ANTIMICROBIAL CHEMOTHERAPY IN CYSTIC FIBROSIS PATIENTS

Høiby, N., Friis, B., Jensen, K., Koch, C, Møller, N.E., Støvring, S. and Szaff, M. (Statens Seruminstitut, Departments of Clinical Microbiology at Rigshospitalet and Hvidovre Hospital, and Paediatric Department TG, Rigshospitalet, Copenhagen, Denmark). Antimicrobial chemotherapy in cystic fibrosis patients. Acta Paediatr Scand 1982; suppl 301: 75-100. — Every effort should be undertaken to combat recurrent and chronic bacterial respiratory tract infections in patients with cystic fibrosis because infections are the main pathogenetic factors of lung damage in these patients. The principles and antibiotics used to treat bacterial infections in the Danish Cystic Fibrosis centre are outlined. The chemotherapy is based on microbiological diagnosis of secretions from the lower respiratory tract. S. aureus infections are efficiently treated with oral fusidic acid in combination with isoxazolyl penicillins or rifampicin in case of penicillin allergy or methicillin-resistant S. aureus. H. influenzae infections are treated efficiently with oral pivampicillin or amoxicillin or with erythromycin sometimes in combination with rifampicin in case of penicillin allergy or ampicillin-resistant H. influenzae . As a result of the efficient chemotherapy S. aureus and H. influenzae infections are now minor problems generally not related to prognosis of cystic fibrosis patients. Chronic P. aeruginosa infections are treated regularly four times per year with intravenous anti-pseudomonas β-lactam antibiotics in combination with tobramycin. P. aeruginosa is rarely permanently eradicated by this treatment, but significantly improved survival of the patients is obtained. The problems of resistant bacterial strains, allergy, and other side effects caused by the antibiotics are discussed.     

Diabetes mellitus in Danish cystic fibrosis patients: prevalence and late diabetic complications

Lanng S, Thorsteinsson B, Lund-Andersen C, Nerup J, Schiatz PO, Koch C. Diabetes mellitus in Danish cystic fibrosis patients: prevalence and late diabetic complications. Acta Pzdiatr 1994;83: 72–7. Stockholm. ISSN 0803–5253.
The prevalences of impaired glucose tolerance (IGT), diabetes mellitus and late diabetic complications were studied in all Danish cystic fibrosis (CF) patients. A total of 311 CF patients were identified with an estimated ascertainment rate above 98%. Glucose tolerdnce was classified in 278 (89%) patients: the prevalences of IGT and diabetes mellitus were 13.7% (38 patients) and 14.7% (41 patients), respectively, with no sex differences. The prevalence of diabetes mellitus increased with age but not with the severity of CF as compared with age- and sex-matched non-diabetic CF patients. Diabetes was diagnosed at a median age of 20 years (range 3–40 years) and the duration of diabetes was 1.7 years (0.1–17 years). Twenty-eight of the diabetic patients (70%) were trcated with insulin, on average 20 (4–90) IU per day. Late diabetic complications were identified in 4 patients (10%) with a duration of diabetes mellitus of 1–17 years: background retinopathy (2 patients), diabetic nephropathy (1 patient), microalbuminuria (1 patient) and neuropathy (2 patients). Thus diabetic CF patients are probably not less prone to develop late diabetic complications than patients with other types of diabetes of equally long duration and comparable glycemic control.     

