30-02: Infections in the Immunocompromised Patient

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.

A. Laboratory Findings

Routine evaluation includes complete blood count with differential, chest radiograph, and blood cultures; urine and respiratory cultures should be obtained if indicated clinically or radiographically. Any focal complaints (localized pain, headache, rash) should prompt imaging and cultures appropriate to the site.

Patients who remain febrile without an obvious source should be evaluated for viral infection (serum CMV antigen test or polymerase chain reaction), abscesses (which usually occur near previous operative sites), candidiasis involving the liver or spleen, or aspergillosis. Serologic evaluation may be helpful if toxoplasmosis or an endemic fungal infection (coccidioidomycosis, histoplasmosis) is a possible cause. Antigen-based assays may be useful for the diagnosis of aspergillosis (detected by galactomannan level in serum or bronchoalveolar lavage fluid), or other invasive fungal disease, including Pneumocystis infection (serum [1 → 3]-beta-D-glucan level).

B. Special Diagnostic Procedures

Special diagnostic procedures should also be considered. The cause of pulmonary infiltrates can be easily determined with simple techniques in some situations—eg, induced sputum yields a diagnosis of Pneumocystis pneumonia in 50–80% of patients with AIDS with this infection. In other situations, more invasive procedures may be required (bronchoalveolar lavage, transbronchial biopsy, open lung biopsy). Skin, liver, or bone marrow biopsy may be helpful in establishing a diagnosis. Next generation DNA-sequencing analysis (eg, of plasma, bronchoalveolar lavage, cerebrospinal fluid) is an increasingly used and validated option for diagnosis of infectious diseases in immunocompromised persons.

Transplant rejection, organ ischemia and necrosis, thrombophlebitis, and lymphoma (posttransplant lymphoproliferative disease) may all present as fever and must be considered in the differential diagnosis.

While prophylactic antimicrobial medications are used commonly, the optimal medications or dosage regimens are debated. Hand washing is the simplest and most effective means of decreasing hospital-associated infections, especially in the compromised patient. Invasive devices such as central and peripheral lines and indwelling urinary (Foley) catheters are potential sources of infection. Some centers use laminar airflow isolation or high-efficiency particulate air (HEPA) filtering in hematopoietic cell transplant patients. Rates of infection and episodes of febrile neutropenia, but not mortality, are decreased if colony-stimulating factors are used (typically in situations where the risk of febrile neutropenia is 20% or higher) during chemotherapy or during stem-cell transplantation.

A. Pneumocystis & Herpes Simplex Infections

Trimethoprim-sulfamethoxazole (TMP-SMZ), one double-strength tablet orally three times a week, one double-strength tablet twice daily on weekends, or one single-strength tablet daily for 3–6 months, is frequently used to prevent Pneumocystis infections in transplant patients. In patients allergic to TMP-SMZ, dapsone, 50 mg orally daily or 100 mg three times weekly, is recommended. Glucose-6-phosphate dehydrogenase (G6PD) levels should be assessed before dapsone is instituted. Acyclovir prevents herpes simplex infections in bone marrow and solid organ transplant recipients and is given to seropositive patients who are not receiving ganciclovir or valganciclovir for CMV prophylaxis. The usual dose is 200 mg orally three times daily for 4 weeks (hematopoietic cell transplants) to 12 weeks (other solid organ transplants).

B. CMV

No uniformly accepted approach has been adopted for prevention of CMV. Prevention strategies often depend on the serologic status of the donor and recipient and the organ transplanted, which determines the level of immunosuppression after transplant. In solid organ transplants (liver, kidney, heart, lung), the greatest risk of developing CMV disease is in seronegative recipients who receive organs from seropositive donors. These high-risk patients usually receive oral valganciclovir, 900 mg daily for 3–6 months (longer in lung transplant recipients). Other solid organ transplant recipients (seropositive recipients) are at lower risk for developing CMV disease, but still usually receive oral valganciclovir for 3 months. The lowest-risk group for the development of CMV disease is in seronegative patients who receive organs from seronegative donors. Typically, no CMV prophylaxis is used in this group. Ganciclovir and valganciclovir also prevent herpes virus reactivation. Because immunosuppression is increased during periods of rejection, patients treated for rejection usually receive CMV prophylaxis during rejection therapy. Alternatively, in a preemptive approach, patients can be monitored without specific prophylaxis by having blood sampled weekly to look for CMV by polymerase chain reaction techniques. If CMV is detected, then therapy is instituted with oral valganciclovir, 900 mg orally twice daily for a minimum of 2–3 weeks.

