immunosuppression & opportunistic infections

The Vulnerable Host

Evaluation requires pinpointing the specific arm of the immune system involved (T-cell, B-cell, Phagocytic, or Complement). Management integrates the Net State of Immunosuppression (host factors + drug effects) with the Timeline of Risk (post-transplant or chemo phase). “Generic” immunosuppression does not exist; risk is pathogen-specific based on the defect.

approach to suspected immunodeficiency

Distinguish Primary (rare, genetic) from Secondary (common: meds, malignancy, HIV, protein loss).

1. clinical clues (“SPUR”)

Suspect immunodeficiency if infections are:

• Severe (requiring IV antibiotics, ICU admission, hospitalization).
• Persistent (poor response to standard therapy).
• Unusual (opportunistic bugs, abscesses in odd organs).
• Recurrent ($\ge$ 2 pneumonias/year, $\ge$ 4 ear infections/year, recurrent abscesses).

2. initial screening (the “consult bundle”)

Before calling Immunology, rule out the big hitters.

• HIV Screen: Mandatory in all adults with recurrent infection. HIV mimics primary T-cell defects.
• CBC + Diff: Screen for neutropaenia, lymphopaenia (T-cell proxy), or thrombocytopaenia (Wiskott-Aldrich).
• Quantitative Immunoglobulins: IgG, IgA, IgM.
  • Low IgG/A/M: Suggests CVID or secondary hypogammaglobulinaemia.
  • Low IgA only: Selective IgA deficiency (common; risk of anaphylaxis with IVIG).
• Anatomic Evaluation: CT Chest (bronchiectasis), structural ENT issues.
• Metabolic: Diabetes (HbA1c), Uraemia, Cirrhosis.

3. advanced/functional testing

If screen is normal but suspicion remains, assess function.

• Humoral (B-Cell): Vaccine Challenge (Tetanus, Pneumococcal). Failure to mount titre rise = Functional Antibody Deficiency.
• Cellular (T-Cell): Flow cytometry for lymphocyte subsets (CD4, CD8, NK cells).
• Phagocyte: Dihydrorhodamine (DHR) flow cytometry (screens for Chronic Granulomatous Disease).
• Complement: CH50/AH50. Screen for recurring Neisseria.

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timelines of risk & stratification

the “net state” of immunosuppression

Integrate drug effects with host factors: age, malnutrition, uncontrolled hyperglycaemia (impaired neutrophil chemotaxis), and hardware (CVLs, urostomies).

solid organ transplant (SOT) timeline

• 0–1 Month (Surgical/Nosocomial): MRSA, VRE, C. diff, SSI, aspiration.
• 1–6 Months (The “Opportunistic Window”): Peak immunosuppression. CMV, PJP, BK virus, Nocardia, Listeria, Toxoplasma.
• >6 Months (Community/Late OI): CAP, UTIs, or late-onset CMV/PJP if prophylaxis stopped.

HSCT & leukaemia phases

• Pre-Engraftment (Days 0–21): Profound neutropaenia ($<0.5$) and mucositis. Risk: Gram-negatives, Candida, HSV.
• Post-Engraftment (Days 21–100): Impaired cellular immunity + GVHD. Risk: CMV, Aspergillus, PJP.
• Late Phase (>100 Days): Functional asplenia (if chronic GVHD). Risk: Encapsulated organisms (S. pneumo).

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immune defects & associated pathogens

Defect Type	Primary/Secondary Causes	Characteristic Pathogens
Neutropaenia (Phagocyte Qty)	Chemo, Aplastic Anaemia, Drug-induced	Pseudomonas, S. aureus, Aspergillus, Candida, Enterobacteriaceae.
Phagocyte Function	CGD, Chediak-Higashi	S. aureus, Aspergillus, Nocardia, Serratia, Burkholderia.
Humoral (B-cell) (Ab deficiency)	CLL, Multiple Myeloma, Asplenia, Rituximab	Encapsulated: S. pneumoniae, H. influenzae, N. meningitidis. Giardia, Enteroviruses.
Cellular (T-cell)	HIV, Organ Transplant, Steroids, Anti-TNF	Intracellular: Listeria, Salmonella, Mycobacteria, Viruses (CMV/VZV), Fungi (PJP, Crypto), Toxoplasma.
Complement	C5-C9 deficiency, Eculizumab	Neisseria species.

clinical pearl : listeria

Listeria monocytogenes is a marker of T-cell deficiency. It is intrinsically resistant to cephalosporins. If suspected, add Ampicillin.

haematological malignancy & immunodeficiency

Malignancy is a major cause of secondary hypogammaglobulinaemia.

multiple myeloma & CLL

• Mechanism: Malignant clone suppresses normal plasma cells (“Immunoparesis”). Therapies (Anti-CD38, Anti-BCMA) further deplete B-cells.
• Diagnosis:

  • the protein gap

  • High Total Protein + Normal Albumin = Elevated Globulin. In Myeloma, this is non-functional IgG. Patient is immunocompromised despite “high” levels.
• Management:
  • IVIG: Indicated only if IgG < 4g/L AND recurrent severe infections (per Canadian Blood Services criteria).

iatrogenic immunosuppression

corticosteroids

Risk is dose and duration dependent.

