Early Respiratory Failure Research Articles

Hereditary myopathy with early respiratory failure: occurrence in various populations

ObjectiveSeveral families with characteristic features of hereditary myopathy with early respiratory failure (HMERF) have remained without genetic cause. This international study was initiated to clarify epidemiology and the genetic underlying...

Effect of nitric oxide inhalation on gas exchange in acute severe pneumonia

Inhaled nitric oxide (NO) causes selective pulmonary vasodilatation and may improve gas exchange. The study was aimed to evaluate the acute effects of inhaled NO on pulmonary gas exchange in severe unilateral pneumonia, where hypoxemia results from increased intrapulmonary shunt. We studied 8 patients without preexisting lung disease (59±18 yr; 4M/4F) with early unilateral severe pneumonia and respiratory failure. Pulmonary and systemic hemodynamics and gas exchange, including ventilation–perfusion (V;A/Q;) distributions, were measured at baseline and while breathing 5 and 40 parts per million (ppm) of NO. Inhaled NO caused a dose-dependent fall in pulmonary vascular resistance (by 12% and 21%, with 5 and 40ppm, respectively; p<0.01, each) and improvement of PaO2 (by 25% and 23%; p<0.05, each), owing to the reduction of intrapulmonary shunt (by 23% and 27%; p<0.05, each), without changes in the amount of perfusion to low V;A/Q; ratio alveolar units. Patients with greater baseline intrapulmonary shunt exhibited greater improvement in arterial oxygenation (r2=0.55, p<0.05). We conclude that low doses of inhaled NO improve pulmonary gas exchange in acute severe pneumonia.

Exome sequencing identifies titin mutations causing hereditary myopathy with early respiratory failure (HMERF) in families of diverse ethnic origins

BackgroundHereditary myopathy with early respiratory failure (HMERF) was described in several North European families and recently linked to a titin gene (TTN) mutation. We independently studied HMERF-like diseases with the purpose to identify the cause, refine diagnostic criteria, and estimate the frequency of this disease among myopathy patients of various ethnic origins.MethodsWhole exome sequencing analysis was carried out in a large U.S. family that included seven members suffering from skeletal muscle weakness and respiratory failure. Subsequent mutation screening was performed in further 45 unrelated probands with similar phenotypes. Studies included muscle strength evaluation, nerve conduction studies and concentric needle EMG, respiratory function test, cardiologic examination, and muscle biopsy.ResultsA novel TTN p.Gly30150Asp mutation was identified in the highly conserved A-band of titin that co-segregated with the disease in the U.S. family. Screening of 45 probands initially diagnosed as myofibrillar myopathy (MFM) but excluded based on molecular screening for the known MFM genes led to the identification of a previously reported TTN p.Cys30071Arg mutation in one patient. This same mutation was also identified in a patient with suspected HMERF. The p.Gly30150Asp and p.Cys30071Arg mutations are localized to a side chain of fibronectin type III element A150 of the 10th C-zone super-repeat of titin.ConclusionsMissense mutations in TTN are the cause of HMERF in families of diverse origins. A comparison of phenotypic features of HMERF caused by the three known TTN mutations in various populations allowed to emphasize distinct clinical/pathological features that can serve as the basis for diagnosis. The newly identified p.Gly30150Asp and the p.Cys30071Arg mutation are localized to a side chain of fibronectin type III element A150 of the 10th C-zone super-repeat of titin.

Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure

ObjectiveTitin gene (TTN) mutations have been described in eight families with hereditary myopathy with early respiratory failure (HMERF). Some of the original patients had features resembling myofibrillar myopathy (MFM), arguing...

Exome sequencing identifies a novel TTN mutation in a family with hereditary myopathy with early respiratory failure

Myofibrillar myopathy (MFM) is a group of chronic muscular disorders that show the focal dissolution of myofibrils and accumulation of degradation products. The major genetic basis of MFMs is unknown. In 1993, our group reported a Japanese family with dominantly inherited cytoplasmic body myopathy, which is now included in MFM, characterized by late-onset chronic progressive distal muscle weakness and early respiratory failure. In this study, we performed linkage analysis and exome sequencing on these patients and identified a novel c.90263G>T mutation in the TTN gene (NM_001256850). During the course of our study, another groups reported three mutations in TTN in patients with hereditary myopathy with early respiratory failure (HMERF, MIM #603689), which is characterized by overlapping pathologic findings with MFMs. Our patients were clinically compatible with HMERF. The mutation identified in this study and the three mutations in patients with HMERF were located on the A-band domain of titin, suggesting a strong relationship between mutations in the A-band domain of titin and HMERF. Mutation screening of TTN has been rarely carried out because of its huge size, consisting of 363 exons. It is possible that focused analysis of TTN may detect more mutations in patients with MFMs, especially in those with early respiratory failure.

