Infections in Hematopoietic Stem Cell Transplant Recipients

Dr. Soumyakanta Sahoo. MD, PDCC (Infectious Diseases)

Hematopoietic Stem Cell Transplant (HSCT) is the infusion of hematopoietic stem cells from a donor into a patient who has received chemotherapy, which is usually marrow-ablative. Increasingly, HSCT has been used to treat neoplastic diseases, hematological disorders, immunodeficiency syndromes, congenital enzyme deficiencies, and autoimmune disorders (e.g., Systemic Lupus Erythematosus or Multiple Sclerosis).

HSCTs are classified as either allogeneic or autologous on the basis of the source of the transplanted hematopoietic progenitor cells. Cells used in allogeneic HSCTs are harvested from a donor other than the transplant recipient. Such transplants are the most effective treatment for persons with severe aplastic anemia and offer the only curative therapy for persons with chronic myelogenous leukemia. Allogeneic donors might be a blood relative or an unrelated donor. Allogeneic transplants are usually most successful when the donor is a human lymphocyte antigen (HLA)-identical twin or matched sibling. Recently, medical centers have begun to harvest hematopoietic stem cells from placental or umbilical cord blood (UCB) immediately after birth. These harvested cells are used primarily for allogeneic transplants among children. 

Immune System Recovery after HSCT
During the first year after an HSCT, recipients typically follow a predictable pattern of immune system deficiency and recovery, which begins with the chemotherapy or radiation therapy (i.e., the conditioning regimen) administered just before the HSCT to treat the underlying disease. Unfortunately, this conditioning regimen also destroys normal hematopoiesis for neutrophils, monocytes, and macrophages and damages mucosal progenitor cells, causing a temporary loss of mucosal barrier integrity. The gastrointestinal tract, which normally contains bacteria, commensal fungi, and other bacteria carrying sources (e.g., skin or mucosa), becomes a reservoir of potential pathogens.

Virtually all HSCT recipients rapidly lose all T- and B-lymphocytes after conditioning, losing immune memory accumulated through a lifetime of exposure to infectious agents, environmental antigens, and vaccines. Because transfer of donor immunity to HSCT recipients is variable and influenced by the timing of antigen exposure among donor and recipient, passively acquired donor immunity cannot be relied upon to provide long-term immunity against infectious diseases among HSCT recipients. During the first month after HSCT, the major host-defense deficits include impaired phagocytosis and damaged mucocutaneous barriers. Additionally, indwelling intravenous catheters are frequently placed and left in situ for weeks to administer parenteral medications, blood products, and nutritional supplements. These catheters serve as another portal of entry for opportunistic pathogens from organisms colonizing the skin (e.g., Coagulase-negative Staphylococci, Staphylococcus aureus, Candida species, and Enterococci ) .

Engraftment for adults and children is defined as the point at which a patient can maintain a sustained absolute neutrophil count (ANC) of >500/mm3 and sustained platelet count of ≥20,000, lasting ≥3 consecutive days without transfusions. Among unrelated allogeneic recipients, engraftment occurs at a median of 22 days after HSCT (range: 6–84 days) .In the absence of corticosteroid use, engraftment is associated with the restoration of effective phagocytic function, which results in a decreased risk for bacterial and fungal infections. 

Infections after HSCT
HSCT recipients experience certain infections at different times post transplant, reflecting the predominant host-defense defect(s) .Immune system recovery for HSCT recipients takes place in three phases beginning at day 0, the day of transplant. Phase I is the preengraftment phase (<30 days after HSCT); Phase II, the post engraftment phase (30–100 days after HSCT); and Phase III, the late phase (>100 days after HSCT).

Phase I, Pre- engraftment. During the first month post transplant, HSCT recipients have two critical risk factors for infection – prolonged neutropenia and breaks in the mucocutaneous barrier resulting from the HSCT preparative regimens and frequent vascular access required for patient care. Consequently, oral, gastro-intestinal, and skin flora are sources of infection. Prevalent pathogens include Candida species, and as neutropenia continue Aspergillus species. Additionally, herpes simplex virus (HSV) reactivation can occur during this phase.

