Mar 1, 2015 - five deceased patients (3, 4), but our patients are the first who survived with favorable neurologic outcome and with no or slight disabilities.
CORRESPONDENCE five deceased patients (3, 4), but our patients are the first who survived with favorable neurologic outcome and with no or slight disabilities after 1 year for three of them. Interestingly, not all patients had hemostasis disorders that could have precipitated the neurological injury. Moreover, vv-ECMO is not a risk factor for cerebral embolism as the extracorporeal circuit is only on the right side. Brain microbleeds are a well-recognized condition that can be diagnosed either on T2* or susceptibility-weighted imaging MRI sequences. They can be related either to an arteriolopathy (cerebral small vessel disease, amyloid angiopathy) or to diffuse emboli (endocarditis, fat emboli) (5). In our four cases, we observed a remarkably similar pattern of diffuse, symmetrical brain microbleeds in the white matter, predominating both in the subcortical white matter (U-fibers) and in the deep white matter (internal and external capsules). This pattern is strikingly similar to what has been reported in patients with fat emboli (5). However, none of our patients had any bone injury that could have caused this condition. Brain microbleeds can also occur in patients with endocarditis, but they appear to be scarcer (6), and none of our patients had endocarditis. Thus, our patients most likely underwent another mechanism of diffuse microemboli that was specifically related to ECMO. Because this complication remains exceptional in patients under ECMO, it should be promoted by another cofactor. Although we did not identify such a common cofactor in our patients, one can notice that two of them (cases 1 and 2) had chronic alcoholism, and one of them (case 4) had a history of multiple sclerosis: both are long-lasting proinflammatory conditions that may have fostered distal microhemorrhages in cerebral small vessels. In our patients, the demonstration on MRI of diffuse, innumerable brain microbleeds would have suggested a poor neurological outcome. However, quite unexpectedly, all four patients had a long-term favorable cognitive outcome. The absence of ischemic lesions on diffusion-weighted imaging (see the online supplement) in all four patients at the acute phase suggests that if microemboli have occurred, they were microscopic enough not to cause ischemic damage in the brain. Areas of edema were present in three patients at the acute phase (cases 1–3); they were associated with elevated apparent diffusion coefficient (see the online supplement), suggesting potentially reversible edema, which was demonstrated by follow-up MRI in case 2. Neurologists and intensivists should be aware of this rare complication of ECMO support and of its potentially favorable outcome. Our series strongly suggests that the occurrence of diffuse brain microbleeds in patients receiving ECMO should not motivate any limitation in active patient care. n Author disclosures are available with the text of this letter at www.atsjournals.org. Lo¨ıc Le Guennec, M.D. Universite´ Pierre et Marie Curie Paris, France Anne Bertrand, M.D., Ph.D. Groupe Hospitalier Pitie-Salp ´ etri ˆ ere ` Paris, France Charles Laurent, MD Centre Hospitalier de la Cote ˆ Basque Bayonne, France
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Hadrien Roze, M.D. Groupe Hospitalier Sud Bordeaux, France Jean Chastre, M.D. Alain Combes, M.D., Ph.D. Charles-Edouard Luyt, M.D., Ph.D. Universite´ Pierre et Marie Curie Paris, France
References 1. Combes A, Brodie D, Bartlett R, Brochard L, Brower R, Conrad S, De Backer D, Fan E, Ferguson N, Fortenberry J, et al.; International ECMO Network (ECMONet). Position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients. Am J Respir Crit Care Med 2014;190:488–496. 2. Luyt CE, Combes A, Becquemin MH, Beigelman-Aubry C, Hatem S, Brun AL, Zraik N, Carrat F, Grenier PA, Richard JC, et al.; REVA Study Group. Long-term outcomes of pandemic 2009 influenza A(H1N1)associated severe ARDS. Chest 2012;142:583–592. 3. Mateen FJ, Muralidharan R, Shinohara RT, Parisi JE, Schears GJ, Wijdicks EF. Neurological injury in adults treated with extracorporeal membrane oxygenation. Arch Neurol 2011;68:1543–1549. 4. Chow FC, Edlow BL, Frosch MP, Copen WA, Greer DM. Outcome in patients with H1N1 influenza and cerebrovascular injury treated with extracorporeal membrane oxygenation. Neurocrit Care 2011;15:156–160. 5. Schrag M, Greer DM. Clinical associations of cerebral microbleeds on magnetic resonance neuroimaging. J Stroke Cerebrovasc Dis 2014; 23:2489–2497. 6. Goulenok T, Klein I, Mazighi M, Messika-Zeitoun D, Alexandra JF, Mourvillier B, Laissy JP, Leport C, Iung B, Duval X; IMAGE study group. Infective endocarditis with symptomatic cerebral complications: contribution of cerebral magnetic resonance imaging. Cerebrovasc Dis 2013;35:327–336.
