Anoop M. Nambiar

Pulmonary function measures predict mortality differently in IPF versus combined pulmonary fibrosis and emphysema

The composite physiologic index (CPI) was derived to represent the extent of fibrosis on high-resolution computed tomography (HRCT), adjusting for emphysema in patients with idiopathic pulmonary fibrosis (IPF). We hypothesised that longitudinal change in CPI would better predict mortality than forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) or diffusing capacity of the lung for carbon monoxide (DL,CO) in all patients with IPF, and especially in those with combined pulmonary fibrosis and emphysema (CPFE). Cox proportional hazard models were performed on pulmonary function data from IPF patients at baseline (n = 321), 6 months (n = 211) and 12 months (n = 144). Presence of CPFE was determined by HRCT. A five-point increase in CPI over 12 months predicted subsequent mortality (HR 2.1, p = 0.004). At 12 months, a 10% relative decline in FVC, a 15% relative decline in DL,CO or an absolute increase in CPI of five points all discriminated median survival by 2.1 to 2.2 yrs versus patients with lesser change. Half our cohort had CPFE. In patients with moderate/severe emphysema, only a 10% decline in FEV1 predicted mortality (HR 3.7, p = 0.046). In IPF, a five-point increase in CPI over 12 months predicts mortality similarly to relative declines of 10% in FVC or 15% in DL,CO. For CPFE patients, change in FEV1 was the best predictor of mortality.

Clinical evaluation of the role of ceftaroline in the management of community acquired bacterial pneumonia

Ceftaroline fosamil (ceftaroline) was recently approved for the treatment of community- acquired pneumonia (CAP) and complicated skin infections. This newly developed cephalosporin possesses a broad spectrum of activity against gram-positive and gram-negative bacteria. Most importantly, ceftaroline demonstrates potent in vitro antimicrobial activity against multi-drug resistant Streptococcus pneumoniae and methicillin-resistant strains of Staphylococcus aureus. In two Phase III, double-blinded, randomized, prospective trials (FOCUS 1 and FOCUS 2), ceftaroline was shown to be non-inferior to ceftriaxone for the treatment of CAP in hospitalized patients. Ceftaroline exhibits low resistance rates and a safety profile similar to that of other cephalosporins. In this review, we will evaluate the pharmacological characteristics, safety, antimicrobial properties, and efficacy of ceftaroline and its applications in the treatment of CAP.

Combination pirfenidone and inhaled N-acetylcysteine therapy for IPF: Does it take these two to tango?

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause that is irreversible, unpredictable and associated with a dismal prognosis with a median survival of only 2–5 years after diagnosis— worse than many common cancers. In three multiple large-phase clinical trials reported in 2014, a landmark year for IPF, two drugs, pirfenidone and nintedanib, were both shown to halve the annual rate of decline in forced vital capacity (FVC) compared with placebo in patients with mild-to-moderate disease (as defined by FVC > 50% and diffusion capacity > 30%). Results of these pivotal studies subsequently led to regulatory approval of both pirfenidone and nintedanib for IPF in the United States (for the first time ever) and the addition of nintedanib to pirfenidone (already approved in many other countries) as commercially available IPF therapies. Also, oral N-acetylcysteine (NAC) monotherapy (previously a commonly employed but unproven therapy) compared with placebo did not significantly alter the rate of FVC decline. Although great strides have occurred in our concerted efforts towards a cure (and away from ineffective therapies), glaring gaps still exist in our evidence base. Among these include high-quality safety and efficacy data for (i) advanced and/or progressive disease and (ii) combination therapy, felt by many to be the future management for IPF. To date, IPF patients with advanced and/or progressive disease have been summarily excluded from clinical trials. This approach likely stems from the prevailing notion among clinical researchers and the pharmaceutical industry that these desperately ill patients (‘the sickest of the sick’ with IPF) have fibrosis that is too advanced and severe. In addition, these patients may have too many complicating comorbidities and possess disease that is less treatment-responsive, and therefore, enrolment of these patients into clinical trials would likely lead to costly negative results. Thus, effective treatments for these advanced IPF patients are sorely needed. Very little data exist on effective combination therapy in IPF, a consequence of multiple prior, failed clinical trials and absence of proven anti-fibrotic monotherapies. Given the complex pathogenesis of IPF involving multiple co-activated pathways leading to fibroproliferation, future therapy for IPF will almost certainly include combinations of various therapeutic agents. Precedent for such a treatment approach already exists in many other respiratory (such as chronic obstructive pulmonary disease and pulmonary arterial hypertension) and non-respiratory diseases (human immunodeficiency virus, cancer), to name a few. Since 2008 in Japan, sequential combination therapy has been employed. For example, inhaled NAC monotherapy for early-stage disease and combination inhaled NAC plus pirfenidone for more advanced disease. However, high-quality published data regarding combination therapy in IPF have been lacking. In this issue of Respirology, Sakamoto et al. attempt to tackle these two important challenges in the future management of IPF. In their single-centre, case–control study of 27 subjects with both advanced (defined as Japanese Respiratory Society stages 3 or 4 based upon resting arterial oxygen partial pressure and/or desaturation on 6-min walk test; see table 1 in Sakamoto et al.) and progressive IPF (defined by a relative FVC decline of greater than 10% in the previous 6 months), they sought to evaluate the effectiveness and safety of combination pirfenidone and inhaled NAC (pirfenidone plus inhaled Nacetylcysteine (PFD + NAC), n = 17) with pirfenidone monotherapy (PFD, n = 10). They report significant reductions in the mean FVC decline at 6 months (−210 mL vs −610 mL, P < 0.01) and at 12 months (−610 mL vs −1320 mL, P < 0.01) in those treated with PFD + NAC compared with PFD alone. Progressionfree survival (PFS; composite of death, 10% decline in FVC, or a 15% decline in diffusion capacity of carbon monoxide (DLCO) from baseline) was significantly longer in the PFD + NAC group compared with PFD (304 vs 168 days, P = 0.016). At 12 months, treatment success (FVC decline of less than 10%) was achieved in 47% (8 of 17 subjects) treated with NAC + PFD compared with 20% (2 of 10 subjects) in the PFD alone. Importantly, combination therapy was generally well tolerated (no adverse events attributable to inhaled NAC). There are a number of study limitations that are appropriately acknowledged by Sakamoto et al. Conflict of interest statement: AMN received scientific advisory board and consultancy fees from Intermune; lecture fees from Boehringer Ingelheim and Intermune, and grants from Intermune, Boehringer Ingelheim, Roche, Sanofi-Aventis, unrelated to the submitted work. bs_bs_banner

