Non-pulmonary Critical Care - part 8 potx

ensues, resulting in microvascular thrombosis, impaired blood supply to various organs, and ultimately multiorgan failure. Consumption of platelets and clotting factors including fibrinogen may result in diffuse hemorrhage. 51 DIC is an acquired syndrome that arises in the setting of another underlying disorder. Disease states known to cause DIC include sepsis, severe trauma, malignancy (both solid tumor and hematological malig- nancies, particularly acute promyelocytic leukemia), obstetrical complications, vascular abnormalities such as giant hemangiomas, and severe liver failure. 51,60–62 Di- agnosis of DIC requires assessment of the underlying clinical scenario in conjunction with appropriate laboratory tests. DIC should be considered in patients with an appropriate clinical syndrome such as sepsis, malignancy, or trauma . Laboratory evaluation in DIC typically reveals a consumptive coagulopathy, as demonstrated by thrombocytopenia and prolongation of global clotting times, including the PT-INR, aPTT, and thrombin time (Table 2). Recent studies have shown that development of an abnormal, biphasic waveform in the automated aPTT coagulation assay may be an early predictor of DIC and may correlate with higher mortality. 63,64 In- creased fibrinolysis is suggested by elevated levels of FDPs and D-dimer. 51,65 Increased thrombin generation may produce diminished levels of fibrinogen, although fibrinogen values may be normal or ev en elevated as an acute-phase reactant in some cases of DIC. 66 Low plasma levels of inhibitors of coagulation such as antithrombin and protein C contribute to the diagnosis. 53–56 Plasma levels of soluble fibrin are highly sensitive in diagnosing DIC. However, they lack specificity, and a reliable assay is not widely available. 67 The subcommittee on DIC of the International Society on Thrombosis and Haemostasis has recently published a scoring system for DIC that incorporates simple and readily available laboratory tests (Table 3). 68 In patients with a condition known to be associated with DIC, a score of 5 or more is compatible with DIC. This scoring system was prospectively validated in a study of 217 critically ill medical and surgical patients admitted to the ICU with a clinical suspicion of DIC. 69 The DIC score was calculated every 48 hours. The score was found to be highly accurate in the diagnosis of DIC, with a sensitivity of 91% and a specificity of 97%. Increasing DIC score also correlated strongly with 28-day mortality. The fundamental approach to treatment of DIC is prompt identification and aggressive management of the underlying disorder. Transfusion of blood products may be required, although there are no consensus guidelines regarding their appropriate use. Transfusion should not be administered purely in response to abnormal laboratory results. A combination of platelets, FFP, and/or cryoprecipitate is indicated in the actively bleeding patient, or if the patient requires an invasive proce- dure or is at high risk for bleeding problems. 41,51,52 Although there are some experimental data suggesting an advantage to using heparin in patients with DIC, 70,71 randomized controlled trials have failed to demonstrate a beneficial effect. 72 Therapeutic doses of heparin are typically limited to patients with clinically overt thrombotic complications associated with DIC, such as acral ischemia and purpura fulminans. 51 Recently, several novel therapeutic agents that target specific elements of the coagulation system have been examined. Antithrombin (AT) is an essential inhibitor of coagulation that acts via neutralization of several enzymes in the clotting cascade, including thrombin and factor Xa. Based on the findings that AT levels are diminished in DIC 53,56 and that lowe r AT levels are associated with poorer outcomes, 53,56,73 AT concentrate has been administered to septic patients in a randomized, placebo-controlled fashion. Although initial trials indicated a mortality benefit of AT in patients with severe sepsis or septic shock, 74,75 a recent large, randomized, placebo-controlled trial of 2314 patients with severe sepsis failed to demonstrate a survival advantage. 