Infections in Hematopoietic Cell Transplant Recipients

Etiologic Agents

Patients who have had HCT have immune deficiencies in the phagocytic, humoral, and cellular arms of the immune system. These immune defects lead to pathogen susceptibility and infectious complications in three predictable risk periods ( Fig. 96.1 ). After the conditioning regimen, a period of neutropenia occurs for 3–4 weeks, during which bacteria and fungi cause most infections. Herpes simplex virus (HSV) and seasonal respiratory viral infections also can occur. ^{, ,}

The middle period occurs after granulocyte recovery and continues until approximately 100 days after HCT. Infectious complications during this period are associated with profound impairment of humoral and cellular immunity. Although bacterial and fungal infections still can occur, they are much less frequent than during the neutropenic period. Cytomegalovirus (CMV) is a major infecting agent, but Pneumocystis jirovecii disease also can occur. With the advent of effective prophylaxis against both of these agents, the incidence of associated disease has decreased. Infections due to adenovirus and Epstein–Barr virus (EBV) can occur, especially with the use of mismatched HCT and T-lymphocyte–depleted HCT.

The late period is associated with deficits in humoral immune responses, cellular immune responses, and reticuloendothelial function and begins 100 days after HCT. Varicella-zoster virus (VZV) and encapsulated bacteria, particularly Streptococcus pneumoniae and Haemophilus influenzae type b (Hib), are major pathogens during this period.

Epidemiology

Among HCT recipients, most infections are derived from their microbial flora or reactivation of latent infections. Many factors account for the high risk for infectious complications among HCT recipients ( Box 96.1 ). Immune deficiency associated with the underlying disease is a determinant of the degree of immune suppression.

Allogeneic HCT recipients (i.e., matched unrelated donor or unrelated cord blood transplantation) are at high risk for graft-versus-host disease (GvHD), which enhances the infection rate by delaying the return of normal immune function and by ulceration of the gastrointestinal tract. Moreover, the risk for infection is directly related to the degree of donor-recipient mismatch. To abrogate GvHD, immune-suppressing medications are administered as prophylaxis. These agents increase the risk for infection by depressing the cell-mediated immune response and by disrupting mucosal barriers.

The conditioning regimen with or without concomitant irradiation compromises the immune system and can disrupt mucosal barriers. Purging of the bone marrow in autologous transplants to reduce the load of malignant cells and T-lymphocyte depletion used in allogeneic transplants to reduce the incidence of GvHD predispose the host to infection.

The serologic status of the donor and the recipient is important because many infections in transplant recipients are caused by reactivation ( Table 96.1 ). This is most notable for the herpesviruses. CMV is a major cause of pneumonitis in allogeneic transplant recipients. Other herpesviruses, especially HSV, VZV, and EBV; Toxoplasma gondii ; and adenovirus infections are prone to reactivate after the transplantation.

All HCT recipients have a central venous catheter (CVC) placed before transplantation, providing a potential site for infection. Patients who have other indwelling medical devices (e.g., cerebrospinal fluid shunts) have an increased risk for infection. Patients with a history of invasive aspergillosis who are undergoing HCT require adequate antifungal prophylaxis and treatment to prevent relapse of the disease.

Knowledge of the epidemiology of pathogens associated with the local hospital and the transplantation unit allows assessment of the risk for environmental organisms such as Aspergillus and Legionella species . Rates of infection can be reduced substantially by preventive mechanisms that inhibit aerosolization of organisms, such as the use of laminar flow rooms or high-efficiency particulate air (HEPA)–filtered rooms.

Clinical Syndromes, Differential Diagnosis, And Clinical Approach

The approach to a patient who has had HCT takes into account the infections that can occur during each of the risk periods ( Fig. 96.1 ). This provides the framework for matching possible causative agents with the clinical syndrome. Because some of these clinical syndromes are highlighted in Chapter 97, Chapter 98 , the following discussion focuses on the clinical approach to the HCT recipient.

Early Period

Several types of infection are more likely to occur during the early period (i.e., before engraftment) of the transplantation process.