EXOME SEQUENCING IN THREE FAMILIES WITH CYTOPLASMIC BODY MYOPATHY WITH EARLY RESPIRATORY FAILURE

IntroductionCytoplasmic body myopathy with early respiratory failure (CBM) is a rare muscular dystrophy with the clinical presentation of early respiratory failure with distal and/or proximal muscle weakness. The genetic defect...

G.O.2 Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin

Hereditary myopathy with early respiratory failure (HMERF) and extensive myofibrillar lesions have been described in sporadic and familial cases and linked to various chromosomal regions. We describe the clinical manifestations, muscle histopathology and genetics in eight individuals from three apparently unrelated families with clinical and pathological features of HMERF. All patients had muscle weakness in the pelvic girdle, neck flexors, respiratory and trunk muscles, and the majority had prominent calf hypertrophy. Examination of pulmonary function showed decreased vital capacity. No signs of cardiac muscle involvement were found. Muscle histopathological features included marked muscle fibre size variation, fibre splitting, numerous internal nuclei and fatty infiltration. Frequent groups of fibres showed eosinophilic inclusions and deposits. At the ultrastructural level there were extensive myofibrillar lesions with marked Z-disc alterations. Whole exome sequencing in four individuals from one family revealed a missense mutation, g.274375, T>C; p.Cys30071Arg, in the titin gene, TTN. The mutation, which changes a highly conserved residue in the myosin binding A-band titin, was demonstrated to segregate with the disease in all three families. High density single nucleotide polymorphism arrays covering the entire genome demonstrated sharing of a 699 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry of this novel and first disease-causing mutation in A-band titin associated with HMERF.

G.P.35 Identical TTN gene A-band mutation causing HMERF occurs in different European populations

Hereditary myopathy with early respiratory failure (HMERF) is characterized by proximal–distal weakness and respiratory insufficiency in ambulant patients. The clinical onset of the disease is variable, ranging from early to late adulthood. Muscle weakness is typical in neck flexors, limb girdle, and in some cases also in distal lower limb muscles. A prominent early finding is respiratory muscle weakness presenting with an acute respiratory failure in many patients. A dominant mutation in the TTN kinase domain leading to HMERF has been described in a few families from Sweden. Very recently, two reports (in press) revealed a novel dominant A-band mutation in titin gene, TTN. This mutation (g.274375T>C; p.Cys30071Arg) was found in eight HMERF patients from three Swedish families and in 31 patients from three families. In our collaborative study we have identified the identical mutation in one Finnish family with four affected HMERF patients. In addition, the mutation was identified in one British patient, in one Italian patient and in one additional Swedish family. The patients had the same phenotype with progressive muscle weakness in the lower limbs and respiratory muscles, cytoplasmic bodies and rimmed vacuolar myopathy in muscle biopsy. Muscle MRI findings are pathognomonic with fatty degenerative changes in semitendinosus, obturatorius, sartorius, gracilis and iliopsoas muscles with variable involvement of anterior and lateral compartment and tibialis posterior on the lower legs. All patients carried the same haplotype including markers D2S2173 and D2S385 at the mutational locus. The shared genomic region is less than 3.3Mb in size suggesting an ancestral founder, and indicating the existence of many undiagnosed families with this mutation.

G.P.95 Two sibs with early onset myopathy with areflexia, respiratory distress, and dysphagia (EMARDD) due to homozygous exon 7 deletion in MEGF10