Silastic catheters for home antibiotic therapy in patients with cystic fibrosis

Repeated 14-day courses of intravenous antibiotic therapy for patients with cystic fibrosis (CF), who have been colonized with Pseudomonas aeruginosa (PA), is one currently accepted treatment. Conventional intravenous cannulas for antibiotic delivery often have a short line life leading to frequent venipunctures. Therefore we used silastic catheters as a peripheral venous access. Silastic catheters (15 cm, 0.6 mm diameter) were inserted 10 cm into a cubital vein in 15 patients with CF (age 5–32 years) for 20 antibiotic courses. After the antibiotic infusion the catheter was flushed with 200 U heparin (2 ml Vetren). In all patients the antibiotic therapy was delivered as a home therapy. In 15 antibiotic courses the silastic catheter could be continuously used for 14 days. One patient with methicillin resistant Staphylococcus aureus received antibiotic therapy for 54 consecutive days using the same silastic catheter. The catheter had to be removed in four courses: once because of thrombophlebitis with local inflammation, once because of burning pain during infusion and occlusion twice. In one case the patient removed his catheter because of technical problems. No other serious side effects occurred. Ten patients had previously received intravenous antibiotics at least once. The median line life of the last used conventional peripheral cannula of all patients was 4 days versus 14 days with the use of the silastic catheter (P < 0.005). All patients preferred the silastic catheter to other venous access. Conclusion Because of the long line life and easy handling, silastic catheters may be an alternative venous access to perform home antibiotic therapy in patients with CF. Received: 9 May 1996 / Accepted: 24 September 1996     

Influence of the development of diabetes mellitus on clinical status in patients with cystic fibrosis

The impact of pre-diabetes on clinical status was retrospectively studied in 38 cystic fibrosis (CF) patients with diabetes mellitus (DM) and 38 non-diabetic CF patients (control patients), matched in pairs for age, sex, and chronicPseudomonas aeruginosa lung infection. Quarterly parameters of CF clinical status were collected for 6 years prior to the diagnosis of DM in the index case. Compared to the control patients, decreases in body weight, body mass index (BMI), forced expiratory volume in 1s (FEV₁), and forced vital capacity (FVC) and an increase in the daily intake of pancreatic enzyme capsules were found in the pre-diabetic patients. Statistically significant differences in body weight, BMI, FEV₁, FVC, and intake of pancreatic enzyme capsules between pre-diabetic and control patients emerged 4, 4, 1.25, 3 and 4.5 years prior to the diagnosis of DM, respectively. The number of lung infections did not differ between the two groups of patients. Thus, when DM develops in CF patients, an insidious decline in overall clinical status is observed for years prior to its diagnosis. Whether clinical deterioration in CF leads to DM, or pre-diabetes results in declining CF clinical status is presently unknown. Accumulating evidence suggests that the latter may be the case since insulin therapy seems to improve lung function in CF.     

Factors affecting diabetes mellitus onset in cystic fibrosis: evidence from a 10-year follow-up study

This study reports the results of genotype characterization and of a 10-y prospective evaluation of clinical status, glucose tolerance and insulin secretion in 28 originally normoglycaemic patients with cystic fibrosis (CF). The aim of the study was to assess whether any genetic, clinical or metabolic parameters could identify in advance those patients at risk of developing diabetes mellitus over time. During the follow-up 42.8% of patients became diabetic. Neither gender, age nor clinical parameters were significantly different at entry in the patients who eventually developed diabetes compared with those who did not. Insulin secretion during oral glucose tolerance tests (OGTT) deteriorated over time in both groups, whereas a progressive deterioration of glucose tolerance was only evident in the patients who developed diabetes and increased baseline glucose areas were the only predictive parameter of diabetes onset. Genotype analysis revealed significant differences between patients with and without diabetes: ΔF508 homozygosis was more frequent in the first group and N1303K mutation in the second group. In conclusion, in CF: (i) increased glucose areas during OGTT and deterioration of glucose tolerance over time can predict the evolution towards diabetes; and (ii) ΔF508 homozygosis may predispose to the risk of diabetes, whilst N1303K mutation seems to play a protective role.     

