Sleep Apnea and Incident Unprovoked Venous Thromboembolism: Data from the Pays de la Loire Sleep Cohort.

BACKGROUND: Previous studies have reported inconsistent findings regarding the association between obstructive sleep apnea (OSA) and incident venous thromboembolism (VTE). More specifically, the association between OSA and unprovoked VTE was barely evaluated. We aimed to evaluate whether apnea hypopnea index (AHI) and nocturnal hypoxemia markers were associated with unprovoked VTE incidence in patients investigated for OSA. MATERIAL AND METHODS: Data from the Pays de la Loire Sleep Cohort were linked to the French health administrative data to identify incident unprovoked VTE in patients suspected for OSA and no previous VTE disease. Cox proportional hazards models were used to evaluate the association of unprovoked VTE incidence with AHI and nocturnal hypoxemia markers including the time spent under 90% of saturation (T90), oxygen desaturation index, and hypoxic burden (HB), a more specific marker of respiratory events related to hypoxia. The impact of continuous positive airway pressure (CPAP) was evaluated in the subgroup of patients who were proposed the treatment. RESULTS: After a median [interquartile range] follow-up of 6.3 [4.3-9.0] years, 104 of 7,355 patients developed unprovoked VTE, for an incidence rate of 10.8 per 1,000 patient-years. In a univariate analysis, T90 and HB predicted incident VTE. In the fully adjusted model, T90 was the only independent predictor (hazard ratio: 1.06; 95% confidence interval: [1.01-1.02]; p = 0.02). The CPAP treatment has no significant impact on VTE incidence. CONCLUSION: Patients with more severe nocturnal hypoxia are more likely to have incident unprovoked VTE.

Two cases of pneumonitis induced by targeted therapy.

Interstitial pneumonitis is a rare drug adverse effect. We report two cases of cobimetinib-induced and vemurafenib-induced reversible interstitial pneumonitis. Two patients presenting a BRAF-mutated metastatic melanoma were treated with cobimetinib and vemurafenib. After 3 months, they developed severe feverish dyspnea. Thoracic imaging showed a pattern of organizing pneumonia in one case and a pattern of hypersensitivity pneumonitis in the other case. Infectious and cardiogenic causes were eliminated. An improvement was noted after discontinuation of cobimetinib, vemurafenib, and introducing steroids. Treatment was switched to dabrafenib (a BRAF inhibitor) with no recurrence of drug pneumonitis. To the best of our knowledge, it appears that cases of targeted-therapy-induced pneumonitis are predominantly an MEK-inhibitor effect. We, therefore, propose a management strategy of discontinuing targeted therapy, introducing steroid treatment and switching to dabrafenib.

Nonspecific interstitial pneumonia: survival is influenced by the underlying cause.

Idiopathic, nonspecific interstitial pneumonia (NSIP) is most often associated with various clinical disorders, including connective tissue diseases (CTDs) and chronic hypersensitivity pneumonitis (cHP). Emerging evidence also suggests that "idiopathic" NSIP may be the lung manifestation of undifferentiated CTD (UCTD). However, whether or not NSIP outcome is influenced by the underlying cause remains uncertain. This retrospective study included 127 biopsy-proven NSIP patients (65 women, mean ± sd age 55 ± 12 years). Survivals were estimated using a Kaplan-Meier curve and compared using the log-rank test. Multivariate analyses were based on a Cox model. 15 (11.8%) patients had cHP, 29 (22.8%) had CTD, 32 (25.2%) satisfied the Kinder criteria for UCTD and 51 (40.1%) had idiopathic NSIP. At the end of follow-up (mean ± sd 64 ± 54 months), a difference in survival was observed between aetiological groups (p=0.002). Survival was better for UCTD than for idiopathic NSIP (p=0.020) and similar to that observed for CTD. cHP survival tended to be poorer than that of idiopathic NSIP (p=0.087) and was an independent predictor of mortality (hazard ratio 2.17, 95% CI 1.05-4.47; p=0.035). NSIP outcome is influenced by its cause. cHP exhibits the highest mortality. UCTD does not differ from CTD supporting the concept of autoimmune NSIP, with a prognosis that is better than that of idiopathic NSIP.

Prognostic relevance of histological variants in nonspecific interstitial pneumonia.