Procalcitonin in acute exacerbations of interstitial pneumonia: Another tool in the toolbox?

Interstitial lung diseases (sometimes also referred to as interstitial pneumonias, or IP) comprise a heterogeneous group of diffuse parenchymal lung diseases that are associated with identifiable causes (such as collagen vascular diseases, like rheumatoid arthritis and scleroderma, or chronic hypersensitivity pneumonitis) and unidentified aetiologies (idiopathic IP, the most common of which is idiopathic pulmonary fibrosis, or IPF). During their slowly progressive decline, many IPF patients may suddenly experience an acute worsening of their disease. In the absence of an identifiable cause such as infection, heart failure or pulmonary embolism, these sudden deteriorations have been defined as acute exacerbations and are associated with a significantly increased risk of morbidity and mortality. Although the majority of the published data is with regards to acute exacerbations of IPF, acute exacerbations of IP (AE-IP) have also been reported in patients with collagen vascular diseases, such as rheumatoid arthritis, non-specific IP and chronic hypersensitivity pneumonitis. Precipitating factors may include occult infection (such as bacterial and viral pathogens, although this may be less likely than previously thought), surgical procedures (both pulmonary and non-pulmonary) and occult aspiration. Pathologically, AE-IP often shows evidence of diffuse alveolar damage or organizing pneumonia superimposed on chronic IP. When confronted with a patient experiencing an AE-IP (with its well-described high mortality without treatment), clinicians often employ highdose parenteral corticosteroids with or without additional immunosuppressives, despite the lack of high-quality efficacy data. Accurate diagnosis (or exclusion) of pulmonary infection is essential in the setting of suspected AE-IP to ensure that appropriate and adequate antimicrobial therapy is administered (or withheld). Recently, procalcitonin (PCT) has emerged as a reliable biomarker for diagnosis, prognosis and as a useful clinical tool to reduce excessive antibiotic use in the setting of a bacterial infection, such as pneumonia. PCT is a peptide precursor of calcitonin that is released by parenchymal cells in response to bacterial toxins. As a result, patients with bacterial infection have elevated serum PCT levels. In contrast, PCT upregulation is blocked by the release of interferon-g in response to viral infections. Thus far, a number of studies, including a recently published systemic review, have shown that PCT testing can help distinguish bacterial pneumonia and viral pneumonia, reduce antibacterial use, predict severity based on the magnitude of the result and may even predict survival. However, among critically ill patients, PCT testing may not accurately distinguish sepsis from non-septic systemic inflammation. In addition, the use of PCT has not been validated as a diagnostic tool in post-surgical or immunosuppressed patients; therefore, its routine use in diagnosing bacterial infection is not recommended. Although it is critical to either include or exclude bacterial infection in suspected AE-IP, the role of PCT testing in IP patients has yet to be studied—until now. In this issue of Respirology, Nagata and colleagues retrospectively evaluated the diagnostic and prognostic role of serum PCT in three cohorts of patients: 20 with AE-IP, 24 with bacterial pneumonia and stable IP, and 13 with bacterial pneumonia and acute respiratory distress syndrome. The authors extrapolated their definition for AE-IP from the consensus criteria established for acute exacerbations of IPF. Importantly, they painstakingly excluded infection by safely performing bronchoscopy with bronchoalveolar lavage in all AE-IP patients without any reported adverse complications, including respiratory failure requiring intubation and mechanical ventilation. They found that baseline PCT levels were significantly lower in the AE-IP group compared with those with bacterial pneumonia and stable IP (mean, 0.62 vs 8.31 ng/mL, P < 0.05) and bacterial pneumonia and acute respiratory distress syndrome (mean, 0.62 vs 30.14 ng/mL, P < 0.001). At a PCT cut-off level of 0.5 ng/mL (higher suggesting bacterial infection and lower suggesting exclusion of bacterial infection), they found 75% (15/20) of AE-IP patients had low PCT values, whereas 79% (19/24) in the bacterial pneumonia and stable IP group and 100% (13/13) in the bacterial pneumonia and acute respiratory distress syndrome group had high PCT levels. Additionally, serial PCT measurements at days 2, 4 and 8 in the AE-IP group did not distinguish 30-day survivors from non-survivors. A number of limitations of this study should be noted. A relatively small number of patients at a single centre were included. The retrospective nature of the study has inherent biases. Although infection was methodically screened for by bronchoscopy with bs_bs_banner

