Life-threatening Pulmonary Complications Research Articles

Abstract PO5-26-08: Caveats behind the improved outcomes observed in recent clinical trials for women with breast cancer: Korean breast cancer consensus meeting 2023

Abstract Introduction Korean Breast Cancer Society has organized the biennial Korean Breast Cancer Consensus Conference to find solutions to clinical situations that cannot be answered by randomized clinical trials or other definitive treatment research data. Unlike guidelines which are designed to apply to the majority of patients with early or advanced breast cancer encountered in daily practice, consensus meetings yield answers from clinicians’ perspectives and experiences. Therefore, this meeting aimed to integrate patient preferences, treatment availability, or other individual circumstances upon recent medical advances and available evidence. Materials and methods. Panelists were invited from various filed, such as medical oncology, surgical oncology, radiation oncology, pathology, radiology, nuclear medicine, hereditary cancer specialist. Results. 1. caveats behind optimizing treatment There had been strong interests in refinening thresholes for treatment and it can be more or less than previous standard treatment. Some patients clearly required escalated treatment, such as ovarian function suppression, combined HER2-targeted treatment, and utilization of immunotherapy during neoadjuvant systemic treatment. However, even same agent which showed great success for high risk patients showed Disappointing results and even failure. Furthermore, we need more sophisticated decision even for successful stories which introduced above, because of their serious adverse events. AntiPd-1/PD-L1 showed different serious adverse events profiles and Trastuzumab-deruxtecan is related with life-threatening pulmonary complication. Therefore, there is a clinical equipoise for an appropriate therapeutic threshold not only for low-risk patients but also high-risk patients who can safely forgo recommend treatment escalation in the newly introduced clinical trials. 2. Completely new serious adverse events observed in new drugs. Unlike chemotherapy, most targeted therapies cause lethal damage that clinicians may not have experienced. Some, such as pulmonary complications from trastuzumab deruxtecan, can be fatal if not treated immediately. Even if patients survive, they may suffer catastrophic outcomes because these agents leave a fatal disability that is too great for the patient's quality of life. Moreover, in South Korea, where government-run health insurance is the only payer and at the same time policy maker, non-medical constraints such as passive reimbursement plans, value-based medicine, and intentional delay or denial of certain drugs, panelist delivered varing opinions on the extent to which new agents can be utilized and which treatment plan could offer equal clinical benefit with less toxicity, or provide for a measurable improvement in outcomes. 3. utilizing genomic signatures Panelist raised issues genetic assay which analyzed genes currently we do not have treatment options which can modify disease process. Many questions were addressed such as, appropriate sampling time, which sample, liquid or tumor, can yield meaningful information. Conclusion Korean Breast Cancer consensus meeting highlighted important caveats behinds new promising findings. Clinical unmet need and uncertainty should be disclosed before patients because what clinician and patients work with is their life. Shared decision making is essential and patients should become well aware of science and medicine. Proactive approach of clinician is critical for these movements. Citation Format: Airi Han, Young-Joon Kang, Sei Hyun Kim, Eui Su Chae, Han Cho Kim, Kyong Hwa Park. Caveats behind the improved outcomes observed in recent clinical trials for women with breast cancer: Korean breast cancer consensus meeting 2023 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-26-08.

Impact of sugammadex and neostigmine on outcome after major orthopaedic surgery: A population-based analysis.

Residual neuromuscular blockade after surgery remains a major concern given its association with pulmonary complications. However, current clinical practices with and the comparative impact on perioperative risk of various reversal agents remain understudied. We investigated the use of sugammadex and neostigmine in the USA, and their impact on postoperative complications by examining national data. This population-based retrospective study used national Premier Healthcare claims data. Patients undergoing total hip/knee arthroplasty (THA, TKA), or lumbar spine fusion surgery between 2016 and 2019 in the United States who received neuromuscular blocking agents. The effects of sugammadex and neostigmine for pharmacologically enhanced reversal were compared with each other and with controls who received no reversal agent. included pulmonary complications, cardiac complications, and a need for postoperative ventilation. Mixed-effects regression models compared the outcomes between neostigmine, sugammadex, and controls. We report odds ratios (OR) and 95% confidence intervals (CI). Bonferroni-adjusted P values of 0.008 were used to indicate significance. Among 361 553 patients, 74.5% received either sugammadex (20.7%) or neostigmine (53.8%). Sugammadex use increased from 4.4% in 2016 to 35.4% in 2019, whereas neostigmine use decreased from 64.5% in 2016 to 43.4% in 2019. Sugammadex versus neostigmine or controls was associated with significantly reduced odds for cardiac complications (OR 0.86, 95% CI, 0.80 to 0.92 and OR 0.83, 95% CI, 0.78 to 0.89, respectively). Both sugammadex and neostigmine versus controls were associated with reduced odds for pulmonary complications (OR 0.85, 95% CI, 0.77 to 0.94 and OR 0.91, CI 0.85 to 0.98, respectively). A similar pattern of sugammadex and neostigmine was observed for a reduction in severe pulmonary complications, including the requirement of invasive ventilation (OR 0.54, 95% CI, 0.45 to 0.64 and OR 0.53, 95% CI, 0.46 to 0.6, respectively). Population-based data indicate that sugammadex and neostigmine both appear highly effective in reducing the odds of severe life-threatening pulmonary complications. Sugammadex, especially, was associated with reduced odds of cardiac complications.