76 Additionally, those patients who received AT in conjunction with heparin had an increased risk of hemorrhage. Another important anticoagulant mediator is tissue factor pathway inhibitor (TFPI), an endogenous inhibitor of the extrinsic, or tissue factor–based, coagulation pathway. Phase II trials with recombinant TFPI (rTFPI) showed some promise with respect to mo rtality in severe sepsis. 77,78 However, a large randomized, placebo-controlled, multicenter phase III trial by Abra- ham et al demonstrated no benefit for rTFPI in patients with severe sepsis and high INR. 79 Patients who received rTFPI had an increased risk of bleeding. Activated protein C (APC) is a serine protease with both antithrombotic and profibrinolytic properties. APC inhibits thrombin generation via inactivation of Table 2 Laboratory Markers in Disseminated Intravascular Coagulation Test Result PT/INR " aPTT " and biphasic waveform Thrombin time " Platelet count # Fibrinogen # D-dimer, FDPs, soluble fibrin " Levels of specific clotting factors (e.g., VII) # Antithrombin # Protein C # PAI-1 " PT, prothrombin time; INR, international normalized ratio; aPTT, activated partial thromboplastin time; FDPs, fibrin degradation products; PAI-1, plasminogen activator inhibitor, type 1; " , increasing; # , decreasing. 290 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006 clotting factors Va and VIIIa; it enhances fibrinolysis by inactivating PAI-1. APC also modulates anti-inflammatory and antiapoptotic pathways. 80 Low levels of protein C are predictive of a poor clinical outcome in septic patients. 54–56 Based on these findings as well as encouraging results from a phase II study, 81 Bernard et al conducted a randomized, double-blind, placebo-controlled, multicenter trial to evaluate the impact of a recombinant human APC (rhAPC), or drotrecogin alfa activated (DrotAA), on 28-day all-cause mortality in patients with severe sepsis. 82 Patients received either placebo (840 patients) or rhAPC as a continuous infusion of 24 mg/kg/h for a total of 96 hours (850 patients). The trial was stopped prematurely after the second planned interim analysis because of a statistically significant reduction in mortality in the patients who received rhAPC. In the rhAPC-treated patients, 28-day mortality was 24.7%, as compared with 30.8% in the placebo population; the reduction in relative risk of death was 19.4%. There was an increased incidence of serious bleeding in those patients treated with rhAPC compared with placebo (3.5% vs 2.0%). Subgroup analysis determined that the largest reduction in mortality occurred among APC-treated patients with more severe disease and higher risk of death, as indicated by Acute Physiology and Chronic Health Evaluation (APACHE II) scores in the third and fourth quartiles. 83 Based on these results, in Nove mber 2001 the United States FDA approved rhAPC for the treatment of adult patients with severe sepsis and a high risk of death. The FDA’s approval required an additional trial evaluating the efficacy and safety of rhAPC in patients with severe sepsis and a low likelihood of death, as defined by APACHE II scores of < 25 or single-organ failure. A randomized, double-blind, placebo-controlled trial of rhAPC in this population was recently reported by Abraham et al. 84 Enrollment was terminated early, after accrual of 2640 patients, due to the low likelihood of achieving a significant reduction in 28 day mortality with rhAPC. Twenty-eight day mortality and in-hospital mortality were the same in the rhAPC and placebo arms; serious bleeding was significantly greater in the rhAPC-treated patients. In light of these results, the use of rhAPC should be considered only in those patients with severe sepsis and a high risk of death. RECOMBINANT FACTOR VIIA In 1999, the FDA approved recombinant factor VIIa (rFVIIa) for the treatment of patients with congenital hemophilia A or B and circulating inhibitors to factors VIII or IX. Recombinant FVIIa has since been evaluated as a hemostatic agent in a growing number of off-label conditions, albeit primarily in case reports or small controlled trials. Areas of active investigation include traumatic bleeding, intracerebral hemorrhage, and coagulopathy of liver disease. Recombinant FVIIa use has also been reported in nonhemophiliacs with acquired inhibitors to various clotting factors, hereditary clotting factor deficiencies, platelet disorders, reversal of anticoagulation, surgical bleeding, and perioperative bleeding prophylaxis. 