Severe Pulmonary Complications Research Articles

WE‐C‐M100F‐03: Underestimation Of Low‐Dose Radiation in Conventional Treatment Planning of Intensity‐Modulated Radiation Therapy

Purpose: In radiation therapy of thoracic cancers (e.g. lung cancers), a high volume of low‐dose radiation may lead to severe and fatal pulmonary complications. The purpose of this work is to investigate dosimetric accuracy in low‐dose regions from commercial treatment planning systems (TPS) and consequent clinical implications for using IMRT in treating lung and thoracic cancers. Methods and Materials: We retrospectively reviewed thoracic‐cancer patients treated with IMRT at our institution and for whom high‐grade lung complications occurred. These IMRT plans were evaluated and were recomputed using a Monte‐Carlo‐based (MC) treatment planning system (TPS) that explicitly accounts for modeling of the machine head and MLCs. Dose calculations from 2 commercial TPSs (Pinnacle and Corvus systems) were compared with those obtained from the MC system and measurements. Various factors that could contribute to the difference in IMRT dose calculations were analyzed, including tissue heterogeneity effect, MLC modeling, and beam modeling. Results: Significant dosimetric errors (∼25%) were found in the low‐dose regions below 5 Gy in the commercial TPSs. Accuracy of dose calculations in the high‐dose tumor regions was acceptable (< 5%). In regions < 5 Gy of IMRT plans, MLC transmission, leakage, and scattering were found to be important contributors to the dose. These factors were also spatially variant and field‐size dependent. Without explicit modeling of the MLCs, severe underestimation of the low‐dose volume could occur in commercial TPS. The degree of low‐dose error was particularly greater in IMRT plans with larger target volumes and higher degrees of beam modulation. Conclusions: Treatment planners should be aware of potentially significant underestimation of low doses in IMRT treatment plans for thoracic and other cancer sites. More accurate modeling of MLCs and low‐dose calculation may be achieved by using a Monte‐Carlo‐based planning system.

Severe pulmonary complications after initial treatment with rituximab for the Asian-variant of intravascular lymphoma

Rituximab improves response to treatment and outcome for patients with CD20+ B-cell lymphoma. Herein, however, we report the occurrence of severe pulmonary complications shortly after rituximab infusion in three patients with the newly diagnosed Asian variant of intravascular lymphoma. It is suggested that patients with this subtype of lymphoma are monitored carefully for possible drug reactions during the use of rituximab.

Lung Injury Associated with Bortezomib Therapy in Relapsed/Refractory Multiple Myeloma in Japan: A Questionnaire-Based Report from the "Lung Injury by Bortezomib" Joint Committee of the Japanese Society of Hematology and the Japanese Society of Clinical Hematology

Bortezomib is a proteasome inhibitor that can be effective in the treatment of refractory and relapsed multiple myeloma. Recently, severe pulmonary complications associated with bortezomib therapy have been reported in Japan. Because bortezomib has not yet been approved for general use in Japan and is imported by attending physicians on the request of patients, The Japanese Society of Hematology and The Japanese Society of Clinical Hematology sent urgent questionnaires to the councilors of both societies to explore the situation and the details of pulmonary complications associated with bortezomib therapy. Clinical details were available for 46 patients who had been treated with personally imported bortezomib in Japan. Seven patients (15.2%), including 3 who died from respiratory failure, showed complications definitely or probably caused by bortezomib. Of the 7 patients, 6 had a prior history of stem cell transplantation (SCT), whereas only 14 of 39 patients without lung injury had received SCT treatment (P = .033, Fisher exact test). Multivariate analysis revealed that the concomitant use of corticosteroids might reduce the risk of lung injury (P = .024; odds ratio, 0.055) and that a previous SCT might increase the risk (P = .042; odds ratio, 13.140). We summarized these data from questionnaires for a limited Japanese cohort and therefore do not know the precise incidence of lung injury linked to fatal progression. Thus, future verification concerning this matter is warranted after the approval of bortezomib for use in Japan. Clinicians should be aware of the possibility of severe pulmonary complications associated with bortezomib therapy.

Long Term Psycho-Social Aspects and Risk Factors for Severe Infections, Ocular, Pulmonary, Bone, Thyroid and Other Complications after Allogeneic Hematopoietic Stem Cell Transplantation for Children with Hematologic Malignancies.

Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective therapy for children with hematologic malignancies. However, many long term complications are observed with a longer follow-up. Few data is available analyzing psycho-social aspects and risk factors of various long term complications in a same cohort of children. We have reviewed the charts of 112 children younger than 16 years, transplanted for hematologic malignancies between 1985 and 2000 at Saint Louis Hospital, and who survived at least 1 year after transplant. Landmark analysis and cumulative incidence using death and relapse as competing events were used to calculate incidences of complications after one year of HSCT. Univariate analysis used the Fine and Gray test and multivariate Cox model was used with chronic GVHD (cGVHD) as time dependent variable. Results: Median age at transplant was 8.3 years (0.73–15 years), median follow-up from 1 year after transplantation was 8 years (0.3–16.5). Most frequently, children had acute leukemia (n=101, 90%) and 92 patients were transplanted with an HLA-identical sibling donor.Total body irradiation (TBI) was used in 87 patients as part of conditioning regimen and fractionated TBI was used since march 1994 in 37 patients. At 10 years, overall survival was 75±5%, transplant related mortality (TRM) was 18%±4 and relapse 14±3%. Ten year cumulative incidence of severe infections (mostly bacterial) was 31%±4 (n=33); it was 44±4% for cataract (n=48); 20±4% for pulmonary dysfunction (mostly restrictive abnormalities) (n=20); 29±5% for osteoarticular complications (mostly osteonecrosis) (n=27); 36±4% for hypothyroidism (n=36); 11±3% for cardiac complications and 7±3% for secondary malignancies (n=8). The number of complications per patient increased with time, from 1 at a median observation time of 73 months to 3 at a median of 120 months. Factors related to patient, disease, donor and transplant characteristics were analyzed in univariate and multivariate analysis for complications with at least 20 events. There was a trend of higher risk of TRM (p=0.06), osteoarticular complications (p=0.09) and infections (p=0.07) for patients presenting cGVHD. cGVHD was significantly associated with higher risk of pulmonary dysfunction (p=0.02). However, single dose TBI (sTBI) or only TBI was the most important factor among other factors that increased the risk of cataract (p<0.001), pulmonary (p=0.004), osteoarticular (p=0.04) and thyroid complications (p<0.0001).Concerning psychological health and social issues; half of the patients had psychological disturbance, 13 patients had signs of depression, 16 history of eating behavior disorders. Half of the patients who had more than 18 years had an employment, 36 patients achieved normal scholarship, 69 had scholar difficulties and 12 patients achieved superior level studies. In conclusion with a longer follow-up in survivors of HSCT long term complications become an important issue. These complications reached no plateau even after 10 years. Development of less toxic conditioning regimen, avoid sTBI and probably better control of cGVHD may prevent late effects and improve quality of life of long term survivors.

Severe Pulmonary Complications in African-American Patient After Bortezomib Therapy

Bortezomib is a proteosome inhibitor with good clinical activity in multiple myeloma. Frequently described side effects are gastrointestinal symptoms, neuropathy, and thrombocytopenia. Even though pneumonia is listed as an infrequent toxicity, severe pneumonitis leading to respiratory distress had not been described until recently. This report was from a single institution in Japan. All these patients had received bone marrow transplant before therapy with bortezomib. To the authors knowledge, this is the first report of life-threatening pulmonary toxicity after bortezomib in a non-Japanese patient and without history of prior autologous peripheral stem cell transplant.

Bronchiolitis obliterans with organizing pneumonia after rituximab therapy for non‐Hodgkin's lymphoma

Rituximab is a chimeric, anti-CD20 monoclonal antibody initially approved for relapsed, refractory indolent B-cell non-Hodgkin's lymphoma (NHL), and is being applied in an increasing variety of clinical scenarios. Most adverse events are due to an infusion-related symptom complex, and severe pulmonary complications are rare. We describe a case of an NHL patient who received rituximab and developed symptomatic, biopsy-proven multinodular bronchiolitis obliterans with organizing pneumonia (BOOP). This is the first reported case of BOOP associated with single-agent rituximab, and along with two other patients we describe, as well as two prior reports of BOOP in NHL patients receiving rituximab-based combinations, strengthens the possibility of a causal relationship. Moreover, these findings suggest that the incidence of BOOP following rituximab therapy may be higher than has been previously appreciated. Physicians utilizing rituximab should be aware of this association given the difficulty of differentiating between presentations of BOOP and neoplastic pulmonary processes.