Diabetes mellitus in cystic fibrosis: genetic and immunological markers

Family history, as well as genetic and immunological markers of diabetes mellitus, were studied in cystic fibrosis (CF) patients with and without diabetes mellitus. Positive family history of diabetes mellitus in first-degree relatives was found in only 6 of 210 (3%) CF patients, with no difference between non-diabetic and diabetic patients. The frequency distributions of the HLA types DR3, DR4 and DR3/4, which normally confer susceptibility to insulin-dependent diabetes mellitus and of HLA-DR2, which normally confers resistance to insulin-dependent diabetcs mellitus, were not different in non-diabetic CF patients, diabetic CF patients and normal subjects. The genotypic frequencies of tumor necrosis factor-β and of heat shock protein 70, located within the HLA region on chromosome 6, in CF patients with diabetes were not different from those in patients with insulin-dependent diabetes mellitus, while non-diabetic CF patients and normal subjects shared other patterns. The frequencies of the interleukin-1β alleles, located on chromosome 2, were not different in non-diabetic and diabetic CF patients, insulin-dependent diabetic patients and normal subjects. Islet cell cytoplasmic antibodies. measured before, at and after the diagnosis of diabetes in 33 diabetic CF patients and in 32 matched non-diabetic CF patients, were detected in only 2 of 236 (0.8%) serum samples; m a pre-diabetic patient and in a non-diabetic control patient. Birth weights were not different in diabetic and non-diabetic CF patients, arguing against the importance of the intrauterine environment as a determinant in the transmission of diabetes mellitus in CF patients. We conclude that diabetes mellitus in CF is without family history of diabetes mellitus, HLA-DR association, and serological evidence for autoimmune destruction of the β-cells. The significance of similar frequcncies of tumor necrosis factor-β and heal shock protein 70 alleles in insulin-dependent diabetic patients and diabetic CF patients remains to bc determined.     

Evaluation of long term tobramycin therapy in patients with cystic fibrosis and advanced pulmonary disease

To nine cystic fibrosis patients with chronic bronchopulmonary infection of severely damaged lungs invaded by Pseudomonas aeruginosa, eleven courses of prolonged tobramycin treatment (5 mg/kg/day) for four to 16 weeks were administered. Pulmonary symptoms improved and a better quality of life was achieved in all but one patient. Objective parameters (chest X-ray, pulmonary function tests) changed to a lesser extent. In only one patient was Pseudomonas eradicated from the sputum but reappeared after discontinuation of therapy. In the rest of the patients Pseudomonas was significantly suppressed or replaced by other pathogens. Four patients showed rises of antibody titres to Candida and two to Aspergillus fumigatus. No nephrotoxic side effects were observed, but vestibular function was reversibly impaired in one patient without corresponding clinical symptoms. No bacterial resistance to tobramycin was observed during therapy.     

2004年肺炎链球菌、流感嗜血杆菌和卡他莫拉菌耐药监测

目的监测2004年呼吸道常见致病菌肺炎链球菌、流感嗜血杆菌和卡他莫拉菌对抗生素的耐药性。方法抗生素药敏试验采用E_test法和K_B法。结果肺炎链球菌对青霉素不敏感率为32.9%,对头孢克洛、头孢呋辛和头孢曲松分别为25.0%、26.4%和5.7%,对红霉素、阿齐霉素和克林霉素不敏感率>90%;流感嗜血杆菌和卡他莫拉菌对氨苄青霉素耐药率分别为14.3%和56.6%,但前者β_内酰胺酶阳性率为14.3%,而后者为90.8%,两者对其他β_内酰胺酶类耐药率较低。结论呼吸道致病菌对抗生素的耐药性正在增加,连续监测抗生素的耐药性对经验治疗呼吸道感染非常必要。     

The relationship between chest radiographic scores and respiratory function tests in children with cystic fibrosis

Chestradiographic scores and respiratory function on 80 sets of results from 50 patients with Cystic Fibrosis were analysed. Chest radiographic scores were assessed independently using the method of Chrispin and Norman. Respiratory function tests were found to correlate well with the chest radiographic score, the best correlation being with the forced expiratory volume in 0.75 sec. to forced vital capacity ratio F.E.V.0.75/ F.V.C. (r=–0.674 n=80 p<0.001).     

Association of vitamin A status with lung function in children and adolescents with cystic fibrosis

Importance:Vitamin A(or retinol)has considerable antioxidative and anti-inflammatory attributes and it may have protective effects on the respiratory health of ...     