85 The typical charge for a 40 mg/kg dose of rFVIIa is approximately $4,000. Important questions remain regarding the efficacy, optimal dose, safety, and cost-effectiveness of rFVIIa in these populations. Recombinant FVIIa is a genetically engineered analogue of the naturally occurring FVII protein, a serine prote ase that becomes activated upon binding to tissue factor exposed at areas of endovascular damage. The rFVIIa-tissue factor complex leads to factor X activation, which results in the conversion of prothrombin to thrombin and, subsequently, the activation of platelets and other clotting factors. Although its precise mechanism of action remains a matter of debate, it has been proposed that rFVIIa at pharmacological doses is able to bind to activated platelets and stimulate factor X directly, in a tissue factor–independent manner. Factor Xa, in the presence of factor Va, generates a thrombin burst resulting in formation of fibrin clot localized to the site of injury. 85–87 Recombinant FVIIa has been investigated as a universal hemostatic agent in patients with uncontrol- lable bleeding due to traumatic coagulopathy. The initial case report, in 1999, described cessation of life-threatening bleeding in a gunshot victim following treatment with two doses of 60 mg/kg of rFVIIa. 88 Subsequent series of patients with uncontrolled traumatic bleeding have also reported improvements in bleeding and base- line coagulation assays, as well as decreased transfusion requirements, after administration of rFVIIa. 89–93 The doses of rFVIIa have varied widely in these studies, ranging from 36 to 218 mg/kg. Table 3 Scoring System for Overt Disseminated Intravascular Coagulation Laboratory Test Points Values Platelet count > 100¼ 0 < 100¼ 1 < 50¼ 2 Elevated fibrin-related markers (e.g., soluble fibrin, fibrin degradation products) No increase ¼ 0 Moderate increase ¼ 2 Strong increase¼ 3 Prolonged prothrombin time < 3 second ¼ 0 > 3 but < 6 second ¼ 1 > 6 second ¼ 2 Fibrinogen > 1g/L¼ 0 < 1 g/L ¼ 1 The above scoring system is for use only in patients with an underlying condition known to be associated with disseminated intravascular coagulation. A score of ! 5 is compatible with overt disseminated intravascular coagulation. Adapted from Taylor et al. 68 HEMATOLOGIC DISORDERS IN CRITICALLY I LL PATIENTS/MERCER ET AL 291 Two parallel randomized, placebo-controlled, double-blind, multicenter trials evaluating the safety and efficacy of rFVIIa as an adjunctive hemostatic agent in severely bleeding trauma patients were recently reported by Boffard et al. 94 One hundred forty-three blunt trauma patients and 134 penetrating trauma patients with severe bleeding randomly received either rFVIIa or placebo. The first dose of rFVIIa, 200 mg/kg, was administered following transfusion of the eighth unit of red blood cells (RBCs), with additional doses of 100 mg/kg delivered 1 and 3 hours later. The primary end point was RBC transfusion requirements within 48 hours of the first dose of rFVIIa. In the blunt trauma study, RBC transfusions were reduced by 2.6 units in the rFVIIa-treated patients as compared with placebo (p ¼ .02); the need for massive transfusion (> 20 RBC units) was also significantly reduced (14% vs 33% of patients, p ¼ .03). Similar trends were noted in the penetrating trauma patients, although these did not meet statistical significance. Of note, no significant differences were observed between treatment arms in either study with respect to transfusion of other blood products including platelets, FFP, and cryoprecipitate. There was no difference in the incidence of adverse events, including thromboembolic complications, between the treatment groups in either study. Although there was a trend toward improved clinical outcomes with rFVIIa, such as 30-day mortality and the development of multiple organ failure, these differences were not statistically significant. However, the study was not powered to evaluate these end points. Patients with acute intracerebral hemorrhage (ICH) are at significant risk of morbidity and mortality, due in part to hematoma expansion caused by continued bleeding or rebleeding within the first few hours after symptom onset. 