Dornase Research Articles

A pulmonary exacerbation risk score among cystic fibrosis patients not receiving recommended care

Pulmonary exacerbations (PEx) lead to substantial morbidity in cystic fibrosis (CF), and guidelines recommend chronic medication including dornase alfa and inhaled tobramycin. However PEx risk and medication use vary across patients. To develop a PEx risk score among CF patients not receiving guideline-recommended chronic respiratory medications. A cohort of patients with FEV1%-predicted between 25% and 75% without evidence of dornase alfa or inhaled tobramycin use in an index year, despite meeting guideline recommended criteria, was identified from the CF Foundation Patient Registry (2002-2008). This sample was randomly split into 2/3 for a development sample and 1/3 for a validation sample. A multivariable risk score was developed to predict PEx requiring hospitalization or home IV treatment using available patient characteristics. Its predictive performance was assessed in the validation sample. Among 3,069 patient-years, 1,275 (42%) had PEx in the subsequent year. The risk score included, in order of decreasing impact on PEx risk, prior PEx, Pseudomonas aeruginosa, allergic bronchopulmonary aspergillosis, depression, methicillin-resistant Staphylococcus aureus, CF-related diabetes, Burkholderia cepacia, prior use of dornase alfa, bronchodilator use, prior use of inhaled tobramycin and lower FEV1%-predicted. Stratifying patients by risk score in the validation sample identified actual risks ranging from 14% in the lowest decile to 90% in the highest. The c-statistic was 0.8. A PEx risk score for CF patients not receiving guideline-recommended chronic therapies was developed and validated, and identified patients with a wide range of risk. This score could identify high-risk patients in whom chronic therapies should be initiated or continued.

The Structure of Human DNase I Bound to Magnesium and Phosphate Ions Points to a Catalytic Mechanism Common to Members of the DNase I-like Superfamily

Recombinant human DNase I (Pulmozyme, dornase alfa) is used for the treatment of cystic fibrosis where it improves lung function and reduces the number of exacerbations. The physiological mechanism of action is thought to involve the reduction of the viscoelasticity of cystic fibrosis sputum by hydrolyzing high concentrations of DNA into low-molecular mass fragments. Here we describe the 1.95 Å resolution crystal structure of recombinant human DNase I (rhDNase I) in complex with magnesium and phosphate ions, both bound in the active site. Complementary mutagenesis data of rhDNase I coupled to a comprehensive structural analysis of the DNase I-like superfamily argue for the key catalytic role of Asn7, which is invariant among mammalian DNase I enzymes and members of this superfamily, through stabilization of the magnesium ion coordination sphere. Overall, our combined structural and mutagenesis data suggest the occurrence of a magnesium-assisted pentavalent phosphate transition state in human DNase I during catalysis, where Asp168 may play a key role as a general catalytic base.

A MUCOLYTIC WITH ANTIINFLAMMATORY QUALITIES FOR CHILDREN SUFFERED FROM CYSTIC FIBROSIS: DORNASE ALFA

научный биометрический журнал, который знакомит читателя с клиническими рекомендациями и особенностями применения лекарственных и вакцинных средств у детей, предоставляет исчерпывающую информацию о воздействии лекарственных средств на плод, о проводимых в

Dornase alfa (Pulmozyme)

Dornase alfa (Pulmozyme) is one of the most commonly used medications to treat the lung disease of cystic fibrosis (CF). As other respiratory medications have entered the clinical market, understanding the proper use and indication for dornase alfa is increasingly important. In addition, dornase alfa is being used to treat other medical conditions. This review covers recent publications and expanding indications. Understanding dornase alfa's mechanism of action and impact on the pathophysiology of CF leads to an improved understanding of optimal therapy, ways to improve adherence and use with other medications. Most importantly, routine use of dornase alfa is associated with improved lung function and survival in patients with CF. Outside of CF, potential uses include treating patients with empyema or on mechanical ventilation. Dornase alfa has been available for clinical use for nearly 20 years and is one of the most commonly used medications in patients with CF. Routine use is associated with a reduced rate of pulmonary deterioration and improved survival. Recent clinical reports suggest that dornase alfa may have clinical value with other medical problems such as complicated pneumonia and mechanically ventilated patients with atelectasis.

