in normals and in patients during non-exacerbation periods. On the other hand, the GH increase registered during exacerbation periods was of an order of magnitude higher than that registered in normals and in patients during non-exacerbation periods. Significant reduction of SBP was registered both in normals and patients (exacerbation and non-exacerbation periods). Some tendency to PRL lowering was observed during exacerbation periods only. A high positive correlation between NE and DBP (pre- and post-clonidine values) was obtained during exacerbation periods in patients, but not in normals or during non-exacerbation periods in the patients. Similarly, a close negative correlation was obtained between CRT and GH (postclonidine values) during exacerbation periods, but not in normals or during non-exacerbation periods. No significant correlation was found between NE and SBP in any group of subjects. The clonidine-induced changes in GH and CRT observed in the patients during exacerbation periods were in striking contrast to the absence of these changes in depressed patients. This finding is consistent with the low rate of depression (6.7%) registered among our patients during exacerbation periods. The high plasma NE and CRT levels registered in chronic severely ill patients during exacerbation periods reflect a central and peripheral sympathetic hyperactivity, accompanied by an overactivity of the pituitary--adrenocortical axis. The strong reduction of DBP, NE and CRT, along with the sharp and great increase of GH, might be useful as indicators in assessing the exacerbation and progression of severe chronic illnesses.
INTRODUCTION: Severe asthma (SA) exacerbations impose a substantial healthcare burden. Microbiological characterization using molecular techniques may improve pathogen identification and contribute to a more individualized therapeutic approach. OBJECTIVE: To characterize the microbiological profile of exacerbations in patients with severe asthma and to analyze the prescription patterns for antibiotics (ATB) and systemic corticosteroids (SC). METHODS: This retrospective observational study was conducted in a Severe Asthma Unit. A total of 103 exacerbations were investigated using conventional microbiological methods and multiplex polymerase chain reaction (FilmArray™) performed on respiratory samples. Bacterial findings were classified according to operational criteria compatible with infection or colonization based on genomic load and culture results. Associations between clinical, microbiological, and therapeutic variables were explored using univariate analyses. RESULTS: Microbiological detection was achieved in 78.6% of exacerbations. Viruses were identified in 59.2% of episodes, with rhinovirus representing the predominant pathogen (62.3% of viral detections). Bacteria were identified in 53.4% of exacerbations (H. influenzae 36,6%), frequently in association with viral coinfection. Bronchiectasis was associated with a higher probability of bacterial detection (OR 2.50; p = 0.031). ATB and SC were prescribed in 61.2% and 44.6% of exacerbations, respectively, with frequent use of combination therapy. No significant differences in overall microbiological detection rates were observed according to biologic therapy status. Considerable microbiological variability was observed across recurrent exacerbations in the same patient. CONCLUSIONS: Microbiological findings were common during severe asthma exacerbations, with respiratory viruses, particularly rhinovirus, being the most frequently identified pathogens. Bronchiectasis was associated with higher rates of bacterial detection and ATB use. The marked variability observed between episodes supports the potential value of individualized microbiological assessment during exacerbations and warrants prospective studies aimed at optimizing therapeutic decision-making.
Interleukin-2 receptor (IL-2R) is expressed and released predominantly by activated T cells. In order to investigate whether disease exacerbations of systemic lupus erythematosus (SLE) are preceded by T cell activation, we prospectively measured levels of IL-2R once a month, from 6 months prior to exacerbations until 1 month afterwards. To assess the temporal relation between T cell activation and B cell activation, we measured, in addition, levels of anti-dsDNA, complement C3/C4, and total IgG. During a mean follow-up period of 23 months, 40 exacerbations occurred in 21 out of the 71 participating patients. For the present study one exacerbation per patient was evaluated. During exacerbation levels of IL-2R were increased in 18 out of the 21 cases and correlated with levels of anti-dsDNA (P less than 0.02), C3 (P less than 0.02), and C4 (P less than 0.01), but not with the score of the disease activity index. Levels of IL-2R rose prior to the exacerbation (P less than 0.02) and fell afterwards following treatment (P less than 0.05). Even in the absence of disease activity or during minor disease symptoms IL-2R levels were higher (P less than 0.01) than in healthy controls. Sixteen out of the 21 exacerbations (76%) were preceded by a significant increase in IL-2R. Changes in levels of anti-dsDNA and complement C3/C4 tended to precede changes in levels of IL-2R. We conclude that increased levels of IL-2R, compatible with T cell activation, are present in SLE already during inactive disease. These levels further increased prior to exacerbations of disease. As such, IL-2R is an indicator of disease activity in SLE. Serial measurement of IL-2R is a sensitive test for predicting disease exacerbations of SLE.
