Combined cervicosternotomy and cervicotomy for true retrosternal goiters: a surgical cohort study.

OBJECTIVE: Intrathoracic goiters are a heterogeneous group characterized by limited or extensive substernal extension. Whereas the former can be treated through cervicotomy, the latter sometimes requires a cervicosternotomy. Whether cervicosternotomy leads to more morbidity remains unclear. This study aimed to compare intra- and postoperative morbidity in patients treated by cervicotomy or cervicosternotomy for intrathoracic goiters and standard thyroidectomy. METHODS: In a prospectively gathered cohort undergoing thyroid surgery (2010-2019) intra- and postoperative morbidity of cervicotomy (N = 80) and cervicosternotomy (N = 15) for intrathoracic goiters was compared to each other and to a 'standard' thyroidectomy (N = 1500). RESULTS: An intrathoracic extension prior to surgery was found in 95 (6%) of all thyroidectomies. Eighty patients (84%) were operated by cervicotomy and 15 (16%) by cervicosternotomy. The risk of temporary recurrent laryngeal nerve palsy was much higher in the cervicosternotomy group (21%) compared to cervicotomy (4%) and standard thyroidectomy (3%). The risk of temporary hypocalcemia after cervicotomy (28%) was comparable to a standard thyroidectomy (32%) but higher after cervicosternotomy (20%). No cases of permanent hypocalcemia or laryngeal nerve palsy were observed in both groups with substernal extension. The need for surgical reintervention was significantly higher in the cervicotomy group (6%) compared to cervicosternotomy (0%) and standard thyroidectomy (3%). CONCLUSION: In patients undergoing thyroid surgery for an intrathoracic goiter, cervicosternotomy was associated with more temporary laryngeal nerve palsy, but none of the interventions resulted in higher risks of permanent nerve damage, permanent hypocalcemia, or reintervention for bleeding. Reintervention was even more common after cervicotomy compared to cervicosternotomy. LEVEL OF EVIDENCE: IV.

Clinical effectiveness and cost-effectiveness of endobronchial and endoscopic ultrasound relative to surgical staging in potentially resectable lung cancer: results from the ASTER randomised controlled trial.

OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of endosonography (followed by surgical staging if endosonography was negative), compared with standard surgical staging alone, in patients with non-small cell lung cancer (NSCLC) who are otherwise candidates for surgery with curative intent. DESIGN: A prospective, international, open-label, randomised controlled study, with a trial-based economic analysis. SETTING: Four centres: Ghent University Hospital, Belgium; Leuven University Hospitals, Belgium; Leiden University Medical Centre, the Netherlands; and Papworth Hospital, UK. INCLUSION CRITERIA: known/suspected NSCLC, with suspected mediastinal lymph node involvement; otherwise eligible for surgery with curative intent; clinically fit for endosonography and surgery; and no evidence of metastatic disease. EXCLUSION CRITERIA: previous lung cancer treatment; concurrent malignancy; uncorrected coagulopathy; and not suitable for surgical staging. INTERVENTIONS: Study patients were randomised to either surgical staging alone (n = 118) or endosonography followed by surgical staging if endosonography was negative (n = 123). Endosonography diagnostic strategy used endoscopic ultrasound-guided fine-needle aspiration combined with endobronchial ultrasound-guided transbronchial needle aspiration, followed by surgical staging if these tests were negative. Patients with no evidence of mediastinal metastases or tumour invasion were referred for surgery with curative intent. If evidence of malignancy was found, patients were referred for chemoradiotherapy. MAIN OUTCOME MEASURES: The main clinical outcomes were sensitivity (positive diagnostic test/nodal involvement during any diagnostic test or thoracotomy) and negative predictive value (NPV) of each diagnostic strategy for the detection of N2/N3 metastases, unnecessary thoracotomy and complication rates. The primary economic outcome was cost-utility of the endosonography strategy compared with surgical staging alone, up to 6 months after randomisation, from a UK NHS perspective. RESULTS: Clinical and resource-use data were available for all 241 patients, and complete utilities were available for 144. Sensitivity for detecting N2/N3 metastases was 79% [41/52; 95% confidence interval (CI) 66% to 88%] for the surgical arm compared with 94% (62/66; 95% CI 85% to 98%) for the endosonography strategy (p = 0.02). Corresponding NPVs were 86% (66/77; 95% CI 76% to 92%) and 93% (57/61; 95% CI 84% to 97%; p = 0.26). There were 21/118 (18%) unnecessary thoracotomies in the surgical arm compared with 9/123 (7%) in the endosonography arm (p = 0.02). Complications occurred in 7/118 (6%) in the surgical arm and 6/123 (5%) in the endosonography arm (p = 0.78): one pneumothorax related to endosonography and 12 complications related to surgical staging. Patients in the endosonography arm had greater EQ-5D (European Quality of Life-5 Dimensions) utility at the end of staging (0.117; 95% CI 0.042 to 0.192; p = 0.003). There were no other significant differences in utility. The main difference in resource use was the number of thoracotomies: 66% patients in the surgical arm compared with 53% in the endosonography arm. Resource use was similar between the groups in all other items. The 6-month cost of the endosonography strategy was £9713 (95% CI £7209 to £13,307) per patient versus £10,459 (£7732 to £13,890) for the surgical arm, mean difference £746 (95% CI -£756 to £2494). The mean difference in quality-adjusted life-year was 0.015 (95% CI -0.023 to 0.052) in favour of endosonography, so this strategy was cheaper and more effective. CONCLUSIONS: Endosonography (followed by surgical staging if negative) had higher sensitivity and NPVs, resulted in fewer unnecessary thoracotomies and better quality of life during staging, and was slightly more effective and less expensive than surgical staging alone. Future work could investigate the need for confirmatory mediastinoscopy following negative endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), the diagnostic accuracy of EUS-FNA or EBUS-TBNA separately and the delivery of both EUS-FNA or EBUS-TBNA by suitably trained chest physicians. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 97311620. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 18. See the HTA programme website for further project information.

Are EUS-FNA and EBUS-TBNA specimens reliable for subtyping non-small cell lung cancer?

With endosonography, the diagnosis and staging of non-small cell lung cancer (NSCLC) increasingly relies on small samples. The discrimination between squamous and non-squamous subtypes is now important for therapy tailoring. We analyzed the agreement between fine needle aspirates obtained by endosonography and matched biopsy samples for subtyping NSCLC. Patients with a positive endoscopic fine needle aspirate and a matched biopsy were identified. The level of diagnostic agreement was estimated with biopsy samples as golden standard. In 951 patients investigated with endosonography, we identified 92 with NSCLC on the positive fine needle aspirate and on the matched biopsy. Squamous cell carcinoma was diagnosed in 34 (37%) and 44 (48%) of fine needle aspirate and biopsy samples; while non-squamous carcinoma was diagnosed in 58 (63%) and 48 (52%) respectively. The agreement between needle aspirate and biopsy for the subtyping of NSCLC was 76% (kappa=0.52). In cases with cell block preparation, the agreement for subtyping was 96% (kappa=0.91) vs 69% (kappa=0.39) in cases without cell blocks. Therefore, the diagnostic agreement between endosonographic fine needle aspirates and biopsy specimens for subtyping NSCLC is moderate with a disagreement in 1 out of 4 patients. However, cell block preparation increased the agreement and thus the reliability of the fine needle specimens obtained during endosonography, for subtyping NSCLC considerably. In conclusion, for patients with NSCLC in whom subtyping is relevant, a diagnostic technique yielding larger samples (FNA with cell block preparation or biopsies) should be preferred.

Endobronchial ultrasound-guided transbronchial needle biopsy for M1 staging of extrathoracic malignancies.

