Immunosuppression: An overview of infection risk

Russell E. Lewis

2026-03-01

Immununosuppression:
An Overview of Infection Risk

Prof. Russell E. Lewis
Department of Molecular Medicine
University of Padua

russelledward.lewis@unipd.it
https://github.com/Russlewisbo

slides available at: www.padovaid.com

Introduction & Epidemiology

The growing population of immunocompromised hosts

• Estimated 5-6% of the Italian population is immunocompromised (Martinson and Lapham, 2024)
• 1% of children fall into cohort of immunocompromised (VERDI project)
• 2.8% meet criteria for drug-induced immunosuppression (Wallace et al., 2021)

This is a rapidly growing population due to advances in transplantation, cancer therapy, and treatment of autoimmune diseases. The definition of “immunocompromised” varies significantly, which affects estimates.

What causes immunocompromise?

Major categories:

• Active treatment (chemotherapy) for malignancies
• Solid organ transplant (SOT)
• Hematopoietic cell transplant (HCT)
• CAR-T cell therapy
• Primary immunodeficiency
• Advanced HIV infection
• High-dose corticosteroids & biologics

The net state of immunosuppression

Defining net state of immunosuppression

A concept by Dr. Robert Rubin (Massachusetts General Hospital-Harvard, Boston):
“Father” of transplant infectious diseases”

“Composite of host factors, underlying disease, treatment, and other factors contributing to infection risk”

This remains one of the most useful conceptual frameworks for thinking about infection risk in immunocompromised patients. It emphasizes that no single test can quantify immunosuppression—clinical judgment integrating multiple factors is required.

Components of the “net immunosuppresed state”

Host Factors

• Advanced age
• Malnutrition
• Diabetes
• Organ dysfunction
• Hypogammaglobulinemia

Treatment Factors

• Immunosuppressive drugs
• Chemotherapy
• Radiation
• Surgery/hardware
• Duration of therapy

Components (continued)

Underlying Disease

• Autoimmune disease
• Malignancy type
• Organ failure stage

Infectious Factors

• HIV, CMV, EBV status
• Microbiome alterations
• Prior infections

Infectious Complications & Mortality

SOT Recipients

• 6% died from infection within first year (Swiss cohort) (Delden et al., 2020)
• 55% had infections in first year (German renal cohort) (Sommerer et al., 2022)
  • Half occurred in first 3 months
  • Bacteria: 66%, Viruses: 29%, Fungi: 5%

SOT recipients face particular risks from surgical complications, hardware-related infections, and the combination of surgical stress plus immunosuppression in the early post-transplant period.

Hematopoetic stem cell transplantation (HSCT) recipients

Type	Stem Cell Source	Donor	Immunosuppression
Autologous	Peripheral blood, Bone marrow	Self	Moderate; no GvHD prophylaxis required; recovery within weeks
Allogeneic — matched related	Peripheral blood, Bone marrow, Umbilical cord blood	HLA-matched sibling or family member	Severe; prolonged due to GvHD prophylaxis and risk of GvHD
Allogeneic — matched unrelated (MUD)	Peripheral blood, Bone marrow, Umbilical cord blood	HLA-matched unrelated donor (registry)	Very severe; higher GvHD risk than matched related; intensive prophylaxis
Allogeneic — haploidentical	Peripheral blood, Bone marrow	Half-matched family member (parent, child, sibling)	Very severe; requires intensive T-cell depletion or post-transplant cyclophosphamide
Allogeneic — umbilical cord blood	Umbilical cord blood	Unrelated cord blood unit	Very severe; delayed immune reconstitution due to low cell dose

Allogeneic hematopoetic stem cell
transplantation (HSCT) recipients

• Infection is 2nd leading cause of mortality (after relapse) (Jenq and Brink, 2010)
• First 100 days: 19-21% mortality attributed to infection (D’Souza and Fretham, 2018)
• Long-term survivors (>2 years): 30% mortality from infection (Norkin et al., 2019)

Timeline of Infection Risk

What is CAR-T therapy?

Immunosuppression timeline with CAR-T

CAR-T: Chimeric antigen receptor T-cell therapy; CRS-cytokine release syndrome; ICANS-Immune cell-associated neurological syndrome (Maus and Lionakis, 2020)

CAR-T cell therapy

• Patients are profoundly immunosuppressed
• Up to 1/3 suffer serious bacterial infection in first 30 days (Stewart and Henden, 2021)
• Cytokine release syndrome complicates assessment
• Prolonged B-cell aplasia → hypogammaglobulinemia

Measuring Immunosuppression

Available Markers

Useful in HIV:

• CD4 count
• CD4 percentage
• CD4/CD8 ratio

General markers:

• Neutrophil count
• Lymphocyte count
• Immunoglobulin levels

Unfortunately, we lack reliable composite markers or algorithms to predict infection risk in most immunocompromised populations outside of HIV. Clinical judgment remains essential.