95 Early intervention with rFVIIa has been evaluated in patients with ICH in an effort to arrest hematoma growth and improve outcomes in this population. Following a phase II dose-escalation safety trial, 96 Mayer et al randomly assigned 399 patients with spontaneous ICH diagnosed within 3 hours of symptom onset to placebo or rFVIIa at doses of 40, 80, or 160 mg/kg, administered within 1 hour of diagnosis. 97 The percent change in intracerebral hematoma volume at 24 hours and clinical outcomes at 90 days were measured. Patients in the placebo arm experienced a significantly greater increase in hematoma volume than those patients who received rFVIIa (29% in the placebo group vs 16, 14, and 11% in groups given 40, 80, and 160 mg/kg of rFVIIa, respectively). Mortality at 90 days was significantly improved in the three rFVIIa groups combined as compared with placebo (18% vs 29%, p ¼ .02). Serious thromboembolic adverse events, including myocardial infarction and cerebral infarction, occurred in 7% of the rFVIIa-treated patients and in 2% of patients in the placebo arm (p ¼ .12). Coagulopathy is a common cause of morbidity and mortality in patients with end-stage liver disease (ESLD). 98 Despite limited literatur e to guide therapy, rFVIIa has been used for both treatment and prophylaxis of bleeding in patients with ESLD. Recombinant FVIIa has been shown to temporarily correct a prolonged PT in nonbleeding patients with advanced cirrhosis. 99 Dura- tion of PT correction was dose dependent; the mean PT normalized for 2 hours, 6 hours, and 12 hours following rFVIIa doses of 5 mg/kg, 20 mg/kg, and 80 mg/kg, respectively. Recombinant FVIIa has also been shown to improve coagulation parameters in patients with fulminant hepatic failure. 100,101 In a retrospective study by Shami et al, patients with fulminant hepatic failure who were given rFVIIa and FFP (seven patients) were compared with those who received FFP alo ne (eight patients). 100 Those in the rFVIIa group were able to undergo placement of intracranial pressure monitors more frequently, had less anasarca, and demonstrated improved survival comp ared with those patien ts given only FFP. The efficacy and safety of rFVIIa in patients with cirrhosis and upper gastrointestinal bleeding (UGIB) was recently evaluated in a randomized, double-blind, placebo-controlled trial. 102 Two hundred forty-five cirrhotic patients with active UGIB were randomized to eight doses of rFVIIa at 100 mg/kg or placebo, in addition to standard treatment measures. Although normalization of PT occurred in the majority of patients in the rFVIIa arm, the study observed no benefit to rFVIIa in terms of the composite primary end point, which included failure to control bleeding within 24 hours of the initial dose, failure to prevent rebleeding between 24 hours and day 5, or death within 5 days. In addition, there was no treatment effect with respec t to RBC transfusion requirement, the number of elective or emergent procedures performed, the length of stay in the ICU or hospital, or in 5 or 42 day mortality rates. The incidence of adverse events, including thromboembolic events, was the same in both groups. Lastly, rFVIIa has been investigated as a prophylactic measure in patients with ESLD undergoing specific procedures such as liver biopsy as well as in liver transplantation. 103–106 In a multicenter, randomized, double- blind study, a single dose of rFVIIa, ranging from 5 to 120 mg/kg, was administered to 71 cirrhotic patients prior to laparoscopic liver biopsy. 103 The PT normalized tran- siently in most patients; a longer duration of correction was observed with higher doses. There was no correla- tion, however, between the time to bleeding cessation postprocedure and the dose of rFVIIa received. Two patients experienced thrombotic events, although the authors concluded that these were not clearly related to the administration of rFVIIa. Lodge et al conducted a multicenter, randomized, double-blind, placebo- controlled trial to evaluate the effect of rFVIIa in 292 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006 182 patients with cirrhosis undergoing orthotopic liver transplantation. 