We prospectively studied the value of measuring C-reactive protein (CRP) levels in patients with systemic lupus erythematosus (SLE) to distinguish between disease exacerbation and infection. During a 2 year followup of 71 lupus patients, 38 episodes of disease exacerbation and 36 episodes of infection could be analyzed. Plasma samples were obtained at least once a month. CRP levels were increased (greater than 6 mg/l) during 25 of the 38 exacerbations and during 32 of the 36 infections. Median CRP levels during infection (60 mg/l; range 1-400) were higher than during disease exacerbation (16.5 mg/l; range 1-375) (p less than 0.05). Levels of CRP rose prior to the exacerbation (p less than or equal to 0.01) and fell afterwards (p less than or equal to 0.01). During exacerbations accompanied by serositis, median levels of CRP (76 mg/l; range 2-375) were higher than during exacerbations without serositis (16 mg/l; range 1-53) (p less than 0.02). CRP levels exceeding 60 mg/l during exacerbations without serositis indicated infection in all cases. Thus, measurement of CRP in SLE is valuable to distinguish between infection and exacerbation only in the absence of serositis.
To evaluate the predictive power of changes in levels of antibodies to double-stranded DNA (anti-dsDNA) as a predictor of disease exacerbations in systemic lupus erythematosus (SLE), we performed a prospective study on 72 unselected patients with SLE (mean duration of study 18.5 months, range 6-35 months). Patients were seen at least once every 3 months, and disease activity was scored according to a specific protocol. Plasma samples were obtained at least once every month and were assessed for anti-dsDNA antibody (by the Crithidia luciliae assay, an enzyme-linked immunosorbent assay [ELISA], and the Farr assay) and for complement components C3 and C4. Twenty-seven of 33 disease exacerbations observed during the study period were accompanied by a positive test result for anti-dsDNA antibody (27 by the Farr assay, 19 by the C luciliae assay, and 23 by the ELISA). Twenty-four of these exacerbations were preceded by a significant increase in anti-dsDNA antibody levels (23 by the Farr assay, 12 by the C luciliae assay, and 17 by the ELISA). The first observance of a significant increase in anti-dsDNA antibody levels preceded the exacerbation by 8-10 weeks. Significant increases in anti-dsDNA antibody levels not followed by an exacerbation were observed in 5 cases by the Farr assay, in 7 cases by the C luciliae assay, and in 3 cases by the ELISA; however, in 3 cases, 2 cases, and 1 case, respectively, these increases were followed by an increase in disease activity that did not fulfill the criteria for an exacerbation. Serial measurement of anti-dsDNA antibody levels was more sensitive for predicting exacerbations than was measurement of C3 and/or C4 levels (P less than 0.03). Serial assessment of anti-dsDNA antibody levels, especially by the Farr assay, is a sensitive and reasonably specific method for predicting disease exacerbations in SLE.
