Page 1416 - Hematology_ Basic Principles and Practice ( PDFDrive )

1262 Part VII Hematologic Malignancies

reaction to insect bites in 8 of 97 patients with CLL over a 13-year RBC aplasia, and JC polyoma virus has been implicated in the
period. The reaction is characterized histologically by the presence of development of progressive multifocal leukoencephalopathy. Man-
a dermal infiltrate composed of a mixed population of T and B cells, agement of these infections depends on early recognition of dissemi-
eosinophils, and eosinophilic granule protein. The extent of eosino- nated viral disease, timely initiation of antiviral therapy in cases of
philic degranulation may also correlate with the severity of symptoms. HSV and EBV, and a low threshold for the introduction of prophy-
Clinically, these patients present with recurrent, painful, bullous lactic acyclovir and supportive therapy. All patients should be provided
eruptions that may be traced to an insect bite in some instances. In instructions to identify the signs and symptoms of herpes virus infec-
limited cases, we have also observed that CLL patients have hyper- tion at the time of diagnosis of CLL.
sensitivity to bed bugs, and this should be considered in the differential Fungal infections are not typically observed in CLL in the absence
diagnosis. Identification and avoidance of known triggers may be of treatment with corticosteroids or other immunosuppressive therapy
useful in some cases, but most patients are unable to identify the for autoimmune complications arising from CLL. Cryptococcal
inciting exposure. Treatment with a short course of steroids is usually meningitis, pneumonia, and fungemia are well-recognized events in
effective, but these patients frequently relapse and may require patients with CLL and are associated with significant morbidity and
multiple courses of therapy. Dapsone and chlorambucil may also be mortality. More cases of P. carinii pneumonia, systemic candidiasis,
useful in severe, recurrent cases. and aspergillosis have been reported since the advent of combination
Other cutaneous conditions are also common in CLL patients, nucleoside analog therapy with steroids. Treatment of the infection
with up to 45% reporting some form of skin involvement. These is dictated by the identification of the particular organism.
include petechial, purpural, or ecchymotic lesions related to throm- Trimethoprim–sulfamethoxazole is routinely used as effective pro-
bocytopenia; infectious eruptions such as herpes simplex and zoster; phylaxis against P. carinii infections, especially during and immedi-
and direct leukemic involvement in fewer than 10% of all patients ately after the use of nucleoside analogs or alemtuzumab. Fungal
with advanced disease. prophylaxis with posaconazole may also be used during protracted
therapy with high-dose steroids to avoid invasive aspergillosis.
INFECTIONS IN PATIENTS WITH CHRONIC
LYMPHOCYTIC LEUKEMIA Prophylactic Strategies for Infections

Infectious complications remain the leading cause of morbidity and Routine use of prophylactic antibiotics is generally not used for CLL
mortality in patients with CLL. The incidence of infectious complica- despite the higher frequency of infections observed in patients with
tions has been estimated to be as high as 80% with a mortality rate this disease. Early recognition of signs and symptoms of infection and
of approximately 60%. Various factors contribute to the increased prompt initiation of empiric broad-spectrum antibiotics is probably
incidence of infectious complications in CLL, the most important a more feasible and cost-effective approach. When chemoimmuno-
being progressive disease affecting host immunity through an therapy is used that includes a nucleoside analog or alemtuzumab
impaired antibody response and hypogammaglobulinemia; weakened therapy, prophylaxis for herpes simplex and varicella zoster should be
host cellular immune responses, including impaired macrophage used, particularly in older patients. Trimethoprim–sulfamethoxazole
function; a decrease in T-regulatory cells; and, finally, the acquired (or other alternative P. carinii pneumonia prophylaxis) should also be
defects after immunosuppressive chemotherapy. administered in this setting. Fortunately, kinase inhibitors result in
Recent studies have examined predictors of acquiring severe infec- continued decline in the incidence of infectious complications with
tions in patients with CLL. In their retrospective analysis of infection- ongoing therapy, primarily as a result of better disease control and
related mortality in 280 patients, advanced age, clinical stage B or C routine prophylactic antibiotics are either not required or can be
disease, unmutated IGHV, and positive CD38 status have been tapered off in the majority of patients.
identified as independent predictors of both shorter time to first Hypogammaglobulinemia is virtually always present in advanced
infection and infection-related mortality. Other risk factors that may CLL, and several studies have examined whether IV immunoglobulin
also have an impact on development of infections include type of (IVIG) replacement therapy can reduce the incidence and severity of
initial therapy and development of renal insufficiency. infectious complications. Patients receiving IVIG in a double-blind,
Historically, sinopulmonary infections from encapsulated bacteria placebo-controlled trial experienced significantly fewer bacterial
such as Streptococcus pneumoniae and Haemophilus influenzae have infections than the placebo group. The therapy was well tolerated
been the most common cause of infectious complications in patients with few adverse reactions, but there was no observed benefit in terms
with CLL. With the recent use of more potent cytotoxic chemo- of preventing viral or fungal infections. However, other studies have
therapy and the resultant profound myelosuppression, an increased shown an almost 50% reduction in the number of serious infections
frequency of severe pulmonary infections, bacteremia, and gram- per year with IVIG infusions. Limited data support the use of IVIG
negative infections has been reported. Infections caused by atypical at a higher dose of 600 mg/kg every 4 weeks to reduce the number
organisms such as Listeria monocytogenes, Nocardia spp., Mycobacte- and severity of respiratory infections. However, the prohibitive cost
rium spp., and Neisseria meningitidis are relatively infrequent in of IVIG therapy and the fact that it has not been shown to prolong
patients who receive conventional chemotherapy. Treatment for survival argues against its empiric use in all patients. IVIG should be
presumed infection should be initiated empirically in CLL patients used judiciously and reserved for patients with advanced disease and
who develop fever because fever in CLL patients usually indicates an recurrent infections. The usual dose used is 200–400 mg/kg every
active infection. Therapy should be tailored to the particular organ 4–6 weeks as needed, with the aim of keeping the trough serum IgG
involved and the sensitivity of the organism. Prophylactic antibiotics concentration greater than 500 mg/dL. Our group routinely uses this
can be initiated for debilitated patients with high-risk disease and strategy for refractory patients or those who have more than two
significant immune dysfunction. infections requiring hospitalization during 1 year.
Viral infections are also commonly encountered in CLL patients Among the strategies for preventing infections in this patient
(see Fig. 77.3D–E). Herpesvirus infections are especially common in population is immunization. CLL patients, however, typically respond
patients treated with nucleoside analogs and alemtuzumab. Chronic, poorly to pneumococcal and influenza vaccines. Advanced age,
indolent oropharyngeal and circumoral herpes simplex virus (HSV) advanced disease stage, hypogammaglobulinemia, and low levels of
outbreaks are more frequent than aggressive, disseminated visceral soluble CD23 influence the rate of responses to immunizations.
disease. Reactivation of Epstein-Barr virus (EBV) has been implicated Soluble CD23, a degradation product of membrane-bound CD23,
in some cases of Richter transformation. Other viruses may cause is involved in several aspects of B-cell activation and proliferation and
severe systemic disease in patients with CLL. Varicella zoster virus has a synergistic effect on histamine release. Histamine has a direct
can cause herpes zoster, herpetic neuralgia, and rarely meningoen- inhibitory effect on immunoglobulin production by B cells in vitro
cephalitis, parvovirus B19 can cause severe polyarthritis and pure via histamine type-2 (H2) receptors and acts as an immune regulatory