PRM139 Including Patients in Multiple Groups and Multiple Times in the Same Group in Longitudinal Observational Research: A Cystic Fibrosis Example

In longitudinal observational studies, patients can meet eligibility criteria for more than one group and can be eligible multiple times for the same group. We used Epidemiologic Study of Cystic Fibrosis data to explore different inclusion decisions when evaluating dornase alfa treatment. The dornase alfa group included patients enrolled ≥2 years before starting consistent dornase alfa therapy. A lung function test (“index”) separated a 2-year pre-index period from a 2-year post-index period for which intercepts and slopes were independently estimated. The comparator group included patients not yet reported to have received dornase alfa; their index lung function test was associated with their eighth or subsequent even-numbered birthday. Comparator patients could contribute more than one set of pre- and post-index periods and could also subsequently be included in the dornase alfa group. To account for the repeated use of patients, variance components were estimated at the patient level as well as the case level. Different subsets of the comparator cases were analyzed. There were 2230 dornase alfa patients; the comparator group included 5970 cases from 3517 patients. The estimated difference in change in slope was 0.73±.31 (P=0.020). Subsetting comparators to 4985 cases from 2836 patients not also in the dornase alfa group gave 0.61±0.32 (P=0.058); including each of those patients only the last time eligible gave 0.68±0.36 (P=0.059). Subsetting to 3662 cases from 2030 patients never on dornase alfa gave 0.32±0.34 (P=0.35). Patient-level variance components corresponding to difference in slope and difference in intercept were near zero and so were dropped. In longitudinal observational studies, patients should be included in each group for which they meet eligibility criteria, possibly multiple times (with appropriate covariance structures). This avoids bias from using future information to decide whether to include a patient and loss of power from limiting cases unnecessarily.

Increased adherence to CFF practice guidelines for pulmonary medications correlates with improved FEV1

CFF practice guidelines recommend patients ≥age 6 use dornase alfa and hypertonic saline daily, and those ≥age 6 colonized with Pseudomonas aeruginosa use inhaled tobramycin and oral azithromycin to improve lung function and reduce pulmonary exacerbations. A decline in FEV1 was noted in our 2008 CF Center Report. We hypothesized that increasing adherence to prescribing guidelines for these pulmonary medications would improve mean FEV1. This was a quality improvement project completed at a US CF center. CFF practice guidelines were reviewed with the center physicians. Patients were identified that were eligible to receive recommended therapies and it was determined whether they were prescribed the therapies. Baseline FEV1 data was collected. Adherence rates and FEV1 were followed quarterly for 1 year. Providers received a quarterly report card with adherence rates, mean FEV1 compared to colleagues, and a list of eligible patients that were not prescribed recommended therapies. Ninety-two patients were included. At baseline, the overall adherence rate was 59%. Overall adherence increased quarterly (P = < 0.001). Each quarter there was improvement in adherence to prescribing for each medication (P < 0.001). Except in quarter 1, FEV1 increased quarterly (P = 0.092). There was moderate correlation (r = 0.533) between improved adherence and improved FEV1. Educating clinicians about guidelines, providing feedback on adherence to guidelines, and monitoring prescribing patterns improves prescribing adherence. FEV1 showed improvement after months of sustained adherence, trending towards significance. Longer follow-up is necessary to determine if improved prescribing adherence translates into improved FEV1 or slows rate of decline in FEV1.

Management of Plastic Bronchitis With Topical Tissue-type Plasminogen Activator

Plastic bronchitis or cast bronchitis is a rare disease of unclear etiology characterized by formation of airway casts that can lead to life-threatening airway obstruction. There is currently limited data regarding optimal treatment of plastic bronchitis. Several therapies have been suggested, but recurrences are common and mortality remains high. We report the case of a 6-year-old boy with refractory eosinophilic bronchial casts, unresponsive to low-dose systemic corticosteroids, inhaled corticosteroids, azithromycin, and dornase alfa, who was treated successfully and safely with direct instillation of tissue-type plasminogen activator (tPA) to the obstructing casts during flexible bronchoscopy and inhaled tPA. Our case illustrates that the current therapy for plastic bronchitis remains inadequate. To our knowledge, this case is the first to show that direct instillation of tPA can be used safely for treatment of this disease. The use of tPA via direct administration into the airways during bronchoscopy and via a nebulizer appeared to be a safe and effective therapy for plastic bronchitis and should be considered early in the course of the disease to prevent complications of severe airway obstruction.