Copyright © 2015 by the American Thoracic Society
Treating Pulmonary Silicosis by Blocking Interleukin 1 To the Editor: Silicosis is an occupational disease caused by inhalation of silica crystals (1). Although inhaled silica crystals are phagocytized, they are not effectively cleared by alveolar macrophages, and they therefore elicit a chronic inflammatory response eventually leading to interstitial pulmonary fibrosis and progressive respiratory insufficiency (1). Recent studies suggest that silica-induced inflammation is driven by the proinflammatory cytokine interleukin (IL)-1b (2–5). Mainly produced by monocytes and tissue macrophages, IL-1b is synthesized as an inactive precursor and remains inactive until converted to an active cytokine after processing by an intracellular cysteine protease, caspase-1. To prevent unwanted release of IL1b, activation of caspase-1 requires conversion from an inactive protease by a complex of proteins termed the inflammasome (6). In silicosis, control of caspase-1 is overcome by phagocytized Author Contributions: G.C. and L.D. were in clinical care of the patient; C.A.D. was consulted for clinical management; F.F. performed imaging studies; and G.C., F.F., C.A.D., and L.D. wrote the manuscript.
American Journal of Respiratory and Critical Care Medicine Volume 191 Number 5 | March 1 2015
CORRESPONDENCE silica crystals, which trigger the activation of the inflammasome and elicit the unregulated release of IL-1b (2–5). The resulting runaway inflammation leads to progressive tissue damage and fibrosis (1). As yet, no treatment to reduce the progressive loss of pulmonary function is available for silicosis, and decline of lung function progresses even after exposure to silica has ceased (7). Given the crucial role of IL-1b in the pathogenesis of silicosis, we evaluated whether IL-1 receptor blockade may dampen pulmonary inflammation and halt the progressive decline in lung function. We have been following a 37-year-old man who had worked as a miner in a marble cave for 7 years without adequate primary prevention measures. He developed cough and shortness of breath and sought medical attention. Pulmonary silicosis was diagnosed on the basis of radiological and histological findings (1). In the following 2 years, he periodically received treatment with corticosteroids and endured occasional hospitalizations for lung infections; nevertheless, as the disease worsened, he required supplemental oxygen and bronchodilators because of progressive dyspnea. During a routine follow-up evaluation, he appeared particularly fatigued and reported a tangible worsening in his dyspnea. The respiratory rate was elevated, oxygen saturation was 91%, and arterial blood gas analysis revealed a partial pressure of arterial oxygen (PaO2) of 64 mm Hg. His vital capacity, forced expiratory volume in 1 second, and carbon monoxide diffusion capacity were 82, 85, and 85% of predicted, respectively. He had mildly elevated C-reactive protein and erythrocyte sedimentation rate. A chest computed tomography (CT) revealed bilateral ground-glass opacities and lymphadenopathies, some of which
were calcific. A positron emission tomography/CT scan showed tracer uptake in the lungs bilaterally (standardized uptake value, 9.3 in the right lung and 8.5 in the left lung; Figure 1A). Blood cultures, serological analyses, and bronchoalveolar lavage ruled out an active infection. Given the progressive deterioration of the patient’s respiratory function and the absence of therapeutic options, we started treatment with anakinra, the recombinant form of the naturally occurring IL-1 receptor antagonist used to treat a broad spectrum of diseases characterized by IL-1b–driven inflammation (8). The patient agreed to this off-label use of anakinra and received 100 mg/day subcutaneously for 6 months. After the 6-month course, he reported a progressive improvement in respiratory symptoms and denied dyspnea or respiratory relapses. Arterial blood gas analysis showed a PaO2 of 91 mm Hg, with an oxygen saturation of 96%. Pulmonary function tests revealed an increase in diffusing capacity of the