106 Although rFVIIa significantly reduced the number of patients needing RBC transfusion, there was no improvement in comparison to placebo with regard to the number of units of RBCs transfused, intraoperative blood loss, hospitalization rate, total surgery time, or the proportion of patients requiring retrans- plantation. Additionally, there was no difference in the rate of thromboembolic events between the two groups. In summary, emerging data suggest that rFVIIa may be an effective drug for control of bleeding in certain nonhemophilic populations. 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Liver Transpl 2005;11:973– 979 296 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006 Major Complications following Hematopoietic Stem Cell Transplantation Bekele Afessa, M.D. 1 and Steve G. Peters, M.D. 1 ABSTRACT Tens of thousands of patients undergo hematopoietic stem cell transplantation (HSCT) annually, 15 to 40% of whom are admitted to the intensive care unit. Pulmonary complications are the most life threatening conditions that develop in HSCT recipients. Both infectious and noninfectious complications occur more frequently in allogeneic HSCT. The management of HSCT recipients requires knowledge of their immune status, appropriate diagnostic evaluation, and early treatment. During the preengraftment phase (0 to 30 days after transplant), the most prevalent pathogens causing infection are bacteria and Candida species and, if the neutropenia persists, Aspergillus species. The early postengraftment phase (30 to 100 days) is characterized by cytomegalovirus (CMV), Pneumocystis jiroveci, and Aspergillus infections. During the late posttransplant phase (> 100 days), allogeneic HSCT recipients are at risk for CMV, community-acquired respiratory virus, and encapsulated bacterial infection s. Antigen and polymerase chain reaction assays are important for the diagnosis of CMV and Aspergillus infections. Diffuse alveolar hemorrhage (DAH) and periengraftment respiratory distress syndrome occur in both allogeneic and autologous HSCT recipients, usually during the first 30 days. Bronchiolitis obliterans occurs exclusively in allogeneic HSCT recipients with graft versus host disease. Idiopathic pneumonia syndrome occurs at any time following transplant. Bronchoscopy is usually helpful for the diagnosis of the infectious pulmonary complications and DAH. KEYWORDS: Aspergillosis, bone marrow transplantation, cytomegalovirus infection, diffuse alveolar hemorrhage, idiopathic pneumonia syndrome, periengraftment respiratory distress syndrome, pneumonia, respiratory insufficiency Tens of thousands of patients und ergo hematopoietic stem cell transplantation (HSCT) annually. 1 In allotransplantation, the 100 day mortality rate ranges between 10 and 40% and the main causes of death are graft versus host disease (GVHD), interstitial pneumo- nitis, and multiple organ failure. 1 In autotransplantation, the 100 day mortality ranges between 5 and 20% and the main cause of death is recurrence of the underlying disease. 1 As a result of life-threatening multiple organ dysfunctions, 15 to 40% of HSCT recipients receive intensive care unit support, the majority of whom require mechanical ventilation. 2–4 The mortality rate of HSCT recipients receiving invasive ventilati on used to exceed 90%. 2,5 Although more recent studies have shown improvement in outcome, the mortality rate of HSCT recipients receiving mechanical ventilation is still high. 3,6,7 297 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota. Address for correspondence and reprint requests: Bekele Afessa, M.D., Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, 200 First St., SW, Rochester, MN 55905. E-mail: Afessa.bekele@mayo.edu. Non-pulmonary Critical Care: Managing Multisystem Critical Illness; Guest Editor, Curtis N. Sessler, M.D. Semin Respir Crit Care Med 2006;27:297–309. Copyright # 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI 10.1055/s-2006-945530. ISSN 1069-3424. This review describes the major post-HSCT complications pertinent to pulmonary and critical care physicians. The management of HSCT recipients requires knowledge of their immune status, appropriate diagnostic evaluation, and early treatment. The conditioning regi- men severely depresses preexisting immunity, which recovers along predictable patterns after transplantation. 