Emerging biomarkers

• Viral reactivation (EBV, CMV, TTV, BK) → correlates with immunosuppression
• QuantiFERON Monitor → may identify over-immunosuppression
• ImmuKnow assay → correlates with infection/rejection risk
• Traditional markers (ESR, CRP, procalcitonin) → NOT predictive

PHA- Phytohemagglutinin (T-cell mitogen-polyclonal activation); 👉 ATP = proxy for T-cell activation strength

Sources of Infection

Community-acquired pathogens

• Most common infections mimic community pathogens
• Immunocompromised patients are often “sentinel cases” in outbreaks
• Respiratory viruses, GI pathogens
• Norovirus, C. difficile

Healthcare-associated pathogens

• Increased risk of MDR organisms due to frequent healthcare contact
• Catheter-related infections
• Pneumonia
• UTI

Reactivation of latent infections

Key pathogens to screen for and monitor:

• Mycobacterium tuberculosis
• Strongyloides
• Hepatitis B
• Coccidioides, Histoplasma
• Trypanosoma cruzi (Chagas)

Donor-derived infections

• Organ transplant
• Stem cell transplant
• Blood products
• Usually within first 6 months
• Most common infections:
  • Cytomegalovirus
  • Epstein-Barr virus (post-transplant lymphoproliferative disease)
  • Herpes simplex and varicella zoster
  • Hepatitis B,C
  • HIV
  • Bacterial infections
  • Fungal infections (Candida, Aspergillus)

Components of Host Defense

Overview of immune system

Innate Immunity

• Granulocytes
• Monocytes/Macrophages
• NK cells
• Complement
• Physical barriers

Acquired Immunity

• Cellular (T cells)
• Humoral (B cells)
• Antibody production

Granulocytes (neutrophils)

• Chemotherapy & radiation → neutropenia

• Duration: 3-4 weeks or longer

• Primary risk factor for infection

• Risk increases with:

  • Depth of neutropenia
  • Duration of neutropenia

• Concurrent organ dysfunction

Corticosteroid effects on neutrophils

Paradoxical effects:

• ↑ Granulocytopoiesis (apparent benefit)
  • BUT: ↓ Accumulation at infection site
• ↓ Adherent capacity
• ↓ Chemotaxis
• ↓ Phagocytosis
• ↓ Intracellular killing

Monocytes & macrophages

• Monocytopenia parallels neutropenia
• Macrophage activation requires T-cell cytokines (IFN-γ)
• Explains cellular immunodeficiency susceptibility
• Targeted therapies can have unexpected effects

Ibrutinib is a good example—designed as a BTK inhibitor for B cells, but has broader effects on macrophage function contributing to aspergillosis risk.

Ibrutinib

Unexpected fungal infections

NK cells and platelets

NK Cells:

• Respond to viruses and malignancy
• CD56 receptor → Aspergillus recognition
• Dysfunction contributes to fungal susceptibility

Platelets:

• Increasingly recognized immune role

• Thrombocytopenia → independent bacteremia risk

• Protection against yeast and molds

Cellular immunity

Drugs that impair T-cell function:

• Corticosteroids
• Azathioprine, cyclosporine, tacrolimus
• mTOR inhibitors (sirolimus, everolimus)
• Purine analogues (fludarabine, cladribine)
• Alemtuzumab

Diseases: Hodgkin lymphoma, CLL

Targeted therapy risks

Drug	Mechanism	Infection Risk
Ruxolitinib	JAK-STAT inhibitor	TB, HBV reactivation
Ibrutinib	BTK inhibitor	Aspergillosis, PJP
Idelalisib	PI3K inhibitor	P. jirovecii

If you see a drug ending in “mab” or “nib” or “sib” ….consider unique infection risk

mab- monoclonal antibody-large protein biologic usually IV that binds extracellular targets (receptors, cytokines, cells); nib-small molecule inhibitor, usually oral- Enters cells and block intracellular signaling pathways;sib- signal inhibitor or nib-like drug

Humoral immunity

• B cells → antibody-secreting plasma cells
• Impaired in CLL, multiple myeloma
• Rituximab, CAR-T → B-cell depletion
• Profound, long-lasting hypogammaglobulinemia

Splenectomy: Loss of encapsulated bacteria defense-big 3

• Streptococcus pneumoniae

• Haemophilus influenzae type B

• Neisseria meningitidis

Less common: Capnocytophaga canimorsus, Salmonella spp. E. coli

PSV and PPSV23 vaccine, MENACWY and MenB vaccine, HIB, Influenzae- Vaccinate 2 weeks before elective splenectomy or 2 weeks after emergency splenetocmy

Physical Barriers

The Integument

Skin:

• Chemotherapy → hair loss, dryness
• Catheters → direct microbial access
• Broken skin → S. aureus, gram-negatives

Oropharynx:

• Xerostomia + antibiotics → thrush, bacterial overgrowth

Alimentary Tract

• Microbiome disruption with antibiotics→ C. difficile
• Mucosal barrier injury from chemotherapy
• Facilitates bacterial translocation
• With concomitant neutropenia allows progression to sepsis

Immunodeficiency-Pathogen Associations

Neutropenia: Gram-positive pathogens

• Coagulase-negative staphylococci more common than
  Staphylococcus aureus (most are from central venous catheter)
• Viridans streptococci
• Enterococci

Neutropenia: Gram-negative pathogens

• Escherichia coli
• Pseudomonas aeruginosa
• Klebsiella pneumoniae
• Enterobacter spp.

