Page 1281 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

888 PART 7: Hematologic and Oncologic Disorders

to >10 years with a median onset of approximately 1 year post-HSCT. studied. It affects 5% to 20% of HSCT recipients with the incidence
Typical symptoms include insidious progression of dyspnea on exer- lower in autologous HSCT and with nonmyeloablative conditioning for
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tion, nonproductive cough, and wheezing. However, patients may be allogeneic transplants. Conditioning agents most often associated with
asymptomatic when abnormalities are detected on routine pulmonary the development of VOD are cyclophosphamide, busulfan, and gem-
function testing. The chest x-ray may be normal or show hyperin- tuzumab. The pathobiology involves sinusoidal subendothelial injury,
flation. Air trapping may be observed on expiratory CT, as well as which results in subendothelial edema. The injured sinusoidal cells
hypoattenuation or bronchial dilatation on standard CT. Histologic slough and embolize, reducing sinusoidal blood flow and precipitating
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findings of fibrinous obliteration of the lumen of the bronchioles are hepatocellular necrosis. Patients at high risk of developing VOD are
found on lung biopsy. Because histologic confirmation is obtained on those with a history of liver disease pretransplant such as viral hepatitis,
only a limited number of patients, BOS is usually a clinical diagnosis iron overload, previous high-dose chemotherapy and radiotherapy, and
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based on symptomatology, PFT results, and radiologic findings. nonalcoholic steatohepatitis. VOD generally presents within the first
A comprehensive infectious disease evaluation and a thorough 30 days after HSCT, though less commonly a late onset form can also
evaluation for GVHD elsewhere should be part of the workup. Because be observed.
of presumed alloimmune pathogenesis of disease, control of chronic
GVHD with immunosuppression remains the backbone of treatment. Diagnosis and Management: There is a wide spectrum of presentation,
ranging from mild hyperbilirubinemia and weight gain to liver and
Current treatment recommendations for BOS include high dose sys-
temic corticosteroids with expected improvements of 8% to 20%. Other multiorgan failure. Patients often complain of abdominal pain and
more specifically right upper quadrant pain. Physical examination
agents used in small studies include inhaled steroids, azithromycin,
extracorporeal photopheresis, TNF blockade, and imatinib. Novel agents may reveal hepatomegaly, ascites, jaundice, and anasarca. Diagnosis
is best made with liver biopsy which must often be performed by the
including leukotriene inhibitors and statins are potential therapeutic
agents. Any suggestion of infection should be aggressively investigated transjugular route as patients may be thrombocytopenic and coagu-
lopathic due to a deficiency of clotting factors normally produced by
while the patient is on immunosuppressive therapy and supportive care
is critical. The prognosis for patients with BOS is poor with an overall the liver. An imaging method that has been useful in the diagnosis of
VOD is hepatic ultrasound with Doppler studies. Several Doppler cri-
survival of 44% at 2 years and 13% at 5 years. Outcomes for BOS have
not improved significantly in the more than 20 years, so participation in teria have been established which determine the probability of VOD.
Generally, reversal of flow in hepatic veins is observed, along with
a clinical trial should be considered. Involvement of the critical care phy-
sician is generally required in the setting of sepsis and acute respiratory hepatomegaly and ascites. Other imaging studies may be performed
to rule out other disorders.
decompensation; following a diagnostic video-assisted thoracoscopy; or
Since there is no approved treatment for VOD, focus is on prevention.
late in the course. Hepatotoxins should be avoided especially in patients with a history of
■ BRONCHIOLITIS OBLITERANS ORGANIZING PNEUMONIA liver disease. Conditioning for the transplant should be adjusted to the
risk of the patient. Many centers will use some form of anticoagulation
Incidence: Bronchiolitis obliterans organizing pneumonia (BOOP) throughout the conditioning and pre-engraftment period as a prophy-
is less common than BO and is characterized by the presence of laxis for VOD. There are limited studies to support the use of ursodiol,
granulation tissue within the alveolar ducts and alveoli. In a recent which is expensive, but a systematic review of the controlled clinical
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case-control study of 5340 patients who received allogeneic HSCT, trials demonstrated benefit of it use. Management, once the diagnosis
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49 cases (0.9%) of histologic BOOP were identified. An association of VOD has been established, includes discontinuation of potentially
between acute and chronic GVHD with the subsequent development hepatotoxic medications, fluid and sodium management, conservative
of BOOP was noted. The onset of BOOP has been reported to vary use of diuretics to avoid intravascular volume depletion which exacer-
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from 5 days to >7 years posttransplant. bates the condition, transfusion to keep the hematocrit >30% to main-
tain renal perfusion, nutrition to support tissue repair, and analgesics
Diagnosis and Management: The clinical presentation typically includes for abdominal pain management. In severe cases, coagulation factor
fever, nonproductive cough, and dyspnea. Rales are common on physical repletion with fresh frozen plasma or factor VII concentrates may be
examination whereas wheezing is generally absent. PFTs typically show needed along with platelet transfusions. The use of tissue plasminogen
a mild to moderate restrictive defect. Diffusing capacity for carbon mon- activator (TPA) has not been supported in clinical trials due to excessive
oxide (DLCO) is commonly decreased. Radiographic presentation is bleeding risk. Although defibrotide (a mixture of porcine oligodeoxy-
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variable and includes diffuse consolidations, ground glass opacities, and ribonucleotides with antithrombotic and profibrinolytic effects) is being
nodularity. Histologic confirmation by transbronchial biopsy or video- used in Europe as treatment for VOD, it continues as an investigational
assisted lung biopsy is necessary to make the diagnosis. Corticosteroids agent in clinical trials in the United States. 68-70 Early trials of defibrotide
are the mainstay of treatment. A prolonged course of prednisone 1 mg/kg have shown activity in severe VOD and is the basis for ongoing phase
for 1 to 3 months followed by a taper over 6 months or more, sometimes III studies including its use for VOD prophylaxis. The majority of
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as long as a year, has been proposed to avoid relapses. Macrolides have patients with hepatic VOD will recover with supportive care, but those
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also been explored in the treatment of BOOP in the transplant setting. with the severe form are at high risk of death as they progress through
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Mortality from idiopathic BOOP ranges from 5% to 15%; however, sur- hepatorenal syndrome and multiorgan system failure.
vival from BOOP post-HSCT may be lower. 65 ■
GRAFT-VERSUS-HOST DISEASE
HEPATIC COMPLICATIONS The clinical presentation of GVHD of the liver can mimic the early picture
The two major transplant-specific hepatic complications are venooc- of VOD, but generally does not include significant ascites. It can present
clusive disease, also known as sinusoidal obstruction syndrome (SOS) as hyperbilirubinemia, generally the elevation is in direct bilirubin, with
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and GVHD of the liver. increased alkaline phosphatase. The alkaline phosphatase is usually out of
proportion to the elevation in the transaminases. A second presentation
■ HEPATIC VENOOCCLUSIVE DISEASE is similar to acute hepatitis with a moderate to marked increase in the
transaminases. The diagnosis of hepatic GVHD is best made with liver
Definition and Incidence: Hepatic venoocclusive disease (VOD) is a form biopsy. Pathology demonstrates focal portal inflammation with bile duct
of toxic liver damage whose incidence in different reports depends on obliteration. Progression from acute to chronic GVHD is manifested as
the definitions and conditioning regimens used, and the populations sclerosis (see the section “Graft-Versus-Host Disease” above).

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