Abstract MEGF10 was recently implicated as the gene causing EMARDD. We present two consanguineous sibs with EMARDD, a 12-yr-old girl of Egyptian descent and her (deceased) older sister. The proband had decreased fetal movements and, at birth, diffuse hypotonia and finger contractures. At 8 months, she underwent a Nissen fundoplication with gastrostomy tube placement and after required ventilatory support resulting in a tracheostomy. She ambulated with a walker at 2 years of age but became non-ambulatory by 9 years. Muscle biopsy was reported as a chronic myopathy with myofiber degeneration and regeneration associated with endomysial fibrosis and fatty replacement. The older sister had perinatal asphyxia with meconium aspiration, central hypotonia, axial hypertonia, and similar bilateral finger contractures. Due to weakness and aspiration, tracheostomy and gastrostomy tubes were placed at 6 months. She developed progressive scoliosis, never stood or walked, and died of a tracheostomy accident at 5 years of age. Muscle biopsy was reported to show nonspecific abnormalities with increased lipid droplets. Exam of the proband revealed end grade restriction of extraocular movements, ptosis, facial and generalized decreased muscle bulk, scoliosis, and proximal muscle strength was in the 2–3 range while distal was in the four range. Our first-reported muscle MRI in EMARDD shows considerable atrophy and fatty replacement of all muscles in the pelvis and thigh; gluteal and quadriceps compartments were more affected than the hamstring, adductors and gracilis. Although exome sequencing lacked coverage of exon 7, SNP analysis predicted a putative deletion within the MEGF10 locus at exon 7 followed by PCR analysis confirming a 757 bp homozygous deletion. Compared to the 10 other reported EMARDD cases, our proband has similar symptoms of decreased fetal movements, hyptonia, contractures, areflexia, and early respiratory failure but presents on the less severe end of the spectrum given her age.

Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin

Hereditary myopathy with early respiratory failure and extensive myofibrillar lesions has been described in sporadic and familial cases and linked to various chromosomal regions. The mutated gene is unknown in most cases. We studied eight individuals, from three apparently unrelated families, with clinical and pathological features of hereditary myopathy with early respiratory failure. The investigations included clinical examination, muscle histopathology and genetic analysis by whole exome sequencing and single nucleotide polymorphism arrays. All patients had adult onset muscle weakness in the pelvic girdle, neck flexors, respiratory and trunk muscles, and the majority had prominent calf hypertrophy. Examination of pulmonary function showed decreased vital capacity. No signs of cardiac muscle involvement were found. Muscle histopathological features included marked muscle fibre size variation, fibre splitting, numerous internal nuclei and fatty infiltration. Frequent groups of fibres showed eosinophilic inclusions and deposits. At the ultrastructural level, there were extensive myofibrillar lesions with marked Z-disc alterations. Whole exome sequencing in four individuals from one family revealed a missense mutation, g.274375T>C; p.Cys30071Arg, in the titin gene (TTN). The mutation, which changes a highly conserved residue in the myosin binding A-band titin, was demonstrated to segregate with the disease in all three families. High density single nucleotide polymorphism arrays covering the entire genome demonstrated sharing of a 6.99 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry. Our results demonstrate a novel and the first disease-causing mutation in A-band titin associated with hereditary myopathy with early respiratory failure. The typical histopathological features with prominent myofibrillar lesions and inclusions in muscle and respiratory failure early in the clinical course should be incentives for analysis of TTN mutations.

Titin mutation segregates with hereditary myopathy with early respiratory failure

In 2001, we described an autosomal dominant myopathy characterized by neuromuscular ventilatory failure in ambulant patients. Here we describe the underlying genetic basis for the disorder, and we define the neuromuscular, respiratory and radiological phenotype in a study of 31 mutation carriers followed for up to 31 years. A combination of genome-wide linkage and whole exome sequencing revealed the likely causal genetic variant in the titin (TTN) gene (g.274375T>C; p.Cys30071Arg) within a shared haplotype of 2.93 Mbp on chromosome 2. This segregated with the phenotype in 21 individuals from the original family, nine subjects in a second family with the same highly selective pattern of muscle involvement on magnetic resonance imaging and a third familial case with a similar phenotype. Comparing the mutation carriers revealed novel features not apparent in our original report. The clinical presentation included predominant distal, proximal or respiratory muscle weakness. The age of onset was highly variable, from early adulthood, and including a mild phenotype in advanced age. Muscle weakness was earlier onset and more severe in the lower extremities in nearly all patients. Seven patients also had axial muscle weakness. Respiratory function studies demonstrated a gradual deterioration over time, reflecting the progressive nature of this condition. Cardiomyopathy was not present in any of our patients despite up to 31 years of follow-up. Magnetic resonance muscle imaging was performed in 21 affected patients and revealed characteristic abnormalities with semitendinosus involvement in 20 of 21 patients studied, including 3 patients who were presymptomatic. Diagnostic muscle histopathology most frequently revealed eosinophilic inclusions (inclusion bodies) and rimmed vacuoles, but was non-specific in a minority of patients. These findings have important clinical implications. This disease should be considered in patients with adult-onset proximal or distal myopathy and early respiratory failure, even in the presence of non-specific muscle pathology. Muscle magnetic resonance imaging findings are characteristic and should be considered as an initial investigation, and if positive should prompt screening for mutations in TTN. With 363 exons, screening TTN presented a major challenge until recently. However, whole exome sequencing provides a reliable cost-effective approach, providing the gene of interest is adequately captured.