8 TIMING AND TYPES OF PULMONAR Y COMPLICATIONS Pulmonary complications, occurring in 30 to 60% of recipients, are the most common life-threatening conditions that develop following HSCT. The complications are more frequent in allogeneic recipients, especially those with GVHD. Both infectious and noninfectious pulmonary complications occur frequently (Table 1) (Fig. 1). Based on the immunosuppression status, the posttransplant period is divided into three phases: preengraftment, early posttransplant, and late posttransplant. 9 The preengraftment phase (0 to 30 days) is characterized by neutropenia and breaks in the mucocutaneous barriers as a result of conditioning regimens and frequent vascular catheterization. During this phase, the most prevalent pathogens causing infection are bacteria and Candida species and, if the neutropenia persists, Aspergillus species. During neutropenia, there is no significant difference in the type of infection between allogeneic and autologous HSCT recipients. 10 The early postengraftment phase Figure 1 Timing of the major infectious and noninfectious complications following hematopoietic stem cell transplantation. BO, bronchiolitis obliterans; DAH, diffuse alveolar hemorrhage; GVHD, graft versus host disease; IPS, idiopathic pneumonia syndrome; P edema, pulmonary edema; PERDS, periengraftment respiratory distress syndrome; PCP, Pneumocystis jiroveci pneumonia; RSV, respiratory syncytial virus. Phase I, preengraftment period; Phase II, early postengraftment period; Phase III, late postengraftment period. Table 1 Major Pulmonary Complications in Hematopoietic Stem Cell Transplant Recipients Infectious Viral Cytomegalovirus Respiratory syncytial virus Influenza B Bacterial Gram-positive Staphylococcus aureus Streptococcus pneumoniae Gram-negative Pseudomonas aeruginosa Fungal Aspergillus spp. Candida spp. Pneumocystis jiroveci Noninfectious Acute pulmonary edema Diffuse alveolar hemorrhage Periengraftment respiratory distress syndrome Bronchiolitis obliterans syndrome Bronchiolitis obliterans organizing pneumonia Idiopathic pulmonary syndrome Delayed pulmonary toxicity syndrome Pulmonary cytolytic thrombotic syndrome 298 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006 (30 to 100 days) is dominated by impaired cell-mediated immunity. The impact of this cell-mediated defect is determined by the development of GVHD and the immunosuppressant medications used to treat it. Cyto- megalovirus (CMV), Pneumocystis jiroveci, and Aspergillus species are the predominant pathogens during this phase. The late posttransplant phase (> 100 days) is characterized by defects in cell-mediated and humoral immunity as well as function of the reticuloendothelial system in allogeneic transplant recipients. During this phase, allogeneic HSCT recipients are at risk for CMV infection, varicella-zoster infection, Epstein-Barr–related lympho- proliferative disease, community-acquired respiratory virus infection, and infection by encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumoniae.In certain parts of the world, pulmonary tuberculosis occurs during the late posttransplant phase. 11,12 Noninfectious pulmonary complications also follow a characteristic time pattern. 13 Pulmonary edema, diffuse alveolar hemorrhage (DAH), and periengraftment respiratory distress syndrome (PERDS) usually occur during the first 30 days following transplant (Fig. 1). Idiopathic pneumonia syndrome (IPS) occurs at any time followi ng transplant. APPROACH TO PULMONARY COMPLICATIONS When HSCT recipients present with pulmonary infiltrates and symptoms and signs of infection, most clini- cians initiate empirical antibacterial therapy, adding antifungal therapy if risk factors are present and there is no response to initial treatment. 