Infections in the Immunocompromised Host: General Principles

Innate Immunity

Impact of Treatment on Cellular Immunity

Both antigen-specific and antigen-nonspecific cells contribute to the development of cellular immunity. The antigen-specific branch of cell-mediated immunity can be divided into two major categories. One category involves cytotoxic effector cells, which are able to lyse virus-infected or foreign cells, including malignant cells. The second category involves subpopulations of helper T cells that mediate differentiated cytokine reactions (e.g., Th1, Th2, Th17) after antigen recognition.

This fine-tuned system can easily be deregulated by congenital defects or defects acquired as a result of a disease or its treatment. Long-term cytotoxic therapy, extensive irradiation, and immunosuppressive drugs such as corticosteroids, azathioprine, cyclosporine, tacrolimus, and mTOR inhibitors (sirolimus, and everolimus) suppress cellular immunity. Some monoclonal antibodies, such as alemtuzumab, are being used as antitumor and immunosuppressive agents and can exert profound and prolonged effects on cellular immunity. Purine analogues, including fludarabine and cladribine, are particularly detrimental to cellular immunity and create a situation similar to acquired immunodeficiency syndrome. Likewise, lymphatic malignancies, particularly Hodgkin lymphoma and chronic lymphocytic leukemia (CLL), are associated with impaired cellular immunity. Emerging targeted therapies—including the TKIs imatinib, dasatinib, and bosutinib; small molecules such as BCL2 inhibitors (venetoclax); JAK-STAT inhibitors; and PI3K inhibitors, often used in heavily pretreated patients—have an impact on specific cellular immunity (see Chapter 6 ). This is exemplified by the occurrence of opportunistic infections with the use of ruxolitinib ( Mycobacterium tuberculosis and hepatitis B reactivation), ibrutinib (aspergillosis), and idelalisib ( Pneumocystis jirovecii ). On the contrary, the use of immunomodulatory drugs (lenalidomide) or proteasome inhibitor drugs (bortezomib) increases the risk of severe nonspecific infections, especially in the relapsed/refractory phase of multiple myeloma, and mostly as a result of therapy-related neutropenia.

Allogeneic stem cell transplantation brings about a long-lasting dysfunction of T and B cells, especially in association with GVHD and its treatment ( Table 305.2 ). The coordination of cellular immunity is often lost, and when aided and abetted by suppressed humoral immunity, the paracrine mediators that are released go on to induce the sepsis cascade, which may culminate in multiorgan failure instead of arresting infection.

Impact of Treatment on Humoral Immunity

The humoral branch of the immune system, which is primarily responsible for clearing extracellular bacteria, involves the interaction of B cells with antigen and their subsequent proliferation and differentiation into antibody-secreting plasma cells (see Chapter 5 ). An important difference in antigen recognition by T cells and B cells is that the latter can recognize some antigens without the help of an antigen-presenting cell. The humoral system can identify a plethora of bacterial or viral microorganisms, in addition to the soluble proteins that they release. When challenged by an antigen, immunoglobulins are produced that bind to the antigen. The specific functions of immunoglobulin G (IgG) and immunoglobulin M (IgM) include neutralization of the antigen, and complement activation and opsonization—that is, enhancement of phagocytosis of the antigen by neutrophils and macrophages. Secretory immunoglobulin A (IgA), which is found on mucosal surfaces, is not an opsonin but nonetheless inhibits the motility of bacteria and prevents them from adhering to epithelial cells. The production of immunoglobulins is decreased in lymphoproliferative disorders such as CLL and multiple myeloma, whereas humoral immunity is generally well preserved in patients with acute leukemia. However, intensive irradiation and chemotherapy will lead not only to neutropenia but also, ultimately, to hypogammaglobulinemia. In particular, monoclonal antibodies such as rituximab and blinatumomab and CD19- and CD22-targeted chimeric antigen receptor (CAR) T cells deplete B lymphocytes, inducing profound and long-lasting hypogammaglobulinemia and, consequently, infections. The impact of new therapies such as BTK and PI3K inhibitors is currently less clear, but considering the fact that they target molecules with vital roles in B-cell maturation and function, disrupted antibody responses can be anticipated. At the least, reduced serologic responses to vaccination indicate impaired humoral immunity.

Cytokines and chemokines are indispensable for communication between innate and acquired immune and nonimmune cells in shaping effective antimicrobial immune reactions. Hence, interference by anticytokine antibodies and cytokine scavengers (e.g., infliximab, anakinra, tocilizumab) results in increased risk for infection in autoimmune diseases, transplantation, and cancer therapy.

Humoral Immunity and the Spleen

The primary immunoglobulin response of spleen-produced specific opsonizing antibodies is necessary for efficient phagocytosis of encapsulated bacteria. Macrophages that occupy strategic positions within the organ are subsequently able to remove them. Splenectomy may result in a reduced level of the complement factor properdin and thereby lead to suboptimal opsonization, a decrease in functional tuftsin, and low levels of circulating IgM. The lack of opsonizing antibodies in serum against common encapsulated bacteria impairs the activity of all phagocytic cells, including granulocytes, monocytes, and macrophages. As a consequence, infections with Streptococcus pneumoniae and Haemophilus influenzae are often more severe in splenectomized patients and in those who have undergone HSCT and are functionally asplenic. Opsonizing antibodies are also important for effective antibody-dependent cell-mediated cytotoxicity of NK cells.

Platelets

The protective role of platelets in healthy individuals is often underestimated but becomes obvious during treatment of patients with malignant disease. Thrombocytopenia is an almost inevitable repercussion of intensive chemotherapy and irradiation, but decreased thrombocyte function is also a matter of concern. Thrombocytopathy is either disease related or caused by concurrent medication. The consequences of both increased susceptibility to infection and a decreased capacity to repair damaged tissues can be considerable and may have an impact on the eventual outcome of a treatment episode. Thrombocytopenia also appears to be an independent risk factor for bacteremia, and the incidence of major hemorrhage at autopsy of patients who die with or of an infection is striking.