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Current concepts of immune dysregulation in cystic fibrosis.

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Current concepts of immune dysregulation in cystic fibrosis.

Int J Biochem Cell Biol. 2014 Feb 2;

Authors: Rieber N, Hector A, Carevic M, Hartl D

Abstract
Cystic fibrosis (CF) lung disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene and is characterized by a perpetuated feedback loop of bacterial infection and inflammation. Both intrinsic (CFTR-dependent) and extrinsic (CFTR-independent) mechanisms contribute to the inflammatory phenotype of CF lung disease. Innate immune cells, initially recruited to combat bacterial pathogens, are acting in a dysregulated and non-resolving fashion in CF airways and cause harm to the host by releasing proteases and oxidants. Targeting harmful immune pathways, while preserving protective ones, remains the challenge for the future. This review highlights current concepts of innate immune dysregulation in CF lung disease. This article is part of a Directed Issue entitled: Cystic Fibrosis: From o-mics to cell biology, physiology, and therapeutic advances.

PMID: 24495876 [PubMed - as supplied by publisher]

Acute rhinosinusitis (ARS). Diagnosis and treatment of adults in general practice.

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Acute rhinosinusitis (ARS). Diagnosis and treatment of adults in general practice.

Dan Med J. 2014 Feb;61(2):B4801

Authors: Hansen JG

Abstract
The idea behind this thesis is to present how ARS and especially acute maxillary sinusitis in adults is diagnosed and treated in general practice. The study extends over many years, beginning with the first survey in 1991. Based on doctors' answers, we then investigated the diagnostic values ​​of the symptoms, signs and examinations which the doctors reported using. All patients over 18 years suspected of acute maxillary sinusitis were included consecutively and only once and, after a clinical examination with the GP, they were offered the opportunity to enter into the prospective study referred to acute CT scan and by changes in the CT, immediately referred to sinus puncture. Both examinations were conducted at Aalborg Hospital. The disease was found most frequently in younger and 2/3 were women. The reason for this gender difference is unknown. We have assessed the diagnostic values of the symptoms, objective findings and investigations ​​using 3 different reference standards: sinus puncture, microbiological diagnosis and CT scan described in three articles. In all examinations, it appeared that the usual signs and symptoms of acute maxillary sinusitis occur almost equally often and with a few exceptions in patients, with and without pus in the sinus cavities. Pain in the sinus cavities occurring in 95% of patients, and only elevated levels of CRP and ESR are significantly and independently associated with pus in the sinus cavities. This finding is surprising, because they are two nonspecific markers. CRP tested by near-patient testing has, within the investigations period, been introduced in general practice, and from 1999 the doctors also get reimbursed for performing the test. We have on this background originally defined a clinical criterion with pain over the sinuses accompanied by elevated values ​​of CRP and/or ESR giving a sensitivity of 0.82, specificity 0.57, ppv 0.68 and npv 0.74. But looking at the ROC curve we suggest that a more clinical relevant diagnose will be based on use of CRP alone, as the test can be made easily and fast while the patient is in the clinic compared to the use of ESR. The disease is over-diagnosed in general practice. In only 53% of patients, who the GP suspected of having acute sinusitis, was there detected pus or mucopus at the sinus puncture, furthermore the patients' statements that they had had sinusitis was significantly negatively associated with current acute maxillary sinusitis. Almost all patients are prescribed topical treatment to the nose in the form of vasoconstrictor, and 50-70% also antibiotics. The most common bacteria that can be isolated are S. pneumoniae and H. influenzae. For many years the first drug of choice has been penicillin V, and treatment with penicillin V has followed Scandinavian recommendations. However, the resistance patterns in respect of H. influenzae have changed over the years and if the dominant flora is H. influenzae, then oral penicillin is not sufficient anymore, and should be replaced by amoxicillin with or without clavulanate. It is reported that the MIC of penicillin V is too high, such that oral dosage cannot provide sufficiently high concentrations. However, in daily clinical practice the doctor does not have the possibility to decide whether the infection is caused by either S. pneumoniae or H. influenzae, unless a sinus puncture is performed and it is not considered as a standard procedure. The recommended treatment is therefore starting with penicillin V, and at treatment failure switching to amoxicillin with or without clavulanate. It is well known that URTI's can exacerbate a chronic pulmonary disease - like asthma - in allergic patients, but this influence is also demonstrated as described in article 6 where ARS in adults without any sign of chronic lung disease or allergy is accompanied by a temporary reduction lung function. Future research should focus on the use of CRP in general practice, analysing cost-effectiveness of the use of CRP patient outcome in relation to antibiotic treatment, clarification of ARS as a female disease, and a detailed exploration of the relationship between URTI's and impaired lung function in lung-healthy patients.

PMID: 24495896 [PubMed - in process]

The evolving genomic classification of lung cancer.

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EGFR gene mutations and ALK gene fusions are well-characterized molecular targets in NSCLC. Activating alterations in a variety of potential oncogenic driver genes have also been identified in NSCLC, including ROS1, RET, MET, HER2, and BRAF. Together with EGFR and ALK, these mutations account for ∼20% of NSCLCs.

The identification of these oncogenic drivers has led to the design of rationally targeted therapies that have produced superior clinical outcomes in tumours harbouring these mutations. Many patients, however, have de novo or acquired resistance to these therapies. In addition, most NSCLCs are genetically complex tumours harbouring multiple potential activating events. For these patients, disease subsets are likely to be defined by combination strategies involving a number of targeted agents. These targets include FGFR1, PTEN, MET, MEK, PD-1/PD-L1, and NaPi2b. In light of the myriad new biomarkers and targeted agents, multiplex testing strategies will be invaluable in identifying the appropriate patients for each therapy and enabling targeted agents to be channelled to the patients most likely to gain benefit.

The challenge now is how best to interpret the results of these genomic tests, in the context of other clinical data, to optimize treatment choices in NSCLC.

Airway epithelial regulation of pulmonary immune homeostasis and inflammation.

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Recent genetic, structural and functional studies have identified the airway and lung epithelium as a key orchestrator of the immune response. Further, there is now strong evidence that epithelium dysfunction is involved in the development of inflammatory disorders of the lung. Here we review the characteristic immune responses that are orchestrated by the epithelium in response to diverse triggers such as pollutants, cigarette smoke, bacterial peptides, and viruses.

We focus in part on the role of epithelium-derived interleukin (IL)-25, IL-33 and thymic stromal lymphopoietin (TSLP), as well as CC family chemokines as critical regulators of the immune response. We cite examples of the function of the epithelium in host defense and the role of epithelium dysfunction in the development of inflammatory diseases.

[Why use long-term macrolide therapy in pediatric pulmonology?]

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Macrolides are well-known antibiotics exerting antimicrobial as well as anti-inflammatory and immunomodulatory effects. Since the observation of a dramatic improvement in lung disease and survival in patients with diffuse panbronchiolitis, macrolides have been used over the long term in several chronic respiratory diseases. This review describes the results of trials that have evaluated long-term macrolides in the treatment of cystic fibrosis, non-cystic fibrosis bronchiectasis, and asthma, particularly focusing on the impact on children. It also provides new insights on the potential effects of macrolides on diffuse parenchymal lung diseases.

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