Electrophysiological correlates of respiratory failure in acute organophosphate poisoning: Evidence for differential roles of muscarinic and nicotinic stimulation

Background. Respiratory failure in acute organophosphate (OP) poisoning can occur early and also relatively late in the clinical course, and the pathophysiology of respiratory failure at these different phases may have important clinical implications. Objective. To compare the electrophysiological findings in patients with early and late respiratory failure following acute OP poisoning. Methods. A prospective observational case series of consenting symptomatic patients with acute OP poisoning were assessed with daily physical examinations and repetitive nerve stimulation (RNS) studies. RNS was done on right and left median and ulnar nerves at 1, 3, 10, 15, 20, and 30 Hz. Outcomes such as need for ventilation and development of intermediate syndrome (IMS) were noted. Early respiratory failure was defined as occurring within 24 hours of ingestion. Results. Seventy-eight patients were recruited for the clinical and electrophysiological study and of those 59 (75.6%) patients had ingested chlorpyrifos. Seven patients developed respiratory failure within 24 hours of ingestion with overt muscarinic signs. They had no electrophysiological abnormalities at median and ulnar nerves before intubation. Three of them later developed “forme fruste” IMS. Five other patients developed late respiratory failure after 24 hours of ingestion, and all of them showed progressive RNS changes indicating severe IMS prior to intubation. Conclusion. The normal RNS in all patients developing early respiratory failure suggests that it is due to a central nervous system (CNS) and muscarinic effect. This emphasizes the need for early rapid atropinisation as a priority, combating the nicotinic effects being less urgent. This is in contrast with the late respiratory failure, which has been shown to be associated with neuromuscular dysfunction. Further studies are needed to quantify CNS and muscarinic dysfunction to assist in the development of better treatments for the severe and early OP poisoning.

Tetanus in adults: Clinical presentation, treatment and predictors of mortality in a tertiary hospital in Ethiopia

BackgroundTetanus remains a major health problem in the developing world. The aim of this study was to evaluate the clinical presentation, risk factors, complications, treatment, outcome and predictors of death in patients with tetanus. MethodsPatients aged ≥13years admitted to Tikur Anbessa Hospital from June 2001 to May 2009 with the diagnosis of tetanus were included in this retrospective study. ResultsData from 68 patients were analyzed; majority (77.9%) were males, the mean age was 33.8years. None of them was vaccinated for tetanus. The types were: generalized (91.2%), cephalic (7.4%), localized (1.5%), severe (72.1%), moderate (19.1%) and mild (8.8%). One or more complication(s) occurred in 75%; dysautonomia (58.8%), pneumonia (44.1%) and hypoxemia (41.2%). Tracheostomy and mechanical ventilation was used in 45.6% and 11.8%, respectively. Case-fatality was 35.3%. Predictors of mortality were age ≥40years, duration of symptoms prior to presentation <4days, severe tetanus, incubation period <7days, period of onset <3days and dysautonomia. The cause of death was early acute respiratory failure due to uncontrolled spasms in 87.5%. ConclusionsMost tetanus patients were young males and there was high case fatality due to acute respiratory failure. Age ≥40years and dysautonomia were independent predictors of mortality. Preventing tetanus by vaccination and treating patients in a well equipped ICU is recommended.

O05 Exome sequencing in three families with cytoplasmic body myopathy with early respiratory failure

O05 Exome sequencing in three families with cytoplasmic body myopathy with early respiratory failure

O06 The satellite cell in male and female, developing and adult mice: evidence for functionally distinct stem cell populations