Comparison of platelet-and endothelial-associated biomarkers of disease activity in people hospitalized with Covid-19 with and without HIV co-infection.

SARS-CoV-2 elicits a hyper-inflammatory response that contributes to increased morbidity and mortality in patients with COVID-19. In the case of HIV infection, despite effective anti-retroviral therapy, people living with HIV (PLWH) experience chronic systemic immune activation, which renders them particularly vulnerable to the life-threatening pulmonary, cardiovascular and other complications of SARS-CoV-2 co-infection. The focus of the study was a comparison of the concentrations of systemic indicators o\f innate immune dysfunction in SARS-CoV-2-PCR-positive patients (n=174) admitted with COVID-19, 37 of whom were co-infected with HIV. Participants were recruited from May 2020 to November 2021. Biomarkers included platelet-associated cytokines, chemokines, and growth factors (IL-1β, IL-6, IL-8, MIP-1α, RANTES, PDGF-BB, TGF-β1 and TNF-α) and endothelial associated markers (IL-1β, IL-1Ra, ICAM-1 and VEGF). PLWH were significantly younger (p=0.002) and more likely to be female (p=0.001); median CD4+ T-cell count was 256 (IQR 115 -388) cells/μL and the median HIV viral load (VL) was 20 (IQR 20 -12,980) copies/mL. Fractional inspired oxygen (FiO2) was high in both groups, but higher in patients without HIV infection (p=0.0165), reflecting a greater need for oxygen supplementation. With the exception of PDGF-BB, the levels of all the biomarkers of innate immune activation were increased in SARS-CoV-2/HIV-co-infected and SARS-CoV-2/HIV-uninfected sub-groups relative to those of a control group of healthy participants. The magnitudes of the increases in the levels of these biomarkers were comparable between the SARS-CoV-2 -infected sub-groups, the one exception being RANTES, which was significantly higher in the sub-group without HIV. After adjusting for age, sex, and diabetes in the multivariable model, only the association between HIV status and VEGF was statistically significant (p=0.034). VEGF was significantly higher in PLWH with a CD4+ T-cell count >200 cells/μL (p=0.040) and those with a suppressed VL (p=0.0077). These findings suggest that HIV co-infection is not associated with increased intensity of the systemic innate inflammatory response during SARS-CoV-2 co-infection, which may underpin the equivalent durations of hospital stay, outcome and mortality rates in the SARS-CoV-2/HIV-infected and -uninfected sub-groups investigated in the current study. The apparent association of increased levels of plasma VEGF with SARS-CoV-2/HIV co-infection does, however, merit further investigation.

Diffuse alveolar hemorrhage: a narrative review

This review discusses clinical presentation of DAH, diagnosis of the underlying histology’s, treatment options, as well as morbidity and mortality rates. Diffuse alveolar hemorrhage (DAH) is considered a life-threatening pulmonary complication in patients with systemic autoimmune disorders, hematologic malignancies, and coagulation disorders. DAH is distinguished by acute onset of hypoxia and alveolar infiltrates that may lead to progressive alveolar bleeding. Early diagnosis and recognition are crucial for survival. Treatment for DAH involves treating both the underlying condition and the autoimmune damage of the alveolar capillary membrane. The gold standard is immunosuppressive agents and corticosteroids. Despite early recognition and proper treatment DAH mortality rates remain high.

Ruxolitinib as an Effective and Steroid-Sparing First-Line Treatment in Newly Diagnosed BOS Patients After Hematopoietic Stem Cell Transplantation.