BACKGROUND: extrathoracic malignancies metastasize to the mediastinum and/or pulmonary hilum. Mediastinoscopy and thoracoscopy are standard to obtain tissue proof of metastatic spread but are invasive. Endobronchial ultrasound with real-time-guided transbronchial fine-needle aspiration (EBUS-TBNA) is a minimally invasive alternative for surgical staging of lung cancer. METHODS: we analysed the test characteristics of EBUS-TBNA in consecutive patients with a suspicion of mediastinal or hilar metastases of various extrathoracic malignancies. RESULTS: ninety-two patients with concurrent (n = 33) or previously diagnosed and treated (n = 59) extrathoracic malignancies were evaluated. EBUS-TBNA detected mediastinal or hilar metastatic spread in 52 patients (57%) [metastasis of extrathoracic tumour in 40 (44%) and second malignancies (lung cancer) in 12 (13%)]. Subsequent surgical staging showed malignancy in another nine patients. With EBUS-TBNA, an alternate diagnosis was found in four. Sensitivity and negative predictive value for mediastinal or hilar metastatic spread were 85% [95% confidence interval (CI) 73-93] and 76% (95% CI 59-88). EBUS-TBNA prevented an invasive surgical procedure in 61% of the patients. One patient had a respiratory arrest during EBUS-TBNA; abortion lead to full recovery without further intervention. CONCLUSIONS: EBUS-TBNA is a minimally invasive method for M staging of patients with extrathoracic malignancies to confirm mediastinal or hilar spread. EBUS-TBNA therefore may qualify as an alternative for surgical staging.

Diagnostic bronchoscopy: state of the art.

Since the introduction of the flexible fibreoptic bronchoscope in the late 1960s there have been relatively few technological advances for three decades, aside from the development of a white light video bronchoscope with a miniature charge-coupled device built in its tip replacing the fibreoptics. White light flexible videobronchoscopy with its ancillary devices (forceps biopsy, bronchial brushing, bronchoalveolar lavage, bronchial washings and transbronchial needle aspiration) has long been the only established diagnostic bronchoscopic technique. With the advances in microtechnology over the past two decades, recent technical developments such as autofluorescence bronchoscopy and endoscopic ultrasound allow better evaluation of endobronchial, mediastinal and parenchymal lesions.

A randomized phase II study comparing two schedules of the 21-day regimen of gemcitabine and carboplatin in advanced non-small cell lung cancer.

PURPOSE: Carboplatin area under the curve (AUC) 5 ml/min on day 1 with gemcitabine 1,250 mg/m(2) on day 1 and day 8 is a widely used regimen in advanced non-small cell lung cancer. Grade 3-4 thrombocytopenia and neutropenia are frequent. The aim of this study is to investigate whether toxicity of gemcitabine/carboplatin could be reduced by administering carboplatin on day 8 instead of day 1 without a decrease in response rate (RR). METHODS: Patients received gemcitabine 1,250 mg/m(2) on days 1 and 8, carboplatin AUC 5 on day 1 (arm A) or day 8 (arm B). Drugs were administered over a 21-day cycle. Toxicity and RR were evaluated weekly and every second cycle, respectively. RESULTS: 71 patients were enrolled into the study. We found 79% (95% CI 61-91%) grade 3-4 toxicity (neutropenia and thrombocytopenia) in arm A and 50% (95% CI 32-68%) in arm B; 66% grade 3-4 thrombocytopenia in arm A and 26% in arm B. We observed 30% grade 4 hematological toxicity in arm A and 3% in arm B. In arm A an overall RR of 20% (95% CI 7.7-38.6%) was seen, and 18.2% (95% CI 7-35.5%) in arm B. CONCLUSIONS: Although the study was prematurely closed, the current data are of interest. The schedule with carboplatin on day 8 is associated with substantially lower grade 3-4 neutropenia and thrombocytopenia with comparable dose intensity and RR.

The value of endoscopic ultrasound after bronchoscopy to diagnose thoracic sarcoidosis.