muscle weakness. In the world literature the genetic defect for this condition has been identified in two families, having the R279W mutation in the sarcomeric protein TTN, although cases without this mutation have already been reported. Methods: Two large pedigrees and an apparently sporadic case with CBM were included in this study. Clinical characteristics and diagnostic investigations of all affected family members was collected from charts and summarised. Western blot of C-terminal TTN protein was performed. Genome-wide 1000 microsatellite analysis was performed in one of the families to identify a linkage region and shared haplotype. Exome sequencing was performed on 4 patients. Results: Onset of disease was usually in middle-age, with tibialis anterior being the earliest and most severely affected muscle. Pulmonary function tests indicated low FEV1 and FVC, with worsening when supine. Cardiac involvement was not present. Muscle pathology was nonspecific in some affected patients. Electromyography demonstrated necrotising myopathic process in the majority of patients. MRI invariably revealed signal abnormalities of semitendinosus muscle. Blot of C-terminal TTN protein was normal. A single 20 cM linkage region on chromosome 2 was identified. Exome sequencing detected the disease mutation and identified other candidates for exclusion with segregation analysis. Conclusions: We report the disease gene for these patients with CBM, and describe in detail the phenotype and diagnostic investigations from these three pedigrees. Genetic testing for these CBM genes should be performed in patients with myopathy and early respiratory failure if muscle pathology reveals cytoplasmic bodies or is nonspecific. Acknowledgements: GP is the recipient of funding from the Clinician Investigator Program from the University of British Columbia in Vancouver, Canada, and a Bisby fellowship from the Canadian Institutes of Health Research. The authors report no competing interests.

Postoperative Respiratory Failure After Cardiac Surgery: Use of Noninvasive Ventilation

To analyze the use of noninvasive ventilation (NIV) in respiratory failure after extubation in patients after cardiac surgery, the factors associated with respiratory failure, and the need for reintubation. Retrospective observational study. Intensive care unit in a university hospital. Patients (n = 63) with respiratory failure after extubation after cardiac surgery over a 3-year period. Mechanical NIV. Demographic and surgical data, respiratory history, causes of postoperative respiratory failure, durations of mechanical ventilation and spontaneous breathing, gas exchange values, and the mortality rate were recorded. Of 1,225 postsurgical patients, 63 (5.1%) underwent NIV for respiratory failure after extubation. The median time from extubation to the NIV application was 40 hours (18-96 hours). The most frequent cause of respiratory failure was lobar atelectasis (25.4%). The NIV failed in 52.4% of patients (33/63) who had a lower pH at 24 hours of treatment (7.35 v 7.42, p = 0.001) and a higher hospital mortality (51.5% v 6.7%, p = 0.001) than those in whom NIV was successful. An interval <24 hours from extubation to NIV was a predictive factor for NIV failure (odds ratio, 4.6; 95% confidence interval, 1.2-17.9), whereas obesity was associated with NIV success (odds ratio, 0.22; 95% confidence interval, 0.05-0.91). Reintubation was required in half of the NIV-treated patients and was associated with an increased hospital mortality rate. Early respiratory failure after extubation (≤24 hours) is a predictive factor for NIV failure.

Myotubular myopathy and the neuromuscular junction: a novel therapeutic approach from mouse models

SUMMARYMyotubular myopathy (MTM) is a severe congenital muscle disease characterized by profound weakness, early respiratory failure and premature lethality. MTM is defined by muscle biopsy findings that include centralized nuclei and disorganization of perinuclear organelles. No treatments currently exist for MTM. We hypothesized that aberrant neuromuscular junction (NMJ) transmission is an important and potentially treatable aspect of the disease pathogenesis. We tested this hypothesis in two murine models of MTM. In both models we uncovered evidence of a disorder of NMJ transmission: fatigable weakness, improved strength with neostigmine, and electrodecrement with repetitive nerve stimulation. Histopathological analysis revealed abnormalities in the organization, appearance and size of individual NMJs, abnormalities that correlated with changes in acetylcholine receptor gene expression and subcellular localization. We additionally determined the ability of pyridostigmine, an acetylcholinesterase inhibitor, to ameliorate aspects of the behavioral phenotype related to NMJ dysfunction. Pyridostigmine treatment resulted in significant improvement in fatigable weakness and treadmill endurance. In all, these results describe a newly identified pathological abnormality in MTM, and uncover a potential disease-modifying therapy for this devastating disorder.

Surfactant, mechanical ventilation or CPAP for treatment of early respiratory failure in preterm infants: A continuing conundrum?

s2view.con/pas/view.php?nu=PAS10L1660. Accessed on January 25, 2010. 4. Sandri F, Plavka R, Simeoni U; CURPAP Advisory Board. The CURPAP study: an international randomized controlled trial to evaluate the efficacy of combining prophylactic surfactant and early nasal continuous positive airway pressure in very preterm infants. Neonatology. 2008;94:60-2. 5. Tsakalidis C, Kourti M, Karayianni P, Rallis D, Porpodi M, Nikolaidis N. Early rescue administration of surfactant and nasal continuous positive airway pressure in preterm infants <32 weeks gestation. Indian Pediatr. 2011;48:601-5.

