Primary Immunodeficiency in Adults — Written Clinical Reasoning

SAQ 1 — Integrated Management of Newly Diagnosed CVID (15 marks, 25 minutes)

Prompt: Outline your integrated management plan for this patient with newly diagnosed common variable immunodeficiency, including: (a) the diagnostic criteria you are applying and why the diagnosis is secure, and the differential you have excluded; (b) the immunoglobulin replacement strategy with exact options, doses, and monitoring; (c) the surveillance plan for the non-infectious complications of CVID; (d) the patient education and lifestyle advice; and (e) the high-yield exam traps in adult humoral immunodeficiency management. [1]

Model Answer

(a) Diagnostic criteria and the excluded differential (3 marks): [1]

The diagnosis of CVID is established by the ICON consensus criteria: a marked decrease in IgG (below 5 g per litre) with a marked decrease in IgA and/or IgM; impaired antibody response to vaccines (this patient has poor pneumococcal polysaccharide response); onset after age 4 (excluding transient hypogammaglobulinaemia of infancy); and exclusion of secondary causes [3]. This patient meets all criteria: IgG 3.2 g per litre, IgA less than 0.07 g per litre, IgM 0.3 g per litre, poor pneumococcal response, onset in adulthood, and the secondary causes excluded — HIV negative, no protein-losing state (no nephrotic-range proteinuria or chronic diarrhoea beyond the resolved Giardia), no immunosuppressive drugs, and a normal serum electrophoresis would be sent to exclude multiple myeloma as a cause of secondary hypogammaglobulinaemia [2]. The clinical phenotype (recurrent sinopulmonary infection with encapsulated organisms, Giardia enteritis, autoimmune thrombocytopenia, splenomegaly) is the classic CVID presentation, and the 6-year diagnostic delay is itself typical — the median delay is 4 to 7 years [1]. Selective IgA deficiency is excluded by the low IgG and IgM; specific antibody deficiency is excluded by the hypogammaglobulinaemia; secondary hypogammaglobulinaemia from HIV or malignancy is excluded by the negative HIV test and the planned electrophoresis.

(b) Immunoglobulin replacement strategy (4 marks): [1]

The standard of care is lifelong immunoglobulin replacement therapy [5]. I would discuss the two routes with the patient and involve the specialist immunoglobulin nursing team:

• Intravenous immunoglobulin (IVIG): 400 to 600 mg per kg every 3 to 4 weeks, administered in a day-unit or clinic, producing peaks and troughs in IgG and carrying a higher rate of systemic reactions (headache, chills, myalgia, rarely aseptic meningitis).
• Subcutaneous immunoglobulin (SCIG): 100 to 200 mg per kg per week, self-administered at home via a pump into the abdominal wall or thighs, producing steady IgG levels without peaks and troughs, with fewer systemic reactions but more local infusion-site reactions. [1]

Both are therapeutically equivalent for preventing serious bacterial infection. The trough IgG target is above 5 to 7 g per litre and above the level at which the patient had breakthrough infection; the dose is individualised by clinical response (infection frequency). I would start at a dose calculated to reach a trough above 8 g per litre given her recent pneumonia with bacteraemia, and titrate over the first months. I would not use intramuscular immunoglobulin (obsolete). The immunoglobulin is NOT indicated for the thrombocytopenia specifically — ITP in CVID is managed with standard ITP treatments (corticosteroids already given, intravenous immunoglobulin for acute severe bleeding, rituximab or splenectomy in refractory cases), with the caveat that rituximab can worsen an unrecognised or partially treated humoral defect and that splenectomy increases the encapsulated-organism risk that is already high in CVID. [1]

(c) Surveillance for the non-infectious complications (4 marks): [1]

CVID is not just about infection — about 25 per cent of patients have autoimmune disease, and the lymphoma risk is markedly increased (non-Hodgkin lymphoma, 30 to 200-fold, predominantly B-cell marginal zone or MALT; and gastric carcinoma). The surveillance plan: [1]

