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CHAPTER 94: Hematopoietic Stem Cell Transplantation and Graft-Versus-Host Disease 885

volume should trigger evaluation for the site(s) of severe or persistent such as tacrolimus and MMF have demonstrated more consistent benefit
bleeding with endoscopic or radiologic procedures. Severe involve- than others. Extracorporeal photophoresis has shown some promise in
ment of the skin resulting in desquamation requires aggressive volume select patients with dermatologic involvement. Ancillary therapy and
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repletion, intense nursing care and consultation with dermatologists, supportive care to prevent infections, optimize nutrition, ameliorate
and plastic surgeons or burn specialists. Depressed peripheral blood morbidity, and optimize functional performance and capacity are critical
counts and poor marrow function may be manifestations of severe acute components of the management of chronic GVHD. Treatment is often
GVHD. Thrombocytopenia due to decreased platelet production may be complicated by infection. All patients with chronic GVHD are at risk for
compounded by rapid turnover in the setting of fever and hemorrhage. infection with encapsulated organisms, particularly Streptococcus pneu-
Maintenance of hemostasis often requires vitamin K supplementa- moniae but also H influenzae and Neisseria meningitides. Prophylactic
tion, transfusions of platelets, and in the setting of hepatic failure, the antibiotics should be given to all patients with chronic GVHD receiving
administration of fresh frozen plasma. systemic immunosuppressive treatment. Patients with chronic GVHD
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■ CHRONIC GVHD are at risk for the development of overwhelming sepsis and involvement
of the critical care physician in such settings is particularly helpful.
Definition: Chronic GVHD is a heterogenous, alloimmune syndrome. It
is the major cause of late nonrelapse mortality after HSCT. 34,35 Advanced INFECTIOUS COMPLICATIONS
age of the recipient, use of peripheral blood stem cells versus bone
marrow stem cells, and a history of acute GVHD are significant risk Infections are frequent after HSCT and are the leading cause of death
factors for chronic disease; however, acute GVHD does not necessarily among patients undergoing allogeneic transplant. Infections in the set-
evolve into chronic disease and chronic GVHD can occur in the absence ting of HSCT are caused by a variety of pathogenic and opportunistic
of prior acute disease. organisms. The approach to the diagnosis and management of these
infections is dependent on the underlying disease and prior therapy,
Immunology: The pathophysiology and immunobiology of chronic timing of the infection relative to the transplant, the type of transplant,
GVHD remain undefined. Several different hypotheses regarding the the patient’s immunologic history and comorbidities. Changes in the
pathogenesis of chronic GVHD have emerged from animal studies spectrum of infections occur as the intensity of the therapy is modified.
including thymic damage caused by acute GVHD, resulting in failure of The diagnosis and management of infections among allogeneic
T-cell selection, cytokine mediators that may propagate autoimmune- HSCT recipients is often driven by the timing of their occurrence “days
like tissue injury, donor B cells and antibody mediated mechanisms, as pre- and posttransplant.” Classic associations between defects in the
well as insufficiency of T regulatory cells. 34 immune system and types of infectious pathogens can be helpful in
the initial approach to the patient. The major factors contributing to
Manifestations: Clinical symptoms of chronic GVHD may involve the infectious complications in the HSCT patient are broadly classified as
skin, nails, mucous membranes, GI tract, and liver. The characteristic (1) neutropenia and qualitative defects in phagocytosis; (2) humoral
pigmentation and sclerosis of the skin, lichenoid oral plaques, esophagitis, immune deficiency; (3) cellular immune deficiency/dysfunction; and
polyserositis, and oral and ophthalmic sicca syndrome resemble the man- (4) impaired mucosal integrity. Often more than one of these factors will
ifestations of autoimmune collagen-vascular disorders. GI involvement be present at a given time.
is often manifested by anorexia, weight loss, and esophageal strictures.
Hepatic involvement presents with cholestasis and jaundice but can also ■ PRE- AND EARLY POSTTRANSPLANT
present with transaminitis. Chronic pulmonary diseases are seen in 10%
to 20% of patients with chronic GVHD and are divided between diffuse Most patients will begin the conditioning (pretransplant period) with an
pneumonias and bronchiolitis obliterans (see the section “Bronchiolitis adequate or near adequate neutrophil count but will soon develop neu-
Obliterans Syndrome”). The diagnosis of chronic GVHD requires at least tropenia as they progress through their conditioning. The chemotherapy
one diagnostic sign that is found only in chronic GVHD or at least one and radiotherapy as well as the immunosuppressive drugs used to pre-
distinctive sign highly suggestive of chronic GVHD. A biopsy may be vent GVHD will impair B- and T-cell function, resulting in increased
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helpful in ruling out other potential diagnoses such as infection or drug susceptibility to viral infections. All fevers must be evaluated promptly.
effect. The NIH consensus has recommended a system of scoring chronic The order of differential diagnosis for an infectious etiology is generally
GVHD manifestations in eight sites on a 0-3 scale. This system was not bacterial, then fungal, then viral in this time frame. The majority of
designed to predict mortality but to assess the severity and functional patients will have indwelling central venous catheters, resulting in a risk
impact of chronic GVHD. It replaces the historical categories of limited for catheter-associated infections. Skin-related pathogens (Staphylococci,
and extensive involvement. Mortality from chronic GVHD tends to be coagulase-negative Staphylococci, Corynebacterium spp) are associated
lower when the disease is limited to the skin and liver and when it occurs with central venous catheter infections. Previous hospitalizations and
in the absence of prior acute GVHD. Death is attributed to GVHD even if chemotherapy that is immunosuppressive increase the risk of the patient
it is due to a complicating infection as a result of the immunosuppressive being colonized with resistant organisms such as vancomycin-resistant
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medications needed to treat the GVHD. enterococcus (VRE) or methicillin-resistant Staphylococcus aureus
(MRSA), which must be considered in the management of fevers. A
Diagnosis and Management: The diagnosis of chronic GVHD is most proportion of patients will have a history of prolonged neutropenia due
often made in the outpatient setting and relies on clinical assessment, to their disease or previous treatment placing them at risk for invasive
laboratory, biopsy, and radiologic evaluation similar to that outlined fungal infections. Early symptoms of infection should prompt consid-
for acute GVHD. When managing patients with chronic GVHD, it is eration of gram-positive bacteria introduced via the central venous
important to remember that although chronic GVHD may be a signifi- catheter even in the setting of adequate neutrophil counts. As mucosal
cant contributor to late transplant morbidity and mortality, it may also barriers are destroyed by the conditioning regimen, evaluation and
be associated with an important therapeutic graft-versus-tumor effect. treatment of fevers should include consideration of bacterial pathogens
Because our understanding regarding the biology of chronic GVHD that colonize the oral and GI tract including α-hemolytic streptococci,
is incomplete, current treatment strategies are based on nonspecific, gram-negative enteric organisms, and enterococci. The choice of initial
global immunosuppression. Use of corticosteroids (with or without a antibiotic regimen should be tailored according to the individual center’s
calcineurin inhibitor) is a standard first-line approach. Multiple second- most common pathogens and antibiogram. Fever with mucositis and
line treatments have been studied but none have achieved widespread abdominal pain raises suspicion of neutropenic enterocolitis (typhlitis).
acceptance. Generally, treatments involve the addition of many of the Seeding of infection from the bloodstream may lead to localized
same drugs as are used for treatment of acute GVHD. A few combinations abscesses that may become clinically apparent after neutrophil recovery.

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