The incidence, clinicopathological features and etiology of acute exacerbation occurring in patients with chronic type B hepatitis were assessed prospectively among 385 patients who had HBeAg and 279 who had anti-HBe in serum. During an average follow-up of 23.5 months, acute exacerbations occurred in 197 HBeAg-positive patients and in 56 anti-HBe positive patients, with a calculated annual incidence of 28.6 and 10.3%, respectively (p less than 0.001). The clinical and laboratory findings of acute exacerbations were similar in the HBeAg-positive and anti-HBe positive patients. The mean serum bilirubin and alpha-fetoprotein levels were higher in anti-HBe positive patients (p less than 0.01), but actual differences were small. The histologic features of acute exacerbations were also similar in the HBeAg-positive patients and anti-HBe positive patients. Lobular alterations were the main histologic findings; in addition, one-fourth of patients had bridging necrosis and one-fourth had piecemeal necrosis. Spontaneous reactivation of hepatitis B was the major cause of these exacerbations in both HBeAg-positive patients (91.5%) as well as anti-HBe positive patients (62.5%). Hepatitis delta virus superinfection accounted for a higher percentage of exacerbations in anti-HBe positive patients (14.3%) than in HBeAg-positive cases (6.5%). Hepatitis A and possibly non-A, non-B virus superinfections also contributed to some episodes of exacerbation. Thus, acute exacerbations of disease occurred more frequently in HBeAg-positive patients than in anti-HBe positive patients with chronic type B hepatitis, but the clinicopathological features and etiologies were similar.
We investigated whether rises in anti-double stranded DNA (anti-ds DNA) antibody levels prior to disease exacerbations of systemic lupus erythematosus (SLE) are part of a restricted immune response or merely the consequence of polyclonal B cell activation. As possible inducers of polyclonal B cell activation, we analyzed, in addition, the role of clinically apparent infections in relation to changes in levels of anti-ds DNA and disease exacerbations. We prospectively followed 72 lupus patients who were examined for disease activity and infections at least every 3 months by history and physical examination according to a protocol. Once a month, we measured levels of IgG-class antibodies to an unrelated recall antigen (tetanus toxoid), levels of IgG-class antibodies to a viral antigen (cytomegalovirus late antigens [CMV-LA]), levels of total immunoglobulins G and M, and levels of anti-ds DNA (by ELISA and Farr assay). Thirty-three exacerbations and 31 infections were observed during a follow-up period of an average of 18.5 patient months. Twenty-four out of the 27 exacerbations accompanied by a positive test for anti-ds DNA were preceded by a significant rise in anti-ds DNA: in 17 cases by ELISA and in 22 cases by Farr assay. These 24 rises in levels of anti-ds DNA prior to the exacerbation were paralleled by a significant rise in levels of IgG-class anti-tetanus antibodies in 8 cases, anti-CMV-LA antibodies in 9 cases, total IgG in 7 cases, and total IgM in 15 cases. Median rise in anti-ds DNA, as measured both by ELISA and Farr assay, exceeded the median rise in anti-tetanus antibodies, anti-CMV-LA antibodies, and total IgG and IgM (P less than 0.0001). Only one infection was recorded within a period of 3 months prior to an exacerbation, whereas infections never occurred within a period of 3 months prior to a rise in anti-ds DNA. We conclude that rises in anti-ds DNA prior to exacerbations of SLE are largely due to preferential activation of anti-ds DNA-specific B cells and not merely to polyclonal B cell hyperactivity. Clinically significant infections are not related to rises in levels of anti-ds DNA nor to the induction of exacerbations in SLE.