lung for carbon monoxide (DLCO) (89% of predicted); other parameters remained unchanged. Inflammatory indexes such as C-reactive protein and erythrocyte sedimentation rate normalized. A repeated positron emission tomography/CT documented a decrease in the tracer uptake in the lungs (standardized uptake value in the right lung: 8.0, 213% variation as compared with baseline; standardized uptake value in the left lung: 5.9, 231% variation; Figure 1B). Patient-reported health status also improved, with a significant amelioration in all domains of the Medical Outcomes Study 36-Item Short-Form Health Survey questionnaire. Sound experimental evidence implicates IL-1b as likely to play a primary role in silica-induced inflammation. Unequivocal confirmation of the role of the inflammasome in regulating
Figure 1. (A) On admission, chest computed tomography scan revealed bilateral ground-glass opacities. Positron emission tomography/computed tomography scan showed marked tracer uptake in the lungs bilaterally: standardized uptake value was 9.3 in the right lung and 8.5 in the left lung. (B) After 6 months of anakinra treatment, repeated positron emission tomography/computed tomography documented a marked decrease in the tracer uptake in both lungs. Standardized uptake value was 8.0 in the right lung and 5.9 in the left lung, with a standardized uptake value variation of 213% in the right lung and 231% in the left lung compared with baseline.
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CORRESPONDENCE IL-1b-mediated inflammation comes from Cyopyrin Associated Periodic Syndromes, a group of genetic diseases characterized by a gain-of-function mutation in NLRP3 (also known as “cryopyrin”), in which activation of caspase-1 is deregulated, resulting in multiorgan sterile inflammation (2, 9). The observation that crystals can induce IL-1b is also not unprecedented, as monosodium urate crystals activate the inflammasome in the pathogenesis of gout (10, 11). In gout and in several other diseases characterized by IL1–driven inflammation, specific antagonism of IL-1 with anakinra results in a rapid and sustained reduction in disease severity (12, 13). Thus, we hypothesized that treatment with anakinra could suppress pulmonary inflammation and reverse inflammationmediated organ impairment in silicosis. After treating a patient with anakinra 100 mg once daily for 6 months, we observed an improvement in functional outcomes and respiratory parameters, along with a reduction in active inflammation. Although this case is promising, the study period may have been too short to fully exploit the antiinflammatory properties of anakinra and to evaluate the effects on fibrosis with clear-cut changes at imaging studies. Moreover, an earlier therapeutic intervention would have been advisable, as it may yield better clinical results than the treatment of established disease. Notably, long-term treatment with anakinra has an excellent record of safety in comparison to other cytokine-blocking agents (8). Pulmonary silicosis is a chronic, progressive disease for which no spontaneous improvement can be expected. As yet, comprehensive management strategies provide some relief from symptoms, but no effective treatment is available (1). Given these promising results and a sound biologic rationale, we advocate that the efficacy of anakinra in pulmonary silicosis is further explored. If proven effective, anakinra may represent the first suitable treatment for this neglected disease. n Author disclosures are available with the text of this letter at www.atsjournals.org. Giulio Cavalli, M.D. University of Colorado Denver Aurora, Colorado and IRCCS San Raffaele Scientific Institute Milan, Italy Federico Fallanca, M.D. IRCCS San Raffaele Scientific Institute Milan, Italy Charles A. Dinarello, M.D. University of Colorado Denver Aurora, Colorado Lorenzo Dagna, M.D. IRCCS San Raffaele Scientific Institute Milan, Italy
References 1. Leung CC, Yu IT, Chen W. Silicosis. Lancet 2012;379:2008–2018. 2. Hoffman HM, Wanderer AA. Inflammasome and IL-1betamediated disorders. Curr Allergy Asthma Rep 2010;10: 229–235.