Toxicity and outcome of a phase II trial of taxane‐based neoadjuvant chemotherapy and 3‐dimensional, conformal, accelerated radiotherapy in locally advanced nonsmall cell lung cancer

The objective of this study was to evaluate prospectively the acute and late adverse effects of taxane/carboplatin neoadjuvant chemotherapy and 3-dimensional, conformal radiotherapy in patients with locally advanced nonsmall cell lung cancer (NSCLC). Forty-two patients were entered into a nonrandomized Phase II study of continuous, hyperfractionated, accelerated radiotherapy (CHART) week-end less (CHARTWEL) to a dose of 60 grays (Gy). Three cycles of chemotherapy were given over 9 weeks before radiotherapy. Dose escalation with paclitaxel was from 150 mg/m2 to 225 mg/m2. Systemic toxicity to chemotherapy was monitored throughout. Radiation-induced, early, adverse effects were assessed during the first 9 weeks from the start of radiotherapy, and late effects were assessed from 3 months onward. Overall survival, disease-free survival, and locoregional tumor control also were monitored. Twenty percent of patients failed to receive chemotherapy as planned, primarily because of neutropenia. The incidence of Dische Dictionary Grade >or=2 and Grade >or=3 dysphagia was 57.5% and 10%, respectively, with an average duration of 1.2 weeks and 1.5 days, respectively. By 9 weeks, <3% of patients were symptomatic; and, eventually, all acute reactions were healed, and there has been no evidence of consequential damage. At 6 months, the actuarial incidence of moderate-to-severe pneumonitis was 10%. During this time, all patients were free of severe pulmonary complications. Actuarial estimates of Grade >or=2 late lung dysfunction were 3% at 1 year, 10% at 2 years, and remained at this level thereafter. The actuarial 3-year locoregional control and overall survival rates were 54% and 45%, respectively. Neoadjuvant chemotherapy followed by 3-dimensional, conformal CHARTWEL 60-Gy radiotherapy in patients with advanced NSCLC was feasible and was tolerated well. Historic comparisons indicated that locoregional tumor control is not compromised by the use of conformal techniques.

Pneumocystis jiroveci-Pneumonie bei immunsupprimierten Patienten ohne AIDS-Erkrankung - eine Fallserie

Patients with pneumonia resistant to treatment are a common problem in chest hospitals. Pneumocystis jiroveci (Pc) should always be considered as an opportunistic pathogen in case of potential, especially T cell-related immunodeficiency, even if AIDS is not obvious. We report on cases of Pneumocystis jiroveci pneumonia (PcP) (n = 1921) without associated AIDS in a chest hospital. We assessed 1921 inpatients presenting with pneumonia during January 1 (st) 1996 and September 30 (th) 2005 in our hospital. Identification of the cases with PcP was based on discharge diagnosis as well as on our microbiological database (detection of Pc by immunofluorescence-test (IFT) and/or PCR). The diagnosis of PcP was made in 14 patients (11 males, 3 females) without associated AIDS. All patients were treated with immunosuppressive medication before admission. CD4 cell-counts were substantially decreased (CD4 cells < 200/microl) in 11 patients. To establish the diagnosis of PcP a Pc-PCR (using broncho-alveolar lavage (BAL) as the best material) was necessary in 8 patients, since the Pc-IFT proved positive only in 6 patients. Severe hypoxemia had to be managed by noninvasive ventilation in 3 patients, while another 4 patients had to be ventilated invasively. The mortality rate was 2 out of 14 patients. PcP is an important disease in the differential diagnosis of pneumonia and at the same time constitutes a severe pulmonary complication in immunodeficient patients. If immunodeficiency is suspected, a CD4 cell-count as well as bronchoscopy with BAL should be performed to diagnose PcP. As expected, Pc-PCR was superior to Pc-IFT and should therefore be used on a routine basis for diagnosing PcP.