In order to investigate whether disease exacerbations of systemic lupus erythematosus (SLE) are accompanied or preceded by changes in antibody levels against the U1RNA associated 70 kDa and A polypeptides, we prospectively collected plasma specimens from 71 patients with SLE. We compared changes in anti-70 kDa/anti-A levels, measured by ELISA using cloned antigens, with changes in levels of anti-dsDNA and total IgG. Measurable levels of anti-70 kDa (n = 10) and/or anti-A antibodies (n = 6) were detected during 10 exacerbations. Four of the 10 exacerbations with a measurable level of anti-70 kDa antibodies were preceded by a significant rise in anti-70 kDa levels, 2 by a significant fall, while levels of anti-70 kDa did not change in the remaining 4 cases. Only one of the 6 exacerbations with detectable anti-A antibody levels was preceded by a significant rise in anti-A antibodies, while levels did not change before exacerbation in the other 5 cases. Six of the 10 exacerbations were preceded by a significant rise in anti-dsDNA; in 4 cases levels of anti-dsDNA did not change before exacerbation. In contrast to anti-dsDNA, no relation was found between changes in levels of anti-70 kDa/anti-A and changes in disease activity. Significant changes in levels of anti-70 kDa/anti-A, occurring in 6 cases, were accompanied by parallel changes in total IgG in 5 of these 6. We conclude that, in contrast to anti-dsDNA, serial measurement of levels of anti-70 kDa/anti-A is not useful for monitoring disease activity or predicting disease exacerbations in SLE.(ABSTRACT TRUNCATED AT 250 WORDS)
Studies in the past have reported an increased risk of exacerbations in multiple sclerosis during the postpartum period; it is not known whether breast-feeding alters this risk. We interviewed 435 women regarding pregnancy and breast-feeding history, providing for analysis 191 pregnancies that had occurred during a nonprogressive phase of the disease. The exacerbation rates during the nine-month postpartum period (34%) were more than three times the exacerbation rate during the nine months of pregnancy (10%). The exacerbation risk was highest in the three-month period following childbirth and appeared to stabilize after the sixth postpartum month. The exacerbation rates in breast-feeding and non-breast-feeding pregnancies were 38% and 31%, respectively. The average time to exacerbation was similar in breast-feeding (3.0 months) and non-breast-feeding (3.1 months) pregnancies. Although differential exacerbation rates during pregnancy and the postpartum period may be related to hormonal effects on the immune system, the hormonal effects of breast-feeding do not appear to similarly affect the risk of exacerbation.
We measured 2',5'-oligoadenylate synthetase activity in peripheral blood mononuclear cells and serum of 14 HBsAg- and HBeAg-positive patients with chronic hepatitis B with or without acute exacerbation. Elevated levels of 2',5'-oligoadenylate synthetase in peripheral blood mononuclear cells and serum were found in seven chronic hepatitis B patients with acute exacerbation, whereas in the remaining seven chronic hepatitis B patients without acute exacerbation, both levels were similar to those of normal subjects despite active hepatitis B virus multiplication. 2',5'-Oligoadenylate synthetase levels in peripheral blood mononuclear cells and serum, which were not statistically different from those of normal subjects prior to acute exacerbation, increased during acute exacerbation from 3- to 23-fold over initial levels following elevations in ALT activity. 2',5'-Oligoadenylate synthetase levels fluctuated over a normal range while ALT levels were elevated, and they returned to a baseline with ALT normalization. This suggests that the in vivo interferon system may be activated during acute exacerbation, and that this activation may not be a result of hepatitis B virus multiplication alone, but also of a host-immune response to hepatitis B virus multiplication. Three patients were treated with interferon during acute exacerbation. All three had elevated levels of 2',5'-oligoadenylate synthetase in peripheral blood mononuclear cells and serum just before treatment. 2',5'-Oligoadenylate synthetase levels increased only 1.1- to 2.2-fold over initial levels during treatment, with none of the patients clearing HBeAg during and after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Three hundred and eighty-six Chinese patients (262 men and 124 women), age 5-74 years, with chronic hepatitis B virus (HBV) infection were prospectively followed for 1-5 years to determine the incidence, predisposing factors and etiology of acute exacerbations that occurred during the course of chronic HBV infection. Group I consisted of 334 patients with serum alanine aminotransferase (ALT) levels below 200 IU/l at presentation. Of these, 29 (8.7%) patients developed 32 episodes of acute exacerbation during follow-up. The cumulative probabilities of developing exacerbations were 