STEPTRACKERIMMUNOLOGY + HEMATOLOGY | HYPERSENSITIVITY | HIGH-YIELD REVIEW

Type IV Hypersensitivity & Transfusion Reactions

Type IV is the only T-cell–mediated hypersensitivity — slow (48–72 h), no antibody, not transferable by serum. Transfusion reactions mix several types and must be told apart quickly.

FOCUS ON
Type IV: sensitized CD4⁺ Th1 cells release IFN-γ → macrophages (delayed-type: PPD, contact dermatitis, granulomas) or CD8⁺ cells kill directly (type 1 diabetes, Hashimoto, graft rejection, SJS/TEN). Examples: contact dermatitis (nickel, poison ivy, neomycin), PPD reaction, MS, Guillain-Barré, RA, celiac, Crohn, sarcoid, candida skin test, drug reactions (DRESS). Transfusion reactions: acute hemolytic (ABO mismatch, type II; fever, flank pain, hemoglobinuria, DIC — minutes), febrile non-hemolytic (cytokines from donor WBCs; leukoreduce), allergic (type I; urticaria; antihistamine), anaphylactic (IgA-deficient recipient with anti-IgA), TRALI (donor anti-HLA/HNA antibodies → noncardiogenic edema within 6 h), TACO (volume overload), delayed hemolytic (anamnestic, 2–10 days), transfusion-associated GVHD (irradiate).
REACTION
MECHANISM · TIMING
CLINICAL PICTURE
PREVENT · TREAT
Contact dermatitis
IV · haptens (nickel, poison ivy urushiol, neomycin, latex additives) · 48–72 h
Itchy, vesicular, sharply bordered rash where contact occurred
Patch test · avoid, topical steroids
Tuberculin (PPD) reaction
IV · memory Th1 cells · 48–72 h
Induration at injection site
Anergy in AIDS, sarcoid, steroids → false negative
Granulomatous inflammation
IV · Th1 + IFN-γ + TNF-α → epithelioid macrophages, giant cells
TB, sarcoidosis, leprosy, Crohn, fungi
TNF blockers break granulomas
CD8⁺-mediated diseases
IV · direct cytotoxicity
Type 1 diabetes (β cells), Hashimoto, viral hepatitis damage, SJS/TEN, acute graft rejection
—
Severe drug reactions
IV · drug-specific T cells (HLA-linked)
SJS/TEN (sulfonamides, allopurinol, carbamazepine, lamotrigine), DRESS (fever, rash, eosinophilia, organ involvement 2–8 weeks)
Stop drug · HLA-B*58:01 (allopurinol), B*15:02 (carbamazepine)
Acute hemolytic transfusion reaction
II · preformed anti-A/anti-B (IgM) → intravascular complement lysis · minutes
Fever, chills, flank pain, hypotension, hemoglobinuria, DIC, AKI
Stop transfusion, fluids · clerical error usual cause · ⁺ direct Coombs, ↓ haptoglobin
Febrile non-hemolytic reaction
Cytokines from donor leukocytes accumulated in stored blood · within 1–6 h
Fever, chills; no hemolysis
Most common · leukoreduced products, antipyretics
Allergic transfusion reaction
I · recipient IgE to donor plasma proteins
Urticaria, itching
Antihistamine; may continue
Anaphylactic transfusion reaction
I · IgA-deficient recipient with anti-IgA
Shock, angioedema within minutes
Epinephrine · future: washed or IgA-deficient products
TRALI
Donor anti-HLA/anti-neutrophil antibodies activate recipient neutrophils in lung · within 6 h
Hypoxemia, bilateral infiltrates, fever, hypotension; normal PCWP
Supportive · defer female multiparous plasma donors
TACO
Volume overload · within hours
Pulmonary edema, hypertension, ↑ BNP, JVD
Slow rate, diuretics
Delayed hemolytic reaction
II · anamnestic IgG to minor antigens (Kidd, Rh) · 2–10 days
Mild fever, falling Hb, jaundice; extravascular
New ⁺ antibody screen, ⁺ DAT
Transfusion-associated GVHD
Donor T cells attack an immunocompromised or HLA-similar recipient · 1–6 weeks
Rash, diarrhea, hepatitis, pancytopenia (marrow attacked) — often fatal
Irradiate products for at-risk patients

Mechanism — delayed-type hypersensitivity

Hapten or antigenProcessed by APC
→
Memory Th1 cells recognize it
→
IFN-γ, TNF-α
→
Macrophages recruited, activatedInduration at 48–72 h

Transferred by T cells, not by serum — the defining experimental feature of type IV.

Four types at a glance

TYPE
MEDIATOR
TIMING
EXAMPLE
I
IgE, mast cells
Minutes
Anaphylaxis
II
IgG/IgM on fixed antigen
Hours–days
AIHA, Goodpasture
III
Immune complexes
Days–weeks
Serum sickness, SLE
IV
T cells
48–72 h
Contact dermatitis, PPD

How it's tested

COMMON CONFUSIONTRALI (normal fluid status, donor antibodies, hypotension) vs TACO (fluid overload, hypertension, ↑ BNP) — both cause pulmonary edema during transfusion.
THE TRAPFever with flank pain and red urine minutes into a transfusion is acute hemolysis until proven otherwise — stop the transfusion first.
YOUR APPROACHTiming after exposure + mediator (antibody vs T cell) → type → for transfusions: minutes vs hours vs days, and fever, urticaria, dyspnea or hemolysis.

If you see… think…

Itchy vesicles under a watch buckle → nickel contact dermatitis (type IV)
Induration 48 h after PPD → type IV (Th1)
Only hypersensitivity not mediated by antibody → type IV
Fever, flank pain, hemoglobinuria minutes into transfusion → ABO acute hemolysis
Fever and chills only, no hemolysis → febrile non-hemolytic (leukoreduce)
Anaphylaxis during transfusion in a patient with recurrent sinusitis → IgA deficiency
Bilateral infiltrates, hypoxemia, normal PCWP within 6 h → TRALI
Jaundice and falling Hb a week after transfusion → delayed hemolytic reaction
Rash, diarrhea, pancytopenia after transfusion in SCID → transfusion-associated GVHD
Prevention of transfusion GVHD → irradiated blood