Herpes Simplex Virus Gingivostomatitis

HSV infection occurs primarily as a result of reactivation in seropositive patients undergoing HCT. The diagnosis is difficult because lip lesions are rare and mucosal ulcerations are similar to those that occur as a result of the conditioning regimen.

Central Venous Catheter–Related Bloodstream Infections

During the neutropenic period, HCT recipients are at high risk for bacterial infection, comparable with the risk for patients with cancer who develop chemotherapy-induced neutropenia. Central line–associated bloodstream infections (CLABSIs) are common because of the uniform use of indwelling CVCs in HCT patients for administration of medications, hyperalimentation, blood products, and blood sampling. Measures to prevent CLABSIs should be followed. ^,

Staphylococcus epidermidis and other coagulase-negative staphylococci are the most common causes of bloodstream infections (BSIs) during the three periods after transplantation. Other gram-positive organisms associated with BSIs in HCT recipients include viridans streptococci and S. aureus. Viridans streptococci infections have been associated with chemotherapy-induced mucositis and poor dental hygiene. ^, Most gram-positive catheter-related infections can be treated successfully without removal of the catheter.

Gram-negative bacillary infections occur after mucosal damage with bacterial translocation from the intestinal mucosa into the bloodstream and are the second most frequent cause of BSI. The predominant organisms in this class include Escherichia coli, Klebsiella spp., and Pseudomonas aeruginosa, although other gram-negative organisms are common. ^, Antibiotic resistance among these organisms is common. Catheter-related infections with some gram-negative bacilli, Candida spp., and Bacillus cereus can be problematic and require catheter removal.

Fungal Infections

The major causes of fungal infection include Aspergillus spp., Candida spp., and agents of mucormycosis (e.g., Mucor, Absidia, Rhizopus spp.). Other fungi recognized as pathogens include Trichosporon spp., Fusarium spp., Curvularia spp., and Alternaría spp. Infection with these organisms usually occurs after a period of antibiotic therapy and correlates with the degree and duration of neutropenia. Although Candida albicans is the most frequent Candida species causing BSI, C. tropicalis may cause more severe disease. Other Candida species, including C. glabrata, C. parapsilosis, and C. krusei, also have emerged because of resistance to fluconazole, which is used as prophylaxis.

The portal of entry for Aspergillus and agents of mucormycosis is the respiratory tract, as opposed to that for Candida spp., which is the gastrointestinal tract. Aspergillus is associated with sinopulmonary disease and dissemination ( Fig. 96.2 ), but it is rarely recovered from blood cultures. Diagnosis usually depends on tissue histology and culture of material obtained from bronchoscopy, lung aspiration, or open-lung biopsy.

Hemorrhagic Cystitis

Hemorrhagic cystitis is associated with a variety of infectious and noninfectious causes ( Box 96.2 ). The onset can occur at any time during the transplantation period; chemotherapy-induced cystitis occurs soon after commencing the conditioning regimen. The most common infectious causes are polyomaviruses (BK virus and JC virus) and adenovirus. Bacterial and fungal pathogens also must be considered.

BOX 96.2

Differential Diagnosis of Hemorrhagic Cystitis in Hematopoietic Stem Cell Transplant Recipients

Infectious Causes

Virus

• Adenovirus

• Cytomegalovirus

• Polyomaviruses, especially BK virus and JC virus

• Herpes simplex virus

Bacteria

• Urinary tract infection, predominantly gram-negative bacilli

Fungus

• Urinary tract infection

• Fungus ball

Noninfectious Causes

• Chemotherapy (e.g., cyclophosphamide)

• Graft-versus-host disease

• Mechanical trauma from Foley catheter

Enteric Infections

Diarrhea after transplantation is caused most commonly by mucositis and GvHD. Enteric infections can occur throughout the transplantation period. Antibiotic-associated diarrhea, including that due to Clostridioides difficile, usually occurs during the neutropenic period, when antimicrobial agents are frequently administered. Other infecting agents, including enteric adenovirus, rotavirus, coxsackievirus, and noroviruses, should also be considered. ^, Infections caused by enteric viruses typically are seasonal in occurrence.