A clinicoradiological presentation of thoracic sarcoidosis requires histopathology in order to establish the diagnosis. Flexible bronchoscopy has a reasonable diagnostic yield and is the procedure of first choice for diagnosis. Endoscopic ultrasound (endoscopic ultrasound-guided fine needle aspiration/endobronchial ultrasound-guided transbronchial needle aspiration) can help in the diagnosis of sarcoidosis. An implementation strategy of endoscopic ultrasound for the diagnosis of sarcoidosis following negative flexible bronchoscopy results was examined prospectively in 15 clinics. A total of 137 patients (92 males; median age 43 yrs) were included, and sarcoidosis was found in 115 (84%). Alternative diagnoses were tuberculosis, lymphangitis carcinomatosa, pneumoconiosis and alveolitis. All patients were sent for flexible bronchoscopy, which was performed in 121 (88%), resulting in a definite diagnosis in 57 (42%). A total of 80 patients were sent for endoscopic ultrasound, which could be performed in 72 (90%), yielding a definite diagnosis in 47 (59%). Endoscopic ultrasound following negative flexible bronchoscopy avoided a surgical procedure in 47 out of 80 patients. The sensitivity of flexible bronchoscopy for sarcoidosis was 45% (95% confidence interval 35-54%), but 62% (50-72%) if biopsy specimens were taken. The sensitivity of endoscopic ultrasound following negative flexible bronchoscopy results was 71% (58-82%). With this strategy, 97 out of 115 (84% (76-90%)) of proven sarcoidosis was diagnosed using endoscopy. This large prospective implementation study (trial number NCT00888212; ClinicalTrials.gov) shows that endoscopic ultrasound is valuable for diagnosing sarcoidosis after negative flexible bronchoscopy results.

Decreased FOXP3 protein expression in patients with asthma.

BACKGROUND: T-regulatory cells (T(reg)) are important in balancing immune responses and maintaining peripheral tolerance. Current evidence suggests that asthma is characterized by a relative deficiency in T(reg), allowing T helper 2 cells to expand. In this study, we aimed to evaluate circulating T(reg), defined by the protein FOXP3, in both control subjects and patients with stable asthma. METHODS: Peripheral blood mononuclear cells (PBMC) of control (n = 14) and asthmatic patients (n = 29) were labeled for CD4, CD25, and intracellular FOXP3 and analyzed using flow cytometry. In CD3/CD28 stimulated PBMC, the effects of dexamethasone on the transcription factors T-bet, GATA-3, FOXP3, and RORc2 and representative cytokines were studied. RESULTS: In control subjects and asthmatic patients, numbers of peripheral blood CD4(+)CD25(high) and CD4(+)CD25(high)FOXP3(+) T-cells were similar. However, FOXP3 protein expression within CD4(+)CD25(high) T-cells was significantly decreased in asthmatic patients. There was a tendency for increased FOXP3 expression within CD4(+)CD25(high) T-cells in glucocorticosteroid-treated patients when compared to steroid-naive asthmatic patients. In stimulated PBMC, dexamethasone treatment increased the anti-/proinflammatory transcription ratios of FOXP3/GATA-3, FOXP3/T-bet, and FOXP3/RORc2. CONCLUSION: Asthmatic patients have decreased FOXP3 protein expression within their CD4(+)CD25(high) T(reg). Our findings also suggest that treatment with inhaled glucocorticosteroids in asthmatics might increase this FOXP3 protein expression within the CD4(+)CD25(high) T-cell population.

Chronic inflammation in asthma: a contest of persistence vs resolution.