AIMS: Although histological non-specific interstitial pneumonia (NSIP) is concisely defined, overlap with other patterns is described. While most frequently idiopathic, NSIP is seen in various clinical contexts such as connective tissue diseases (CTDs) and chronic hypersensitivity pneumonitis (cHP). This study was designed to determine if NSIP could be separated into subgroups based on minor histological features and to correlate these subgroups with clinical associations and survival. METHODS AND RESULTS: One hundred and thirty-six patients with biopsy-proven NSIP were included [clinical diagnosis: CTDs (23%), cHP (12%), idiopathic (65%)]. In addition to the agreed NSIP criteria, seven subgroups were identified: essential NSIP and six overlap subgroups according to superimposed minor histological features. Interobserver concordance resulted in the following consensus: essential NSIP (36%), usual interstitial pneumonia (UIP) overlap (26%), cHP overlap (10%), organizing pneumonia (OP) overlap (6%), organizing diffuse alveolar damage (DAD) overlap (10%), desquamative interstitial pneumonia overlap (7%) and lymphoid interstitial pneumonia overlap (2%). OP overlap was associated with CTDs (P = 0.04) and cHP overlap with a cHP clinical diagnosis (P = 0.02). Survival was different between subgroups (P = 0.0002). Organizing DAD overlap exhibited poorer survival at 5 years (32%), followed by UIP overlap (57%). Independent predictors of mortality were organizing DAD overlap (HR = 4.99, 95% CI = 2.15-11.58, P = 0.0002), UIP overlap (HR = 2.11, 95% CI = 1.12-3.99, P = 0.02) and a clinical diagnosis of cHP (HR = 2.17, 95% CI = 1.05-4.47, P = 0.035). CONCLUSIONS: Non-specific interstitial pneumonia subdivision into pathological subgroups is clinically relevant from a prognostic and causal perspective.

Multimodal treatment of thymic carcinoma: Report of nine cases.

Thymic carcinoma (TC) is thymic epithelial tumor which differs from thymoma because of its rarity, agressiveness and poor prognosis. We studied nine patients with TC according to the WHO (World Health Organization) criteria. Three of these nine patients had stage III disease and six patients had stage IV disease with the classification of Masaoka. Epidermoid TC was the most common subtype. Six patients received VIP chemotherapy comprising cisplatin, ifosfamide, uromitexan and etoposide. Five patients underwent surgical resection, preceded by neoadjuvant chemotherapy for four patients. After surgery, one patient received adjuvant radiotherapy and two patients received adjuvant radiochemotherapy. Six deaths were related to TC progression. The survival time ranged from 1 to 54 months with a median survival of 20 months for the group as a whole. Our descriptive study, based on nine stages III and IV TC, shows a documented efficacy of multimodal treatment (neoadjuvant chemotherapy, surgery and adjuvant treatment). VIP protocol was used for neoadjuvant chemotherapy. High-dose cisplatin (120mg/m(2)cycle), ifosfamide (6g/m(2)cycle) and etoposide (450mg/m(2)cycle) achieved better results than VIP (cisplatin 80mg/m(2)cycle), ifosfamide (4.8g/m(2)cycle) and etoposide (300mg/m(2)cycle). Surgical resection remains the main step in the treatment of TC and the modalities of adjuvant treatment must be defined in further studies.

Apparent absence of Pneumocystis jirovecii in healthy subjects.

We prospectively investigated 30 healthy subjects with normal CD4+ T cell counts in blood and normal findings of spirometry and chest radiography for the presence of Pneumocystis jirovecii, by performing polymerase chain reaction on sputum specimens. Fifty patients with chronic obstructive pulmonary disease were investigated at the same time in the same manner; this group was used as controls for the diagnosis of pulmonary colonization with P. jirovecii. None of the healthy subjects had positive test results, whereas the fungus was detected in 8 patients with chronic obstructive pulmonary disease. The results suggest that in our region (Amiens, France), P. jirovecii is apparently uncommon in healthy subjects and that this population, therefore, plays a minor role in circulation of the fungus within human communities.

Similar genotypes of Pneumocystis jirovecii in different forms of Pneumocystis infection.

This study describes the genotyping of Pneumocystis jirovecii organisms isolated from three groups of patients that developed diverse forms of P. jirovecii infection; the patients were monitored in the same French hospital. Forty archival specimens from 13 adults with Pneumocystis pneumonia, eight adults colonized by P. jirovecii and 19 immunocompetent infants infected with the fungus contemporaneously with a bronchiolitis episode were analysed retrospectively. Genotyping was performed by analysis of sequences of the internal transcribed spacer (ITS)1 and ITS2 regions, and of the dihydropteroate synthase (DHPS) locus. At the ITS regions, a high diversity of genotypes, identical main genotypes (B(1)a(3) and B(2)a(1)) and the occurrence of mixed infections (more than one genotype) were observed in the three patient groups. At the DHPS locus, the results indicated the presence of mutants in the two adult groups, as well as in the infant group. Consequently, at these two independent genomic regions, P. jirovecii isolates from patients who developed different forms of infection and who lived in the same geographical region presented common characteristics. These results suggest that patients infected with P. jirovecii, whatever the form of infection they present, are part of a common human reservoir for P. jirovecii.

Multilocus genotyping of Pneumocystis jirovecii in patients developing diverse forms of parasitism: implication for a wide human reservoir for the fungus.

Pneumocystis jirovecii ITS and DHPS genotypes were identified in 3 patient groups developing diverse forms of P. jirovecii infections: 13 patients with Pneumocystis pneumonia, 8 patients merely colonized by the fungus, and 19 immunocompetent infants with bronchiolitis developing mild P. jirovecii infection. Common P. jirovecii genotypes were found in the 3 patient groups, suggesting that common sources of P. jirovecii were involved in the fungus acquisition, and that transmission cycles of P. jirovecii infections in these patient groups are not independent. Parasitized patients, whatever the form of parasitism they present, may be part of a common reservoir for P. jirovecii.