• Respiratory: baseline and annual lung function (spirometry), and biennial chest computed tomography for bronchiectasis (she already has bilateral crackles and a history of recurrent pneumonia — bronchiectasis is likely present and requires airway clearance physiotherapy).
• Autoimmunity: annual full blood count (for autoimmune cytopenia — her ITP may relapse), thyroid function (for thyroiditis), and clinical vigilance for new autoimmune disease.
• Malignancy: I would counsel the patient that any new lymphadenopathy, B-symptoms (night sweats, fever, weight loss), or unexplained cytopenia warrants urgent investigation (imaging, biopsy) for lymphoma; and that upper gastrointestinal symptoms warrant prompt endoscopy for gastric carcinoma. The splenomegaly noted on examination is a common finding in CVID (lymphoproliferation) but should be characterised at baseline and monitored.
• Vaccination: annual inactivated influenza; age-appropriate inactivated vaccines (pneumococcal, COVID-19); live vaccines (MMR, varicella, yellow fever, live attenuated influenza, BCG) are generally avoided in significant combined immunodeficiency but may be considered in isolated humoral defects on specialist advice; household contacts should be fully vaccinated. [1]

(d) Patient education and lifestyle advice (2 marks): [1]

I would explain that CVID is a condition in which the immune system does not make enough protective antibodies, that the treatment replaces those antibodies, and that with treatment most people live full and active lives [1]. Practical advice: a standby antibiotic plan for early respiratory infection (with clear thresholds for self-initiation and for attending hospital); airway clearance physiotherapy for the bronchiectasis; avoidance of unnecessary immunosuppression; and a medical alert documenting the diagnosis and the IgRT. I would refer her to a patient organisation (Immune Deficiencies Foundation in ANZ) for peer support, and arrange psychological support for a chronic disease diagnosed after years of delay.

(e) High-yield exam traps (2 marks): [1]

The traps are: (1) the diagnostic delay — measure immunoglobulins in any adult with recurrent sinopulmonary infection, unexplained bronchiectasis, or autoimmune cytopenia; (2) a normal immunoglobulin panel does NOT exclude PID (specific antibody deficiency and complement deficiency have normal immunoglobulins); (3) immunoglobulin replacement is NOT indicated for isolated IgA deficiency (it contains minimal IgA); (4) the non-infectious complications (autoimmunity, lymphoma) drive much of the morbidity; (5) always exclude HIV before attributing hypogammaglobulinaemia to a primary defect; (6) rituximab for autoimmune cytopenia in CVID can worsen the underlying humoral defect — the cytopenia management must account for the immunodeficiency. [1]

SAQ 2 — Acute Management of Hereditary Angioedema in the Emergency Department (10 marks, 10 minutes)

Prompt: A 26-year-old woman is brought to the emergency department with rapidly progressive swelling of her tongue and oropharynx over 3 hours. She has had recurrent episodes of facial and abdominal swelling since adolescence; her father has the same condition. There is no urticaria, pruritus, or wheeze. She has been given intramuscular adrenaline, intravenous hydrocortisone, and chlorphenamine without improvement, and the airway swelling is worsening. Outline: (a) the clinical diagnosis and the pathophysiology; (b) the immediate treatment with exact agent and dose; (c) why the treatments already given are ineffective; (d) the investigation to confirm the diagnosis once the acute episode is controlled; and (e) the long-term prophylactic and procedure-related prophylaxis plan. [1]

Model Answer

(a) Clinical diagnosis and pathophysiology (2 marks): [1]

The diagnosis is an acute attack of hereditary angioedema (HAE) due to C1 inhibitor deficiency, with laryngeal involvement. The clues are the recurrent non-urticarial, non-pruritic angioedema since adolescence, the family history (autosomal dominant, her father affected), the abdominal swelling (bowel wall oedema), and the lack of response to adrenaline, antihistamines, and corticosteroids. The pathophysiology is deficiency (type 1) or dysfunction (type 2) of C1 inhibitor, which normally inhibits activated kallikrein (and hence bradykinin generation) and activated C1 (and hence classical pathway complement consumption). The deficiency allows uncontrolled bradykinin-mediated vascular permeability, producing angioedema — a bradykinin-mediated, not a histamine-mediated, process [4].

