Although initial trials indicated a mortality benefit of AT in patients with severe sepsis or septic shock,74,75a recent large, randomized, placebo-controlled trial of 2314 patients with
Trang 1ensues, 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),
ob-stetrical 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
labo-ratory tests DIC should be considered in patients with
an appropriate clinical syndrome such as sepsis,
malig-nancy, 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.51,65Increased thrombin generation
may produce diminished levels of fibrinogen, although
fibrinogen values may be normal or even elevated as an
acute-phase reactant in some cases of DIC.66 Low
plasma levels of inhibitors of coagulation such as
antith-rombin 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
guide-lines 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
bleed-ing 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 throm-botic 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 DIC53,56 and that lower
AT levels are associated with poorer outcomes,53,56,73
AT concentrate has been administered to septic pa-tients in a randomized, placebo-controlled fashion Although initial trials indicated a mortality benefit of
AT in patients with severe sepsis or septic shock,74,75a 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 in-creased risk of hemorrhage
Another important anticoagulant mediator is tis-sue factor pathway inhibitor (TFPI), an endogenous inhibitor of the extrinsic, or tissue factor–based, coagu-lation pathway Phase II trials with recombinant TFPI (rTFPI) showed some promise with respect to mortality
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.79Patients 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
D-dimer, FDPs, soluble fibrin "
Levels of specific clotting factors (e.g., VII)
#
PT, prothrombin time; INR, international normalized ratio; aPTT, activated partial thromboplastin time; FDPs, fibrin degradation prod-ucts; PAI-1, plasminogen activator inhibitor, type 1; " , increasing; # , decreasing.
Trang 2clotting factors Va and VIIIa; it enhances fibrinolysis by
inactivating PAI-1 APC also modulates
anti-inflam-matory 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,81Bernard et al
conducted a randomized, double-blind,
placebo-con-trolled, 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.82Patients 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
statisti-cally 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
anal-ysis 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.83Based on
these results, in November 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.84Enrollment 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 coa-gulopathy 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 anti-coagulation, surgical bleeding, and perioperative bleeding prophylaxis.85The typical charge for a 40mg/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 protease 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 prothrom-bin to thromprothrom-bin 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-threat-ening 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.89–93The doses of rFVIIa have varied widely in these studies, ranging from 36 to 218mg/kg
Table 3 Scoring System for Overt Disseminated
Intravascular Coagulation
< 100 ¼ 1
< 50 ¼ 2 Elevated fibrin-related markers
(e.g., soluble fibrin, fibrin
degradation products)
No increase ¼ 0 Moderate increase ¼ 2 Strong increase ¼ 3 Prolonged prothrombin time < 3 second ¼ 0
> 3 but < 6 second ¼ 1
> 6 second ¼ 2
< 1 g/L ¼ 1 The above scoring system is for use only in patients with an
under-lying condition known to be associated with disseminated
intra-vascular coagulation.
A score of 5 is compatible with overt disseminated intravascular
coagulation.
Adapted from Taylor et al 68
HEMATOLOGIC DISORDERSINCRITICALLY ILL PATIENTS/MERCER ET AL 291
Trang 3Two 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
re-ported by Boffard et al.94One 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,
be-tween the treatment groups in either study Although
there was a trend toward improved clinical outcomes
with rFVIIa, such as 30-day mortality and the
develop-ment 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
pop-ulation 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
diag-nosis.97The 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
160mg/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,
in-cluding 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 literature 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 correcDura-tion 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.100,101In 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 alone (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 compared with those patients 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.102Two hundred forty-five cir-rhotic 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 respect 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 prophy-lactic measure in patients with ESLD undergoing specific procedures such as liver biopsy as well as in liver trans-plantation.103–106In a multicenter, randomized, double-blind study, a single dose of rFVIIa, ranging from 5 to
120mg/kg, was administered to 71 cirrhotic patients prior
to laparoscopic liver biopsy.103The 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
Trang 4182 patients with cirrhosis undergoing orthotopic liver
transplantation.106 Although rFVIIa significantly
re-duced 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
sur-gery 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 At present, there is
insuffi-cient information to recommend the use of rFVIIa in
many off-label scenarios, particularly in light of concerns
regarding its cost and unclear risk:benefit ratio Further
randomized data are needed to clarify the efficacy, safety,
and cost-effectiveness of rFVIIa in a variety of clinical
settings
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Trang 8Major Complications following
Hematopoietic Stem Cell Transplantation
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 infections 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 undergo
hemato-poietic stem cell transplantation (HSCT) annually.1In
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.1In autotransplantation,
the 100 day mortality ranges between 5 and 20% and the
main cause of death is recurrence of the underlying
disease.1As 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.2–4The mortality rate of HSCT recipients receiving invasive ventilation used to exceed 90%.2,5 Although more recent studies have shown im-provement in outcome, the mortality rate of HSCT re-cipients 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.
Trang 9This review describes the major post-HSCT
complica-tions 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 PULMONARY
COMPLICATIONS
Pulmonary complications, occurring in 30 to 60% of
recipients, are the most common life-threatening
con-ditions 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:
preen-graftment, 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
Trang 10(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
character-ized by defects in cell-mediated and humoral immunity as
well as function of the reticuloendothelial system in
allogeneic transplant recipients During this phase,
allo-geneic HSCT recipients are at risk for CMV infection,
varicella-zoster infection, Epstein-Barr–related
lympho-proliferative disease, community-acquired respiratory
vi-rus 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
fol-low a characteristic time pattern.13 Pulmonary edema,
diffuse alveolar hemorrhage (DAH), and
periengraft-ment respiratory distress syndrome (PERDS) usually
occur during the first 30 days following transplant
(Fig 1) Idiopathic pneumonia syndrome (IPS) occurs
at any time following transplant
APPROACH TO PULMONARY
COMPLICATIONS
When HSCT recipients present with pulmonary
infil-trates 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.14Cultures 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
diag-nosis If tolerated, we advocate early bronchoalveolar
lavage (BAL) with or without transbronchial lung
bi-opsy, transthoracic fine needle aspiration, or
video-as-sisted 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 the most
com-mon viral pathogen causing lower respiratory tract
in-fection.15–17 Other viruses, including herpes simplex,
varicella-zoster, Epstein-Barr, and human herpesvirus
6 and 8 may also cause pulmonary infections.18During
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 prophylaxis, it continues to
be a major cause of morbidity and mortality in the late posttransplant period With early detection and prophy-lactic 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 trans-plant.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 asympto-matic 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.29,32,33CMV antigen and PCR assays are used for the early detection
of infection in urine, blood, and respiratory secre-tions.34,35 In the appropriate clinical setting, the diag-nosis 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 pla-telets, 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 pre-emptive 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, PETERS 299