Recipients of hematopoietic cell transplants are more severely immunosuppressed than recipients of solid organ transplants, are at greater risk for developing serious CMV infection (usually CMV reactivation), and thus usually receive more aggressive prophylaxis. Like in solid organ transplant recipients, two approaches have been used: universal prophylaxis or preemptive therapy. In the former, all high-risk patients (seropositive patients who receive allogeneic transplants) may receive oral valganciclovir, 900 mg daily to day 100. However, valganciclovir is associated with significant bone marrow toxicity. Letermovir is being used increasingly, and it is not associated with bone marrow toxicity. Universal prophylaxis may be costly. Because of the possibility of bone marrow toxicity and the expense, many clinicians traditionally preferred the preemptive approach over the universal prophylaxis approach for recipients of hematopoietic stem cell transplants. However, while this preemptive approach is effective, it does miss a small number of patients in whom CMV disease would have been prevented had prophylaxis been used. Other preventive strategies include use of CMV-negative or leukocyte-depleted blood products for CMV-seronegative recipients.

C. Other Organisms

Routine decontamination of the gastrointestinal tract to prevent bacteremia in the neutropenic patient is not recommended. The use of prophylactic antibiotics in the afebrile, asymptomatic neutropenic patient is debated, although many centers have adopted this strategy. Rates of bacteremia are decreased, but overall mortality is not affected and emergence of resistant organisms takes place. Use of intravenous immunoglobulin is reserved for the small number of patients with severe hypogammaglobulinemia following hematopoietic stem cell transplantation and should not be routinely administered to all transplant patients.

Prophylaxis with antifungal agents to prevent invasive mold (primarily Aspergillus) and yeast (primarily Candida) infections is routinely used, but the optimal agent, dose, and duration are also debated. Lipid-based preparations of amphotericin B, aerosolized amphotericin B, intravenous and oral fluconazole or voriconazole, and oral posaconazole solution and tablets are all prophylactic options in the neutropenic patient. Because voriconazole is superior to amphotericin for documented Aspergillus infections and because posaconazole prophylaxis (compared with fluconazole) has been shown to result in fewer cases of invasive aspergillosis among allogeneic stem cell transplant recipients with graft-versus-host disease, one approach to prophylaxis is to use oral fluconazole (400 mg/day) for patients at low risk for developing fungal infections (those who receive autologous stem cell transplants) and oral voriconazole (200 mg twice daily) or oral posaconazole (200 mg suspension three times daily or 300 mg [three 100-mg tablets] sustained-release tablets once daily) for those at high risk (allogeneic transplants, graft-versus-host disease) at least until engraftment (usually 30 days). In solid organ transplant recipients, the risk of invasive fungal infection varies considerably (1–2% in liver, pancreas, and kidney transplants and 6–8% in heart and lung transplants). Whether universal prophylaxis or observation with preemptive therapy is the best approach has not been determined. Although fluconazole is effective in preventing yeast infections, emergence of fluconazole-resistant Candida and molds (Fusarium, Aspergillus, Mucor) has raised concerns about its routine use as a prophylactic agent in the general solid organ transplant population. However, liver transplant recipients with additional risk factors, such as having undergone a choledochojejunostomy, having had a high transfusion requirement or having developed kidney disease, may benefit from abbreviated postoperative Candida prophylaxis.

Given the high risk of reactivation of tuberculosis in patients taking TNF inhibitors, all patients should be screened for latent tuberculosis infection (LTBI) with a tuberculin skin test or an interferon-gamma release assay prior to the start of therapy. If LTBI is diagnosed, treatment with the TNF inhibitors should be delayed until treatment for LTBI is completed. There is also a marked risk of reactivation of hepatitis B and hepatitis C in patients taking TNF inhibitors; patients should also be screened for these viruses when TNF inhibitor treatment is being considered. Providers should also ensure that patients’ vaccinations are up-to-date before starting TNF inhibitors therapy.