14 Cultures of blood, urine, and respiratory secretions should be obtained. In the appropriate clinical setting, antigen and polymerase chain reaction (PCR) assays for Aspergillus and CMV may be helpful. Pulmonary function testing (PFT) and high-resolution computed tomography (HRCT) of the chest play important roles in suggesting specific diagnosis. If tolerated, we advocate early bronc hoalveolar lavage (BAL) with or without trans bronchial lung biopsy, transthoracic fine needle aspiration, or video-assisted thoracoscopic lung biopsy because specific diagnoses may lead to appropriate treatment and avoid unnecessary and potentially harmful therapy (Fig. 2). INFECTIOUS COMPLICATIONS Viral Pneumonia Viral infections are a major cause of morbidity and mortality in HSCT recipients. CMV is th e most common viral pathogen causing lower respiratory tract infection. 15–17 Other viruses, including herpes simplex, varicella-zoster, Epstein-Barr, and human herpesvirus 6 and 8 may also cause pulmonary infections. 18 During endemic seasons, respiratory syncytial virus, adenovirus, picornavirus, influenza virus, and parainfluenza virus should be included in the differential diagnoses of respiratory symptoms in the HSCT recipient. 19,20 This section will focus on CMV. CYTOMEGALOVIRUS PNEUMONIA Epidemiology Although the frequency of CMV pneumonia in the early posttransplantation period has been substantially reduced by pro phylaxis, it continues to be a major cause of morbidity and mortality in the late posttransplant period. With early detection and prophylactic and preemptive treatment, the rate of CMV pneumonia has declined to less than 5%. 21–23 Risk factors for CMV pneumonia include older age, positive CMV serology, allogeneic graft, and GVHD. 24–28 Clinical Findings and Diagnostic Evaluation CMV infections result from primary infection or reactivation, and most occur between 6 and 12 weeks after transplant. 29,30 With the wider use of prophylactic therapy, CMV pneumonia may occur beyond 100 days after transplant. 12,31 Although rare, CMV pneumonia may develop prior to engraftment, especially in recipients with positive CMV serology. 31 The clinical manifesta- tions of CMV infection vary from completely asymptomatic to multiple organ dysfunction. HSCT recipients with CMV pneumonia typically present with fever, non- productive cough, dyspnea, and hypoxemia. 31 Plain chest radiographs and HRCT usually show subtle patchy or diffuse ground-glass opacities, often with small concurrent pulmonary nodules. 29,32,33 CMV antigen and PCR assays are used for the early detection of infection in urine, blood, and respiratory secretions. 34,35 In the appropriate clinical setting, the diagnosis of CMV pneumonia relies on the identification of CMV from the lower respiratory tract by BAL and transbronchial or surgical lung biopsy. The definitive diagnosis requires positive culture results from BAL fluid samples, and identification of the characteristic cytopathic feature of intranuclear inclusions in either BAL fluid or biopsy tissue. 36 Prevention and Treatment The transfusion of CMV seronegative blood products and leukocyte-depleted platelets, and prophylaxis and preemptive use of acyclovir, valacyclovir, valganciclovir, ganciclovir, or foscarnet have reduced the rate of CMV infection in high-risk patients. Although ganciclovir and foscarnet are effective for CMV prophylaxis, their use is limited by marrow and renal toxicities, and they are usually reserved for preemptive therapy or treatment. For the treatment of CMV disease, intravenous immunoglobulin is usually used in combination with ganciclovir or foscarnet. 37 COMPLICATIONS FOLLOWING HEMATOPOIETIC STEM CELL TRANSPLANTATION/AFESSA, PETER S 299 [...]