Recent investigations have highlighted that endogenous anti-inflammatory mediators and immune regulating mechanisms are important for the resolution of inflammatory processes. A disruption of these mechanisms can be causally related not only to the initiation of unnecessary inflammation, but also to the persistence of several chronic inflammatory diseases. In asthma, chronic Th-2 driven eosinophilic inflammation of the airways is one of the central abnormalities. To date, elucidating the role of the different pro-inflammatory mediators involved in orchestrating the inflammatory processes in asthma has been the subject of intense research in both humans and animal models. However, the counter-regulatory mechanisms that co-determine the outcome in the contest of resolution vs persistence of the eosinophilic airway inflammation remain poorly understood. These are currently being investigated in animal models of chronic asthma. Elucidating these mechanisms is of relevance, since it can give rise to a new therapeutic approach in the treatment of chronic airway inflammation in asthmatics. This novel concept of treatment involves the stimulation of endogenous anti-inflammatory pathways, rather than solely antagonising the various pro-inflammatory mediators. Here, we review and discuss the current knowledge about these endogenous anti-inflammatory mediators in clinical and experimental asthma.

Integrated FDG-PET/CT does not make invasive staging of the intrathoracic lymph nodes in non-small cell lung cancer redundant: a prospective study.

BACKGROUND: Staging of non-small cell lung cancer (NSCLC) is important for determining choice of treatment and prognosis. The accuracy of FDG-PET scans for staging of lymph nodes is too low to replace invasive nodal staging. It is unknown whether the accuracy of integrated FDG-PET/CT scanning makes invasive staging redundant. METHODS: In a prospective study, the mediastinal and/or hilar lymph nodes in patients with proven NSCLC were investigated with integrated FDG-PET/CT scanning. Pathological confirmation of all suspect lymph nodes was obtained to calculate the accuracy of the fusion images. In addition, the use of the standardised uptake value (SUV) in the staging of intrathoracic lymph nodes was analysed. RESULTS: 105 intrathoracic lymph node stations from 52 patients with NSCLC were characterised. The prevalence of malignancy in the lymph nodes was 36%. The sensitivity of the integrated FDG-PET/CT scan to detect malignant lymph nodes was 84% and its specificity was 85% (positive likelihood ratio 5.64, negative likelihood ratio 0.19). SUV(max), SUV(mean) and the SUV(max)/SUV(liver) ratio were all significantly higher in malignant than in benign lymph nodes. The area under the receiver operating curve did not differ between these three quantitative variables, but the highest accuracy was found with the SUV(max)/SUV(liver) ratio. At a cut-off value of 1.5 for the SUV(max)/SUV(liver )ratio, the sensitivity and specificity to detect malignant lymph node invasion were 82% and 93%, respectively. CONCLUSION: The accuracy of integrated FDG-PET/CT scanning is too low to replace invasive intrathoracic lymph node staging in patients with NSCLC. The visual interpretation of the fusion images of the integrated FDG-PET/CT scan can be replaced by the quantitative variable SUV(max)/SUV(liver) without loss of accuracy for intrathoracic lymph node staging.

Mycobacterium avium complex with a distinct clinical and iconographic presentation: the Lady Windermere syndrome.

Clinically significant pulmonary disease caused by non-tuberculous mycobacteria such as Mycobacterium avium Complex (MAC) usually occurs upon pre-existing lung diseases or immune-deficiency. In 1992, a particular presentation of pulmonary MAC, occuring in otherwise healthy middle-aged women, was described with pulmonary consolidations localized in lingula and middle lobe. For this specific, rare condition, the term Lady Windermere syndrome was introduced. We report a particular case of this syndrome, in which an otherwise healthy individual developed clinically significant disease upon MAC (subtype: Mycobacterium avium) infection of the right middle lobe and lingula of the lung. The patient did not have the classical risk factors for developing this syndrome (e.g. habitual cough suppression, long and narrow bronchi) indicating their modest contribution in the pathogenesis. In our case, guideline based therapy was found to be inadequate because of multi-drug resistance, so an alternative treatment regime was given with good clinical result.

Animal models of allergen-induced tolerance in asthma: are T-regulatory-1 cells (Tr-1) the solution for T-helper-2 cells (Th-2) in asthma?