Initial insulin therapy in children and adolescents with type 1 diabetes mellitus

Weitzel D, Pfeffer U, Dost A, Herbst A, Knerr I, Holl R. Initial insulin therapy in children and adolescents with type 1 diabetes mellitus. Objective: The aim of the study was to define parameters that influence the initial insulin dosage in young subjects with type 1 diabetes regarding the amount of daily insulin, the ratios of basal and prandial insulin, and the insulin/carbohydrate ratios. Study design: We used a computer‐based registry (with prospectively collected data) in Germany and Austria, a software for the management and data documentation of diabetic patients (DPV), to analyze the initial insulin therapy in 2247 children with newly diagnosed type 1 diabetes to identify factors that influence diabetes therapy within the first 10 d. Results: For both genders, glucosylated hemoglobin A1c (HbA1c), blood pH at diabetes onset, and pubertal status are the major factors determining the initial insulin dosage calculated as the amount of daily insulin per kilogram body weight (kg), the basal and prandial insulin dose per kilogram, and day and the insulin/carbohydrate ratios for meals. The frequency of hypoglycemia correlated with increasing quotient of applied to calculated insulin dosage. Conclusion: The predictive factors of insulin requirement may exert beneficial effects on the assessment and adjustment of insulin therapy in young diabetic subjects at disease onset. On the basis of a multiple, linear regression, we suggest a formula to calculate the initial insulin therapy.     

应用胰岛素泵治疗儿童及青少年1型糖尿病对糖代谢的影响

为观察应用胰岛素泵治疗儿童及青少年1型糖尿病(T1DM)对糖代谢的影响 ,随访10例胰岛素泵治疗的T1DM患儿 ,分别观察胰岛素泵治疗前、后6个月的糖化血红蛋白值(HbA1c)、胰岛素用量、严重低血糖及酮症酸中毒发生次数的变化情况。结果显示 ,胰岛素泵治疗6个月后HbA1c 显著下降 ,治疗前为8.97 %±1.69 %,治疗后为7.51 %±1.17 % (t=2.52 ,P<0.05) ;胰岛素用量无显著下降 ;未发生严重低血糖和酮症酸中毒。表明胰岛素泵治疗可有效控制血糖 ,明显降低HbA1c,减少低血糖及酮症酸中毒的发生 ,是儿童及青少年T1DM常规治疗的较好选择。     

Longitudinal evaluation of glucose tolerance and insulin secretion in non-diabetic children and adolescents with cystic fibrosis: results of a two-year follow-up

Thirty-two patients with cystic fibrosis and repeatedly normal fasting blood glucose underwent oral glucose tests and islet-cell antibody assessments on two occasions approximately two years apart. Fourteen patients underwent two iv glucose tolerance tests also. Although in the group as a whole mean glucose areas in response to the oral test remained substantially unmodified over the two-year period, the prevalence of glucose tolerance abnormalities increased from 37.5 to 50%. Insulin output in response to both oral and iv tolerance tests decreased over time. Worsening of insulin secretion and/or of glucose tolerance was never accompanied by deteriorating clinical status. Islet-cell antibodies were detected in no patients, even in those who developed a diabetic glucose tolerance. These results support, on a longitudinal basis, the view of a progressive impairment of B-cell function in cystic fibrosis, which may precede the onset of metabolic abnormalities and is not triggered by autoimmunity.     

Restoration of exocrine pancreatic function in older children with cystic fibrosis on ivacaftor

Prior to the use of cystic fibrosis (CF) modulator therapy, exocrine pancreatic insufficiency in CF was thought to be irreversible. Improvement in pancreatic function on ivacaftor has been reported in open label studies in 1–5 year olds. The mechanism by which ivacaftor might improve exocrine pancreatic function is unclear. Although the effect of ivacaftor on pancreatic function may be more significant in younger children, evidence is mounting that there may still be potential for improvement in older children on long term therapy.     