Systematic Review to Improve FESS Outcomes in Cystic Fibrosis Patients

Objective: 1) Review the literature for intraoperative techniques and postoperative practices after functional endoscopy sinus surgery (FESS) that may improve outcomes in patients with cystic fibrosis (CF). Method: A systematic review of the literature was performed. PubMed was searched from 1970-2011 using the terms “sinus surgery” and “cystic fibrosis” with papers limited to English. Abstracts were reviewed to identify relevant original and review manuscripts. Bibliographies of review articles were examined to identify additional manuscripts. Results: The initial PubMed search identified 183 articles. After reviewing the abstracts, selected studies were examined in detail and the bibliographies of review articles checked to identify any additional articles. Intraoperative techniques included medial maxillectomy, image guidance, and intraoperative antibiotic irrigation. Postoperative management included nasal saline irrigation, dornase alfa inhalation, and serial antibiotic lavage. Most studies were limited to case reviews with relatively small numbers of patients. Very few randomized controlled studies were identified. Conclusion: Despite the prevalence of recurrent sinonasal disease after FESS in CF patients, sparse Level I data exists to support perioperative techniques that improve outcomes in this population. Most recommendations are based on small case series. Multicenter studies to evaluate perioperative strategies that improve FESS outcomes in CF patients are warranted.

Successful use of bronchoscopic lung insufflation to treat left lung atelectasis

We report first use of bronchoscopic lung insufflation in a child to treat acute left lung collapse. The patient is a 6-year old male asthmatic who was hospitalized with a 2-day history of cough, chest pain, and abdominal pain. He was tachypneic and hypoxemic on room air. Chest exam revealed diminished breath sounds on the left side. Chest X-ray and Chest CT showed complete left lung collapse. He underwent bronchoscopic lung insufflation procedure by injecting total of 200 ml air via flexible bronchoscope in the left upper lobe using 50cc syringe aliquots followed by similar injection of 200 ml of air in left lower lobe. After air insufflations, 6 ml of bovine surfactant (calfactant) were instilled in each lobe. Chest fluoroscopy was done immediately after procedure and showed expansion of entire left lung with no pneumothorax. The procedure was well tolerated. The patient's symptoms and hypoxemia resolved soon after procedure. However, left lower lobe atelectasis recurred next day and persisted for 6 days despite treatments with chest physical therapy, systemic steroids, oral azithromycin, nebulized dornase alpha, and endoscopic removal of secretions from left lower lobe. Bronchoscopic insufflation of left lower lobe was repeated resulting in immediate expansion of that lobe as demonstrated by intraoperative fluoroscopy. The patient was discharged home next day. This case suggests that brochoscopic lung insufflation can be safe and effective in treating acute lung collapse and in treating atelectasis which is refractory to conventional therapy.

CLINICAL CHARACTERISTICS OF RESPIRATORY INVOLVEMENT IN CHILDREN WITH CYSTIC FIBROSIS IN THE CHUVASH REPUBLIC

Cystic fibrosis is a common hereditary disease, characterized by multiple organ dysfunction, including early and severe involvement of respiratory system. The disease is caused by CFTR (cystic fibrosis transmembrane conductance regulator) gene mutation. Respiratory tract involvement is a main factor, predicting outcome, mortality, life quality and morbidity of patients. Genetic examination of Chuvash children demonstrated, that 53,5% of patients’ chromosomes are carriers of E92K mutation. According to genetic epidemiology of cystic fibrosis, Chuvash ethnic group is unique, as the prevalence of mutation E92K in it is almost twice higher than the most common and «severe» mutation in the world — F508del. The significant predominance of E92K determined the clinical presentation of cystic fibrosis in the examined group, because this mutation refers as «mild». The critical moment in treatment of this disorder is influence on sputum viscosity. Dornase alpha proved itself as an effective drug, which advantages among other agents, improving sputum rheological properties, are caused not only by unique mucolytic effect, but also anti-inflammatory and antibacterial actions.