Bronchiolitis obliterans syndrome (BOS) is a life-threatening pulmonary complication of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). In this study, we retrospectively identified seven patients newly diagnosed with BOS post HSCT and analyzed the outcomes in those patients treated with ruxolitinib as a first-line treatment. All seven patients achieved symptom responses within 2 weeks after ruxolitinib administration. Three months after treatment, five patients (71.43%) achieved a CR, and two (28.57%) achieved a PR. The overall response rate (ORR) was 100%. In addition, the steroid therapy was determined within 2 months after ruxolitinib treatment, indicating ruxolitinib as a steroid-sparing agent. We also found that ruxolitinib was well-tolerated and safe in treating newly diagnosed BOS. According to our results, ruxolitinib would be a promising and safe option in newly diagnosed BOS post HSCT.

A Rare Case of Pulmonary Renal Syndrome Secondary to Microscopic Polyangiitis – A Case Report

Diffuse Alveolar Hemorrhage (DAH) is one of the life-threatening pulmonary complications of AAV (ANCA-Associated Vasculitis). Pulmonary Renal Syndrome (PRS) is defined as concurrent autoimmune-induced DAH and Rapidly progressive glomerulonephritis (RPGN). Major organs involved in MPA (Microscopic Polyangiitis) are the kidneys and the lungs. The gold standard to confirm alveolar hemorrhage is bronchoalveolar lavage (BAL). We hereby describe a case in which our patient presented to the emergency room after being sent by his nephrologist for kidney biopsy in the setting of unexplained worsening renal functions. Patient ultimately developed PRS and was started on remission treatment with pulse dose steroids, plasmapheresis, and cyclophosphamide. Unfortunately, the patient deceased from multiorgan failure secondary to septic shock. PRS, once suspected, appropriate autoimmune workup should be undertaken, usually followed by renal biopsy.

Risk factors and outcomes of diffuse alveolar haemorrhage after allogeneic haematopoietic stem cell transplantation.

Diffuse alveolar haemorrhage (DAH) is a life-threatening pulmonary complication occurring after allogeneic haematopoietic stem cell transplantation (allo-HSCT) without an explicit aetiology or a standard treatment. This study aimed to explore the occurrence and prognosis of DAH after allo-HSCT, in addition to comparing discrepancies in the incidence, clinical characteristics and outcomes of DAH between patients undergoing haploidentical HSCT (HID-HSCT) and matched related donor HSCT (MRD-HSCT). We retrospectively evaluated 92 consecutive patients among 3987 patients with a confirmed diagnosis of DAH following allo-HSCT (HID: 71 patients, MRD: 21 patients). The incidence of DAH after allo-HSCT was 2.3%, 2.4% after HID-HSCT and 2.0% after MRD-HSCT (P = 0.501). The prognosis of patients with DAH after transplantation is extremely poor. The duration of DAH was 7.5 days (range, 1–48 days). The probabilities of overall survival (OS) were significantly different between patients with and without DAH within 2 years after transplantation (P < 0.001). According to the Cox regression analysis, a significant independent risk factor for the occurrence of DAH was delayed platelet engraftment (P < 0.001), and a high D-dimer level (>500 ng/ml) was a significant risk factor for the poor prognosis of DAH. HID-HSCT is similar to MRD-HSCT in terms of the outcomes of DAH.

Treatment of Diffuse Alveolar Hemorrhage: Controlling Inflammation and Obtaining Rapid and Effective Hemostasis.

Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary complication in patients with hematologic malignancies or systemic autoimmune disorders. Pathologic findings show pulmonary capillaritis, bland hemorrhage, diffuse alveolar damage, and hemosiderin-laden macrophages, but in the majority of cases, pathogenesis remains unclear. Despite the severity and high mortality, the current treatment options for DAH remain empirical. Systemic treatment to control inflammatory activity including high-dose corticosteroids, cyclophosphamide, and rituximab and supportive care have been applied, but largely unsuccessful in critical cases. Activated recombinant factor VII (FVIIa) can achieve rapid local hemostasis and has been administered either systemically or intrapulmonary for the treatment of DAH. However, there is no randomized controlled study to evaluate the efficacy and safety, and the use of FVIIa for DAH remains open to debate. This review discusses the pathogenesis, diverse etiologies causing DAH, diagnosis, and treatments focusing on hemostasis using FVIIa. In addition, the risks and benefits of the off-label use of FVIIa in pediatric patients will be discussed in detail.