相对胰岛素敏感性指数在肥胖症和糖尿病中的临床应用

目的探讨肥胖儿童和糖尿病儿童外周组织的胰岛素敏感性及其与血浆胰岛素浓度的相关性。方法随机选择单纯性肥胖儿童３２例分为糖耐量正常组（ＮＧＴ组）和糖耐量低减组（ＩＧＴ组）各１６例。Ⅰ型糖尿病组（ＩＤＤＭ组）１６例。健康儿童１６例（对照组）。用放射免疫法测定血浆胰岛素，葡萄糖氧化酶法测定血浆葡萄糖。以相对胰岛素敏感性指数（ＲＩＳＩ）来判断组织的胰岛素敏感性。结果肥胖组、糖尿病组ＲＩＳＩ值均明显低于对照组（Ｐ＜０．０１）。以对照组ＲＩＳＩ均值减去一个标准差值衡量不同机体组织的胰岛素敏感性表明，对照组、ＨＧＴ组、ＩＧＴ组、ＩＤＤＭ组在此值以上者分别占８１．２％、５６．２％、１２．５％、０。后两组与对照组比较均有极显著差异（Ｐ＜０．０１）。肥胖组ＲＩＳＩ与ＦＰＩ间呈显著负相关（ｒ＝０．４６，Ｐ＜０．０１），而糖尿病组相关不显著（ｒ＝０．２８９，Ｐ＞０．０５）。结论肥胖组（尤其ＩＧＴ组）与糖尿病组普遍存在组织的胰岛素敏感性下降，是导致肥胖儿童血浆胰岛素升高的一个原因。ＲＩＳＩ判断组织的胰岛素敏感程度有实用价值。     

Structural lung changes,lung function,and non‐invasive inflammatory markers in cystic fibrosis

Robroeks CMHHT, Roozeboom MH, de Jong PA, Tiddens HAWM, Jöbsis Q, Hendriks HJ, Yntema J‐BL, Brackel HL, van Gent R, Robben S, Dompeling E. Structural lung changes, lung function, and non‐invasive inflammatory markers in cystic fibrosis.
Pediatr Allergy Immunol 2010: 21: 493–500.
© 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard Cystic fibrosis (CF) lung disease is characterized by chronic airway inflammation and recurrent infections, resulting in (ir)reversible structural lung changes and a progressive decline in lung function. The objective of this study was to investigate the relationship between non‐invasive inflammatory markers (IM) in exhaled breath condensate (EBC), lung function indices and structural lung changes, visualized by high resolution computed tomography (HRCT) scans in CF. In 34 CF patients, lung function indices (forced expiratory volume in 1 s, forced vital capacity [FVC], residual volume, and total lung capacity [TLC]) and non‐invasive IM (exhaled nitric oxide, and condensate acidity, nitrate, nitrite, 8‐isoprostane, hydrogen peroxide, interferon‐gamma) were assessed. HRCT scans were scored in a standardized and validated way, a composite score and component scores were calculated. In general, the correlations between non‐invasive IM and structural lung changes, and between IM and lung function were low (correlation coefficients <0.40). Patients with positive sputum Pseudomonas cultures had higher EBC nitrite levels and higher parenchymal HRCT subscores than patients with Pseudomonas‐negative cultures (p < 0.05). Multiple linear regression models demonstrated that FVC was significantly predicted by hydrogen peroxide in EBC, and the scores of bronchiectasis and mosaic perfusion (Pearson correlation coefficient R = 0.78, p < 0.001). TLC was significantly predicted by 8‐isoprostane, nitrate, hydrogen peroxide in EBC, and the mucous plugging subscore (R = 0.92, p < 0.01). Static and dynamic lung function indices in this CF group were predicted by the combination of non‐invasive IM in EBC and structural lung changes on HRCT imaging. Future longitudinal studies should reveal whether non‐invasive monitoring of airway inflammation in CF adds to better follow‐up of patients.