Recurrent lobar atelectasis in a child with cystic fibrosis

Cystic fibrosis pulmonary exacerbations in children usually manifest with increased cough and a fall in lung function. We report a challenging case where an 8-year-old girl has had frequent prolonged exacerbations over the last 3 years needing aggressive management, associated with multi-lobar collapse. She was born at term and presented with meconium ileus needing bowel resection and stoma formation which was reversed during first year of life. Cystic fibrosis was diagnosed on sweat testing, with a ΔF508 homozygous genotype. She has a younger brother aged 5 years, who also has cystic fibrosis. She was admitted as an infant with respiratory syncytial virus bronchiolitis at 7 months of age, requiring CPAP for few days. She was later admitted at 15 months of age with a pulmonary exacerbation, and a chest X-Ray showed left lower lobe collapse. Pseudomonas aeruginosa was isolated for the first time from bronchoalveolar lavage and she was treated with intravenous and nebulized antibiotics; she had a normal chest X-ray few weeks later. Nebulized dornase alpha (DNase) was started at 3 years of age and a gastrostomy inserted at age 6. A port-a-cath was inserted at age 7. Over the last 3 years she has had 2 to 3 pulmonary exacerbations per year requiring prolonged hospital admissions for up to 3 weeks. During these admissions she is treated with intravenous antibiotics, intensive physiotherapy, up to 4 times per day of nebulised hypertonic saline and twice daily DNase. In 2011 she had 5 hospital admissions for pulmonary exacerbations. Pulmonary exacerbations are preceded by trivial viral upper respiratory tract infection followed a few days later by acute onset of tachypnoea, dyspnoea and profound hypoxemia (oxygen saturations of 80–82% on admission). The chest X-ray shows lobar collapse with the left lower lobe most frequently involved as well as involvement of other lobes. Our approach is to treat her with humidified high flow oxygen, intravenous antibiotics, intensive physiotherapy and at least one early therapeutic bronchoscopy to re-inflate the collapsed lobe. Bronchoscopy is usually performed on the first or second day of admission and reveals very thick tenacious mucus, which is difficult to clear. We instill DNase during the procedure, and on some occasions she has chest physiotherapy under general anesthesia. Large mucus plugs can be removed, sometimes as bronchial casts. We believe that early bronchoscopy results in clinical and radiological improvement and she can be discharged home after 2 weeks with no respiratory distress and normal oxygen saturations (Figure 1). Open in a separate window Figure 1 Serial chest X-rays in a typical pulmonary exacerbation. a) X-ray on day of admission showing left, right lower & middle lobe collapse; b) X-ray 36 hr post bronchoscopy showing good inflation of right lung; c) X-ray 6 weeks later showing no lobar collapse

Ivacaftor, vismodegib, and ingenol mebutate

Ivacaftor, vismodegib, and ingenol mebutate

DORNASE ALFA IN RUSSIA: 15 YEARS LATER. EFFICACY OF THE DRUG IN THE BASIC TREATMENT IN CHILDREN WITH CYSTIC FIBROSIS

The 15-years practice of Pulmozyme (dornase alfa) usage showed its high efficacy and safety in cystic fibrosis treatment in children of various age, including infants. The efficacy of the drug is associate with clinical effects: strong mucolytic, anti-inflammatory and antibacterial effects. The appropriateness of including this into the complex of the basic therapy of cystic fibrosis in order to prevent and treat chronic bronchitis and chronic polypous pansinusitis as soon as the disease is diagnosed was confirmed in studies. Regular use of this drug results in relapse rate decrease, remission periods prolongation and maintenance of external respiration at stable level, which enable patients to live active life. The therapeutic effect of dornase alfa depends on strict compliance to directions of its usage, as this agent is a proteolytic enzyme.

Dornase Alpha Compared to Hypertonic Saline for Lung Atelectasis in Critically Ill Patients

Despite the lack of randomized trials, nebulized Dornase alpha and hypertonic saline are used empirically to treat atelectasis in mechanically ventilated patients. Our objective was to determine the clinical and radiological efficacy of these medications as an adjunct to standard therapy in critically ill patients. Mechanically ventilated patients with new onset (<48 h) lobar or multilobar atelectasis were randomized into three groups: nebulized Dornase alpha, hypertonic (7%) saline or normal saline every 12 h. All patients received standard therapy, including chest percussion therapy, kinetic therapy, and bronchodilators. The primary endpoint was the change in the daily chest X-ray atelectasis score. A total of 33 patients met the inclusion criteria and were randomized equally into the three groups. Patients in the Dornase alpha group showed a reduction of 2.18±1.33 points in the CXR score from baseline to day 7, whereas patients in the normal saline group had a reduction of 1.00±1.79 points, and patients in the hypertonic saline group showed a score reduction of 1.09±1.51 points. Pairwise comparison of the mean change of the CXR score showed no statistical difference between hypertonic saline, normal saline, and dornase alpha. Airway pressures as well as oxygenation, expressed as PaO(2)/F(I)O(2) and time to extubation also were similar among groups. During the study period the rate of extubation was 54% (6/11), 45% (5/11), and 63% (7/11) in the normal saline, hypertonic saline, and Dornase alpha groups, respectively (p=0.09). No treatment related complications were observed. There was no significant improvement in the chest X-ray atelectasis score in mechanically ventilated patients with new onset atelectasis who were nebulized with Dornase alpha twice a day. Hypertonic saline was no more effective than normal saline in this population. Larger randomized control trials are needed to confirm our results.