6.3% and 15% at the end of 1 and 4 years, respectively. Group II included 52 patients with ALT levels above 200 IU/l at presentation. Of these, 19 (37%) patients developed 26 episodes of exacerbation during follow-up. The cumulative probabilities of developing eacerbations were 24% and 47% at the end of 1 and 4 years, respectively. In both groups, the probability of developing exacerbations was slightly higher in men and significantly higher in those above the age of 20 and those who were HBeAg positive. Logistic regression analysis showed that HBeAg positivity (p less than 0.00001), elevated ALT levels (greater than 200 IU/l) at presentation (p less than 0.0001) and male sex (p = 0.03) were associated with a significantly higher probability of developing exacerbations. Twenty eight (48%) episodes of exacerbation were accompanied by symptoms of acute hepatitis.(ABSTRACT TRUNCATED AT 250 WORDS)
To determine whether respiratory virus infections (URI) are associated with exacerbation of nephrotic syndrome (NS) in childhood, a prospective two-winter study of 32 children with NS was done. We obtained pre- and post-season viral serologic studies, biweekly nose and throat viral cultures, daily urinalysis, biweekly telephone follow-up for URI and renal complaints, and clinical assessments as indicated. When a URI occurred, viral cultures were done weekly if the child was at home and twice weekly if hospitalized. Sixty-one URIs occurred; the agent was identified in 33 (51.6%) (respiratory syncytial virus 14, influenza virus five, parainfluenza virus five, varicella zoster virus four, adenovirus three, Mycoplasma pneumoniae one, and Chlamydia trachomatis one). Forty-one exacerbations occurred, 71% with URI; 29% had no URI during the preceding 10 days (P less than 0.01). Total relapse occurred in 29 of 41 exacerbations, 69% with URI and 31% without URI (P less than 0.01). Patients with unstable NS had more exacerbations than those with stable NS (15 of 19 (79%) vs four of 13 (31%), P less than 0.001) and more URI (2.32 vs 1.46 per child, P less than 0.05). Exacerbations in patients with minimal change, mesangioproliferative, and focal glomerulosclerosis occurred in 40%, 60%, and 64%, respectively. We conclude that exacerbations and relapses of childhood NS are temporally related to URI. Inasmuch as multiple viral agents were associated with exacerbations, nonspecific host response to infection, not viral antigen or antibody response, may be the link to NS.
RATIONALE: Platelet activation is elevated in chronic obstructive pulmonary disease (COPD) and associated with self-reported respiratory symptoms. Observational studies link the antiplatelet drug aspirin to lower exacerbation rates and fewer symptoms. However, it is unknown if platelet activation predicts incident respiratory exacerbations or mortality. OBJECTIVE: Is systemic platelet activation prospectively associated with respiratory exacerbations and mortality among ever-smokers with or at risk for COPD? METHODS: We measured two systemic platelet activation biomarkers, urinary 11-dehydro-thromboxane B2 (11dTxB2) and plasma soluble CD40 ligand (sCD40L), at baseline in self-reported aspirin non-users in the longitudinal SPIROMICS cohort. Adjusted generalized negative binomial and linear mixed-effects models assessed associations between these biomarkers and prospective rates of total and severe exacerbations, plus cross-sectional and longitudinal respiratory health (St. George's Respiratory Questionnaire, COPD Assessment Test, modified Medical Research Council questionnaire, and six minute walk distance). Cox proportional hazard and competing risk models evaluated associations between platelet activation biomarkers and all-cause and cause-specific mortality. RESULTS: Among 2,711 participants, 1,572 (58.0%) reported aspirin non-use; of these, 1,433 and 1,437 had 11dTxB2 and sCD40L measured, respectively. Over a median 6.6 years, a two-fold higher baseline 11dTxB2 was associated with increased rates of total (8.8%; 95%CI: 0.4-17.8%) and severe (18.1%; 95%CI: 5.1-32.6%) exacerbations. Although there were no significant interactions, there was a trend toward higher severe exacerbation rates among current cigarettes smokers and those with COPD. There were no significant results for sCD40L. Among aspirin non-users, higher 11dTxB2, but not sCD40L, was associated with worse cross-sectional respiratory health and modestly increased all-cause mortality over a median 8.2 years (adjusted hazard ratio 1.11; 95%CI: 1.00-1.24). After covariate adjustment, there were no associations with longitudinal respiratory health or cause-specific mortality. CONCLUSIONS: Systemic platelet activation, measured by urinary 11dTxB2, is a statistically significant but modest predictor of respiratory exacerbations and all-cause mortality in individuals with or at risk for COPD, suggesting its potential utility as a prognostic and predictive biomarker for antiplatelet therapy trials. CLINICAL TRIAL REGISTRATION: NCT01969344.