Severe pulmonary complications in Japanese patients after bortezomib treatment for refractory multiple myeloma

Bortezomib is a novel proteasome inhibitor with significant antimyeloma activity. Its frequent adverse effects are manageable, including gastrointestinal symptoms, peripheral neuropathy, and thrombocytopenia. Severe lung toxicity has not previously been reported. Between June 2004 and September 2005, 13 Japanese patients with multiple myeloma were treated with bortezomib in Toranomon Hospital, Juntendo University School of Medicine, and Jichi Medical School. Four of them developed severe pulmonary complications, and 2 died of respiratory failure without progression of underlying disease. To our knowledge, this is the first report on life-threatening pulmonary adverse effects after bortezomib therapy. Previous clinical studies on bortezomib, mostly in the United States and Europe, have shown low incidences of pulmonary adverse effects. Our study suggests that bortezomib can cause serious lung injury, and that its incidence might vary among different ethnicities. Clinicians need to be alert to the possibility.

Neuromuskuläre Restblockaden

Even after administration in routine clinical dosages, muscle relaxants can lead to long-lasting residual blockades which increase the risk of severe postoperative pulmonary complications. Even without the additional effects from analgetics, sedatives or anaesthetics, a partial neuromuscular blockade, which cannot reliably be avoided either by the anaesthetist alone or by the additional use of nerve stimulators (train-of-four [TOF] ratio 0.5-0.9), can cause reductions in the vital capacity and the hypoxic breathing response, as well as obstruction of the upper airway and disruption of pharangeal function. The extent of neuromuscular recovery after an operation depends on the muscle relaxant used, the duration of administration, the anaesthetic technique and possible accompanying illnesses of the patient. It must basically be assumed that residual neuromuscular blockades are more frequent after administration of slow acting muscle relaxants such as pancuronium, than after the use of medium or rapid acting substances. If the course of a neuromuscular blockade is continually monitored during the whole anaesthetic procedure using the TOF ratio and not only occasionally at the end, a TOF ratio of 1 measured with an acceleromyograph (e.g. TOF-watch) promises an adequate neuromuscular recovery from the effects of muscle relaxants.

A case of dysphagia developing in a patient after a partial laryngectomy, who had severe pulmonary and cardiac complications

A case of dysphagia developing in a patient after a partial laryngectomy, who had severe pulmonary and cardiac complications

Neue Konzepte zur Pathophysiologie und Therapie der Mukoviszidose

Today, the majority of cystic fibrosis (CF) patients treated in Germany have reached adulthood. However, with increasing age the morbidity and frequency of severe pulmonary complications continues to rise. Further optimization of conventional therapy alone will be insufficient to compensate for this development. In recent years, there has been impressive progress in our understanding of the molecular basis of the CF gene and its product, the cystic fibrosis transmembrane conductance regulator (CFTR). This knowledge can now be applied to develop new therapeutic strategies. However, important questions remain to be solved, i. e., little is known about the pathways that link the malfunctioning of the CFTR protein with the observed clinical phenotype. This review briefly touches on CF genetics as it applies to lung disease and will focus on the current hypotheses of CFTR (dys)function and its impact on pulmonary fluid homeostasis. New treatment options that target the molecular basis of the disease will be discussed.

Asp f6, an Aspergillus allergen specifically recognized by IgE from patients with allergic bronchopulmonary aspergillosis, is differentially expressed during germination

Aspergillus fumigatus is a pathogenic mould causing allergic and invasive respiratory diseases. Allergic bronchopulmonary Aspergillosis (ABPA) is a severe pulmonary complication resulting from hypersensitivity to A. fumigatus proteins. Aspergillus allergen Asp f6 is recognized by IgE from ABPA patients, but not from sensitized individuals, a fact that can be used to differentiate between these two groups of allergic patients. Proteins from hyphae, resting and germinating conidia of A. fumigatus were compared by SDS-PAGE. Protein identification was performed using MALDI-TOF mass spectrometry. Recombinant A. fumigatus allergens were used to isolate specific monoclonal antibodies (mab) from a hybridoma bank generated against Aspergillus proteins. A hyphae-specific 23 kDa A. fumigatus protein was identified as the allergen Asp f6/manganese-dependent superoxide dismutase (MnSOD). Differential expression of MnSOD was confirmed by immunoblot using a specific mab. In contrast, Asp f8 another intracellular, but not ABPA-specific allergen, was detected in hyphae and conidia. Aspergillus fumigatus is able to colonize its environment by the formation of hyphae. Hyphae are found in the lung of ABPA patients, but not in patients suffering from atopic asthma. Our finding that Asp f6 is specifically expressed in hyphae might explain why an IgE response to Asp f6 is specific for ABPA patients.