Safety of recombinant human deoxyribonuclease as a rescue treatment for persistent atelectasis in newborns

BACKGROUND AND OBJECTIVEPulmonary problems are vitally important in newborns. Increased intense and mucoid secretions may lead to atelectasis, pulmonary infections, respiratory distress, prolonged mechanical ventilation or even death. The aim of this study was to evaluate the safety of recombinant human deoxyribonuclease (rhDNase) in the management of persistent atelectasis in term and preterm newborns, unresponsive to the conventional treatment.DESIGN AND SETTINGProspective study of patients admitted to a general community setting of a neonatal intensive care unit between December 2007 and December 2009.PATIENTS AND METHODSThe study included 22 patients (12 premature and 10 term) who were admitted to the neonatal intensive care unit because of respiratory distress and developed atelectasis, and were unresponsive to conventional treatment. Nebulized rhDNase was administered to all patients at a dose of 1 mg/m2 twice daily for 3 days. In patients who did not respond to 3 days of treatment, endotracheal rhDNase was administered at a dose of 1 mg/m2. We assessed the clinical (respiratory rate and oxygen requirement) and radiologic responses (chest radiographic score), recurrence of atelectasis, the need for a repetitive treatment, and mortality rate.RESULTSA clinical and radiologic improvement of atelectasis was observed in 18 of 22 patients following 3 days of nebulized rhDNase treatment. Atelectasis relapsed in 4 patients. Following the administration of combined endotracheal and nebulized rhDNase treatment, an improvement of atelectasis was noted in all four recurrent cases. No adverse events were observed in patients because of the rhDNase treatment.CONCLUSIONSrhDNase treatment is a safe option and may be used as an effective method for the management of persistent atelectasis in newborns, which is resistant to other conventional treatment methods.

Resource Use, Costs, and Utility Estimates for Patients with Cystic Fibrosis with Mild Impairment in Lung Function: Analysis of Data Collected Alongside a 48-Week Multicenter Clinical Trial

ObjectivesTransport of ions to generate epithelial rehydration (TIGER)-1 was a randomized trial conducted to evaluate the safety and efficacy of denufosol versus placebo in patients with cystic fibrosis with mild impairment in lung function. The trial met its primary end point at 24 weeks, but a subsequent trial did not show a sustained effect of denufosol at 48 weeks. By using the 48-week data, we characterized resource use, direct medical costs, indirect costs, and utility estimates. MethodsData on medications, outpatient and emergency visits, hospital admissions, tests, procedures, and home nursing were captured on study case report forms. Sources for unit costs included the Medicare Physician Fee Schedule, the Nationwide Inpatient Sample, and the Red Book. Health utilities were derived from the Health Utilities Index Mark 2/3. We used multivariable regression to evaluate the impact of baseline covariates on costs. ResultsCharacteristics of the 352 participants at enrollment included mean age of 14.6 years, history of Pseudomonas aeruginosa colonization in 45.2%, use of dornase alfa in 77.0%, and long-term use of inhaled antibiotics in 37.2%. Over 48 weeks, 22.4% of participants were hospitalized and, on average, participants missed 7.4 days of school or work. Mean total costs (excluding denufosol) were $39,673 (SD $26,842), of which 85% were attributable to medications. Female sex and P. aeruginosa colonization were independently associated with higher costs. ConclusionsProspective economic data collection alongside a clinical trial allows for robust estimates of cost of illness. The mean annual cost of care for patients with cystic fibrosis with mild impairment in lung function exceeds $43,000 and is driven by medication costs.