• Mechanism: Demargination (apparent neutrophilia), T-cell sequestration.
• Threshold: $\ge$ 20 mg/day Prednisone (or equivalent) for $\ge$ 4 weeks warrants PJP prophylaxis. Consider starting at 2 weeks if patient remains steroid-dependent.

biologic & targeted agents

• Anti-TNF$\alpha$ (Infliximab): High risk for TB/Hep B reactivation.
• Anti-CD20 (Rituximab) & BTK Inhibitors (Ibrutinib): B-cell depletion. High risk for HBV reactivation.
• Anti-CD52 (Alemtuzumab): Profound, sustained T/B-cell depletion. Requires extended prophylaxis (PJP/Viral/Fungal).
• JAK Inhibitors: High risk Herpes Zoster.
• Immune Checkpoint Inhibitors (ICIs):
  • Risk stems from immunosuppression used to manage irAEs (e.g., high dose steroids for colitis).
  • Start PJP prophylaxis if on prolonged steroids for irAEs.

screening & monitoring

pre-treatment screening

Mandatory before potent immunosuppression (chemo, biologics, transplant):

1. Hepatitis B: Check HBsAg, Anti-HBc (total), Anti-HBs.
   • Action: If Anti-HBc positive (even if HBsAg negative), start prophylaxis (e.g., Entecavir or Tenofovir) to prevent fulminant hepatitis.
2. Latent TB: IGRA (preferred) or TST.
3. Endemic Infections:
   • Strongyloides: Serology for anyone with travel/residence in endemic areas. Treat (Ivermectin) before steroids to prevent hyperinfection.

monitoring during treatment

• Viral Loads: Quantitative CMV/EBV/BK PCR in transplant (D+/R-).
• Fungal Markers:
  • Galactomannan (GM): Specific for Aspergillus.
  • 1,3-Beta-D-Glucan (BDG): “Pan-fungal” (Candida, PJP, Aspergillus).
• Drug Interactions:

  • interaction alert

  • Azole antifungals (Voriconazole) inhibit CYP450, drastically increasing Calcineurin Inhibitors levels.

prophylaxis guidelines

Canadian Context: General oncology follows IDSA/ASCO guidelines. HIV protocols follow BC Centre for Excellence.

PJP (Pneumocystis jirovecii)

• Indications:
  • HIV: CD4 < 200 cells/mm${}^3$ or CD4% < 14%.
  • Non-HIV: See BC Renal / Ontario Renal Network guidelines. Generally:
    • Prednisone $\ge$ 20mg for $\ge$ 4 weeks.
    • Fludarabine or Cladribine (mandatory).
    • Cyclophosphamide or Alemtuzumab use.
    • “Triple Therapy” in transplant.
• Regimens:
  1. First Line: Cotrimoxazole (TMP-SMX) 1 DS daily or TIW.
  2. Alternatives: Dapsone (Check G6PD!), Atovaquone.

HIV specific thresholds

CD4 Count	Pathogen	Prophylaxis
< 200	PJP	Septra DS daily
< 100	Toxoplasma	Septra DS daily (covers both)
< 100	Cryptococcus	Serum CrAg screen (no primary prophylaxis)
< 50	MAC	(Rarely used if ART started immediately)

clinical pearl : IRIS

Immune Reconstitution Inflammatory Syndrome: Clinical worsening after starting ART. Immune system “wakes up” and attacks an existing OI (TB/Crypto). Do not stop ART; treat inflammation.

viral prophylaxis

• VZV/HSV: Acyclovir/Valacyclovir for HSCT/Leukemia induction and proteasome inhibitors.
• Measles (Post-Exposure):

  • public health pearl

  • Public Health Ontario/CIG: Immunocompromised contacts of measles require Ig Prophylaxis (IVIG or IMIG) regardless of vaccination status. MMR vaccine is contraindicated.
• CMV: Pre-emptive therapy (monitor PCR) preferred over universal prophylaxis in many centres.

asplenia management

For patients with functional or surgical asplenia (e.g., Sickle Cell, Trauma).

• Vaccines: “Big 3” (Pneumococcal, Meningococcal, H. influenzae b).
• Emergency Supply: Standby Amoxicillin-Clavulanate or Levofloxacin for immediate use if Temp > 38.3°C or rigors.

vaccination principles

Reference: Canadian Immunization Guide (Part 3).

1. Live Vaccines: Generally CONTRAINDICATED. (MMR, Varicella, Yellow Fever).
2. Inactivated Vaccines: Safe but immunogenicity reduced.
   • Pneumococcal: PCV20 (or PCV15 + PPSV23).
   • Influenza: Annual inactivated injection mandatory.
3. Paediatrics: Refer to Canadian Paediatric Society (CPS) position statements for “Safe Living Strategies” (school, pets, travel) for the immunocompromised child.

immune reconstitution & biologic therapy

immunoglobulin replacement (IVIG/SCIG)

• Supply: Managed by Canadian Blood Services. No cost to patient if criteria met.
• Indications:
  • Primary: CVID, XLA.
  • Secondary: IgG < 4 g/L AND recurrent severe infections.
• Routes:
  • IVIG: Hospital based. Peak/trough effects.
  • SCIG: Home based. Steady levels. Fewer systemic side effects.

G-CSF (Filgrastim)

• Indications:
  1. Severe Congenital Neutropenia: Lifelong.
  2. Chemotherapy: Primary prophylaxis if Febrile Neutropenia risk > 20% (ASCO/CCO Guidelines).
  3. Febrile Neutropenia: Only if high risk for sepsis/death.

red flag : febrile neutropaenia

Defined as Temp > 38.0°C (sustained 1hr) or >38.3°C (single) + ANC < 0.5.

• Action: Medical Emergency. Door-to-needle target < 60 mins. Cultures x2 $\to$ Empiric Anti-Pseudomonal Beta-lactam (Piperacillin-Tazobactam or Meropenem).
• Imaging: CXR lacks sensitivity. Early CT Chest is gold standard (look for “Halo Sign” of Aspergillus).
• Do NOT wait for imaging or lumbar puncture.

related pages: Febrile Neutropaenia, HIV, Sepsis, Pneumonia, Multiple Myeloma