Non-specific anti-inflammatory medication is actually the treatment of choice for controlling the T-helper type 2 (Th-2) cell-driven airway inflammation in asthma. The induction of counterbalancing Th-1 cell clones, long considered a promising approach for immunotherapy, has failed to fulfil its promise because of potentially detrimental side-effects. This is therefore probably not a valid option for the treatment of asthma. With the increasing awareness that active immune mechanisms exist to control inflammatory responses, interest rises to investigate whether these can be exploited to control allergen-induced airway disease. The induction of antigen-specific T cells with suppressive characteristics (regulatory T cells) is therefore a potentially interesting approach. These regulatory T cells mediate tolerance in healthy, non-atopic individuals and have the potential of becoming an effective means of preventing allergen-induced airway inflammation and possibly of suppressing ongoing allergic immune responses. Here we review the available knowledge about allergen-induced suppressive immunity obtained from animal models taking into account the different developmental stages of allergic airway disease.

A case of recurrent non-small-cell lung carcinoma and paraneoplastic Cushing's syndrome.

Secretion of ectopic adrenocorticotropic hormone (ACTH) with consequently Cushing's syndrome is a rare paraneoplastic phenomenon. It has been described in a variety of malignancies, like bronchial carcinoids, small-cell lung carcinoma, thymoma, pancreatic carcinoma and other. In many cases of suspected ectopic ACTH secretion, it is difficult to histologically or cytochemically confirm the diagnosis. We present a 63-year-old woman with a recurrent poorly differentiated squamous cell lung carcinoma with clinical and biochemical features consistent with ectopic Cushing's syndrome. Immunocytochemical staining confirmed the secretion of ACTH by tumour cells.

Modulatory role of tachykinin NK1 receptor in cholinergic contraction of mouse trachea.

The role of the NK1 receptor in airway contraction induced by electrical field stimulation (EFS) was evaluated by comparing the response in NK1 receptor knockout mice (NK1R-/-) with that of NK1 receptor wild-type controls (WT). A frequency/response curve on tracheas from NK1R-/- mice and NK1R WT littermates was constructed. After incubation with [3H]choline, [3H]acetylcholine release upon EFS was measured by high-performance liquid chromatography and liquid scintillation counting. The effects of atropine (1 x 10(-6) M), tetrodotoxin (1 x 10(-6) M) and a specific NK1R antagonist (SR140333, 1 x 10(-8) M) were studied, as well as the effects of substance P (1 x 10(-5) M) on precontracted tracheas. Upon EFS, NK1R-/- mice had a significant lower trachea contractility than the NK1R WT animals, accompanied with less [3H]acetylcholine release. Pretreatment with atropine or tetrodotoxin abolished the EFS-induced contraction in both strains. Pretreatment with the NK1R antagonist SR140333 significantly reduced the contractility in the NK1R WT but not in the NK1R-/- mice. Substance P caused a small contraction in both NK1R WT and NK1R-/- mice. Substance P induced a relaxation in precontracted tracheas in NK1R WT but not in NK1R-/- mice. The data presented here provide direct evidence that the NK1 receptor augments cholinergic neurotransmission in mouse trachea.

New anti-asthma therapies: suppression of the effect of interleukin (IL)-4 and IL-5.

Asthma is currently defined as a chronic inflammatory disorder of the airways. The central role of allergen-specific Th2 cells in the regulation of this mucosal airway inflammation has been highlighted. Hence, there is large interest in the therapeutic potential of an anti-Th2 cell approach. One of the strategies which has been developed, is to inhibit the effect of interleukin (IL)-4 or IL-5, two main Th2 cell derived cytokines. Interleukin-4 is pivotal in the pathogenesis of allergic disorders through its wide range of effects. An important observation, especially during secondary antigen exposure, is the possible redundancy with IL-13. Both cytokines share common elements in their receptor and intracellular signalling pathway. As a result, compounds can be developed that selectively inhibit the effect of either IL-4 or IL-13, or alternatively, by interfering with the common pathway, inhibit the effect of both cytokines. Eosinophils are generally seen as a particularly harmful element in the allergic inflammation. The importance of IL-5 on eosinophil biology has clearly been established. Conversely, in man, the biological effects of IL-5 are largely limited to eosinophil function. Therefore, IL-5 antagonists offer the unique opportunity of selectively neutralizing the effect of eosinophils. Several strategies have now been developed that successfully inhibit the biological effect of interleukin-4 or interleukin-5. Some of these compounds have proven to be biologically active in man. The challenge now is to establish their therapeutic role in asthma.