Phase II, Post- engraftment. Phase II is dominated by impaired cell-mediated immunity for allogeneic or autologous recipients. Impacts of this defect for allogeneic recipients are determined by the extent of Graft Versus Host Disease (GVHD) and its immunosuppressive therapy. After engraftment, the herpes viruses, particularly CMV, are critical pathogens. At 30–100 days after HSCT, CMV causes pneumonia, hepatitis, and colitis and potentates super infection with opportunistic pathogens, particularly among patients with active GVHD. Other dominant pathogens during this phase include Pneumocystis jirovecii and Aspergillus species.

Phase III, late phase. During phase III, autologous recipients usually have more rapid recovery of immune system function and, therefore, a lower risk for oppertunistic infections than do allogeneic recipients. Because of cell-mediated and humoral immunity defects and impaired reticuloendothelial system function, allogeneic patients with chronic

GVHD and recipients of alternate donor allogeneic transplants are at risk for certain infections during this phase. Alternate donors include matched unrelated, UCB, or mismatched family-related donors. These patients are at risk for infections that include CMV, Varicella-Zoster virus (VZV), EBV-related post transplant lymphoproliferative disease, community-acquired respiratory viruses (CRV), and infections with encapsulated bacteria (e.g., H. influenzae and Strept. pneumoniae).

Preventing Transmission of Infections from HSCT Donors to Recipients
All prospective HSCT donors should be evaluated through a physical history and examination to determine their general state of health and whether they pose a risk for transmitting infectious diseases to the recipient. Initial donor screening and physical examination should be performed ≤ 8 weeks before the planned donation. Donor serologic testing should be done ≤30 days before donation to detect potentially transmissible infections. Screening and testing should be done on all allogeneic or syngeneic donors. Screening and testing of autologous donors is recommended to ensure the safety of laboratory personnel and to prevent cross contamination. Acute or chronic illness in the prospective donor should be investigated to determine the etiology. Generally, persons who are ill should not be HSCT donors. A flu-like illness in a prospective donor at the time of evaluation or between the time of evaluation and donation should prompt evaluation of and serologic testing for infections that might pose a risk to the recipient (e.g., EBV, CMV, Toxo. gondii). Prospective donors with symptoms of active TB should be evaluated for that disease.

The medical history of the prospective HSCT donor should include the following:

  1. History of vaccinations during the 4 weeks before donation.
  2. Travel history to determine whether the donor has ever resided in or traveled to countries with endemic diseases that might be transmitted through HSCT (e.g., Malaria)
  3. History of any deferral from plasma or blood donation.
  4. History of Viral hepatitis.
  5. History of blood product transfusion, solid organ transplantation, or transplantation of tissue within the last 12 months.
  6. Past medical history that indicates the donor has clinical evidence of or is at high risk for acquiring a blood borne infection (e.g., HIV-1 or -2, Human T-lymphotropic virus [HTLV]-I or -II, Hepatitis C, or Hepatitis B). 

The following serologic tests should be performed for each prospective donor:

1.HIV-1 antigen, anti-HIV-1 and -2, anti-HTLV-I and -II, hepatitis B surface antigen, total antihepatitis B core antigen, antihepatitis C, anti-CMV, and a serologic test for syphilis.

2. Nucleic acid tests to detect hepatitis C virus RNA and HIV RNA are currently being used to screen blood donors and could be used for screening HSCT donors.

All infectious disease testing and results should be reported to the HSCT physician before the candidate’s conditioning regimen begins.

Preventing infections among HSCT recipients is preferable to treating infections. However, despite recent technologic advances, more research is needed to optimize health outcomes for HSCT recipients. Efforts to improve immune system reconstitution, particularly among allogeneic transplant recipients, and to prevent or resolve the immune dysregulation resulting from donor-recipient histo-incompatibility and GVHD remain substantial challenges for preventing recurrent, persistent, or progressive infections among HSCT patients.

Dr. Soumyakanta Sahoo. MD, PDCC (Infectious Diseases)
Asst. Professor, Department. of   Microbiology,
Kalinga Institute of Medical Sciences, Bhubaneswar
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