Adherence to the 2007 cystic fibrosis pulmonary guidelines: A national survey of CF care centers

To examine cystic fibrosis (CF) physician adherence to the 2007 CF Foundation (CFF) Pulmonary Guidelines for Chronic Medications. Specifically adherence and barriers to prescribing level A medication recommendations (i.e., inhaled tobramycin and dornase alfa) and level B medication recommendations (i.e., macrolide antibiotics and hypertonic saline) were studied. During Spring 2010, the CFF emailed survey invitations to directors of 136 accredited CF care centers treating 50+ CF patients. Directors were asked to forward the invitations to their physician colleagues. One hundred thirty-three surveys were included in the analyses, representing 92 centers. Barriers were conceptualized based on Cabana et al.'s framework for adherence to guidelines. Adherence was assessed via a case vignette. Logistic regression analysis revealed that higher outcome expectancy (OR = 1.099, CI 1.010-1.196) and fewer environmental/system barriers (OR = 1.484, CI 1.158-1.902) were significantly associated with Vignette Adherence. A trend for an association between Familiarity and Vignette Adherence (OR = 1.642, CI 0.953-2.828) was evident, while no demographic variables were significantly associated with Vignette Adherence. Targeting outcome expectancy and external barriers with multifaceted, ongoing interventions may improve guideline adherence. Pulmonologists are clearly looking for empirical evidence that these medications benefit their patients over the long-term and offset patient treatment burden with improved health.

Mannitol Dry Powder for Inhalation

Mannitol dry powder for inhalation has been developed for the treatment of patients with cystic fibrosis. Two randomized, double-blind, multinational, 26-week, phase III trials (CF-301 and CF-302) examined the efficacy of inhaled dry powder mannitol in patients aged ≥ 6 years with cystic fibrosis who were receiving standard care (with a substantial proportion of patients receiving dornase alfa and antibacterials at baseline). Good compliance was seen in both studies. A sustained, significant (p<0.001) improvement in forced expiratory volume in 1 second (FEV(1)) [mean absolute change from baseline over 26 weeks; primary endpoint] was seen in patients with cystic fibrosis who received inhaled mannitol, compared with the control group, in the CF-301 trial, but not in the CF-302 trial (p=0.059). In both CF-301 and CF-302, the relative increase from baseline in percent predicted FEV(1) and the improvement from baseline in forced vital capacity were significantly greater in patients receiving inhaled mannitol than in the control group. In a pooled analysis of the CF-301 and CF-302 trials, the relative risk of a pulmonary exacerbation requiring intravenous antibacterials was significantly reduced by 29% for inhaled mannitol recipients versus the control group (relative risk 0.71; 95% CI 0.51, 0.98) [p=0.039]. Inhaled dry powder mannitol was generally well tolerated in adults with cystic fibrosis in the CF-301 and CF-302 studies, with most treatment-emergent adverse events being of mild to moderate severity.

Survival trends of cystic fibrosis patients in Moscow and Moscow region in 1992–2001 and 2002–2011

Summary. The aim of this study was to evaluate changes in survival of patients with cystic fibrosis (CF) in Moscow and Moscow region and to determine factors influencing the survival. We analyzed outpatient medical records of patients followed-up in Moscow CF centers by the 1st of January, 2002, and by the 1st of January, 2012. Median survival for 2002–2012 was 37.2 years; this was significantly higher that the similar value for the previous decade (25.9 years). A total number of CF patients was more than doubled due to increased survival and improved diagnosis of the disease. Improved survival was due to improved work of CF centers and to implementation of effective medications, primarily dornase alfa (Pulmozyme) and some inhaled and systemic antibiotics and macrolides in subinhibitory concentrations, in routine clinical practice. Gram-negative infection, especially Burkholderia cepacia, was shown to decrease survival in CF patients in contrary to mild mutations that are better prognostic factors.

Nonpharmacologic Treatment of Chronic Graft-versus-Host Disease in Children and Adolescents

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many children with life-threatening diseases. One of the most significant long-term complications of transplantation is chronic graft-versus-host disease (cGVHD). Although the rates of cGVHD after HSCT are lower in the pediatric population than in adults, cGVHD remains a significant cause of morbidity and mortality. Medicines used to prevent and treat cGVHD remain unsatisfactory, with protracted use of immune suppression necessary and high rates of first-line treatment failure. Efforts to improve salvage treatment are urgently required. Nonpharmacologic strategies attempt to modulate the cellular inflammation response and possibly allow reduction or cessation of immunosuppressive drugs. Mesenchymal stromal cells (MSC) have been shown invitro to mediate a wide variety of immune responses. MSC have been used in the prophylaxis of acute GVHD (aGVHD) and for the treatment of established steroid refractory aGVHD and, more recently, in the management of cGVHD. Extracorporeal photochemotherapy (ECP) has shown promising efficacy in graft-versus-host disease, and may allow a significant reduction in the use of systemic steroids and other immunosuppressants, reducing long-term morbidity and mortality. The accumulated experience shows ECP to be well tolerated, with no clinically significant side effects.