Effectiveness and safety of mycophenolate mofetil in idiopathic pulmonary fibrosis

Background Currently available antifibrotic treatments may slow down disease progression in idiopathic pulmonary fibrosis (IPF), but are associated with potentially significant side effects and are costly. Mycophenolate mofetil (MMF) is well known for its potent immunosuppressive properties and possesses important antiproliferative and antifibrotic effects. The safety and effectiveness of MMF in IPF is unknown. Methods We performed a retrospective multicohort analysis of IPF patients treated with MMF compared to those treated with either ineffective/harmful treatments or no treatment. Longitudinal change in forced vital capacity (FVC) between the groups was analyzed using a mixed model with random intercept and slope allowing for repeated measures within subjects. Categorical change in FVC, median overall survival, and adverse events were also assessed. Results Forty-one IPF patients were included: 11 treated with MMF, 20 treated with ineffective/harmful agents (such as prednisone, azathioprine, and/or NAC), and 10 did not receive any specific treatment for their IPF. After one year, there was a trend towards reduced FVC decline in the MMF-treated group (-76.3 mL, -2.4% of predicted) compared to the non-MMF-treated (-165 mL, -8.9% of predicted) and the no-treatment (-239 mL, -11.5% of predicted) groups, respectively. By categorical change, there was a trend towards greater FVC stability in the MMF-treated group (87.5%) compared to the non-MMF-treated (57%) and the no-treatment groups (50%), respectively. MMF-treated IPF patients had a trend towards improved median overall survival (40.3 months) compared to the non-MMF-treated (25.5 months) and the no-treatment (29.3 months) groups, respectively. Treatment-related adverse events were not different between groups; however, very few adverse events were reported overall. Conclusions MMF treatment was associated with potentially clinically important trends toward reduced annual FVC decline (similar to approved antifibrotics), greater FVC stability and improved overall survival in IPF patients. MMF was generally safe, well tolerated, and relatively inexpensive. Future prospective studies of MMF in combination with antifibrotic therapy in IPF are needed.

Diagnosis and Management of Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) is a specific type of primary thrombotic microangiopathy syndrome characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ failure. Although relatively rare, if left unrecognized and untreated, multisystem organ failure ensues and survival is poor. Early use of therapeutic plasma exchange has significantly improved mortality and the subsequent risk of relapse. Therefore, prompt recognition of this medical emergency is essential. Diagnosis rests on maintaining a low index of suspicion for TTP in a patient presenting with microangiopathic hemolytic anemia and thrombocytopenia in the absence of an alternative diagnosis. Adjunctive testing including ADAMTS13 activity levels and ADAMTS13 autoantibody testing may help confirm the diagnosis and predict relapse risk. In addition to plasma exchange, aggressive immunosuppression with high-dose corticosteroids is recommended. Refractory TTP may require intensification of plasma exchange and the addition of rituximab. In this chapter, we will review the essential practical diagnostic and management considerations for TTP in the context of a clinical case.

Acute Lower Gastrointestinal Bleeding

Hemodynamically unstable hematochezia is an uncommon manifestation of lower gastrointestinal bleeding. However, given the usually older age and multiple comorbidities of the typical patient, acute lower gastrointestinal bleeding can be associated with poor outcomes unless emergent life-saving care is delivered. In this context, early recognition and aggressive resuscitation is essential for a patient presenting with hemodynamically significant hematochezia. Accurate discrimination between upper and lower gastrointestinal sources of hemorrhage is of utmost importance as this has significant implications with respect to prognosis, differential diagnosis, and provides guidance for additional diagnostic testing, such as endoscopy, as well as life-saving therapeutic interventions. Depending on clinical stability and severity of bleeding, diagnosis may require urgent colonoscopy, nuclear red blood cell scan, multidetector CT of the abdomen, and/or mesenteric angiography. Colonoscopy and mesenteric angiography may be both diagnostic and therapeutic when performed. Optimal management of a patient with acute lower gastrointestinal bleeding requires consultation and coordination of a multidisciplinary team of expert specialists to improve patient outcomes.