Key Considerations for Managing Infections in the Compromised Host

Antineoplastic Therapy

During antineoplastic treatment, cytotoxic agents frequently are administered in combination with other immunosuppressive therapies, such as corticosteroids or radiation therapy. A diverse array of cytotoxic agents, such as methotrexate, cyclophosphamide, 6-mercaptopurine, and azathioprine, impair cell-mediated immunity. Many of the drugs themselves (e.g., cyclophosphamide) also impair humoral responses and profoundly suppress lymphocyte counts particularly when administered at high doses in multiple cycles. Fludarabine, a purine analogue used for chronic lymphocytic leukemia (CLL), myeloid leukemias, lymphoma, and conditioning chemotherapy for HSCT produces prolonged and profound defects in cell-mediated immunity, thereby increasing susceptibility to Pneumocystis, Mycobacterium , cryptococcus, Listeria monocytogenes and herpes group viruses (herpes simplex virus [HSV], varicella-zoster virus [VZV], and cytomegalovirus [CMV]).

The use of monoclonal antibody therapy for hematologic disorders results in dysfunction of particular aspects of the immune system. Rituximab results in a sustained depletion of B lymphocytes for 6 to 9 months and has been specifically associated with reactivation of hepatitis B virus infection. Blinatumomab is a bi-specific T cell engaging (BiTE) anti-CD19 antibody used for the treatment of Philadelphia-chromosome negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Following infusion, blinatumomab causes B-cell aplasia, prolonged hypogammaglobulinemia, neutropenia, and may be associated with a cytokine release syndrome (CRS) similar to other T-cell activating therapies. Consideration for immunoglobulin substitution should be considered in patients with severe infections. Alemtuzumab administration causes profound lymphopenia and an increased risk for a variety of viral and fungal infections.

Exogenous administration of glucocorticoids leads to increased susceptibility to infection. The degree of immunosuppression and the relative risk for infection depend on the dose and duration of use. The major effect of steroids on granulocyte function is a decrease in chemotactic activity. This explains, in part, the clinical observation that the signs and symptoms of severe infections may be masked or greatly reduced in patients receiving steroids. Steroids may enhance susceptibility to infection by means of negative effects on glucose homeostasis, wound healing, skin fragility, monocyte and lymphocyte function, production of cytokines, and humoral immune responses.

Radiation therapy has been associated with granulocyte dysfunction and delayed wound healing. Defects in cell-mediated immunity may persist for more than 1 year after intensive radiation therapy or after HSCT.

Acute Leukemias

In patients with acute leukemias, a major cause of morbidity is infection due to drug-associated mucositis and therapy-induced neutropenia. Most infections occurring during neutropenia are bacterial, but patients with prolonged neutropenia are at additional risk for development of yeast and mold infections. Patients with acute leukemia who progress to hematopoietic cell transplant have added risk for infections associated with acquired deficiencies in cell-mediated and humoral immunity, such as Pneumocystis jirovecii and CMV infections.

Chronic Leukemias

Infections in patients with chronic myeloid leukemia are most commonly associated with aggressive chemotherapy or HSCT. Host defense defects with tyrosine kinase inhibitors, such as imatinib or dasatinib, have not been well defined. Chemotherapy for blast crisis resembles therapy for acute leukemia. Patients with CLL are predisposed to infection because of immunodeficiency related to the leukemia itself (humoral and cellular immune dysfunction) and to therapy-related immunosuppression. In early B-cell CLL, the infectious risk is mainly related to unbalanced immunoglobulin chain synthesis and resultant hypogammaglobulinemia. In patients with advanced CLL, particularly after the introduction of therapy with purine analogues and monoclonal agents (e.g., rituximab, alemtuzumab), neutropenia and defects in cell-mediated immunity are other factors predisposing to infection. The risk for infectious complications increases with the duration of CLL, reflecting the cumulative immunosuppression related to its treatment. The incidence of infection correlates with the serum levels of immunoglobulins (particularly IgG), which may be further impaired by use of anti-CD20 therapies.

Ibrutinib, the first Bruton tyrosine kinase inhibitor approved for the treatment of CLL, is associated with hypogammaglobulinemia and inhibits B-cell signaling. In clinical trials one-third of patients developed respiratory tract infections, of which 15% were categorized as severe pneumonia requiring hospitalization and intravenous antibiotics. Other opportunistic infections including P. jirovecii pneumonia, cryptococcosis, histoplasmosis, and fusariosis, have been reported. Aspergillus infections with high rates of central nervous system involvement have been observed in patients receiving ibrutinib for CLL or for primary central nervous system lymphoma. At present there are no standard recommendations for antimicrobial or antifungal prophylaxis with ibrutinib therapy.

Idelalisib and duvelisib inhibit B-cell receptor signaling by targeting the delta isoform of phosphoinositide 3-kinase (PI3K). Serious infections have been reported in 20% to 30% of patients with CLL receiving these agents alone or in combination with rituximab, including pneumocystis pneumonia and CMV reactivation. Therefore, a high index of suspicion is important for these infections in patients receiving these agents.

