Immunocompromised patients have defects in their natural defense mechanisms resulting in an increased risk for infection. In addition, infection is often severe, rapidly progressive, and life threatening. Organisms that are not usually problematic in the immunocompetent person may be important pathogens in the compromised patient (eg, Staphylococcus epidermidis, Corynebacterium jeikeium, Propionibacterium acnes, Bacillus species). Therefore, culture results must be interpreted with caution, and isolates should not be disregarded as solely contaminants. Although the type of immunodeficiency is associated with specific infectious disease syndromes, any pathogen can cause infection in any immunosuppressed patient at any time. Thus, a systematic evaluation is required to identify a specific organism.
A. Impaired Humoral Immunity
Defects in humoral immunity are often congenital, although hypogammaglobulinemia can occur in multiple myeloma, chronic lymphocytic leukemia, small lymphocyte lymphoma, and in patients who have undergone splenectomy. Patients with ineffective humoral immunity lack opsonizing antibodies and are at particular risk for infection with encapsulated organisms, such as Haemophilus influenzae, Neisseria meningitides, and Streptococcus pneumoniae. Although rituximab is normally thought of as being linked to impaired cellular immunity, it has been associated with the development of Pneumocystis jirovecii infection and progressive multifocal leukoencephalopathy (PML) as well as with hepatitis B reactivation.
B. Granulocytopenia (Neutropenia)
Granulocytopenia is common following hematopoietic cell transplantation (“stem cell transplantation”) and among patients with solid tumors—as a result of myelosuppressive chemotherapy—and in acute leukemias. The risk of infection begins to increase when the absolute granulocyte count falls below 1000/mcL, with a dramatic increase in frequency and severity when the granulocyte count falls below 100/mcL. The infection risk is also increased with a rapid rate of decline of neutrophils and with a prolonged period of neutropenia. The granulocytopenic patient is particularly susceptible to infections with gram-negative enteric organisms, Pseudomonas, gram-positive cocci (particularly Staphylococcus aureus, S epidermidis, and viridans streptococci), Candida, Aspergillus, and other fungi that have recently emerged as pathogens such as Trichosporon, Scedosporium, Fusarium, and the mucormycoses.
C. Impaired Cellular Immunity
Patients with cellular immune deficiency encompass a large and heterogeneous group, including patients with HIV infection (see Chapter 31); patients with lymphoreticular malignancies, such as Hodgkin disease; and patients receiving immunosuppressive medications, such as corticosteroids, cyclosporine, tacrolimus, and other cytotoxic medications. This latter group—those who are immunosuppressed as a result of medications—includes patients who have undergone solid organ transplantation, many patients receiving therapy for solid tumors, and patients receiving prolonged high-dose corticosteroid treatment (eg, for asthma, temporal arteritis, systemic lupus erythematosus). Patients taking tumor necrosis factor (TNF) inhibitors, such as etanercept and infliximab, are also included in this category. Patients with cellular immune dysfunction are susceptible to infections by a large number of organisms, particularly ones that replicate intracellularly. Examples include bacteria, such as Listeria, Legionella, Salmonella, and Mycobacterium; viruses, such as herpes simplex, varicella, and CMV; fungi, such as Cryptococcus, Coccidioides, Histoplasma, and Pneumocystis; and protozoa, such as Toxoplasma.
D. Hematopoietic Cell Transplant Recipients
The length of time it takes for complications to occur in hematopoietic cell transplant recipients can be helpful in determining the etiologic agent. In the early (preengraftment) posttransplant period (days 1–21), patients will become severely neutropenic for 7–21 days. Patients are at risk for gram-positive (particularly catheter-related) and gram-negative bacterial infections, as well as herpes simplex virus, respiratory syncytial virus, and fungal infections. In contrast to solid organ transplant recipients, the source of fever is unknown in 60–70% of hematopoietic cell transplant patients. Between 3 weeks and 3 months posttransplant, infections with CMV, adenovirus, Aspergillus, and Candida are most common. P jirovecii pneumonia is possible, particularly in patients who receive additional immunosuppression for treatment of graft-versus-host disease. Patients continue to be at risk for infectious complications beyond 3 months following transplantation, particularly those who have received allogeneic transplantation and those who are taking immunosuppressive therapy for chronic graft-versus-host disease. Varicella-zoster is common, and Aspergillus and CMV infections are increasingly seen in this period as well.