A. General Measures

Because infections in the immunocompromised patient can be rapidly progressive and life-threatening, diagnostic procedures must be performed promptly, and empiric therapy is usually instituted.

While reduction or discontinuation of immunosuppressive medication may jeopardize the viability of the transplanted organ, this measure may be necessary if the infection is life-threatening. Hematopoietic growth factors (granulocyte and granulocyte-macrophage colony-stimulating factors) stimulate proliferation of bone marrow stem cells, resulting in an increase in peripheral leukocytes. These agents shorten the period of neutropenia and have been associated with reduction in infection.

B. Specific Measures

Antimicrobial medication therapy ultimately should be tailored to culture results. While combinations of antimicrobials are used with the intent of providing synergy or preventing resistance, the primary reason for empiric combination therapy is broad-spectrum coverage of all likely pathogens.

Empiric therapy is often instituted at the earliest sign of infection in the immunosuppressed patient because prompt therapy favorably affects outcome. The antibiotic or combination of antibiotics used depends on the degree of immune compromise and the site of infection. For example, in the febrile neutropenic patient, an algorithmic approach to therapy is often used. Febrile neutropenic patients should be empirically treated with broad-spectrum agents active against selected gram-positive bacteria, Pseudomonas aeruginosa, and other aerobic gram-negative bacilli (such as cefepime 2 g every 8 hours intravenously). The addition of vancomycin, 10–15 mg/kg/dose intravenously every 12 hours, should be considered in those patients with suspected infection due to methicillin-resistant Staphylococcus aureus (MRSA), S epidermidis, enterococcus, and resistant viridans streptococci. Continued neutropenic fever necessitates broadening of antibacterial coverage from cefepime to agents such as imipenem 500 mg every 6 hours or meropenem 1 g every 8 hours intravenously with or without tobramycin 5–7 mg/kg intravenously every 24 hours. Antifungal agents (such as voriconazole, 200 mg intravenously or orally every 12 hours, or caspofungin, 50 mg daily intravenously) should be added if fevers continue after 5–7 days of broad-spectrum antibacterial therapy. Regardless of whether the patient becomes afebrile, therapy is usually continued until resolution of neutropenia. There is some evidence to support earlier discontinuation of antibiotics in the neutropenic patient who becomes afebrile if no signs or symptoms of infection persist.

Patients with fever and low-risk neutropenia (neutropenia expected to persist for less than 10 days, no comorbid complications requiring hospitalization, and cancer adequately treated) can be treated with oral antibiotic regimens, such as ciprofloxacin, 750 mg every 12 hours, plus amoxicillin-clavulanic acid, 500 mg every 8 hours. Antibiotics are usually continued as long as the patient is neutropenic even if a source is not identified. In the organ transplant patient with interstitial infiltrates, the main concern is infection with Pneumocystis or Legionella species, so that empiric treatment with a macrolide or fluoroquinolone (Legionella) and TMP-SMZ, 15 mg/kg/day orally or intravenously, based on trimethoprim component (Pneumocystis) would be reasonable in those patients not receiving TMP-SMZ prophylaxis. If the patient does not respond to empiric treatment, a decision must be made to add more antimicrobial agents or perform invasive procedures (see above) to make a specific diagnosis. By making a definite diagnosis, therapy can be specific, thereby reducing selection pressure for resistance and superinfection.

• Any immunocompromised patient with an opportunistic infection.

• Patients with potential drug toxicities and drug interactions related to antimicrobials where alternative agents are sought.

• Patients with latent tuberculosis, HBV, and HCV infection in whom therapy with TNF inhibitors is planned.

Immunocompromised patients who are febrile, or those without fevers in whom an infection is suspected, particularly in the following groups: solid-organ or hematopoietic stem cell transplant recipient (particularly in the first 6 months), neutropenic patients, patients receiving TNF inhibitors, and transplant recipients who have had recent rejection episodes (including graft-versus-host disease).