REFRACTORY GRANULOMATOSIS WITH POLYANGIITIS FLARE? HOW ABOUT PLASMA EXCHANGE?

SESSION TITLE: Medical Student/Resident Lung Pathology SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: ANCA-negative granulomatosis with polyangiitis (GPA) patients often have limited disease, but they may evolve to have life-threatening renal and pulmonary complications. In general, patients are treated with glucocorticoids and immunosuppression. We present a patient with GPA flare-up refractory to initial therapy who improved after undergoing plasma exchange. CASE PRESENTATION: A 78-year-old male with a past medical history of ANCA-negative GPA and chronic kidney disease (baseline Cr 2.5 mg/dL) presented to the hospital with dyspnea. He was discharged from the hospital one week prior where he was managed for a GPA flare-up (i.e., sudden onset bilateral lower extremity nonpalpable purpura) after he stopped methotrexate due to transaminitis. At that time, he was treated with pulse IV methylprednisolone and discharged home to begin rituximab. When he returned to the hospital with worsening dyspnea, vital signs were: BP 106/47, HR 83, RR 18, 93% O2 saturation on room air. His hospital course was complicated by copious amount of hemoptysis. Labs revealed: Hgb 5.2 g/dL (which dropped from 8.5 g/dL a week ago) and worsening renal function with BUN >150 mg/dL and Cr 5.1 mg/dL. Chest x-ray showed diffuse bilateral alveolar opacities. He had respiratory failure secondary to pulmonary hemorrhage, which led to intubation and transfusion of blood products. A decision was made to start the patient on seven sessions of plasma exchanges. The patient responded well to the therapy and was eventually extubated with pulmonary and renal function returning to baseline. DISCUSSION: In the past, plasma exchange in GPA was based upon the efficacy of removing autoantibodies in Goodpasture's syndrome. More recently, the PEXIVAS clinical trial demonstrated that plasma exchange neither reduced the risk of end-stage renal disease nor had a treatment effect on pulmonary hemorrhage in ANCA-associated vasculitis. Some statistical analyses regarding pulmonary hemorrhage had wide confidence intervals, suggesting that plasma exchange could still be useful. In addition, a kidney biopsy was not required to enter the PEXIVAS trial, making it difficult to delineate if mild or severe disease was present (as vasculitides patients often have a relapsing and remitting course). Those with minimal tubulointerstitial and glomerular scarring could theoretically benefit from plasma exchange. The patient in this case underwent plasma exchange as he was thought to be among a select subgroup whose benefits outweighed risks. CONCLUSIONS: The use of plasma exchange in vasculitides should be tailored according to the characteristics of each patient and the previous treatments that each patient received. Reference #1: 1. Pagnoux C. Updates in ANCA-associated vasculitis. Eur J Rheumatol. 2016; 3(3):122-133. DOI:10.5152/eurjrheum.2015.0043 Reference #2: 2. Walsh M et al. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis. N Engl J Med. 2020; 382(7):622-631. DOI: 10.1056/NEJMoa1803537 Reference #3: 3. Jayne D.R.W et al. Randomized Trial of Plasma Exchange or High-Dosage Methylprednisolone as Adjunctive Therapy for Severe Renal Vasculitis. JASN. 2007; 18(7):2180-2188; DOI: 10.1681/ASN.20070100904. Derebail V, Falk R. ANCA-Associated Vasculitis -- Refining Therapy with Plasma Exchange and Glucocorticoids. N Engl J Med. 2020; 382:671-673. DOI: 10.1056/NEJMe1917490

Clinical Features of SARS-CoV-2 Infection

AbstractViral diseases continue to emerge and represent a serious issue to public health. Since viral transmission occurs through respiratory droplets, most patients with coronavirus disease 2019 (COVID-19) predominantly have respiratory tract involvement. The clinical spectrum of COVID-19 ranges from asymptomatic to symptomatic with mild, moderate, and severe degrees of illnesses. There are no specific clinical features that can yet reliably distinguish COVID-19 from other viral respiratory infections. Unexplained worsening of underlying chronic illnesses and comorbidities should raise the suspicion of COVID-19. Beyond the life-threatening pulmonary complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the widespread organ-specific manifestations of COVID-19 are increasingly being appreciated. Given that angiotensin-converting enzyme 2, the entry receptor for the SARS-CoV-2, is expressed in multiple extrapulmonary tissues and that all might contribute to these extrapulmonary manifestations of COVID-19, here we review the pulmonary and extrapulmonary presentations for patients with COVID-19.