Perioperative Evaluation der Lungenfunktion

Respiratory diseases contribute significantly to perioperative morbidity and mortality. Severe pulmonary complications usually emerge postoperatively. To minimise pulmonary risk, the perioperative evaluation of lung function is of major significance, allowing the identification of patient and surgery-related risk factors. In particular, the significance of the intraoperative assessment of lung function has gained in importance over the last few years. The following article describes the possibilities and frontiers of the perioperative assessment of lung function, and focuses especially on the significance of preoperative pulmonary function tests and the intraoperative interpretation of respiratory pressure, flow, and volume loops.

Immunity against the opportunistic fungal pathogenPneumocystis

Species of the genus Pneumocystis exist as opportunistic fungal pathogens and are associated with severe pneumonia and pulmonary complications in immunocompromised individuals. Although prophylactic therapy for Pneumocystis has significantly decreased the overall incidence of infection, more than 80% of cases in current patient populations are considered breakthrough cases. In the HIV-infected population, in the years following the initiation of highly active antiretroviral therapy (HAART), significant reductions in the incidence of Pneumocystis infection were observed, although trends over the last several years suggest that the incidence of Pneumocystis has plateaued rather than decreased. Furthermore, with the more prominent usage of immunosuppressive therapies, the frequency of Pneumocystis infection in the HIV-negative population, such as those with hematologic malignancies and those who have undergone transplantation, has risen significantly. Investigating host defense mechanisms against P. carinii has historically been problematic due to the difficulty in achieving continuous in vitro propagation of proliferating Pneumocytis organisms. Nevertheless, clinical and experimental studies have documented that host defense against Pneumocystis involves a concerted effort between innate, cell-mediated (T lymphocyte) and humoral (B lymphocyte) responses. However, the pulmonary environment is a tissue site where heightened inflammatory responses can often lead to inflammation-mediated injury, thereby contributing to the pathogenesis of Pneumocystis infection. Accordingly, clearance of Pneumocystis from the pulmonary environment is dependent on a delicate equilibrium between the inflammatory response and immune-mediated clearance of the organism. Furthermore, innate and adaptive responses against Pneumocystis are strikingly similar to those against other medically-important fungi, thus providing additional evidence that Pneumocystis exists as a fungal organism.

Anesthetic Experience in Ex Situ Resection of The Liver: A case report

Ex situ resection of the liver is an alternative surgical procedure for patients with conventionally unresectable hepatic tumors, and with contraindications to liver transplantation. We experienced a case of ex situ resection of the liver in a 40-year-old female patient suffering from sclerosing hepatocellular carcinoma. Preoperative liver function was normal. The duration of the anhepatic period was 2 hours and 55 minutes. No severe hemodynamic or pulmonary complications, and no significant metabolic or coagulatory disorders occurred. To obtain good results by ex situ resection of the liver, anesthesiologist should understand the physiology of the anhepatic period and guard against possible problems during the operation.

Severe cardiopulmonary complications consistent with systemic inflammatory response syndrome caused by leukemia cell lysis in childhood acute myelomonocytic or monocytic leukemia.

Life-threatening pulmonary complications that coincide with cell lysis during early chemotherapy and that mimic systemic inflammatory response syndrome (SIRS) have been reported in patients with acute myeloid leukemia (AML). We reviewed the records of patients with de novo AML, excluding M3 and Down syndrome, treated at our institution between 1991 and 2002 to determine the prevalence of severe SIRS with grade 3/4 pulmonary complications and to identify AML subtypes associated with severe SIRS. To examine the role of cell lysis, we compared leukocyte reduction in AML subtypes affected by severe SIRS with that in unaffected subtypes. Of 155 patients, 5 (3 with M4eo and 2 with M5) experienced severe pulmonary complications attributed to tumor lysis, met the criteria for severe SIRS, and showed no clear evidence of infection. Four required pressor support for severe hypotension. Severe SIRS was significantly more common in myelomonocytic or monocytic AML (M4/M4eo/M5) than in other subtypes (P = 0.010) and significantly more common in M4eo than in M4/M5 (P = 0.008). Among 112 cases for which information was available, leukocyte reduction was significantly greater in patients with M4/M4eo/M5 than among others during the first 4 days of chemotherapy (P = 0.015). Leukocyte reduction was significantly more rapid among patients who had severe SIRS than among others (P = 0.008). Patients with M4/M4eo/M5 AML, especially M4eo, experience life-threatening cardiopulmonary complications of tumor lysis that meet the criteria for severe SIRS. This observation may reflect more rapid cell reduction and the unique biology of this subtype.

