Infections After High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation

Risk factor for infection

Risk category

Low

High

1. Pretransplant

General condition including organ function

Performance status

Good

Poor

Renal failure

Yes

Diabetes mellitus

Yes

Iron stores [1]

Normal or decreased

Increased

Age

Younger (<40 years)

Older (>65 years)

Smoking [1]

Yes

Underlying disease and its treatment

Tumor burden

None

Large

Disease-related immunosuppression^a

Absent

Present

Prior chemotherapy

None or minimal

Extensive

Receipt of purine analogues (fludarabine, cladribine, clofarabine) or monoclonal antibodies (rituximab, alemtuzumab)

Yes

Exposure to pathogens

Prior history of infection^b

Yes

Colonization with pathogens (bacteria, fungi)

Yes

Immunogenetics

Deficiency of MBL [2, 3]

Yes

2. Pre-engraftment period

Duration of neutropenia [1]

Short (<7 days)

Long (>10 days)

Stem cell source

Peripheral blood

Bone marrow

Quantity of stem cells infused^c

>5 × 106/Kg CD34+ cells

<2 × 106/Kg CD34+ cells

Severity of oral and gastrointestinal mucositis

Absent or mild

Severe

Conditioning regimen

Less intensive

Intensive

Polymorphisms of genes associated with metabolism of chemotherapeutic agents (pharmacogenetics)

Absent

Present

Renal failure^d

Absent

Present

Exposure to pathogens

Nosocomial exposure to potential pathogens (water and airborne pathogens such as Legionella, Aspergillus spp. and other molds, resistant bacteria, respiratory viruses)

Yes

3. Post-engraftment

T cell immune reconstitution

Fast

Delayed

Prior chemotherapy [4]

Minimal

Extensive

CMV serostatus [5]

Negative

Positive

Need for additional chemotherapy to control the underlying disease^e

Yes

In vitro manipulation of stem cells^c [6, 7]

Yes

Exposure to pathogens

Prior history of infection^b

Yes

Community-acquired infections, especially respiratory viruses

Yes

MBL mannose-binding lectin, TLR Toll-like receptors, CMV cytomegalovirus

^aMost common disease-related immunosuppression include: hypogammaglobulinemia (multiple myeloma, low-grade B-cell non-Hodgkin’s lymphoma, chronic lymphocytic leukemia), T-cell mediated immunodeficiency (Hodgkin’s lymphoma and certain types of non-Hodgkin’s lymphoma) and neutrophil dysfunction (acute myeloid leukemia with myelodysplasia)

^bInfections with higher risk of recurrence after autologous hematopoietic stem cell transplantation include: mycobacteriosis (tuberculosis and others), aspergillosis, pneumocystosis, cytomegalovirus, herpes simplex and varicella-zoster virus, and toxoplasmosis and strongyloidiasis

^cIn vitro manipulation of stem cells decreases the content of CD34+ and T cells, increasing the duration of neutropenia in the early post-transplant period and delaying T cell immune reconstitution after transplant

^dRenal failure increases the risk of severe mucositis in patients with multiple myeloma receiving melphalan-based conditioning regimens

^eNeed for additional chemotherapy in lymphoma and acute myeloid leukemia is usually related to relapse of the underlying disease, whereas in multiple myeloma additional chemotherapy is usually part of the treatment strategy

An important and difficult element of risk assessment in autologous HSCT recipients is to quantify the risk associated with the status of the underlying disease and prior therapies. For example, a patient with MM who undergoes a first autologous HSCT after having received a short course of induction therapy with dexamethasone plus thalidomide and whose disease is under control is at lower risk for certain infections compared with a patient with the same underlying disease, but who is receiving a third or fourth autologous HSCT in the setting of relapse after multiple treatment lines.

4.2 Risk for and Epidemiology of Infection

Immunodeficiency is the key risk factor for infection in autologous HSCT recipients. It is a result of interplay between the underlying disease and its therapy and may involve breakdowns in skin and mucous membrane barriers, qualitative and quantitative defects in various arms of the immune system including innate immunity (neutropenia, neutrophil dysfunction), impaired production of immunoglobulins, and defective cell-mediated immunity (CMI). While autologous HSCT recipients have deficits in various arms of the immune system, the nature of the pathogens causing infection is frequently determined by the immunodeficiency that is predominant at a given time (Tables 4.2 and 4.3).

Table 4.2

Immunodeficiency in autologous hematopoietic cell transplantation

	Disruption of skin and mucous membranes	Hypogamma‑globulinemia	T-cell mediated immunodeficiency	Neutropenia and neutrophil dysfunction
Immunodeficiency associated with untreated underlying disease
Acute lymphoid leukemia	+	+	+++	++
Acute myeloid leukemia	+	+	+	+++
Hodgkin’s lymphoma	+	−/+	+++	−/+
Non-Hodgkin’s lymphoma	+	−/+	+/+++	−/+
Multiple myeloma	−	+++	−/+	+
Immunodeficiency associated with the conditioning regimen
Corticosteroids	+	−	+++	+
Cytotoxic chemotherapy	−/+++^a	+/++	+/+++^a	−/+++^a
Monoclonal antibodies	−	+/++	+/+++	+/++
Use of catheters	+++	−	−	−

(−) no, (+) mild, (++) moderate, (+++) severe

^aSeverity of mucositis and neutropenia depend on the intensity of the conditioning regimen; duration of neutropenia also depends on the stem cell dose infused and the in vitro manipulation of the stem cell product

Table 4.3

Frequent pathogens causing infection according to immunodeficiency

	Disruption of skin and mucous membranes	Hypogamma‑globulinemia	T-cell mediated immunodeficiency	Neutropenia and neutrophil dysfunction
Bacteria
Gram-positive cocci
Coagulase-negative staphylococci	+++	−	−	++
Staphylococcus aureus	+++	−	−	++
Viridans streptococci	+++	−	−	++
Enterococci	++	−	−	++
Streptococcus pneumoniae	−	+++	−	−
Gram-positive bacilli
Bacillus spp.	++	−	+	++
Corynebacterium jeikeium	++	−	+	++
Listeria monocytogenes	−	−	+++	−
Gram-negative bacilli
Enterobacteriaceae^a	++	−	−	+++
Pseudomonas aeruginosa	++	−	−	+++
Other nonfermentative bacteria^b	++	−	−	+++
Salmonella spp.	+	+	++	+
Legionella spp.	−	++	++	−
Anaerobes
Clostridium difficile	++	−	−	++
Clostridium septicum	++	−	−	++
Fungi
Yeasts
Candida spp.^c, mucosal disease	+	−	+++	−
Candida spp.^c, invasive disease	++	−	−	+++
Cryptococcus neoformans ^a	−	−	+++	−
Trichosporon spp.	++	−	+	++
Molds (mainly Aspergillus spp.)^d	−	−	++	+++
Other
Pneumocystis jirovecii	−	−	+++	−
Viruses
Herpes simplex	++	−	+++	++
Varicella-zoster	−	−	+++	−
Cytomegalovirus	−	−	+++	−
Epstein-Barr virus	−	+	+++	−
Respiratory viruses^e	+	+	++	−
Hepatitis A, B and C	−	+	+	−
Parvovirus B 19	−	++	++	−
Parasites
Strongyloides stercoralis	−	−	++	−
Toxoplasma gondii	−	−	++	−
Cryptosporidium parvum	−	+	++	−
Mycobacteria
Mycobacterium tuberculosis	−	−	+++	−
Rapid growing mycobacteria	++	−	+	−
Mycobacterium avium complex	−	−	+++	−