Pulmonary Complications After Allogeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma: A Case Report

We present a case of a young patient with life-threatening pulmonary complications after allogeneic hematopoietic stem cell transplantation (HSCT). The 25-year-old woman, after HSCT for multiple myeloma, developed severe chronic graft-vs-host disease (GvHD), including bronchiolitis obliterans syndrome. During the treatment of chronic GvHD, 18 months after HSCT, she experienced sudden massive pulmonary hemorrhage with cardiac arrest. The computed tomography imaging revealed lesions suggestive of fungal etiology, with cavity adjacent to the pulmonary vessels. Disqualified from invasive treatment due to poor pulmonary performance, she was treated conservatively with broad-spectrum antibiotics and antifungals. The microbiological workup consistently revealed only Pseudomonas aeruginosa colonization. Her condition steadily improved on treatment. Over 18 months after the incident, she did not experience recurrent bleeding nor serious infection, her primary disease remains in remission, and GvHD symptoms are controlled. Allogeneic HSCT offers possibility of sustained immune-mediated disease control and sometimes even cure, but despite reduced transplant related mortality, GvHD and infections may be detrimental for transplant recipients. Our report illustrates atypical manifestation of pulmonary lesions and highlights the importance of infection control during GvHD treatment.

Clinical Characteristics and Outcomes of Acute Lung Injury Caused by Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma: A Retrospective Cohort Study from a Single Institution in China

Background Acute lung injury (ALI) is a rare but life-threatening pulmonary complication of transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). The aim of this study was to characterize the common risk factors, clinical features, imaging findings, treatments, and outcomes of acute lung injury caused by TACE. Methods A retrospective study was performed on all TACE-associated ALI cases that were diagnosed at authors' hospital from January 2015 to June 2018. Results The study included 14 ALI cases where the mean age of patients was 60.9 ± 11.7 years (range 41-82 years), with a mean onset time of 2.4 ± 1.6 d after TACE. Of the 14 patients, 8 patients (57.1%) developed acute respiratory distress syndrome (ARDS). 7 patients (50%) had underlying chronic respiratory disease and hepatic arteriovenous fistula was detected in 6 patients (42.6%), both of which were significantly higher than control group (P < 0.05). Dyspnea (92.9%) was the most common symptoms. Pleural effusion (64.3%), diffuse pulmonary infiltration (42.9%), and accumulation of Lipiodol in lung field (42.9%) were frequent radiologic abnormalities. 11 patients (78.6%) achieved remission after treatment, and the 30-day mortality rate was approximately 21.4%. Patient's median survival time after the development of ALI was merely 4.3 months, which was obviously worse than control group (4.3 months vs. 13.5 months, P < 0.05). Conclusion This study illustrates that TACE-associated ALI is a rare pulmonary complication with a high mortality rate. We infer that pulmonary Lipiodol embolization might be one of the main causes of TACE-associated ALI. Thus, HCC patients who are at high risk should be closely evaluated and monitored during TACE to avoid such potentially fatal complication.

High-dimensional analysis reveals a pathogenic role of inflammatory monocytes in experimental diffuse alveolar hemorrhage.

Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary complication associated with systemic lupus erythematosus, vasculitis, and stem cell transplant. Little is known about the pathophysiology of DAH, and no targeted therapy is currently available. Pristane treatment in mice induces systemic autoimmunity and lung hemorrhage that recapitulates hallmark pathologic features of human DAH. Using this experimental model, we performed high-dimensional analysis of lung immune cells in DAH by mass cytometry and single-cell RNA sequencing. We found a large influx of myeloid cells to the lungs in DAH and defined the gene expression profile of infiltrating monocytes. Bone marrow-derived inflammatory monocytes actively migrated to the lungs and homed adjacent to blood vessels. Using 3 models of monocyte deficiency and complementary transfer studies, we established a central role of inflammatory monocytes in the development of DAH. We further found that the myeloid transcription factor interferon regulatory factor 8 is essential to the development of both DAH and type I interferon-dependent autoimmunity. These findings collectively reveal monocytes as a potential treatment target in DAH.