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3. Dostert C, Petrilli ´ V, Van Bruggen R, Steele C, Mossman BT, Tschopp J. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 2008;320:674–677. 4. Cassel SL, Eisenbarth SC, Iyer SS, Sadler JJ, Colegio OR, Tephly LA, Carter AB, Rothman PB, Flavell RA, Sutterwala FS. The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci USA 2008;105:9035–9040. 5. Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, Fitzgerald KA, Latz E. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 2008;9:847–856. 6. Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol 2009;27:229–265. 7. Petsonk EL, Rose C, Cohen R. Coal mine dust lung disease. New lessons from old exposure. Am J Respir Crit Care Med 2013;187:1178–1185. 8. Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 2012;11:633–652. 9. Dinarello CA. Unraveling the NALP-3/IL-1beta inflammasome: a big lesson from a small mutation. Immunity 2004;20:243–244. 10. Giamarellos-Bourboulis EJ, Mouktaroudi M, Bodar E, van der Ven J, Kullberg BJ, Netea MG, van der Meer JW. Crystals of monosodium urate monohydrate enhance lipopolysaccharide-induced release of interleukin 1 beta by mononuclear cells through a caspase 1-mediated process. Ann Rheum Dis 2009;68:273–278. 11. Gross O, Yazdi AS, Thomas CJ, Masin M, Heinz LX, Guarda G, Quadroni M, Drexler SK, Tschopp J. Inflammasome activators induce interleukin1a secretion via distinct pathways with differential requirement for the protease function of caspase-1. Immunity 2012;36:388–400. 12. Dinarello CA, van der Meer JW. Treating inflammation by blocking interleukin-1 in humans. Semin Immunol 2013;25:469–484. 13. McGonagle D, Tan AL, Shankaranarayana S, Madden J, Emery P, McDermott MF. Management of treatment resistant inflammation of acute on chronic tophaceous gout with anakinra. Ann Rheum Dis 2007;66:1683–1684.
Copyright © 2015 by the American Thoracic Society
Air Contamination with Bacteria in Cystic Fibrosis Clinics: Implications for Prevention Strategies To the Editor: Patient-to-patient transmission of cystic fibrosis (CF) pathogens in nonhealthcare and hospital settings is well described. Recent data support the potential for patient-to-patient transmission in a CF clinic, the setting in which most care for individuals with CF is provided (1). However, the risks and potential strategies to reduce these risks in the CF clinic are less well defined, including the potential effect of mask use by patients with CF (1). The primary aim of the current study was to determine whether mask use by patients with CF reduced air contamination during CF clinic visits. We also investigated whether air contamination occurred more frequently during spirometry, whether such contamination would The research for this article was supported by Cystic Fibrosis Foundation Grant ZUCKER10A0. Author Contributions: Conception and design: J.B.Z., J.J.Z., J.J.M., S.A.C., B.S.P., L.W.L., and L.S.; analysis and interpretation: J.B.Z., B.S.P., J.J.M., F.L.L., and L.S.; and drafting the manuscript for important intellectual content: J.B.Z., S.A.C., J.J.M., F.L.L., and L.S. This letter has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org
American Journal of Respiratory and Critical Care Medicine Volume 191 Number 5 | March 1 2015