Prospective phase II study of tumor response assessment by CT and FDG-PET/CT following 8 weekly doses of cetuximab in patients with metastatic/recurrent head and neck squamous cell carcinoma (HNSCC).

5569 Background: The likelihood of tumor response (CR/PR) to cetuximab is 13% as assessed by CT with IV contrast in patients with incurable HNSCC; however, stable disease occurred in an additional 33% (Vermorken JCO, 2007). Tumor response to cetuximab has not been formally assessed by FDG-PET/CT, nor have FDG-PET/CT results been correlated with CT results. Methods: A key objective of this trial was to determine the metabolic response (MR) of the tumor to cetuximab as assessed by FDG-PET/CT performed at baseline and then after 8 weekly doses of cetuximab (400mg/m2 loading dose, 250 mg/m2 weekly doses). A secondary objective was to correlate the MR as assessed by FDG-PET/CT with the anatomic tumor response as assessed by CT (RECIST). Standard criteria were used to determine MR by FDG-PET/CT (complete MR [CMR]=complete resolution; partial MR [PMR]=20% or more decrease in SUVmax; progressive metabolic disease [PMD]=new lesions, 20% or more increase in SUVmax, or increased SUV of non-target lesions; stable MD [SMD]=other). Results: To date, 24 patients were enrolled of whom 14 were evaluable for the objectives and 8 were non-evaluable because of early progressive disease (5), infection, respiratory failure, and allergic reaction to cetuximab. An additional two patients have been enrolled, but have not yet reached the 8 week timepoint. Tumor responses as assessed by FDG-PET/CT and CT are shown in the table. Of the 14 evaluable patients who received the first 8 weekly doses of cetuximab, 8 (57%) had favorable tumor MR (PMR-4 and SMD-4) and 6 (43%) had unfavorable tumor MR; whereas, all had favorable tumor anatomic response (SD-13 and PR-1). Discordance in FDG-PET/CT and CT results occurred in 6 of 14 patients (43%). Conclusions: The early results of this trial suggest a poor correlation of tumor response assessment by CT and FDG-PET/CT imaging in patients with incurable HNSCC treated with cetuximab. Evaluable patient No. PET CT MR RECIST * Target lesions 1 PMD SD 14% ↓ 2 PMD SD 8% ↑ 3 PMD SD 11% ↓ 8 PMD SD 11% ↓ 20 PMD SD 26% ↓ 21 PMD SD 17% ↓ 5 SMD SD 7% ↑ 10 SMD SD 2% ↓ 12 SMD SD 25% ↓ 22 SMD SD 5% ↑ 15 PMR SD 25% ↓ 16 PMR SD 2% ↑ 18 PMR SD 20% ↓ 19 PMR Partial response 36% ↓

Cigarette Smoking and Outcomes after Allogeneic Hematopoietic Stem Cell Transplantation

Abnormal lung function is a known risk factor for poor outcomes in the allogeneic hematopoietic stem cell transplantation (HSCT) population, although the specific causes of these abnormalities have not been well explored. There is limited data on the effect of cigarette smoking on transplantation outcomes. We conducted a retrospective observational cohort study of 845 consecutive patients age ≥ 18 years who underwent allogeneic HSCT at the Seattle Cancer Care Alliance/Fred Hutchinson Cancer Research Center. Smoking exposure was defined by quit time, smoking status (never, former, and current), and log(2)-transformed pack-years. The main outcomes were time to respiratory failure within 100 days of transplantation, relapse, and nonrelapse mortality. In multivariable analyses, a 2-fold increase in pack-years smoked was associated with an increased risk of early respiratory failure (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.09 to 1.64, P = .006). This association was observed independent of pretransplantation lung function. A 2-fold increase in pack-years smoked was associated with an increased risk of relapse, but this finding was not statistically significant (HR 1.16, 95% CI 0.92-1.46, P = .21). An association was not observed between cigarette smoking and nonrelapse mortality. Cigarette smoking is associated with an increased risk of respiratory failure and relapse within 100 days of allogeneic HSCT. The association with respiratory failure is mediated in part by abnormal lung function before transplantation and likely through other mechanisms as well. Given the adverse effects associated with cigarette smoking before transplantation, future studies should focus on obtaining accurate smoking histories, tracking prospective changes in smoking status, and assessing the benefits of tobacco cessation on outcomes in this population.