Hyaluronic acid-induced diffuse alveolar hemorrhage: unknown complication induced by a well-known injectable agent

Hyaluronic acid (HA) is widely used in medicine, especially for contouring or volumizing soft tissue and intra-articular injection. However, it is not well known that HA injection can cause life-threatening pulmonary complications. We recently experienced a case of a woman who was diagnosed with diffuse alveolar hemorrhage (DAH) after receiving an illegal vaginal HA filler injection. A 54-year-old female visited our clinic complaining of hemoptysis and dyspnea. Chest computed tomographic (CT) scan showed diffuse ground glass opacities and consolidation in both lower lobes. Bronchoalveolar lavage (BAL) disclosed hemorrhagic feature in sequential samples compatible with DAH. There were no relevant drugs or past medical histories, and no positive result in autoantibodies tests. During detailed history taking, she recalled that she got an illegal HA filler injection in her vaginal wall performed by nonmedical personnel the very day before the onset of symptoms. Although the procedure itself or an additive of HA preparation could be a cause, HA that might have been introduced into circulation was thought to be the most possible cause for the development of DAH. The clinical symptoms and lung lesions were dramatically improved after the treatment with systemic steroid. Pulmonary complications after HA injections were scarcely reported. Only one case of HA-related DAH has been previously described so far. Our present case emphasizes that physician and other health care providers must be aware of possible pulmonary complications of this most widely-using injectable agent.

Pulmonary complications in patients with brain injury: crosstalk between brain and lung

Background Pulmonary complications after severe brain injury often happened. It could include neurogenic pulmonary edema, acute lung injury/acute respiratory distress syndrome (ALI/ARDS) and ventilator-associated pneumonia. Objective This review is to summarize research advances in recent years in pulmonary complications in patients with brain injury. Content Direct brain injury, depressed level of consciousness and inability to protect the airway, decreased mobility, and secondary neurological injury results from severe brain damage are main causes of pulmonary complications of severe brain damage patients in neurological department. Prevention strategies was implemented to avoid the development of these life-threatening pulmonary complications and current therapy methods are discussed. Trend The mechanism, specific treatment methods of pulmonary complications in patients with brain injury still need further research. Key words: Brain injury; Pulmonary edema; Ventilator-associated pneumonia; Acute lung injury; Acute respiratory distress syndrome

Fat Embolism Syndrome: Fact or Myth?

Fat embolism syndrome (FES) is thought to occur most commonly in patients who suffer severe trauma and orthopedic injuries and may be associated with potentially life-threatening pulmonary complications. However, despite its original description hundreds of years ago, it remains a difficult diagnosis to establish and the process by which a fat embolism leads to the clinical syndrome of FES is poorly understood. Some wonder, therefore, if it is a unique syndrome or just part of the spectrum of systemic inflammatory response syndrome (SIRS) common to other critically ill patients. In this review, we will summarize the clinical and experimental evidence that supports FES as a unique clinical condition.

Diffuse alveolar hemorrhage and recombinant factor VIIa treatment in pediatric patients.

Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary complication in patients with hematologic malignancies or autoimmune disorders. The current treatment options, which include corticosteroids, transfusions, extracorporeal membrane oxygenation (ECMO), and immunosuppressants, have been limited and largely unsuccessful. Recombinant activated factor VII (rFVIIa) has been successfully administered, either systemically or bronchoscopically, to adults for the treatment of DAH, but there are few data on its use in pediatric patients. The current literature in the PubMed database was reviewed to evaluate the efficacy and risk of rFVIIa treatment for DAH in pediatric patients. This review discusses the diagnosis and treatment of DAH, as well as a new treatment paradigm that includes rFVIIa. Additionally, the risks and benefits of off-label use of rFVIIa in pediatric patients are discussed.

Air-leak Syndrome by Pleuroparenchymal Fibroelastosis after Bone Marrow Transplantation.