... aspergillosis ranges between 29 and 87 %.46,47, 58 One-year survival rate is 20%.42 PNEUMOCYSTIS JIROVECI PNEUMONIA The incidence of Pneumocystis jiroveci pneumonia (PCP) in HSCT recipients has decreased sharply with trimethoprim-sulfamethoxazole (TMP-SMZ) prophylaxis In three recent studies of 2356 HSCT recipients, PCP developed in 33 (1.4%), all in patients who were not receiving TMP-SMZ prophylaxis.12,16,40... first-line therapy Amphotericin B, caspofungin, micafungin, and itraconazole are alternatives The optimal duration of antifungal therapy is unknown and depends on the extent of the infection, response to treatment, and improvement of the underlying immune deficit.51 Because spore inhalation is the usual route of Aspergillus infection, nursing of HSCT recipients in high-efficiency particulate air (HEPA )- ltered...300 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 27, NUMBER 3 2006 Figure 2 Diagnostic approach to the hematopoietic stem cell transplant recipient with pulmonary complication BAL, bronchoalveolar lavage; HRCT, high-resolution computed tomography of the chest; PFT, pulmonary function test; TBB, transbronchial lung biopsy; VATS, video-assisted thoracoscopic surgery Clinical Course/Prognosis... Fred Hutchinson Cancer center, 58% of late-onset pneumonias were diagnosed clinically without tissue or microbial documentation.40 The etiology of bacterial infection in neutropenic patients is in flux.65 Gram-negative bacteria, especially Pseudomonas aeruginosa, used to be the predominant bacterial pathogens.66 However, with the use of prophylactic antibiotics against gram-negative infection, and the... consist of air-space disease.16 Candida fungemia is responsive to early antifungal therapy and removal of foreign objects such as central lines Fluconazole prophylaxis will prevent invasive disease due to susceptible Candida spp.52 BACTERIAL PNEUMONIA Epidemiology Bacterial infections are common during the neutropenic period However, because most of 301 302 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME... without transbronchial lung biopsy.17,61,62 The drug of choice for both the prevention and the treatment of PCP is TMP-SMZ For patients who do not tolerate TMP-SMZ, dapsone, aerosolized pentamidine, and atovaquone are alternatives for prophylaxis, although they are not as effective as TMP-SMZ.52 PULMONARY CANDIDIASIS Candida infections, especially of the bloodstream, are common during the neutropenic... prevent infection with encapsulated 2006 organisms in allogeneic recipients with chronic GVHD The 23-valent pneumococcal polysaccharide vaccine should be administered at 12 to 24 months after transplant.66 NON-INFECTIOUS PULMONARY COMPLICATIONS Pulmonary Edema Although pulmonary edema has been described as part of the capillary leak syndrome, it usually results from large volumes of fluid and blood products... mortality rate associated with untreated CMV pneumonia may exceed 90%.25 Although the prognosis has improved as a result of effective prophylactic and preemptive treatment in high-risk patients, mortality still exceeds 50%.25, 38, 39 Fungal Pneumonia With improved prevention and treatment of other infections, invasive fungi have become the leading infectious cause of morbidity and mortality in HSCT recipients.40... aspergillosis are nonspecific and include fever, cough, sputum production, and pleuritic chest pain.47, 48 Hemoptysis is uncommon The radiographic findings of pulmonary aspergillosis include nodules, diffuse infiltrates, and cavitations.33,49 The ‘‘halo sign’’ consists of a nodule surrounded by ground-glass attenuation and is seen most often in neutropenic patients Cavitation is a late finding The ‘‘hypodense... methicillin-resistant Staphylococcus aureus Because bacteria are carried on the hands, appropriate hand washing should be practiced by all individuals in contact with HSCT recipients.52 The data are insufficient to recommend routine use of gut decontamination and systemic antibiotics for afebrile, asymptomatic patients However, some advocate using fluoroquinolone prophylaxis to reduce infection by gram-negative . Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, 200 First St., SW, Rochester, MN 55905. E-mail: Afessa.bekele@mayo.edu. Non-pulmonary Critical Care: Managing Multisystem Critical. 1996 ;88 :88 1 88 6 54. Mesters RM, Helterbrand J, Utterback BG, et al. Prognostic value of protein C concentrations in neutropenic patients at high risk of severe septic complications. Crit Care. the intensive care unit. Chest 1993; 104:1243–1247 4. Vanderschueren S, De WA, Malbrain M, et al. Thrombo- cytopenia and prognosis in intensive care. Crit Care Med 2000; 28: 187 1– 187 6 5. Stephan

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