E. Solid Organ Transplant Recipients
The length of time it takes for infection to occur following solid organ transplantation can also be helpful in determining the infectious origin. Immediate postoperative infections often involve the transplanted organ. Following lung transplantation, pneumonia and mediastinitis are particularly common; following liver transplantation, intra-abdominal abscess, cholangitis, and peritonitis may be seen; after kidney transplantation, urinary tract infections, perinephric abscesses, and infected lymphoceles can occur.
Most infections that occur in the first 2–4 weeks posttransplant are related to the operative procedure and to hospitalization itself (wound infection, intravenous catheter infection, urinary tract infection from an indwelling urinary [Foley] catheter) or are related to the transplanted organ. In rare instances, donor-derived infections (eg, West Nile virus, tuberculosis) may present during this time period. Compensated organ transplants obtained abroad through “medical tourism” can introduce additional risk of infections, which vary by country and by transplant setting. Infections that occur between the first and sixth months are often related to immunosuppression. During this period, reactivation of viruses, such as herpes simplex, varicella-zoster, and CMV is quite common. Opportunistic infections with fungi (eg, Candida, Aspergillus, Cryptococcus, Pneumocystis), Listeria monocytogenes, Nocardia, and Toxoplasma are also common. After 6 months, if immunosuppression has been reduced to maintenance levels, infections that would be expected in any population occur. Patients with poorly functioning allografts receiving long-term immunosuppression therapy continue to be at risk for opportunistic infections.
F. Tumor Necrosis Factor Inhibitor Recipients
Patients taking TNF inhibitors have specific defects that increase risk of bacterial, mycobacterial (particularly tuberculosis), viral (HBV reactivation and HCV progression), and fungal infections (Pneumocystis, molds, and endemic mycoses). Infection risk may be highest shortly after therapy is initiated (within the first 3 months) and with a higher dose of medications.
G. Recipients of Other Biologics
In addition to TNF inhibitors, other biologics target a variety of immunologic pathways that are involved in immunologic mediated disease and in cancer replication. Disruption of these pathways include, but are not limited to impact on B cells, T cells, complement, and leukocytes. This may result in not only serious infections, but the development of autoimmune disease and malignancies as well. Some medications have been observed to have specific associations with opportunistic infections (eg, natalizumab and PML, or eculizumab and meningococcal disease). Other biologics such as chimeric antigen receptor T (CAR-T) cells may have unintended infectious risks that are currently unknown, or may have adverse effects that mimic infection (eg, cytokine release syndrome). Checkpoint inhibitors (eg, anti-PD-1 and CTLA antibodies) used for the treatment of advanced malignancies also may have effects that mimic infection via immune enhancement. Prolonged immunosuppression used to treat immune-associated adverse events in CAR-T and checkpoint inhibitor therapy (eg, TNF inhibitors and corticosteroids) can then result in opportunistic and other infections. As more biologics are developed and used, clinicians must remain vigilant for the possibility of serious infectious disease risk.
H. Other Immunocompromised States
A large group of patients who are not specifically immunodeficient are at increased risk for infection due to debilitating injury (eg, burns or severe trauma), invasive procedures (eg, chronic central intravenous catheters, indwelling urinary [Foley] catheters, dialysis catheters), central nervous system dysfunction (which predisposes patients to aspiration pneumonia and decubitus ulcers), obstructing lesions (eg, pneumonia due to an obstructed bronchus, pyelonephritis due to nephrolithiasis, cholangitis secondary to cholelithiasis), and use of broad-spectrum antibiotics. Patients with diabetes mellitus have alterations in cellular immunity, resulting in mucormycosis, emphysematous pyelonephritis, and foot infections.