Objective Air-leak syndrome (ALS) is a life-threatening pulmonary complication following allogeneic bone marrow transplantation (allo-BMT) which is thought to be associated with graft-versus-host disease (GVHD). Recently, it has been reported that pleuroparenchymal fibroelastosis (PPFE) also occurs after allo-BMT and often causes ALS. We sought to extract common features of ALS caused by PPFE after allo-BMT. Methods The clinical data of patients who developed ALS caused by PPFE after undergoing allo-BMT (ALS-PPFE) between April 1996 and December 2007 at our institution were collected and reviewed retrospectively. The clinical findings, radiological and pathological features and treatment outcomes of ALS-PPFE were assessed. Results Five patients who developed ALS had histologically proven PPFE (four men, one woman: median age, 37 years). The age of onset of ALS-PPFE was 13 to 109 months (median, 68.8 months) after BMT. Alkylating agents were used as conditioning chemotherapy for BMT in all patients. Only one patient developed chronic GVHD (limited type). The common radiological findings were subpleural thickening and traction bronchiectasis predominantly in the bilateral upper lung fields. The histological pulmonary specimens showed no findings of bronchiolitis obliterans or GVHD. Immunosuppressive therapy was not effective in any of the cases, and all patients died of respiratory failure with or without lung transplantation. Conclusion ALS-PPFE is an extremely late-onset noninfectious pulmonary complication of allo-BMT. This complication is progressive, resistant to immunosuppressive treatment and has a poor prognosis. No association was found between PPFE and GVHD.

Regulation of pulmonary graft-versus-host disease by IL-26+CD26+CD4 T lymphocytes.

Obliterative bronchiolitis is a potentially life-threatening noninfectious pulmonary complication after allogeneic hematopoietic stem cell transplantation and the only pathognomonic manifestation of pulmonary chronic graft-versus-host disease (cGVHD). In the current study, we identified a novel effect of IL-26 on transplant-related obliterative bronchiolitis. Sublethally irradiated NOD/Shi-scidIL2rγ(null) mice transplanted with human umbilical cord blood (HuCB mice) gradually developed clinical signs of graft-versus-host disease (GVHD) such as loss of weight, ruffled fur, and alopecia. Histologically, lung of HuCB mice exhibited obliterative bronchiolitis with increased collagen deposition and predominant infiltration with human IL-26(+)CD26(+)CD4 T cells. Concomitantly, skin manifested fat loss and sclerosis of the reticular dermis in the presence of apoptosis of the basilar keratinocytes, whereas the liver exhibited portal fibrosis and cholestasis. Moreover, although IL-26 is absent from rodents, we showed that IL-26 increased collagen synthesis in fibroblasts and promoted lung fibrosis in a murine GVHD model using IL-26 transgenic mice. In vitro analysis demonstrated a significant increase in IL-26 production by HuCB CD4 T cells following CD26 costimulation, whereas Ig Fc domain fused with the N-terminal of caveolin-1 (Cav-Ig), the ligand for CD26, effectively inhibited production of IL-26. Administration of Cav-Ig before or after onset of GVHD impeded the development of clinical and histologic features of GVHD without interrupting engraftment of donor-derived human cells, with preservation of the graft-versus-leukemia effect. These results therefore provide proof of principle that cGVHD of the lungs is caused in part by IL-26(+)CD26(+)CD4 T cells, and that treatment with Cav-Ig could be beneficial for cGVHD prevention and therapy.

Intrapulmonary recombinant factor VIIa for diffuse alveolar hemorrhage in children.

Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary complication in patients with hematologic malignancies or autoimmune disorders, and it has a high mortality rate. The current treatment options of corticosteroids, transfusions, and immunosuppressants have been limited and largely unsuccessful, and they can be accompanied by multiple complications. Intrapulmonary administration of recombinant activated factor VII (rFVIIa) has been reported in adults, but there are scarce data on its use in children. The present article reviews our institutional experience with intrapulmonary rFVIIa for the treatment of DAH in children. The study included 6 pediatric patients with acute, bronchoscopically confirmed DAH treated between 2011 and 2013. The median age was 11 years, and patient diagnoses were as follows: acute myeloid leukemia (2 patients), myelodysplastic syndrome (1 patient), hemophagocytic lymphohistiocytosis (1 patient), T-cell lymphoblastic lymphoma (1 patient), and idiopathic pulmonary hemosiderosis (1 patient). These patients were treated with intrapulmonary rFVIIa concurrent with methylprednisolone, fresh-frozen plasma, and maintenance of the platelet count >50 000/mm(3). Complete and sustained hemostasis after rFVIIa treatment and an absence of adverse events were observed in all patients. The PaO2/fraction of inspired oxygen ratio increased significantly, and rapid clinical improvements were observed. Two patients who received hematopoietic stem cell transplantation died of subsequent respiratory syncytial virus and Acinetobacter baumannii infections, but the other 4 patients exhibited rapid improvement, were successfully weaned from ventilators, and experienced long-term survival. Our findings indicate that intrapulmonary administration of rFVIIa is an effective and safe treatment option for children with DAH; however, further clinical studies are needed.