The allergen-induced airway hyperresponsiveness in a human-mouse chimera model of asthma is T cell and IL-4 and IL-5 dependent.

The cellular and molecular mechanisms involved in the airway hyperresponsiveness (AHR) of patients with allergic asthma remain unclear. A role for Th2 inflammatory cells was suggested based on murine asthma models. No direct evidence exists on the role of these cells in human asthma. The development of a mouse-human chimera might be useful, allowing the in vivo study of the components of the human immune system relevant to asthma. We investigated the role of allergen-reactive T lymphocytes in a human-mouse SCID model. SCID mice were reconstituted intratracheally with human PBMC from healthy, nonallergic, nonasthmatic donors and exposed to an aerosol of house dust mite allergen after i.p. injection with Dermatophagoides pteronyssinus I Ag and alum. The donor T lymphocytes had a Th1 cytokine phenotype. The reconstituted and allergen-challenged mice developed AHR to carbachol. The mouse airways and lungs were infiltrated with human T lymphocytes. No eosinophils or increases in human IgE were observed. The intrapulmonary human T lymphocytes demonstrated an increase in intracytoplasmic IL-4 and IL-5 and a decrease in IFN-gamma after exposure to allergen adjuvant. Antagonizing human IL-4/IL-13 or IL-5 resulted in a normalization of the airway responsiveness, despite a sustained intracellular Th2 cytokine production. These results provide evidence that the activated human allergen-reactive Th2 cells producing IL-4 or IL-5 are pivotal in the induction of AHR, whereas no critical role for eosinophils or IgE could be demonstrated. They also demonstrate that human allergen-specific Th1 lymphocytes can be driven to a Th2 phenotype.

Counterbalancing of TH2-driven allergic airway inflammation by IL-12 does not require IL-10.

BACKGROUND: Asthma is characterized by allergen-induced airway inflammation orchestrated by TH2 cells. The TH1-promoting cytokine IL-12 is capable of inhibiting the TH2-driven allergen-induced airway changes in mice and is therefore regarded as an interesting strategy for treating asthma. OBJECTIVE: The antiallergic effects of IL-12 are only partially dependent of IFN-gamma. Because IL-12 is a potent inducer of the anti-inflammatory cytokine IL-10, the aim of the present study was to investigate in vivo whether the antiallergic effects of IL-12 are mediated through IL-10. METHODS: C57BL/6J-IL-10 knock-out (IL-10(-/-)) mice were sensitized intraperitoneally to ovalbumin (OVA) and subsequently exposed from day 14 to day 21 to aerosolized OVA (1%). IL-12 was administered intraperitoneally during sensitization, subsequent OVA exposure, or both. RESULTS: IL-12 inhibited the OVA-induced airway eosinophilia, despite the absence of IL-10. Moreover, a shift from a TH2 inflammatory pattern toward a TH1 reaction was observed, with concomitant pronounced mononuclear peribronchial inflammation after IL-12 treatment. Allergen-specific IgE synthesis was completely suppressed only when IL-12 was administered along with the allergen sensitization. Furthermore, treating the animals with IL-12 at the time of the secondary allergen challenge resulted not only in a significant suppression of the airway responsiveness but also in an important IFN-gamma-associated toxicity. CONCLUSIONS: These results indicate that IL-12 is able to inhibit allergen-induced airway changes, even in the absence of IL-10. In addition, our results raise concerns regarding the redirection of TH2 inflammation by TH1-inducing therapies because treatment with IL-12 resulted not only in a disappearance of the TH2 inflammation but also in a TH1-driven inflammatory pulmonary pathology.