Lymphomas

Hodgkin and non-Hodgkin lymphoma are commonly associated with impaired cell-mediated immunity. The degree of immune impairment may correlate with the extent of disease and often is compounded by administration of immunosuppressive therapy. The intrinsic impairment of cell-mediated immunity in Hodgkin lymphoma can persist even after an apparent cure. Splenectomy-related infections occur with sepsis caused by encapsulated bacterial organisms at a median of 22 months, but sometimes many years after surgery. The risk of viral and fungal infection is elevated in patients who have undergone extensive treatment and are undergoing salvage chemoimmunotherapy after relapsing (typically rituximab-based regimens) followed by autologous HCT or allogeneic HSCT following the relapse.

Myelodysplastic Syndrome

Neutrophils and band forms from patients with myelodysplastic syndrome are functionally defective and probably are derived from a malignant clone of myeloid precursor cells. Neutrophils from patients with myelodysplastic syndrome have deficiencies in myeloperoxidase, elastase, and integrins. A significant portion of myelodysplastic syndrome patients die within 3 years of diagnosis from infections, bleeding complications, or progression to acute leukemia.

Multiple Myeloma

Malignant plasma cells produce a variety of immunomodulatory molecules such as transforming growth factor beta (TGF-β) that suppress B-cell function, which contribute to defects in humoral immunity. Patients having myeloma with IgG paraprotein have an increased rate of catabolism of normal and clonal IgG. They also may have defects in complement and granulocyte function. Cell-mediated immunity is not impaired by the disease but is compromised by corticosteroids or cytotoxic therapy. Prolonged and intense multiple myeloma therapy, including autologous stem cell transplant, can eventually result in a profoundly immunocompromised state resembling that seen in acute leukemia or allogenic stem cell transplant recipients.

Uncommon Malignancies

Patients with hairy cell leukemia frequently develop infections with atypical mycobacteria. Effective treatment of hairy cell leukemia can reverse host cellular immune defects with eradication of mycobacterial infection.

Defects in cell-mediated immunity have been postulated to explain the incidence of infection caused by intracellular pathogens in patients with the relatively rare T-cell malignancies mycosis fungoides and T-cell CLL.

Aplastic Anemia

Chronic neutropenia is the main cause of recurrent bacterial and fungal infections among patients. Periodontal infections are particularly common. Treatment of the underlying hematologic disease is required to stop recurrent infections and cure some chronic infections.

Paroxysmal Nocturnal Hemoglobinuria

Patients with paroxysmal nocturnal hemoglobinuria are at some increased risk for bacterial infection due to a deficiency of decay-accelerating factor on the membrane of neutrophils. Modest and progressive granulocytopenia, progression to aplasia or leukemia may compound these risks. Vaccination against meningococcus is required before treatment with the terminal complement inhibitor eculizumab.

Granulocytic Phagocyte Disorders

The clinical approach to infections in patients with granulocytic phagocyte disorders is specific to each of these disorders and is beyond the scope of this chapter. However, chronic granulomatous disease is discussed because patients with this congenital immunodeficiency who survive into adulthood are at risk for severe infections. Chronic granulomatous disease is a heterogeneous group of disorders resulting from defective or malfunctioning oxidative metabolism capacity of phagocytes. Recurrent infections with bacteria and fungi are common and occasionally life threatening, despite optimal antimicrobial therapy. Infections with Staphylococcus species and Aspergillus species can be particularly aggressive. Granulomata may form in response to infection, especially in the gastrointestinal (GI) and genitourinary tracts.

Erythrocyte Disorders

Glucose-6-phosphate dehydrogenase deficiency is a sex-linked disorder. Deficiency of this enzyme limits glucose metabolism through the hexose monophosphate shunt, resulting in an abnormal respiratory burst in neutrophils. Bacterial infections can occur if the deficiency is severe.

Hemoglobin Gene Variants

Patients with chronic hemolytic states may develop bilirubin gallstones, which can serve as a nidus for infection. Defects in cell-mediated immunity have been described in patients with thalassemia. Patients with sickle cell disease have an increased susceptibility to bacterial infections. Defective alternative complement pathway function, especially in conjunction with asplenia, contributes to the propensity to bacterial infection. Splenic involution results in depressed synthesis of the alternate pathway factor(s) of complement and decreased phagocytic clearance of bacteria. Phagocytosis of Streptococcus pneumoniae is abnormal, in part because of an inability to use the alternate pathway for C3 fixation as a means of opsonization. An increased risk for Salmonella infection appears to be unique to the sickle cell population. Suppurative arthritis can occur after repeated episodes of hemarthrosis among patients with sickle cell disease.

Coagulation Disorders

Hemophilias are sex-linked deficiencies of clotting factor VIII or IX. Septic arthritis should be considered in the differential diagnosis of any hemophiliac with repeated episodes of hemarthrosis whose articular signs and symptoms fail to improve quickly after administration of appropriate coagulation factor replacement.

Blood Groups

The Duffy blood group antigen serves as a receptor for Plasmodium vivax to invade erythrocytes. Blood group O is associated with Helicobacter pylori infection and an associated increase in peptic ulceration because the Lewis (b) blood group antigen mediates H. pylori attachment to human gastric mucosa.