Impaired cellular immunity

Bacteria/Mycobacteria:

• Listeria monocytogenes

• Nocardia spp.

• M. tuberculosis

• Nontuberculous mycobacteria

Fungi/Parasites:

• P. jirovecii

• Aspergillus spp.

• Cryptococcus spp.

• Toxoplasma gondii

Impaired cellular immunity (viruses)

• Herpesviruses (HSV, VZV, CMV, EBV)
• Respiratory viruses
• Polyomaviruses (BK, JC)
• Human papillomavirus

Impaired humoral immunity

• Streptococcus pneumoniae
• Haemophilus influenzae
• Neisseria meningitidis
• Norovirus
• Hepatitis B virus

Prevention Strategies

Prophylaxis principles

TMP-SMX for PJP :typically 1 DS tablet daily also covers:

• Toxoplasma
• S. aureus
• Nocardia
• Many gram-positives/negatives

Antiviral prophylaxis: Val(acyclovir) for CMV (weak activity), HSV, VZV prevention. Valganciclovir or letermovir for higher risk CMV patients

Problem with TMP/SMX- rash, GI upset, and cytopenias—often limits adherence. Can use - 1 DS tablet 3×/week (e.g., Mon–Wed–Fri) or even single-strength daily. Add folic acid if patient has anemia or leukopenia. Valganciclovir is assocaited with dose-limiting myelosuppression. Letermovir has fewer adverse effects but is more expensive

Patient education

High-risk exposures to avoid:

• Gardening without protection (molds, Nocardia)
• Poor dental hygiene (Actinomyces, bacteremia)
• Marijuana smoking (Aspergillus)
• Raw seafood (Vibrio)
• Warm ocean swimming

Key Takeaways

Summary points

1. 6% of population is immunocompromised
2. Net state of immunosuppression = composite assessment
3. First 100 days after transplant = highest risk period
4. No single marker predicts infection risk
5. Know pathogen associations with specific defects
6. Prophylaxis significantly alters risk profile

Clinical Pearls

Remember

• TMP-SMX provides broader coverage than just PJP prophylaxis
• Timing matters—early vs late infections differ
• Targeted therapies have unexpected infection risks
• Consider the whole patient, not just the lab values

References

D’Souza A, Fretham C. Current uses and outcomes of hematopoietic cell transplantation (HCT): CIBMTR summary slides 2018.

Delden C van, Stampf S, Hirsch HH, et al. Burden and timeline of infectious diseases in the first year after solid organ transplantation in the Swiss transplant cohort study. Clinical Infectious Diseases 2020;71:e159–69. https://doi.org/10.1093/cid/ciz1113.

Jenq RR, Brink MRM van den. Allogeneic haematopoietic stem cell transplantation: Individualized stem cell and immune therapy of cancer. Nature Reviews Cancer 2010;10:213–21. https://doi.org/10.1038/nrc2804.

Martinson ML, Lapham J. Prevalence of immunosuppression among US adults. JAMA 2024;331:880–2.

Maus MV, Lionakis MS. Infections associated with the new ’nibs and mabs’ and cellular therapies. Current Opinion in Infectious Diseases 2020;33:281289. https://doi.org/10.1097/QCO.0000000000000656.

Norkin M, Shaw BE, Brazauskas R, et al. Characteristics of late fatal infections after allogeneic hematopoietic cell transplantation. Biology of Blood and Marrow Transplantation 2019;25:362–8. https://doi.org/10.1016/j.bbmt.2018.09.031.

Sommerer C, Schröter I, Gruneberg K, et al. Incidences of infectious events in a renal transplant cohort of the German Center of Infectious Diseases (DZIF). Open Forum Infectious Diseases 2022;9. https://doi.org/10.1093/ofid/ofac243.

Stewart AG, Henden AS. Infectious complications of CAR T-cell therapy: A clinical update. Therapeutic Advances in Infectious Disease 2021;8:20499361211036773. https://doi.org/10.1177/20499361211036773.

Wallace BI, Kenney B, Malani PN, et al. Prevalence of immunosuppressive drug use among commercially insured US adults, 2018-2019. JAMA Network Open 2021;4:e214920. https://doi.org/10.1001/jamanetworkopen.2021.4920.