(b) Immediate treatment (2 marks): [1]

I would give C1 inhibitor concentrate immediately — plasma-derived (Berinert) at 20 units per kilogram intravenously, or recombinant (conestat alfa, Ruconest) at 50 units per kilogram (maximum 4,200 units) intravenously. An equivalent first-line alternative is icatibant (a bradykinin B2 receptor antagonist) at 30 mg subcutaneously, with one repeat dose if symptoms recur. For a laryngeal attack the dose is given immediately and the airway secured with anaesthetic and intensive care support — early intubation is preferable to an emergency surgical airway in a distorted airway. I would have a low threshold for activating the difficult-airway team. [1]

(c) Why the treatments given are ineffective (2 marks): [1]

Acute attacks of HAE are bradykinin-mediated. Adrenaline, antihistamines (H1 blockers such as chlorphenamine), and corticosteroids target histamine-mediated (allergic) angioedema and anaphylaxis — they have no effect on bradykinin-mediated angioedema. The failure of this patient to respond to all three is itself a diagnostic clue and is the classic presentation of HAE in the emergency department. Repeating these agents, as is sometimes done, is the documented cause of fatal delay in securing the airway. The teaching point is: angioedema without urticaria and without response to adrenaline, antihistamines, and corticosteroids is HAE (or an acquired C1 inhibitor deficiency, or an angiotensin-converting enzyme inhibitor-induced bradykinin-mediated angioedema) until proven otherwise, and requires specific C1 inhibitor or bradykinin-targeted therapy. [1]

(d) Investigation to confirm the diagnosis (2 marks): [1]

Once the acute episode is controlled, I would measure C4 (low during and between attacks), C1 inhibitor antigenic level (low in type 1, the commoner form), C1 inhibitor functional level (low in both type 1 and type 2), and C1q (normal in hereditary HAE). The functional C1 inhibitor assay is essential because type 2 HAE has normal or high antigenic levels with a dysfunctional protein. A low C1q would indicate acquired C1 inhibitor deficiency (seen in older adults with B-cell lymphoproliferative disease or autoantibodies), which this patient's family history and young age exclude. I would also offer genetic testing and family screening, because HAE is autosomal dominant with about 75 per cent penetrance, and first-degree relatives should be tested. [1]

(e) Long-term prophylaxis and procedure-related prophylaxis (2 marks): [1]

For long-term prophylaxis, the WAO guideline recommends lanadelumab (an anti-kallikrein monoclonal antibody, 300 mg subcutaneously every 2 weeks, reducing attack frequency by 80 to 90 per cent), berotralstat (an oral kallikrein inhibitor, 150 mg daily), regular C1 inhibitor concentrate (intravenous or subcutaneous dosing), or attenuated androgens (danazol 50 to 200 mg daily, used as second-line because of androgenic side effects — hirsutism, acne, voice deepening, hepatic adenoma) [4]. For short-term (procedure-related) prophylaxis, I would give C1 inhibitor concentrate 1 to 6 hours before dental work or surgery, because trauma and airway manipulation are classic triggers and can precipitate fatal laryngeal oedema. I would issue a medical alert, ensure the patient carries an emergency dose of C1 inhibitor concentrate or icatibant for self-administration (with training), and educate the patient, her family, and her general practitioner about the condition and its specific treatment. I would advise avoidance of angiotensin-converting enzyme inhibitors (which can worsen bradykinin-mediated angioedema) and caution with oestrogen-containing medications.