Immunotherapy of allergic bronchopulmonary aspergillosis: a clinical and experimental approach.

Allergic bronchopulmonary aspergillosis (ABPA) is a severe allergic pulmonary complication caused by the saprophytic fungus Aspergillus fumigatus. The present review examines the pathogenesis of this disease describing in detail the role of innate and acquired immunity in the induction of sensitivity to A.fumigatus. Different approaches in developing specific immunotherapeutic treatments such as induction of anergy, regulatory cells, a switch from Th2 to Th1 type of immune response, CpG and genetic immunization and the usage of altered peptides or modified allergens are critically examined.

Feeding Management of Children with Severe Cerebral Palsy and Eating Impairment

Some children with cerebral palsy and severe feeding impairment experience pulmonary complications from aspiration and gastroesophageal reflux. This exploratory study examined whether pulmonary function would improve following one year of intervention with optimal positioning for feeding, control of gastroesophageal reflux and use of food textures that would minimize aspiration from swallowing. Two children showed a 28% and 45% improvement, respectively, in functional residual capacity. One child experienced a 37% improvement in total respiratory resistance and a 284% improvement in respiratory compliance. All children gained sufficient weight to maintain their growth trajectories but only one who was changed from oral to tube feeding due to aspiration showed catch-up growth in length. One child showed pathological gastroesophageal reflux that was controlled medically throughout the study period. Although all children experienced pulmonary illnesses during the one year of follow up, control of aspiration permitted a clinically significant improvement of their pulmonary obstructive syndrome. Further study is needed to more fully determine the effect of this treatment approach on pulmonary function.

Pancreatic Transection from Blunt Abdominal Trauma: Early versus Delayed Diagnosis and Surgical Management

Background and Aims: Pancreatic trauma is relatively uncommon, but carries high morbidity and mortality rates, especially when diagnosis is delayed or inappropriate surgery is attempted. Patient Material: The clinical course and surgical management of 14 patients with distal pancreatic transection or severe laceration with or without main pancreatic duct (MPD) injury caused by blunt abdominal trauma were analyzed in a university teaching hospital. The average age of the 14 patients (12 male, 2 female) was 28.9 years (range 5–56). Six patients had isolated pancreatic trauma, and intra-abdominal and extra-abdominal (mean 0.8) injuries associated with pancreatic transection were seen in the other 8 patients. Results: Nine patients were diagnosed and operated on within the first 24 h. Eight of them underwent transection of the gland with MPD injury; distal pancreatectomy with splenectomy was performed in 3 and without splenectomy in 2, distal pancreatogastrostomy in 1, and – due to associated duodenal laceration and/or contusion of the pancreatic head – pylorus-preserving pancreatoduodenectomy in 2. In 1 case (grade II laceration) only external drainage was necessary. All the patients with early, correctly diagnosed parenchymal and ductal injury survived. Only 1 patient required reoperation due to haemorrhage after pancreatoduodenectomy. The other 5 cases were referred elsewhere after initial treatment, and all of them underwent some kind of external drainage. Three had undetected MPD injury, and in the other 2 cases the parenchymal lesions were either underestimated or missed. All of these cases required subsequent resection (1), internal drainage due to fistula (2), or drainage of developed abscess (2). Three of them had severe septic and pulmonary complications; 1 patient with MPD injury was lost to follow-up. Conclusion: Patients requiring delayed surgical intervention after an unsuccessful period of observation or a subsequent operation due to undected MPD injury demonstrated a higher rate of pancreas-specific mortality and morbidity.